Renal Vasoconstrictor Responses Research Articles

Renal vascular control during normothermia and passive heat stress does not differ between healthy younger men and women.

Men are likely at greater risk for heat-induced acute kidney injury compared with women, possibly due to differences in vascular control. We tested the hypothesis that the renal vasoconstrictor and vasodilator responses will be greater in younger women compared with men during passive heat stress. Twenty-five healthy adults [12 women (early follicular phase) and 13 men] completed two experimental visits, heat stress or normothermic time-control, assigned in a block-randomized crossover design. During heat stress, participants wore a water-perfused suit perfused with 50°C water. Core temperature was increased by ∼0.8°C in the first hour before commencing a 2-min cold pressor test (CPT). Core temperature remained clamped and at 1-h post-CPT, subjects ingested a whey protein shake (1.2 g of protein/kg body wt), and measurements were taken pre-, 75 min, and 150 min post-protein. Beat-to-beat blood pressure (Penaz method) was measured and segmental artery vascular resistance (VR, Doppler ultrasound) was calculated as segmental artery blood velocity ÷ mean arterial pressure. CPT-induced increases in segmental artery VR did not differ between trials (trial effect: P = 0.142) nor between men (heat stress: 1.5 ± 1.0 mmHg/cm/s, normothermia: 1.4 ± 1.0 mmHg/cm/s) and women (heat stress: 1.4 ± 1.2 mmHg/cm/s, normothermia: 2.1 ± 1.1 mmHg/cm/s) (group effect: P = 0.429). Reductions in segmental artery VR following oral protein loading did not differ between trials (trial effect: P = 0.080) nor between men (heat stress: -0.6 ± 0.8 mmHg/cm/s, normothermia: -0.6 ± 0.6 mmHg/cm/s) and women (heat stress: -0.5 ± 0.5 mmHg/cm/s, normothermia: -1.1 ± 0.6 mmHg/cm/s) (group effect: P = 0.204). Renal vasoconstrictor responses to the cold pressor test and vasodilator responses following an oral protein load during heat stress or normothermia do not differ between younger men and younger women in the early follicular phase of the menstrual cycle.NEW & NOTEWORTHY The mechanisms underlying greater heat-induced acute kidney injury risk in men versus women remain unknown. This study examined renal vascular control, including both vasodilatory (oral protein load) and vasoconstrictor (cold presser test) responses, during normothermia and heat stress and compared these responses between men and women. The results indicated that in both conditions neither renal vasodilatory nor vasoconstrictor responses differ between younger men and younger women.

Angiotensin II-independent abnormal renal vascular reactivity during puromycin nephropathy.

Experimental glomerulonephritis results in hypertension that is sensitive to salt. Nevertheless, salt retention alone cannot explain the increase in blood pressure. Angiotensin antagonistic therapy reduces hypertension caused by puromycin amino nucleosides (PAN). We investigated the hypothesis that PAN modifies renal vascular reactivity through processes dependent on angiotensin. Long-Evans rats were given an intraperitoneal injection of either puromycin (150 mg/kg) or saline (controls). Group 1 was fed a normal sodium diet (NSD, n = 9). Group 2 was given 30 mg/L of quinapril (Q) in addition to NSD (NSD + Q; n = 6). Group 3 received a high sodium diet (HSD, n = 7), and Group 4 received HSD + Q (n = 7). Systolic blood pressure (SBP), plasma creatinine, proteinuria, and sodium balance were monitored for 12 days. On day 15, renal vascular reactivity was assessed by administering increasing doses of angiotensin II, acetylcholine (ACh), and sodium nitroprusside (SNP) directly into the renal artery. SBP progressively increased in all PAN groups. This increase in SBP was greater in the HSD groups and was not significantly altered by Q treatment. SBP increased by 22 ± 4% (NSD), 51 ± 5% (NSD + Q), 81 ± 10% (HSD), and 65 ± 8% (HSD + Q). The renal blood flow of PAN rats did not return to baseline despite their normal renal vasoconstrictor responses to angiotensin II. Additionally, they showed reduced renal vasodilator responses to SNP and Ach. The vasodilator responses to both vasodilators were surprisingly unaffected by the inhibition of the angiotensin-converting enzyme (ACE). Renal vasodilator responses to both endothelium-dependent and independent variables were reduced in early PAN-induced hypertension. We found that the angiotensin-mediated mechanism is not responsible for this altered renal vasoreactivity.

Hydration as a modulator of renal vascular control during physical work in the heat

Occupational heat stress increases the risk of developing kidney injury (KI), which is due to the development of hyperthermia and/or hypohydration. It is speculated that this KI is caused by a relative mismatch in oxygen supply (i.e., reductions in renal perfusion) and demand (due to increased sodium reabsorption) in the renal tubules. That said, the modulatory role of hydration on renal vascular control during physical work in the heat is largely unknown. Recent observations indicate that ad lib drinking largely prevents hypohydration during simulated occupational heat stress. Thus, we tested the hypothesis that, compared to ad libitum drinking, fluid restriction induces a pro-vasoconstrictor state in the renal vasculature during physical work in the heat.On two occasions, six healthy adults (1 woman) completed 2 h of exercise in a wet bulb globe temperature of 30±0°C, conditions that are commonly experienced by U.S. outdoor workers. Exercise consisted of completing eight circuits involving treadmill walking (10 min) and rowing (5 min) at a workload eliciting an oxygen uptake of 1.2 L/min, the work intensity observed during agriculture work. In the drinking trial (Drink), subjects were provided 237 mL of sport drink every 15 min and drank ad libitum, which is compliant with workplace hydration recommendations. In the fluid restriction trial (NoDrink), no fluid was provided. Rectal temperature and body mass loss were recorded in each trial. Blood pressure and right renal segmental blood velocity (BV, Doppler ultrasound) was measured before, and following 60 and 120 min of exercise. Before and following exercise, a cold pressor test (CPT) was used to assess the renal vasoconstrictor response to sympathetic activation by immersing the subject’s foot in an agitated ice slurry for 2 min. Blood pressure and segmental BV were measured during each minute of the CPT. Segmental artery vascular resistance (VR) was calculated as mean arterial pressure divided by segmental BV. Data presented as mean ± SD.Average rectal temperature was not different between Drink (37.8±0.4°C) and NoDrink (37.9±0.4°C, p=0.517). Body mass loss was greater in NoDrink (3.1±0.7%) vs. Drink (1.8±0.8%, p=0.014). Segmental BV did not change differently between trials (interaction: p=0.651). Segmental VR did not differ between trials before (Drink: 2.7±0.6, NoDrink: 2.5±0.6 mmHg/cm/s) or after 60 (Drink: 2.8±0.7, NoDrink: 2.6±0.6 mmHg/cm/s) and 90 (Drink: 2.5±0.3, NoDrink: 2.3±0.8 mmHg/cm/s) min of exercise (interaction: p=0.988). Peak increases in segmental VR during the CPT did not differ between trials before (Drink: 0.5 ± 0.7, NoDrink: 0.9 ± 0.6 mmHg/cm/s) or after (Drink: 0.4 ± 0.7, NoDrink: 0.4 ± 0.6 mmHg/cm/s) exercise (interaction: p=0.405).These findings preliminarily indicate that fluid replacement does not modify renal vascular control during physical work in the heat. NCT: NCT05458843. Supported by: R01OH011528 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The renin-angiotensin system modulates endotoxic postconditioning of exacerbated renal vasoconstriction in preeclamptic offspring

We recently reported exacerbated endotoxic signs of neuroinflammation and autonomic defects in offspring of preeclamptic (PE) dams. Here, we investigated whether PE programming similarly modifies hemodynamic and renal vasoconstrictor responsiveness to endotoxemia in PE offspring and whether this interaction is modulated by gestational angiotensin 1–7 (Ang1-7). Preeclampsia was induced by gestational treatment with L-NAME. Adult offspring was challenged with lipopolysaccharides (LPS, 5 mg/kg) and systolic blood pressure (SBP) and renal vasoconstrictions were assessed 4 h later. Male, but not female, offspring of PE rats exhibited SBP elevations that were blunted by LPS. Renal vasoconstrictions induced by angiotensin II (Ang II), but not phenylephrine, were intensified in perfused kidneys of either sex. LPS blunted the heightened Ang II responses in male, but not female, kidneys. While renal expressions of AT1-receptors and angiotensin converting enzyme (ACE) were increased in PE offspring of both sexes, ACE2 was upregulated in female offspring only. These molecular effects were diminished by LPS in male offspring. Gestational Ang1-7 caused sex-unrelated attenuation of phenylephrine vasoconstrictions and preferentially downregulated Ang II responses and AT1-receptor and nuclear factor-kB (NFkB) expressions in females. Together, endotoxemia and Ang1-7 offset in sexually-related manners imbalances in renal vasoconstriction and AT1/ACE/ACE2 signaling in PE offspring.

Glomerular filtration rate reserve is reduced during mild passive heat stress in healthy young adults.

We tested the hypothesis that, compared with normothermia, the increase in glomerular filtration rate (GFR) after an oral protein load (defined as the GFR reserve) is attenuated during moderate passive heat stress in young healthy adults. Sixteen participants (5 women; 26 ± 2 yr) completed two experimental visits, heat stress or a normothermic time-control, assigned in a block-randomized crossover design. During the heat stress trial, core temperature was increased by 0.6°C in the first hour before commencing a 2-min cold pressor test (CPT) to assess renal vasoconstrictor responses. One-hour post-CPT, subjects ingested a whey protein shake (1.2 g of protein/kg body wt), and measurements were taken pre-, 75, and 150 min postprotein. Segmental artery vascular resistance was calculated as the quotient of Doppler ultrasound-derived segmental artery blood velocity and mean arterial pressure and provided an estimate of renal vascular tone. GFR was estimated from creatinine clearance. The increase in segmental artery vascular resistance during the CPT was attenuated during heat stress (end CPT: 5.6 ± 0.9 vs. 4.7 ± 1.1 mmHg/cm/s, P = 0.024). However, the reduction in segmental artery vascular resistance in response to an oral protein load did not differ between heat stress (at 150 min: 1.9 ± 0.4 mmHg/cm/s) and normothermia (at 150 min: 1.8 ± 0.5 mmHg/cm/s; P = 0.979). The peak increase in creatinine clearance postprotein, independent of time, was attenuated during heat stress (+26 ± 19 vs. +16 ± 20 mL/min, P = 0.013, n = 13). GFR reserve is diminished by mild passive heat stress. Moreover, renal vasoconstrictor responses are attenuated by mild passive heat stress, but renal vasodilator responses are maintained.

Consequent Endotoxemia Relieves Abnormalities in Renal Vasoconstriction and AT1/ACE/ACE2 Signaling in Preeclamptic Offspring: Roles of Sex and Antenatal Ang 1‐7 Therapy

The renin angiotensin system plays a pathogenic role in the altered renal homeostasis in inflammatory states such as preeclampsia and endotoxemia. Here, we investigated whether preeclamptic fetal programming modifies hemodynamic and renal vasoconstrictor responsiveness to endotoxemia in adult offspring and whether these interactions are modulated by gestationally administered Ang 1‐7. Preeclampsia was induced by oral administration of L‐NAME (50 mg/kg/day) to pregnant dams. Adult offspring was challenged with lipopolysaccharides (LPS, 5 mg/kg) and changes in blood pressure (BP) and renal vasoconstrictor reactivity were assessed 4 hours later. Contrary to female counterparts, male offspring of PE rats exhibited significant rises in BP that were dramatically reduced after LPS administration. Vasoconstrictions induced by Ang II (0.25‐32 ng), but not phenylephrine (0.41‐900 ng), in isolated perfused kidneys of male and female offspring of PE dams were intensified compared with non‐PE offspring. The heightened Ang II responses were blunted by LPS in male, but not female, preparations. Further, gestational Ang 1‐7 supplementation had no effect on endotoxic hypotension in male offspring, but caused sex‐unrelated attenuation of Ang II and phenylephrine renal vasoconstrictions. Immunohistochemical studies showed that while the renal tubular expression of AT1 receptors and ACE was increased in PE offspring of both sexes, increased ACE2 expression was noted only in female offspring. The upregulation in these molecules was diminished after LPS exposure, an effect that was more apparent in the male gender. Additionally, gestational treatment with Ang1‐7 failed to modify expression patterns of AT1/ACE/ACE2 signaling in PE/LPS offspring. Together, sexual dimorphism exists in the ability of ensuing endotoxic challenge of adult offspring to offset imbalances in renal vasoconstriction and tubular AT1/ACE/ACE2 signaling caused by early PE insult. Further, antenatal Ang 1‐7 therapy rectifies the erupted vasoconstriction anomalies through yet unidentified mechanisms.

Diet-induced hypertension in rats is associated with increased renal vasoconstrictor response to angiotensin II after imitated endothelial dysfunction.

The mechanisms behind development of diet-induced hypertension remain unclear. The kidneys play a paramount role in blood volume and blood pressure regulation. Increases in renal vascular resistance lead to increased mean arterial blood pressure (MAP) due to reduced glomerular filtration rate and Na+ excretion. Renal vascular resistance may be increased by several factors, e.g. sympathetic output, increased activity in the renin-angiotensin system or endothelial dysfunction. We examined if a 14-week diet rich in fat, fructose or both led to increased renal vascular resistance and blood pressure. Sixty male Sprague-Dawley rats received normal chow (Control), high-fat chow (High Fat), high-fructose in drinking water (High Fructose), or a combination of high-fat and high-fructose diet (High Fat + Fruc) for 14weeks from age 4-weeks. Measurements included body weight (BW), telemetry blood pressures, renal blood flow in anesthetized rats, plasma concentrations of atrial natriuretic peptide and glucose, as well as vessel myography in renal segmental arteries. Body weight increased in both groups receiving high fat, whereas MAP increased only in the High Fat + Fruc group. Renal blood flow did not differ between groups showing that renal vascular resistance was not increased by the diets. After inhibiting nitric oxide and prostacyclin production, renal blood flow reductions to Angiotensin II infusions were exaggerated in the groups receiving high fructose. MAP correlated positively with heart rate in all rats tested. Our data suggest that diet-induced hypertension is not caused by an increase in renal vascular resistance. The pathophysiological mechanisms may include altered signaling in the renin-angiotensin system and increases in central sympathetic output in combination with reduced baroreceptor sensitivity leading to increased renal vasoconstrictor responses.

Renal Vasoconstrictor, but Not Vasodilator, Responses are Modified by Mild Passive Heat Stress in Humans

Purpose The effect of heat stress on renal vascular control is not well studied. For instance, moderate passive heat stress attenuates the renal segmental artery vasoconstrictor response to the cold pressor test (CPT), a sympathoexcitatory stimulus. Whether this occurs with mild passive heat stress is unknown. Additionally, the vasodilatory response of the kidneys has never been studied during heat stress. Oral protein loading is a common approach used to elicit increases in renal blood flow. The purpose of this study was to test the hypothesis that both renal segmental artery vasoconstriction and vasodilation are attenuated during mild passive heat stress. Methods Twelve healthy adults (26 ± 1 y, 3 females) completed two experimental visits where they underwent passive heat stress or a normothermic time control trial in a randomized crossover design. In the heat stress trial, core temperature was increased ~0.5°C within the first hour and was maintained thereafter. Subjects completed a CPT one hour into heat stress which involved subjects immersing their right hand in an agitated ice slurry for 2 min. One hour post-CPT, subjects ingested a whey protein shake (1.2 g of protein/kg of body weight mixed with water). Renal segmental artery blood velocity (BV, Doppler ultrasound) and beat-to-beat blood pressure (Penaz method) were measured pre-CPT, in the final minute of CPT, pre-protein, and 150 min post-protein. Segmental artery vascular resistance (VR) was calculated as mean arterial pressure (MAP) divided by segmental artery BV. Data are presented as mean ± SD. Results Core temperature was higher pre-CPT (37.6 ± 0.5 vs 37.1 ± 0.5°C, P<0.01) and pre-protein (37.7 ± 0.4 vs 37.0 ± 0.4°C, P<0.01), and body fluid loss was greater (3.0 ± 0.9% vs. 1.5 ± 0.4%, P<0.01) in heat stress compared to normothermia. MAP did not differ pre-CPT between heat stress (80 ± 11 mmHg) and normothermia (84 ± 9 mmHg, P=0.76), but during the CPT was lower during heat stress (88 ± 18 vs. 113 ± 14 mmHg, P<0.01). Segmental BV did not differ pre-CPT between heat stress (22 ± 3 cm/s) and normothermia (22 ± 4 cm/s, P=0.99) or during the CPT (P = 0.56). Segmental VR pre-CPT did not differ between heat stress (3.8 ± 0.6 mmHg/cm/s) and normothermia (4.0 ± 0.7 mmHg/cm/s, P=0.91) but was lower in heat stress during the CPT (5.7 ± 1.1 vs. 4.6 ± 1.5 mmHg/cm/s, P=0.01). MAP did not differ pre-protein between heat stress (83 ± 9 mmHg) and normothermia (85 ± 9 mmHg, P=0.93), or post-protein (P=0.94). Segmental BV did not differ pre-protein between heat stress (22 ± 3 cm/s) and normothermia (22 ± 3 cm/s, P=0.99), or post-protein (P=0.36). Segmental VR was not different pre-protein between heat stress (3.9 ± 0.8 mmHg/cm/s, P=0.97) and normothermia (3.9 ± 0.6 mmHg/cm/s). Segmental VR decreased post-protein (P=0.03) but did not differ between heat stress (3.4 ± 0.9 mmHg/cm/s) and normothermia (3.5 ± 0.5 mmHg/cm/s, P=0.98). Conclusion Compared to normothermia, renal segmental artery vasoconstriction during a sympathetic stimulus is attenuated, but renal segmental artery vasodilation following a protein load is not affected by mild passive heat stress.

Knockout of γ-Adducin Promotes NG-Nitro-L-Arginine-Methyl-Ester-Induced Hypertensive Renal Injury.

Previous studies identified a region on chromosome 1 associated with NG-nitro-L-arginine methyl ester (L-NAME) hypertension-induced renal disease in fawn-hooded hypertensive (FHH) rats. This region contains a mutant γ-adducin (Add3) gene that impairs renal blood flow (RBF) autoregulation, but its contribution to renal injury is unknown. The present study evaluated the hypothesis that knockout (KO) of Add3 impairs the renal vasoconstrictor response to the blockade of nitric oxide synthase and enhances hypertension-induced renal injury after chronic administration of L-NAME plus a high-salt diet. The acute hemodynamic effect of L-NAME and its chronic effects on hypertension and renal injury were compared in FHH 1Brown Norway (FHH 1BN) congenic rats (WT) expressing wild-type Add3 gene versus FHH 1BN Add3 KO rats. RBF was well autoregulated in WT rats but impaired in Add3 KO rats. Acute administration of L-NAME (10 mg/kg) raised mean arterial pressure (MAP) similarly in both strains, but RBF and glomerular filtration rate (GFR) fell by 38% in WT versus 15% in Add3 KO rats. MAP increased similarly in both strains after chronic administration of L-NAME and a high-salt diet; however, proteinuria and renal injury were greater in Add3 KO rats than in WT rats. Surprisingly, RBF, GFR, and glomerular capillary pressure were 41%, 82%, and 13% higher in L-NAME-treated Add3 KO rats than in WT rats. Hypertensive Add3 KO rats exhibited greater loss of podocytes and glomerular nephrin expression and increased interstitial fibrosis than in WT rats. These findings indicate that loss of ADD3 promotes L-NAME-induced renal injury by altering renal hemodynamics and enhancing the transmission of pressure to glomeruli. SIGNIFICANCE STATEMENT: A mutation in the γ-adducin (Add3) gene in fawn-hooded hypertensive rats that impairs autoregulation of renal blood flow is in a region of rat chromosome 1 homologous to a locus on human chromosome 10 associated with diabetic nephropathy. The present results indicate that loss of ADD3 enhanced NG-nitro-L-arginine methyl ester-induced hypertensive renal injury by altering the transmission of pressure to the glomerulus.

Microvascular Vasodilatory Consequences of Acute Consumption of a High Fructose Caffeinated Soft Drink

PurposeExcessive intake of high fructose sugar sweetened beverages is associated with a greater risk of cardiovascular disease. This increased risk may be attributed, in part, to fructose‐mediated elevations in vasoconstrictor tone. Compared to water, consumption of a high fructose caffeinated soft drink elicits vasoconstriction in the kidneys and augments the renal vasoconstrictor response during sympathetic stimulation. It is unknown if these observed effects are specific to the kidneys or are indicative of a systemic vascular response. Endothelial dysfunction, which is characterized by a pro‐vasoconstrictor shift mostly due to reductions in nitric oxide bioavailability, is one of the earliest pathogenic vascular changes leading to cardiovascular disease. Experimental investigation of microvascular endothelial function may offer insight into the mechanisms contributing to the elevated cardiovascular disease risk associated with intake of high fructose sugar sweetened beverages. Therefore, the purpose of this study was to test the hypothesis that acute consumption of a high fructose caffeinated soft drink attenuates the cutaneous microvascular vasodilatory response to local heating, a primarily nitric oxide mediated response.MethodsIn a randomized cross‐over design, 8 healthy adults (26 ± 2 y, 4 women) consumed either 500 mL of a high‐fructose caffeinated beverage (Mountain Dew®, Soda) or 500 mL of water (H2O) while resting supine. Red blood cell flux, an index of skin blood flow, was measured at two sites on the dorsal aspect of the forearm using laser‐Doppler flowmetry probes seated in a local heater. Skin blood flow, blood pressure (finger photoplethysmography) and heart rate (ECG) were continuously measured. Data were analyzed at baseline, 30 min post‐consumption, and the last 5 min following 40 min of local heating at 39°C and 20 min of local heating at 44°C. Heating at 39°C was chosen because at this skin temperature and duration of heating the skin blood flow response is primarily nitric oxide dependent. Skin blood flow measures were averaged between sites and expressed as cutaneous vascular conductance (CVC), calculated as skin blood flow divided by mean arterial pressure. Data are presented as a percentage of the CVC response to local heating at 44°C (CVCmax).ResultsMean arterial pressure did not differ between Soda and H2O at any time‐point (P=0.82). Heart rate was higher in Soda during local heating to 44°C (56 ± 7 vs. 52 ± 8 bpm, P=0.04), but did not differ at any other time‐point (P≥0.35). CVCmax did not differ between the Soda (3.5 ± 1.2 PU/mmHg) and H2O (3.4 ± 0.5 PU/mmHg) trials (P=0.82). CVC 30 min post‐consumption (Soda: 9 ± 7, H2O: 13 ± 18% CVCmax, P=0.53) or during local heating at 39°C (Soda: 58 ± 17, H2O: 58 ± 18% CVCmax, P=0.91) were not different between Soda and H2O.ConclusionsThese preliminary findings suggest the cutaneous microvascular vasodilator response to local heating is not affected by acute consumption of high fructose caffeinated beverage. It is possible that the vasoconstrictor response following acute high fructose caffeinated soft drink consumption may be specific to the kidneys and that systemic changes may not occur.

Neurohumoral interactions contributing to renal vasoconstriction and decreased renal blood flow in heart failure

In heart failure (HF), increases in renal sympathetic nerve activity (RSNA), renal norepinephrine spillover, and renin release cause renal vasoconstriction, which may contribute to the cardiorenal syndrome. To increase our understanding of the mechanisms causing renal vasoconstriction in HF, we investigated the interactions between the increased activity of the renal nerves and the renal release of norepinephrine and renin in an ovine pacing-induced model of HF compared with healthy sheep. In addition, we determined the level of renal angiotensin type-1 receptors and the renal vascular responsiveness to stimulation of the renal nerves and α1-adrenoceptors. In conscious sheep with mild HF (ejection fraction 35%-40%), renal blood flow (276 ± 13 to 185 ± 18 mL/min) and renal vascular conductance (3.8 ± 0.2 to 3.1 ± 0.2 mL·min-1·mmHg-1) were decreased compared with healthy sheep. There were increases in the burst frequency of RSNA (27%), renal norepinephrine spillover (377%), and plasma renin activity (141%), whereas the density of renal medullary angiotensin type-1 receptors decreased. In anesthetized sheep with HF, the renal vasoconstrictor responses to electrical stimulation of the renal nerves or to phenylephrine were attenuated. Irbesartan improved the responses to nerve stimulation, but not to phenylephrine, in HF and reduced the responses in normal sheep. In summary, in HF, the increases in renal norepinephrine spillover and plasma renin activity are augmented compared with the increase in RSNA. The vasoconstrictor effect of the increased renal norepinephrine and angiotensin II is offset by reduced levels of renal angiotensin type-1 receptors and reduced renal vasoconstrictor responsiveness to α1-adrenoceptor stimulation.

Modification of the Renal Vasoconstrictor Response to Sympathetic Stimulation by Soft Drink Consumption

BackgroundIncreases in dietary fructose are associated with a greater risk of renal disease. Fructose consumption promotes the release of vasopressin, stimulates uric acid production, and elevates blood pressure. Consumption of a high‐fructose, caffeinated soft drink acutely reduces kidney function during exercise in the heat. These reductions were likely caused by elevations in circulating vasopressin and uric acid, which have vasoconstrictor actions in the kidneys. Thus, it is possible that soft drink‐mediated reductions in renal blood flow contributed to the reduced kidney function. However, the effect of soft drink consumption on the renal vasoconstrictor response is unknown.PurposeThe cold pressor test (CPT) is a sympathetic stimulus that can be used to examine renal vasoconstrictor responsiveness. This study tested the hypothesis that soft drink consumption exacerbates the increase in renal vascular resistance (RVR) to the CPT.MethodsEleven euhydrated healthy adults (22 ± 2 y, 3 F) completed a CPT by immersing their right hand in an agitated ice slurry mixture for 2 min, 1 h after drinking 250 mL of tap water (Water) and again 30 min following consumption of 500 mL of decarbonated Mountain Dew® (Soft Drink). Heart rate (3 lead ECG), mean arterial pressure (MAP, finger photoplethysmography), and renal blood velocity (RBV, n=8) were measured at 1 min pre‐CPT, at 1 and 2 min into the CPT (CPT1 and CPT2), and 1 min post‐CPT. RBV was assessed in the same location of the same segmental artery during the same phase of the respiratory cycle via Doppler ultrasound (GE Vivid iQ). The coronal approach was utilized using a linear‐array transducer with a 2.5 MHz pulsed frequency while participants were in the left lateral recumbent position. All measurements were obtained by the same sonographer (intraoperator coefficient of variation: 3.8 ± 0.9%) with the focal zone set to the artery's depth, and the transducer held in the same location at an insonation angle &lt;60°. RVR was calculated as MAP/RBV. RBV and RVR were averaged across three cardiac cycles.ResultsHeart rate was not different between Water (61 ± 10 bpm) and Soft Drink (65 ± 10 bpm) at pre‐CPT (P=0.14). Heart rate increased during the CPT (P=0.01), but there were no differences between Water and Soft Drink (P≥0.35). MAP was not different between Water (76 ± 10 mmHg) and Soft Drink (79 ± 13 mmHg) at pre‐CPT (P=0.62). MAP increased with the CPT (P&lt;0.01), and was higher in Soft Drink at CPT1 (104 ± 13 vs. 98 ± 12 mmHg, P=0.04) and post‐CPT (90 ± 13 vs. 80 ± 12 mmHg, P&lt;0.01), with no differences between Water (106 ± 13 mmHg) and Soft Drink (106 ± 11 mmHg) at CPT2 (P=0.99). RBV was lower in Soft Drink throughout (20.8 ± 1.2 vs. 18.3 ± 0.4 cm/s, main effect: P&lt;0.01), and did not change during the CPT in Water or Soft Drink (P=0.64). RVR was elevated at pre‐CPT in Soft Drink (4.5 ± 1.3 vs. 3.9 ± 1.0 mmHg/cm/s, P=0.05). RVR increased during the CPT in Water and Soft Drink (P&lt;0.01), and was higher in Soft Drink at CPT1 (6.1 ± 1.3 vs. 5.0 ± 1.3 mmHg, P&lt;0.01) and at post‐CPT (5.3 ± 1.5 vs. 3.8 ± 1.3 mmHg, P&lt;0.01), with no differences between Water (5.5 ± 1.6 mmHg) and Soft Drink (6.0 ± 1.6 mmHg) at CPT2 (P=0.13).ConclusionSoft drink consumption augments the renal vasoconstrictor response to a sympathetic stimulus.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Altered Renal Vascular Responsiveness to Vasoactive Agents in Rats with Angiotensin II-Dependent Hypertension and Congestive Heart Failure

Objective: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs). Methods: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation). Results: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR. Conclusion: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF.

Renal Medullary Oxygenation Decreases in a Dose‐Dependent Manner with Graded Lower Body Negative Pressure in Healthy Young Adults

BackgroundIncrease in sympathetic nerve activity (SNA) evokes a renal vasoconstrictor response that is powerfully opposed by autoregulatory influences. In the renal medulla, increases in SNA serve to increase Na+/K+‐ATPase activity (an oxygen dependent process) in the distal tubule, a process contributing to salt and water retention. In this report, we engaged SNA with lower body negative pressure (LBNP) as we employed magnetic resonance imaging to examine an index of renal medullary oxygenation, T2*. At a separate time we applied LBNP as we measured changes in renal blood flow velocity. This is an index that largely reflects changes in renal cortical blood flow.MethodsThirteen healthy (mean age 28 ± 1 yr) men (n = 7) and women (n = 6) participated in one or both of the experimental visits. Graded negative pressure (−10, −20, and −30 mmHg) was applied during 2 visits; visit 1 was for Doppler and visit 2 for MRI. Blood pressure (BP) and heart rate (HR) were also measured at baseline and at each stage of LBNP and recovery. RBV was obtained in all 13 subjects while T2* was obtained in 8 of 13 subjects.ResultsLBNP −30 mmHg led to a lower T2* (−0.65 ± 0.14 ms; P &lt; 0.001). RBV decreased and renal vascular resistance (RVR) increased at −30 mmHg (ΔRBV −7.44 ± 3.87 cm/s, P = 0.041; ΔRVR arbitrary units 0.28 ± 0.11, P = 0.028). During recovery, T2* remained below baseline for the first and the second minutes of the recovery.ConclusionsThese data suggest that −30 mmHg LBNP leads to renal vasoconstriction and medullary deoxygenation. We suspect that changes in T2* are due to a sympathetically mediated, oxygen requiring, accentuation of Na/K ATP activity in the distal tubule. We postulate that this leads to salt and water retention as the SNS is engaged.Support or Funding InformationCommonwealth Universal Research Enhancement Program (CURE); P01 HL134609 (Sinoway)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Omega-3 polyunsaturated fatty acid supplementation reduces blood pressure but not renal vasoconstrictor response to orthostatic stress in healthy older adults.

Older adults exhibit augmented renal vasoconstriction during orthostatic stress compared to young adults. Consumption of omega‐3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil (FO), modulates autonomic nerve activity. However, the effect of omega‐3 polyunsaturated fatty acid consumption on the renal vasoconstrictor response to orthostatic stress in young and older adults is unknown. Therefore, 10 young (25 ± 1 years; mean ± SEM) and 10 older (66 ± 2 years) healthy adults ingested 4 g FO daily for 12 weeks, and underwent graded lower body negative pressure (LBNP; −15 and −30 mmHg) pre‐ and post‐FO supplementation. Renal blood flow velocity (RBFV; Doppler ultrasound), arterial blood pressure (BP; photoplethysmographic finger cuff), and heart rate (electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as mean BP/RBFV. All baseline cardiovascular values were similar between groups and visits, except diastolic BP was higher in the older group (P < 0.05). FO supplementation increased erythrocyte EPA and DHA content in both groups (P < 0.05). FO did not affect RVR or RBFV responses to LBNP in either group, but attenuated the mean BP response to LBNP in the older group (older −30 mmHg: pre‐FO −4 ± 1 vs. post‐FO 0 ± 1 mmHg, P < 0.05; young −30 mmHg: pre‐FO −5 ± 1 vs. post‐FO −5 ± 2 mmHg). In conclusion, FO supplementation attenuates the mean BP response but does not affect the renal vasoconstrictor response to orthostatic stress in older adults.

The Role of Renal Vascular Reactivity in the Development of Renal Dysfunction in Compensated and Decompensated Congestive Heart Failure

Background/Aims: Reduction of renal blood flow (RBF) is commonly thought to be a causative factor of renal dysfunction in congestive heart failure (CHF), but the exact mechanism of the renal hypoperfusion is not clear. Apart from the activation of neurohormonal systems controlling intrarenal vascular tone, the cause might be altered reactivity of the renal vasculature to endogenous vasoactive agents. Methods: To evaluate the role of this mechanism, we assessed by an ultrasonic transient-time flow probe maximum RBF responses to renal artery infusion of angiotensin II (ANG II), norepinephrine (NE) and acetylcholine (Ach) in healthy male rats and animals with compensated and decompensated CHF. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF) in Hannover Sprague-Dawley rats. Results: Maximum responses in RBF to ANG II were similar in rats studied five weeks (compensated phase) and 20 weeks (decompensated phase) after ACF creation when compared to sham-operated rats. On the other hand, NE elicited larger maximum decreases in RBF in rats with CHF (five and 20 weeks post-ACF) than in sham-operated controls. We observed greater maximum vasodilatory responses to Ach only in rats with a compensated stage of CHF (five weeks post-ACF). Conclusion: Greater renal vasoconstrictor responsiveness to ANG II or reduced renal vasodilatation in response to Ach do not play a decisive role in the development of renal dysfunction in ACF rats with compensated and decompensated CHF. On the other hand, exaggerated renal vascular responsiveness to NE may be here a contributing causative factor, active in either CHF phase.

Genetically increased angiotensin I-converting enzyme alters peripheral and renal vascular reactivity to angiotensin II and bradykinin in mice.

Angiotensin I-converting enzyme (ACE) levels in humans are under strong genetic influence. Genetic variation in ACE has been linked to risk for and progression of cardiovascular and renal diseases. Causality has been documented in genetically modified mice, but the mechanisms underlying causality are not completely elucidated. To further document the vascular and renal consequences of a moderate genetic increase in ACE synthesis, we studied genetically modified mice carrying three copies of the ACE gene (three-copy mice) and littermate wild-type animals (two-copy mice). We investigated peripheral and renal vascular reactivity to angiotensin II and bradykinin in vivo by measuring blood pressure and renal blood flow after intravenous administration and also reactivity of isolated glomerular arterioles by following intracellular Ca2+ mobilization. Carrying three copies of the ACE gene potentiated the systemic and renal vascular responses to angiotensin II over the whole range of peptide concentration tested. Consistently, the response of isolated glomerular afferent arterioles to angiotensin II was enhanced in three-copy mice. In these mice, signaling pathways triggered by endothelial activation by bradykinin or carbachol in glomerular arterioles were also altered. Although the nitric oxide (NO) synthase (NOS)/NO pathway was not functional in arterioles of two-copy mice, in muscular efferent arterioles of three-copy mice NOS3 gene expression was induced and NO mediated the effect of bradykinin or carbachol. These data document new and unexpected vascular consequences of a genetic increase in ACE synthesis. Enhanced vasoconstrictor effect of angiotensin II may contribute to the risk for cardiovascular and renal diseases linked to genetically high ACE levels. NEW & NOTEWORTHY A moderate genetic increase in angiotensin I-converting enzyme (ACE) in mice similar to the effect of the ACE gene D allele in humans unexpectedly potentiates the systemic and renal vasoconstrictor responses to angiotensin II. It also alters the endothelial signaling pathways triggered by bradykinin or carbachol in glomerular efferent arterioles.

Muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction in healthy humans.

Reflex renal vasoconstriction occurs during exercise, and renal vasoconstriction in response to upper-limb muscle mechanoreflex activation has been documented. However, the renal vasoconstrictor response to muscle mechanoreflex activation originating from lower limbs, with and without local metabolite accumulation, has not been assessed. Eleven healthy young subjects (26 ± 1 yr; 5 men) underwent two trials involving 3-min passive calf muscle stretch (mechanoreflex) during 7.5-min lower-limb circulatory occlusion (CO). In one trial, 1.5-min 70% maximal voluntary contraction isometric calf exercise preceded CO to accumulate metabolites during CO and stretch (mechanoreflex and metaboreflex; 70% trial). A control trial involved no exercise before CO (mechanoreflex alone; 0% trial). Beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; photoplethysmographic finger cuff), and heart rate (electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. All baseline cardiovascular variables were similar between trials. Stretch increased RVR and decreased RBFV in both trials (change from CO with stretch: RVR - 0% trial = Δ 10 ± 2%, 70% trial = Δ 7 ± 3%; RBFV - 0% trial = Δ -3.8 ± 1.1 cm/s, 70% trial = Δ -2.7 ± 1.5 cm/s; P < 0.05 for RVR and RBFV). These stretch-induced changes were of similar magnitudes in both trials, e.g., with and without local metabolite accumulation, as well as when thromboxane production was inhibited. These findings suggest that muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction, with and without muscle metaboreflex activation, in healthy humans.

Fish Oil Supplementation Attenuates Blood Pressure Response but Not Renal Vasoconstrictor Response to Orthostatic Stress in Healthy Older Humans

During orthostatic stress, sympathetically mediated renal vasoconstriction redirects blood flow from the kidneys to the systemic circulation to maintain blood pressure (BP) (Momen et al., 2006). Healthy older people exhibit an augmented renal vasoconstrictor response to lower body negative pressure (LBNP) compared to healthy young people (Clark et al., 2015). Dietary intake of omega‐3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil (FO), can attenuate (Carter et al., 2013) or augment (Monahan et al., 2004) sympathetic responses to neural and physiological stressors. However, the effect of FO on the renal vasoconstrictor response to orthostatic stress is unknown. Therefore, ten healthy young (5 men; mean ± SEM 25 ± 1 y) and ten healthy older (3 men; 66 ± 2 y) subjects ingested 4 g FO daily for 12 weeks, and underwent graded LBNP (−15 and −30 mmHg) pre‐ and post‐FO supplementation. Renal blood flow velocity (RBFV; Doppler ultrasound), mean, systolic, and diastolic BP (photoplethysmographic finger cuff), and heart rate (HR; electrocardiogram) were recorded during both trials. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as mean BP/RBFV, and pulse pressure (PP) was calculated as systolic BP ‐ diastolic BP. Statistical analysis involved repeated measures analysis of variance. Baseline values were similar between age groups for RVR (older: 2.0 ± 0.2 AU; young: 1.7 ± 0.1 AU), RBFV (older: 51 ± 6 cm.sec−1; young: 53 ± 3 cm.sec−1), SBP (older: 125 ± 3 mmHg; young: 118 ± 3 mmHg), PP (older: 53 ± 3 mmHg; young: 52 ± 3 mmHg), and HR (older: 63 ± 3 b.min−1; young: 58 ± 2 b.min−1). The older group had higher baseline diastolic BP than the young group (older: 72 ± 1 mmHg; young: 66 ± 2 mmHg; P &lt; 0.05). FO supplementation did not affect baseline cardiovascular values, but did increase erythrocyte EPA (older: pre‐FO 0.6 ± 0.1 % vs. post‐FO 3.2 ± 0.6 %; young: pre‐FO 0.5 ± 0.0 % vs. post‐FO 1.9 ± 0.5 %; P &lt; 0.05) and DHA content (older: pre‐FO 3.6 ± 0.3 % vs. post‐FO 7.0 ± 0.6 %; young: pre‐FO 4.3 ± 0.2 % vs. post‐FO 6.0 ± 0.6 %; P &lt; 0.05) in both age groups. FO did not affect responses to LBNP in either age group of RVR (older −30 mmHg: pre‐FO 20 ± 5 %, post‐FO 22 ± 3 %; young −30 mmHg: pre‐FO 6 ± 2 %, post‐FO 13 ± 6 %) or RBFV (older −30 mmHg: pre‐FO −10 ± 2 cm.sec−1, post‐FO −9 ± 1 cm.sec−1; young −30 mmHg: pre‐FO −6 ± 1 cm.sec−1, post‐FO −8 ± 2 cm.sec−1). However, FO attenuated the mean BP response to LBNP in the older but not the young group (older −30 mmHg: pre‐FO −4 ± 1 mmHg vs. post‐FO 0 ± 1 mmHg, P &lt; 0.05; young −30 mmHg: pre‐FO −5 ± 1 mmHg vs. post‐FO −5 ± 2 mmHg). FO tended to attenuate the HR response to LBNP in the older group (older −30 mmHg: pre‐FO 9 ± 2 b.min−1, post‐FO 5 ± 1 b.min−1, P = 0.06; young −30 mmHg: pre‐FO 9 ± 3 b.min−1, post‐FO 10 ± 2 b.min−1). FO did not affect systolic or diastolic BP, or PP, responses to LBNP in either age group. In conclusion, FO supplementation attenuates the mean BP response but does not affect the renal vasoconstrictor response to LBNP in healthy older humans. These findings suggest that FO affects factors involved in the BP response but not the renal vasoconstrictor response to orthostatic stress in older people.Support or Funding InformationSupported by National Institutes of Health grants HL092309, AG024420, UL1 TR000127, and P01 HL096570.

Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptor.

Recent data suggest that exercise training (ExT) is beneficial in chronic heart failure (CHF) because it improves autonomic and peripheral vascular function. In this study, we hypothesized that ExT in the CHF state ameliorates the renal vasoconstrictor responses to hypoxia and that this beneficial effect is mediated by changes in α1-adrenergic receptor activation. CHF was induced in rabbits. Renal blood flow (RBF) and renal vascular conductance (RVC) responses to 6 min of 5% isocapnic hypoxia were assessed in the conscious state in sedentary (SED) and ExT rabbits with CHF with and without α1-adrenergic blockade. α1-adrenergic receptor expression in the kidney cortex was also evaluated. A significant decline in baseline RBF and RVC and an exaggerated renal vasoconstriction during acute hypoxia occurred in CHF-SED rabbits compared with the prepaced state (P < 0.05). ExT diminished the decline in baseline RBF and RVC and restored changes during hypoxia to those of the prepaced state. α1-adrenergic blockade partially prevented the decline in RBF and RVC in CHF-SED rabbits and eliminated the differences in hypoxia responses between SED and ExT animals. Unilateral renal denervation (DnX) blocked the hypoxia-induced renal vasoconstriction in CHF-SED rabbits. α1-adrenergic protein in the renal cortex of animals with CHF was increased in SED animals and normalized after ExT. These data provide evidence that the acute decline in RBF during hypoxia is caused entirely by the renal nerves but is only partially mediated by α1-adrenergic receptors. Nonetheless, α1-adrenergic receptors play an important role in the beneficial effects of ExT in the kidney.