Renal Vascular Resistance Responses Research Articles

Age- and Gender-Related Differences in Renal Vascular Responses to Angiotensin II in Rats: The Role of the Mas Receptor.

Renal hemodynamic is influenced by both gender difference and age. Also, the Mas receptor (MasR) as one of the depressor components of the renin-angiotensin system which has more expression in females could postpone some dysfunctions associated with age, although the association between MasR and age in renal vascular responses to angiotensin II (Ang II) in male and female rats was well undefined. Therefore, the current study examined the effects of age and sex on systemic and renal vascular responses to graded doses of Ang II in Wistar rats with or without MasR antagonists (A779). Anesthetized Wistar male and female rats with two age ranges of 8-12 and 24-28 weeks were exposed to cannulate venous and arterial vessels. After stability, mean arterial pressure (MAP), renal perfusion pressure (RPP), renal vascular resistance (RVR), and renal blood flow (RBF) were measured in response to the infusion of Ang II with or without A779. There were no significant differences in the base values of MAP, RPP, RBF, and RVR between the two genders in both the age ranges of 8-12 and 24-28 weeks. In addition, no significant gender difference was observed in the age ranges of the above mentioned parameters among the groups receiving vehicle or A779. Also, the infusion of vehicle or A779 could not significantly change the base values. On the other hand, the responses of RBF and RVR to Ang II revealed gender differences among 8-12-week groups (P < 0.05) but not in 24-28-week groups, while the blockade of MasR could not influence the responses in the age ranges. It was concluded that age could impress sex difference in RBF and RVR responses to Ang II infusion and that MasR alone could not participate in these responses. In other words, MasR is not active under normal and acutely elevated Ang II levels.

Maladaptation of renal hemodynamics contributes to kidney dysfunction resulting from thoracic spinal cord injury in mice.

Renal dysfunction is a hallmark of spinal cord injury (SCI). Several SCI sequalae are implicated; however, the exact pathogenic mechanism of renal dysfunction is unclear. Herein, we found that T3 (T3Tx) or T10 (T10Tx) complete thoracic spinal cord transection induced hypotension, bradycardia, and hypothermia immediately after injury. T3Tx-induced hypotension but not bradycardia or hypothermia slowly recovered to levels in T10Tx SCI and uninjured mice ∼16 h after injury as determined by continuous radiotelemetry monitoring. Both types of thoracic SCI led to a marked decrease in albuminuria and proteinuria in all phases of SCI, whereas the kidney injury marker neutrophil gelatinase-associated lipocalin rapidly increased in the acute phase, remaining elevated in the chronic phase of T3Tx SCI. Renal interstitial and vascular elastin fragmentation after SCI were worsened during chronic T3Tx SCI. In the chronic phase, renal vascular resistance response to a step increase in renal perfusion pressure or a bolus injection of angiotensin II or norepinephrine was almost completely abolished after T3Tx SCI. Bulk RNA-sequencing analysis showed enrichment of genes involved in extracellular matrix remodeling and chemokine signaling in the kidney from T3Tx SCI mice. The serum level of interleukin-6 was elevated in the acute but not chronic phase of T3Tx and T10Tx SCI, whereas the serum amyloid A1 level was elevated in both acute and chronic phases. We conclude that tissue fibrosis and hemodynamic impairment are involved in renal dysfunction resulting from thoracic SCI; these pathological alterations, exacerbated by high thoracic-level injury, is mediated at least partly by renal microvascular extracellular matrix remodeling.NEW & NOTEWORTHY Urinary complications resulting from thoracic spinal cord injury (SCI) greatly affects quality of life and contributes to morbidity and mortality in patients with SCI. Herein, we showed that thoracic SCI initiates changes in the structure and function of the renal microvasculature that leads to autoregulation failure in the chronic phase of high thoracic-level injury. Our study identified extracellular matrix regulators and cytokine/chemokine signaling as potential targets for developing novel therapeutics for restoring renal function following SCI.

Estradiol Supplement or Induced Hypertension May Attenuate the Angiotensin II Type 1 Receptor Antagonist-Promoted Renal Blood Flow Response to Graded Angiotensin II Administration in Ovariectomized Rats.

Backgrounds Estrogen replacement therapy (ERT) and hypertension may influence females' renin-angiotensin system (RAS) and its components. The angiotensin II (Ang II) type 1 receptor (AT1R) antagonist (losartan) may promote renal blood flow (RBF), and it is widely used in the clinic to control hypertension. The main objective of this study was the effects of estradiol or induced hypertension on RBF response to Ang II in losartan-treated ovariectomized (OVX) rats. Methods Two groups of OVX rats were treated with placebo (group 1) and estradiol (group 2) for period of four weeks, and another group of OVX rats was subjected to induce hypertension by two-kidney one clip (2K1C) model (group 3). All the groups were subjected to the surgical procedure under anesthesia, and AT1R was blocked by losartan. RBF and renal vascular resistance (RVR) responses to Ang II administration were determined and compared. Results Mean arterial (MAP) and renal perfusion (RPP) pressures in group 3 and uterus weight (UT) in group 2 were significantly more than other groups (P < 0.05). Ang II infusion resulted in dose-related percentage change increase in RBF and decrease in RVR. However, these responses in the OVX-estradiol and OVX-hypertensive rats were significantly lower than in the OVX-control group (P < 0.05). For instance, at the dose of 1000 ng/kg/min of Ang II administration, the percentage change of RBF was 45.1 ± 10.4%, 17.9 ± 2.3%, and 16.7 ± 4.7% in the groups of 1 to 3, respectively. Conclusion Losartan prescription in some conditions such as hypertension or ERT could worsen RBF and RVR responses to Ang II.

Sex Differences in the Renal Vascular Responses of AT1 and Mas Receptors in Two-Kidney-One-Clip Hypertension.

Background The prevalence and severity of hypertension, as well as the activity of the systemic and local renin angiotensin systems (RASs), are gender related, with more symptoms in males than in females. However, the underlying mechanisms are not well understood. In this study, we investigated sex differences in renal vascular responses to angiotensin II (Ang II) administration with and without Ang II type 1 and Mas receptor (AT1R and MasR) antagonists (losartan and A779) in the 2K1C rat model of renovascular hypertension. Methods Male and female 2K1C rats were divided into 8 experimental groups (4 of each sex) treated with vehicle, losartan, A779, or A779+losartan. Responses of mean arterial pressure (MAP), renal blood flow (RBF), and renal vascular resistance (RVR) to Ang II were determined. Results In both sexes, the basal MAP, RBF, and RVR were not significantly different between the four groups during the control period. The Ang II administration decreased RBF and increased RVR in a dose-related manner in both sexes pretreated with vehicle or A779 (Pdose < 0.0001), but in vehicle pretreated groups, RBF and RVR responses were different between male and female rats (Pgroup < 0.05). AT1R blockade increased RBF and decreased RVR responses to Ang II, and no difference between the sexes was detected. Coblockades of AT1R and MasR receptors increased RBF response to Ang II significantly in males alone but not in females (Pgroup=0.04). Conclusion The impact of Ang II on RBF and RVR responses seems to be gender related with a greater effect on males, and this sex difference abolishes by Mas receptor blockade. However, the paradoxical role of dual losartan and A779 may provide the different receptor interaction in RAS between male and female rats.

Extra- And Intra- Renal Vascular Responses To Sympathetic Activation Are Not Modified Following Cooling Recovery

Elevated renal vascular resistance (RVR) during heat stress may provoke localized ischemia, especially when exposed to multiple sympathetic stressors. Whole-body cooling reduces risks associated with heat stress. However, this cooling raises RVR and could therefore exacerbate increases in RVR caused by prior heat stress, particularly during sympathetic activation. PURPOSE: To test hypotheses that increases in both extra- and intra- RVR to the cold pressor test (a sympathoexcitatory stimulus, CPT) are exacerbated by whole-body cooling following heat stress. METHODS: Nineteen healthy adults (22 ± 2 y) underwent passive heat stress sufficient to raise core temperature 1.2°C above normothermic baseline (NT), after which they underwent passive cooling recovery (CR) to within 0.2°C of NT. Participants completed a 2 min CPT at NT and at the end of CR. Changes in body weight provided an indication of dehydration. Heart rate (HR), mean arterial pressure (MAP), and renal blood velocity (RBV) were measured pre-CPT (Pre) and at the end of the CPT (End). RBV was measured using the coronal approach with Doppler ultrasound at the distal segment of the right renal artery (Extra-, n=11) or in the same segmental artery within participants in the right kidney (Intra-, n=8). RVR was calculated as MAP/RBV. Data are presented as mean ± SD. RESULTS: The change in body weight was -1.2 ± 0.5%. In Extra- at Pre, MAP was elevated in CR compared to NT (95 ± 9 vs. 85 ± 7 mmHg, P<0.01) with no differences in HR (58 ± 7 vs 56 ± 9 bpm, P=0.24). MAP and HR in Intra- at Pre did not differ from Extra- (P≥0.72). In Extra- at Pre, RBV (33 ± 4 vs 36 ± 5 cm/s, P=0.01) and RVR (0.35 ± 0.06 vs 0.43 ± 0.08 mmHg/cm/s, P<0.01) were lower in CR compared to NT. RBV was lower and RVR was higher in Intra- compared to Extra- (P<0.02) at Pre. At End, increases in HR (12 ± 9 vs 14 ± 7 bpm, P=0.50) and MAP (24 ± 16 vs 24 ± 16 mmHg, P>0.99) were not different between CR and NT in Extra-. Changes in RBV (-3 ± 5 vs -2 ± 7 cm/s, P=0.59) and increases in RVR (1.24 ± 0.97 vs 0.95 ± 0.99 mmHg/cm/s, P=0.29) did not differ between CR and NT in Extra- at End. There were no differences in the HR, MAP, RBV, or RVR response to CPT in Intra- compared to Extra- (P≥0.10). CONCLUSION: Whole-body cooling following passive heat stress does not affect the extra- or intra- renal vascular responses to sympathetic activation.

Mas receptor antagonist (A799) alters the renal hemodynamics responses to angiotensin II administration after renal moderate ischemia/reperfusion in rats: gender related differences.

Moderate renal ischemia/reperfusion (I/R) injury is one of the major causes of kidney failure. We examined the role of Mas receptor (MasR) antagonist (A779) alone and combined with angiotensin II (Ang II) type 2 receptor (AT2R) antagonist (PD123319) on renal hemodynamic responses to Ang II after moderate I/R in male and female rats. Anaesthetized Wistar rats underwent 30 min partial ischemia by reduction of renal perfusion pressure (RPP) and subjected to block vasodepressor receptors followed by Ang II (100 and 300 ng/kg/min) infusion. Mean arterial pressure (MAP), renal blood flow (RBF), and renal vascular resistance (RVR) responses were assessed during graded Ang II infusion at controlled RPP. Thirty min post reperfusion, the Ang II infusion reduced RBF and increased RVR in a dose-related fashion (P < 0.05). However, A779 alone or A779 plus PD123319 infusion increased the RBF and RVR responses to Ang II infusion significantly (P < 0.05) in female but not in the male rats. MasR antagonist altered the RBF and RVR responses to Ang II infusion in female, and these responses were not altered statistically in dual blockade of MasR and AT2R. These findings suggest the important role of Mas receptor in renal vascular response to Ang II in female rats after moderate I/R.

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 pivotal role of renal vasodysfunction in salt sensitivity and the initiation of salt-induced hypertension.

For decades, it has been widely accepted that initiation of salt-induced hypertension involves a type of kidney dysfunction (natriuretic handicap), which causes salt-sensitive subjects to initially excrete less of a sodium load than normal subjects and undergo abnormal increases in cardiac output, and therefore blood pressure. Here we discuss emerging views that renal vasodysfunction, not natriuretic dysfunction (subnormal sodium excretion), is usually a critical factor initiating salt-induced hypertension. Serious logical issues have been raised with arguments supporting historical views that natriuretic dysfunction initiates hypertension in response to increased salt intake. Most salt-sensitive humans do not have a 'natriuretic handicap' causing them to excrete a sodium load more slowly and retain more of it than salt-resistant normal subjects. Mounting evidence indicates that in most salt-sensitive subjects, renal vasodysfunction, defined as impaired renal vasodilation and abnormally increased renal vascular resistance in response to increased salt intake, in the absence of greater sodium retention than in salt-loaded normal subjects, is involved in initiation of salt-induced hypertension. To advance discovery, prevention, and treatment of primary abnormalities causing salt-induced hypertension, greater research emphasis should be placed on identifying mechanisms mediating subnormal renal vasodilation and abnormally increased renal vascular resistance in response to high-salt diets.

Renal vascular response to angiotensin 1-7 in rats: the role of Mas receptor.

Recently a cross talk between angiotensin 1-7 (Ang1-7) receptor (MasR) and angiotensin II receptors types 1 and 2 (AT1R and AT2R) has been highlighted. The effects of MasR antagonist (A779) compared to the vehicle on the renal blood flow (RBF) and renal vascular resistance (RVR) responses to Ang1-7 (300 ng/kg/min) infusion in the absence of Ang II receptors in male and female rats were determined at controlled renal perfusion pressure. Ang1-7 infusion did not alter mean arterial pressure in male and female rats. However, A779 compared to vehicle increased RBF (18% vs 3%) and decreased RVR (13% vs 4%) responses to Ang1-7 infusion significantly (P < 0.05) in male when AngII receptors were blocked. Such observation was not occurred in female animals. Finally it was concluded that renal vascular responses to Ang1-7 administration may not be exerted by MasR in male rats, and these responses are not mediated with AngII receptors.

Renal blood flow and vascular resistance responses to angiotensin II in irreversible and reversible unilateral ureteral obstruction rats; the role of angiotensin II type 1 &amp; 2 receptors

Background: Unilateral ureteral obstruction (UUO) alters the expression of renin-angiotensin system (RAS) components and angiotensin II (Ang II) as the main arm of RAS is affected by UUO. Objectives: In this study the role of Ang II subtypes 1 and 2 receptors (AT1R and AT2R) antagonists (losartan and PD123319) was examined in renal hemodynamic responses to graded Ang II infusion in sham, 3-day UUO and removal UUO (RUUO) models in rats. Materials and Methods: Seventy-one male Wistar rats randomly divided into three different sets of animal models; sham-operated, UUO and RUUO that each set contains three groups treated with vehicle, losartan, and PD123319. Renal vascular responses to Ang II infusion were measured at controlled renal perfusion pressure (RPP). Results: The graded Ang II infusion decreased renal blood flow (RBF), increased renal vascular resistance (RVR) and mean arterial pressure (MAP) in vehicle or PD123319 treated groups significantly (P<0.005), but no significant difference was found between these treated groups. However, RBF, RVR and MAP responses to graded Ang II infusion in losartan-treated rats were attenuated significantly when compared with vehicle or PD123319 treated groups (P<0.05). In addition, the RBF, RVR and MAP responses to Ang II were not similar in sham, UUO and RUUO rats treated with losartan. Conclusions: Vascular responses to Ang II in UUO and RUUO rat model treated with losartan is not as the normal pattern.

Renal vascular reactivity to AVP in wild type and CD38‐/‐ mice: modulation by nitric oxide, prostanoids, and superoxide (692.9)

Renal vascular responses to AVP were tested in anesthetized wild‐type (WT) and CD38‐/‐ mice that lack the calcium mobilizing second messenger cyclic ADP ribose. Iv injections of AVP (3‐25ng) produced a dose‐dependent decrease in renal blood flow with a minimum of 25±2% below control in WT and 27±2% in CD38‐/‐ mice at the 25ng dose. Renal vascular resistance (RVR) increased by 75±6% in WT and 78±6% in CD38‐/‐ mice. Inhibition of NO synthase with L‐NAME increased the maximum RVR response to AVP from 71±7 to 308±76% in WT and from 86±7 to 388±81% in CD38‐/‐. Cyclooxygenase inhibition with indomethacin increased the maximum RVR response to 125±15% in WT and 120±14% in CD38‐/‐ mice (P&lt;0.001, &lt;0.05). Superoxide suppression with tempol inhibited the maximum RVR response to AVP by 38% in both strains (p&lt;0.005). All vascular responses to AVP were abolished by an AVP V1a receptor antagonist. Thus, vasoconstriction by AVP in the mouse is caused by V1a receptor activation with no concomitant vasodilatation by V2 receptors. However, renal vasoconstrictor responses to AVP are strongly buffered by vasodilatory actions of NO and prostanoids and augmented by the vasoconstrictor actions of superoxide. Unlike AVP, other vasoconstrictor agents show attenuated vasoconstrictor activity in CD38‐/‐ mice which points to a distinct activation mechanism for AVP that appears to be independent of CD38 and its downstream calcium signaling pathway.Grant Funding Source: Supported by HL‐02334

Renal vasoconstriction by vasopressin V1a receptors is modulated by nitric oxide, prostanoids, and superoxide but not the ADP ribosyl cyclase CD38

Renal blood flow (RBF) responses to arginine vasopressin (AVP) were tested in anesthetized wild-type (WT) and CD38(-/-) mice that lack the major calcium-mobilizing second messenger cyclic ADP ribose. AVP (3-25 ng) injected intravenously produced dose-dependent decreases in RBF, reaching a maximum of 25 ± 2% below basal RBF in WT and 27 ± 2% in CD38(-/-) mice with 25 ng of AVP. Renal vascular resistance (RVR) increased 75 ± 6% and 78 ± 6% in WT and CD38(-/-) mice. Inhibition of nitric oxide (NO) synthase with nitro-L-arginine methyl ester (L-NAME) increased the maximum RVR response to AVP to 308 ± 76% in WT and 388 ± 81% in CD38(-/-) (P < 0.001 for both). Cyclooxygenase inhibition with indomethacin increased the maximum RVR response to 125 ± 15% in WT and 120 ± 14% in CD38(-/-) mice (P < 0.001, <0.05). Superoxide suppression with tempol inhibited the maximum RVR response to AVP by 38% in both strains (P < 0.005) but was ineffective when administered after L-NAME. The rate of RBF recovery (relaxation) after AVP was slowed by L-NAME and indomethacin (P < 0.001, <0.005) but was unchanged by tempol. All vascular responses to AVP were abolished by an AVP V1a receptor antagonist. A V2 receptor agonist or antagonist had no effect on AVP-induced renal vasoconstriction. Taken together, the results indicate that renal vasoconstriction by AVP in the mouse is strongly buffered by vasodilatory actions of NO and prostanoids. The vasoconstriction depends on V1a receptor activation without involvement of CD38 or concomitant vasodilatation by V2 receptors. The role of superoxide is to enhance the contractile response to AVP, most likely by reducing the availability of NO rather than directly stimulating intracellular contraction signaling pathways.

Role of Mas receptor in renal blood flow response to angiotensin (1-7) in male and female rats

Epidemiologic and clinical studies have shown that progression of renal disease in male is faster than that in female. However, the exact mechanisms are not well recognized. Angiotensin (1-7) (Ang 1-7) receptor, called "Mas", is an element in the depressor arm of renin angiotensin system (RAS), and its expression is enhanced in females. We test the hypothesis that Mas receptor (MasR) blockade (A779) attenuates renal blood flow (RBF) in response to infusion of graded doses of Ang 1-7 in female rats. Male and female Wistar rats were anesthetized and catheterized. Then, the mean arterial pressure (MAP), RBF, and controlled renal perfusion pressure (RPP) responses to infusion of graded doses of Ang 1-7 (100-1000 ng/kg/min i.v.) with and without A779 were measured in the animals. Basal MAP, RPP, RBF, and renal vascular resistance (RVR) were not significantly different between the two groups. After Ang 1-7 administration, RPP was controlled at a constant level. However, RBF increased in a dose-related manner in response to Ang 1-7 infusion in both male and female rats (Pdose<0.0001), but masR blockade significantly attenuated this response only in female (Pgroup=0.04) and not male (Pgroup=0.23). In addition, A779 increased the RBF response to Ang 1-7 to a greater extent. This is while the increase in male was not significant when compared with that in female (Pgender=0.08). RVR response to Ang 1-7 was insignificantly attenuated by A779 in both genders. The masR differently regulated RBF response to Ang 1-7 in the two genders, and the effect was greater in female rats. The masR may be a target for improvement of kidney circulation in renal diseases.

Thromboxane-induced renal vasoconstriction is mediated by the ADP-ribosyl cyclase CD38 and superoxide anion

The present renal hemodynamic study tested the hypothesis that CD38 and superoxide anion (O2(·-)) participate in the vasoconstriction produced by activation of thromboxane prostanoid (TP) receptors in the mouse kidney. CD38 is the major mammalian ADP-ribosyl cyclase contributing to vasomotor tone through the generation of cADP-ribose, a second messenger that activates ryanodine receptors to release Ca(2+) from the sarcoplasmic reticulum in vascular smooth muscle cells. We evaluated whether the stable thromboxane mimetic U-46619 causes less pronounced renal vasoconstriction in CD38-deficient mice and the involvement of O2(·-) in U-46619-induced renal vasoconstriction. Our results indicate that U-46619 activation of TP receptors causes renal vasoconstriction in part by activating cADP-ribose signaling in renal resistance arterioles. Based on maximal renal blood flow and renal vascular resistance responses to bolus injections of U-46619, CD38 contributes 30-40% of the TP receptor-induced vasoconstriction. We also found that the antioxidant SOD mimetic tempol attenuated the magnitude of vasoconstriction by U-46619 in both groups of mice, suggesting mediation by O2(·-). The degree of tempol blockage of U-46619-induced renal vasoconstriction was greater in wild-type mice, attenuating renal vasoconstriction by 40% compared with 30% in CD38-null mice. In other experiments, U-46619 rapidly stimulated O2(·-) production (dihydroethidium fluorescence) in isolated mouse afferent arterioles, an effect abolished by tempol. These observations provide the first in vivo demonstration of CD38 and O2(·-) involvement in the vasoconstrictor effects of TP receptor activation in the kidney and in vitro evidence for TP receptor stimulation of O2(·-) production by the afferent arteriole.

Involvement of protein kinase C-CPI-17 in androgen modulation of angiotensin II-renal vasoconstriction

Previous studies suggested that androgens augmented renal vascular responses to angiotensin II (Ang II). The protein kinase C (PKC)-CPI-17 pathway is involved in vascular constriction. We tested the hypothesis that this pathway may contribute to androgenic amplification of Ang II-renal vasoconstriction in the New Zealand genetically hypertensive (NZGH) rat. NZGH underwent sham operation, castration, or castration with testosterone replacement at 5 weeks of age. When the rats were 16-17 weeks of age, mean arterial pressure (MAP) and renal vascular resistance (RVR) responses to intravenous Ang II infusion (20, 40, and 80 ng/kg/min) were recorded before and after treatment with a PKC inhibitor, chelerythrine. mRNA expression of PKC isoforms and CPI-17 protein expression were analysed in renal cortex. MAP and RVR responses to Ang II were enhanced in androgen-replete NZGH. The Ang II-induced increase in RVR was significantly lower in castrated NZGH (ranged from 100 +/- 8% to 161 +/- 9% of baseline) than in sham-operated NZGH (ranged between 123 +/- 3% and 237 +/- 19% of baseline). Testosterone treatment restored RVR responses to Ang II in castrated rats. Chelerythrine treatment markedly reduced the MAP and RVR responses to Ang II in each group and attenuated the differential MAP and RVR responses to Ang II amongst the three groups. PKCdelta and PKCepsilon mRNA levels were significantly reduced by castration and increased by testosterone treatment. In contrast, no significant differences in protein expression were detected for these PKC isoforms. Castration decreased while testosterone treatment increased CPI-17 and phospho-CPI-17 expression. Collectively, these results suggest that androgens modulate renal vascular responses to Ang II in part via an effect on the PKC-CPI-17 signalling pathway.

Aldosterone and Alterations of Hypertension-Related Vascular Function in African Americans

African Americans have a high prevalence of hypertension and hypertension-related vascular disease. We previously reported that plasma aldosterone concentrations are relatively high in hypertensive African Americans. This study evaluates the hypothesis that hypertension and hypertension-related alterations of peripheral vascular and renal vascular function are associated with aldosterone. Twenty four-hour blood pressures, cardiac output, renal blood flow (RBF), plasma renin activity (PRA), and plasma aldosterone were measured in hypertensive and normotensive African Americans. Hemodynamic measurements were repeated in response to graded infusions of norepinephrine (NE). Ambulatory blood pressures in hypertensives and normotensives were 142 +/- 1/86 +/- 1 and 117 +/- 1/70 +/- 1 mm Hg, respectively. Cardiac index (CI) was lower (P < 0.01), peripheral vascular resistance was higher (P < 0.0001), arterial compliance was lower (P < 0.0001), RBF was lower (P = 0.04), and renal vascular resistance (RVR) was higher (P < 0.0001) in the hypertensives. Overall, blood pressures were positively correlated with peripheral vascular resistance (P < 0.0001) and inversely correlated with vascular compliance (P < 0.0001). In response to NE, hypertensives had greater increases of systolic blood pressure (P < 0.004) and pulse pressure (P < 0.005). PRA was lower (P < 0.0001) and plasma aldosterone was higher (P < 0.0001) in the hypertensives. Overall, blood pressures and pulse pressure were correlated with aldosterone (P < or = 0.01). Vascular compliance, RVR, and the increment of RVR in response to NE were also correlated with aldosterone (P < or = 0.03). Aldosterone may contribute to hypertension and to hypertension-related alterations of peripheral vascular and renal vascular function in African Americans.

Relationships between Endogenous Sex Hormone Concentrations and Vascular Function in Postmenopausal Women

Differences in postmenopausal endogenous sex hormone concentrations are associated with varying risks of a growing number of common diseases. The relationships between postmenopausal endogenous sex hormone concentrations and vascular function are not well understood. We examined in postmenopausal women the relationships between endogenous sex hormone concentrations and both blood pressure (BP) and renal vascular resistance (RVR), at baseline and in response to infused angiotensin II (AngII). SUBJECTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: A total of 34 hypertensive, postmenopausal women were studied in low-sodium and/or high-sodium balance. Serum estradiol, serum progesterone, BP, and RVR were measured at baseline. BP and RVR were remeasured after AngII infusion. In low-sodium balance, the increases in systolic and diastolic BP in response to infused AngII were blunted with increased serum progesterone concentrations (P < 0.05). The increase in RVR in response to infused AngII was also blunted with increased serum progesterone concentrations (P < 0.005). The relationships between progesterone concentration and vascular response to AngII were independent of age, body mass index, and estradiol concentration. There were no significant correlations between estradiol concentration and BP or RVR response to AngII. There were no significant correlations between sex hormone concentrations and baseline BP or RVR. In high-sodium balance, there were no significant associations between sex hormone concentrations and vascular measures. In postmenopausal women in low-sodium balance, the pressor and renovascular responses to AngII are blunted with increased endogenous progesterone concentrations. Our findings suggest a role for endogenous progesterone in modulating vascular function, even within the low postmenopausal range.

Protein kinase C signaling contributes to androgen amplification of angiotensin II‐induced renal vasoconstriction.

Androgens exacerbate hypertension development. Previously we showed that androgens increased pressor and renal responses to angiotensin II (Ang II). Protein kinase C (PKC) is a major signaling mechanism activated by Ang II. We tested the hypothesis that PKC contributes to androgen amplification of AII renal vascular responses. Five week old male New Zealand genetically hypertensive (NZGH) rats underwent sham operation, castration, or castration with testosterone replacement. At 16–17 weeks of age, rats were anesthetized and fitted with arterial and venous catheters and a renal artery flow probe. Mean arterial pressure (MAP) and renal vascular resistance (RVR) responses to Ang II infusion (20–80 ng/kg/min) were obtained before and after treatment with a PKC inhibitor (chelerythrine 80 ug/kg/min). Expression of PKC isoforms and CPI-17, a downstream target of PKC, was assessed by RT-PCR and/or Western blot. Both the MAP and RVR responses to Ang II were significantly exaggerated in androgen-replete groups compared with the castrated group. Chelerythrine treatment significantly attenuated these differences. Expression of PKC delta mRNA and of CPI-17 protein in the kidney was reduced by castration but restored with testosterone replacement. Collectively, these data suggest that androgen amplification of Ang II-induced renal constrictor responses involves changes in PKC signaling mechanisms. These changes may contribute to androgen-induced facilitation of hypertension development. Supported by NIH #63053, #69886, #74852 and INBRE 2P20RR016479 and AHA #0515443Z.

Angiotensin II mediates renal blood flow reduction in chronic heart failure

The cardio-renal syndrome represents a major complication in the treatment of patients with heart failure (HF). To study this process, renal arterial flow probes were placed on the left kidney of New Zealand white rabbits. Rapid ventricular pacing was carried out for three weeks to induce HF. Renal blood flow (RBF) decreased significantly following induction of HF (49.9±5.1 ml/min normal vs. 34.8±3.2 ml/min HF, P<0.05). Losartan (los) (10 mg/kg), an angiotensin II (AngII) type 1 receptor antagonist, restored RBF to normal levels (48.6±3.0 ml/min, P<0.05). Similarly, as depicted in Table 1, renal vascular resistance (RVR) was significantly increased in HF and los decreased RVR in HF, but not in normal rabbits. The response to renal sympathetic nerve activation by nasopharyngeal smoke was augmented in HF, and los reduced this response. These data suggest AngII plays a role in the decrease in renal blood flow seen in HF. Table 1. Baseline and peak RVR response to renal sympathetic nerve activation by smoke. † P<0.05 from pre pace baseline value. ‡P<0.05 from post pace pre los value. ∗P<0.05 from pre pace peak response value. nP<0.05 from baseline. #P<0.05 from peak response pre los.

Androgens potentiate renal vascular responses to angiotensin II via amplification of the Rho kinase signaling pathway

This study assessed whether the Rho kinase signaling pathway contributes to androgenic amplification of angiotensin II (Ang II) induced pressor and renal constrictor responses. Mean arterial pressure (MAP) responses to angiotensin II receptor 1 (AT1) inhibition were measured in conscious male New Zealand genetically hypertensive rats (NZGH) subjected to sham operation, castration or castration+testosterone replacement. MAP and renal vascular resistance (RVR) responses to Ang II were recorded with and without a Rho kinase inhibitor, fasudil, in anesthetized NZGH. Western blot was used to analyze target protein expression in the kidney. MAP responses to AT1 receptor inhibition and exogenous Ang II were attenuated in castrated NZGH. The increase in RVR (mm Hg/ml/min/g kidney) at the maximum dose of Ang II was significantly lower in castrated NZGH than in sham operated NZGH. Testosterone replacement restored RVR responses to Ang II in castrated rats. Fasudil treatment reduced both MAP and RVR responses to Ang II in each group. In addition, the differential MAP and RVR responses to Ang II amongst the three groups were significantly attenuated by Rho kinase inhibition. Western blot showed that Rho kinase protein expression was reduced by castration, while testosterone replacement restored the Rho kinase protein levels in castrated rats. The phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a downstream target of Rho kinase, was also increased by androgens. Collectively, these results indicate that androgens potentiate Ang II-induced renal vascular responses, an effect mediated at least partly via up-regulation of the Rho kinase signaling pathway.