Reduction Of Renal Perfusion Pressure Research Articles

Effects of traumatic brain injury on blood pressure regulation and cardio-renal function in rats

Traumatic Brain Injury (TBI) affects around 68 million people worldwide annually. While the neurologic effects of TBI have been extensively studied, potential effects on the autonomic nervous system have received less attention, despite clinical observations of autonomic dysfunction. We therefore sought to develop a rat model of repeated traumatic brain injury to examine the effects on cardiovascular and renal regulation, and we hypothesized that TBI would result in autonomic dysregulation of cardio-renal function. TBI was induced in male rats (250-300 gBW) under brief isoflurane anesthesia by dropping a 245g weight from a height of 1-1.5 meters onto the mid-sagittal area of the skull while the rat was suspended on a perforated tear-away platform. In the first series of experiments, blood pressure was measured continuously by telemetry over a two-week period, while rats were subjected to three successive injuries, each separated by 48 hours (repeated TBI, rTBI). Mean blood pressure was found to increase by about 7 mmHg following the third TBI (104.0 ± 1.1 to 111.0 ± 1.3 mmHg; p < 0.001, n=9). Though mild, the elevation in blood pressure was highly consistent, occurring in all of the injured rats. There were no correlate changes in heart rate observed in these rats. We then sought to examine the underlying causes of these blood pressure changes. Balance studies were performed using metabolic cages to examine salt and water intake and output before and during rTBI. Though intake of food and water were slightly affected by rTBI, no measurable effect of rTBI was observed on salt and water balance in these rats. We next measured cardiac function in anesthetized rats following rTBI and found no significant differences in any major contractile variables (LV systolic pressure, dP/tmax, dP/dtmin). In a final series of experiments, we evaluated renal blood flow during step-wise reductions in renal perfusion pressure using an aortic clamp and found that, while blood flow autoregulation was not impaired in rTBI rats, baseline renal blood flow was mildly reduced in injured rats compared to uninjured controls (3.44 ± 0.16 vs 3.94 ± 0.05 mL/min/gKW). In summary, we have generated a rat model of repeated traumatic brain injury that results in a consistent elevation of resting arterial blood pressure. Speculation that these observed changes may result from autonomic dysregulation remains to be investigated. University of Cincinnati College of Medicine Innovation Seed Grant 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.

Screening of QTc interval and global autonomic activity in autosomal dominant polycystic kidney disease and atherosclerotic renal artery stenosis hypertensive patients.

Arterial hypertension (AH) represents a major risk factor for cardiovascular disease and is associated to several complications, such as prolonged corrected QT (QTc) interval and impaired heart rate variability (HRV). Secondary causes of AH include autosomal dominant polycystic kidney disease (ADPKD) and atherosclerotic renal artery stenosis (ARAS), both known to be related to arrhythmic risk and autonomic imbalance. The aim of the study is to evaluate whether global autonomic activity and QTc interval differently affect ADPKD and ARAS hypertensive patients. An observational study was performed on 59 patients: 16 ADPKD patients and 19 diagnosed with ARAS, compared to 24 healthy controls (HC). All patients underwent clinical evaluation, biochemical lab tests, 24-hour electrocardiogram (ECG) and renal Doppler ultrasound. HRV was assessed through the analysis of 24-hour ECG to detect standard deviation of normal-to-normal RR intervals (SDNN). QTc interval was defined as prolonged when > 440 msec. SDNN was significantly lower in ADPKD and ARAS patients than HC (p < 0.0001) and no significant differences were found between ADPKD and ARAS patients (p > 0.05). QTc was found significantly higher in ARAS patients than HC (p = 0.001) and in ARAS patients than ADPKD patients (p = 0.004). The pathogenesis of hypertension in ADPKD and ARAS patients is related to the activation of the renin angiotensin aldosterone system (RAAS). In ADPKD, cyst enlargement leads to kidney ischemia and renin release, associated to endothelial dysfunction, low nitric oxide and sympathetic tone activation. Differently, reduction in renal perfusion pressure activates RAAS and renal adrenergic nerves in ARAS patients. We can speculate that prolonged QTc interval is more present in ARAS vs. ADPKD hypertensive patients due to a greater activation of RAAS. We suggest adding 24-hour HRV evaluation in association with traditional risk factors in course of ADPKD and ARAS hypertension to better stratify cardiovascular risk in these groups of patients.

Impairment of Whole Kidney Blood Flow Autoregulation in the Transition from Acute to Chronic Kidney Disease in Ischemia‐Reperfusion Rats

Efficient autoregulation of renal blood flow (RBF) is an essential mechanism of renal microcirculation to protect against glomerular injury. Patients surviving an episode of acute kidney injury (AKI) develops chronic kidney disease (CKD). Renal ischemia-reperfusion (IR) is a major cause of AKI and triggers inflammation and reactive oxygen species (ROS) accumulation. We hypothesized that IR‑induced inflammation and ROS accumulation leads to a persistent reduction of RBF and impairment of RBF autoregulation contributing to CKD progression. Whole kidney RBF autoregulation was assessed in vivo in Sprague-Dawley male IR induced by bilateral arterial ischemia for 60 minutes followed by 24 hours, 1-week and 4‑weeks of reperfusion. Plasma creatinine increased in IR at 24 hours (3.9±0.2 vs. 1.0±0.1 mg/dl in sham, P<0.05, n=6-7/group) and week 1 (1.4±0.1 vs. 1.1±0.0 mg/dl in sham, P<0.05, n=7-8/group). Systolic blood pressure was similar between sham and IR over the 4 weeks post-IR (113-135 mmHg). IR reduced baseline RBF (5.8±0.5 vs. 9.1±0.5 ml/min.gkw in sham, P<0.05, n=6/group) at 24 hours and further decreased RBF at week 1 (3.7±0.7 vs. 9.1±1.1 ml/min.gkw in sham, n=5-6/group). At week 4, RBF was still significantly low in IR (6.9±0.4 vs. 10.4±0.3 ml/min.gkw in sham, P<0.05, n=6/group). RBF remained stable during step reduction of renal perfusion pressure (RPP) from 120 to 100 mmHg in all shams with autoregulatory index (AI) less than 0.2, indicating intact autoregulation. RBF autoregulation, however, was completely impaired in IR at 24 hours, week 1 and week 4 as RBF passively decreased during reduction of RPP, yielding AI of 0.8±0.2, 1.1±0.2 and 0.9±0.3, respectively. Preglomerular microvessels (PGMV) were collected for mRNA measurement (n=6-8/group). IR elevated mRNA expression of p67phox 7‑fold at 24 hours and 2‑fold at week 1 (P<0.05 vs. respective shams). IR also elevated gp91phox mRNA expression 5-fold at 24 hours and 2-fold at week 1 (P<0.05 vs. shams). IR tended to elevate p47phox mRNA expression at 24 hours and reached a significance at week 1 (2-fold, P<0.05 vs. sham). Inflammatory mediators, monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1), were also assessed in PGMV. MCP-1 mRNA expression was increased in IR with a peak of 10-fold at 24 hours and then decreased at week 1 but still elevated compared to shams (2-fold, P<0.05). VCAM-1 mRNA expression remained unchanged at 24 hours but increased 2-fold at week 1 (P<0.05). We also assessed profibrotic markers (TGF-β, collagen IV and fibronectin). TGF-β mRNA expression started to increase in IR at 24 hours (2-fold) and reached a significance at week 1 (3-fold, P<0.05 vs. sham) and further increased at week 4 (4-fold). IR also increased mRNA expression of collagen IV 5-fold at week 1 and 4-fold at week 4 (P<0.05). Fibronectin mRNA expression was also increased in IR 4-fold at week 1 and remained at the same level at week 4 (P<0.05). In conclusion, these results demonstrate that IR leads to a persistent reduction of RBF and impairment of RBF autoregulation in male rats and suggest that renal hemodynamic dysfunction might be associated with activation of NADPH oxidase, MCP-1 and TGF-β in PGMV of IR.

Roles of Insulin Receptor Substrates (IRS) in renal function and renal hemodynamics.

We have reported previously that renal hemodynamic abnormalities exist in the prediabetic stage of type II diabetic rats. At this prediabetic stage these rats have hyperinsulinemia, insulin resistance and metabolic syndrome. It is well known that insulin resistance is frequently associated with renal abnormalities, but the mechanism underlying this association has remained speculative. Although insulin is known to modify renal hemodynamics, little is known about the roles of insulin receptor substrates (IRS1, IRS2) in the renal actions of insulin. To address this issue, the effects of insulin on renal function and renal hemodynamics were investigated in C57BL/6 (WT: wild type), insulin receptor substrate 1- knockout (IRS1–/–), and IRS2-knockout (IRS2–/–) mice. IRS2–/–mice had elevated glucose level as expected. 24-h urine collections and serum creatinine revealed that creatinine clearance did not significantly differ between these groups. Albuminuria was found in IRS1–/–and IRS2–/–groups. We examined the effects on the IRS during the administration of Losartan, which is widely used for diabetic nephropathy. After the administration of Losartan the IRS displayed improved renal hemodynamics. Moreover, the subjects were also given Pioglitazone, which improves insulin resistance. Losartan significantly reduced albuminuria in both groups. Pioglitazone also showed similar results. We assessed the autoregulatory responses of the total renal blood flow (RBF), the superficial (SBF) and the deep renal cortical blood flow (DBF) with stepwise reductions of renal perfusion pressure (RPP), which was induced by a manual clamp on the abdominal aorta. During the clamp induced reductions of the RPP by 10 to 20mm HG, RBF, SBF and the DBF fell significantly more in the IRS1 and IRS2 than in the WT mice. Furthermore micropuncture studies showded that compared to the WT tubuloglomerular feedback (TGF) responses of the stop flow pressure (Psf) were reduced in both the IRS1 -/- and IRS2 -/-. The results of the IRS1 and IRS2 mice displayed the pressence of hemodynamic abnormalities. Losartan and Pioglitazone have shown the potential to improve these abnormalities. In conclusion the results indicate that IRS plays a major role in the stimulation of renal functions and renal hemodynamics in type type II diabetes.

Renal Ischemia‐Reperfusion Impairs Whole Kidney Blood Flow Autoregulation in Male and Female Rats

Renal autoregulation is critical in maintaining a stable renal blood flow (RBF) and glomerular filtration rate over a wide range of renal perfusion pressure. Our recent in vitro work demonstrated that accumulating reactive oxygen species (ROS) contribute to loss of renal autoregulatory capability in ischemia reperfusion (IR)‐induced acute kidney injury (IR‐AKI) in male rats. Evidence shows that sex differences might contribute to differential injury in IR‐AKI. Therefore, we hypothesized that renal IR leads to impaired RBF autoregulation which may be associated with ROS accumulation and inflammation in male and female rats. IR was induced by occluding both renal arteries for 60 minutes followed by 24 hours or 1 week of reperfusion. Plasma creatinine was markedly increased in IR rats but more so in males than females at 24 hours (3.8±0.2 vs 1.9±0.4 mg/dl, P&lt;0.05, n=7/group). Plasma creatinine was still elevated in IR males one week post‐IR (1.3±0.1 vs 1.1±0.0 mg/dl in sham, P&lt;0.05, n=13–14/group). Whole kidney autoregulation was assessed in vivo. IR significantly lowered baseline RBF in males (5.9±0.6 vs. 9.1±0.5 ml/min/gkw in sham, P&lt;0.05, n=6/group) but not in females (8.3±0.6 vs. 10.3±0.9 ml/min/gkw in sham, P&gt;0.05, n=5–8/group) 24 hours post‐IR. RBF was lower in IR males compared to IR females (P&lt;0.05). RBF decreased further in IR rats at week 1 (4.1±1.0 ml/min/gkw in males and 4.5±0.2 ml/min/gkw in females, n=2–3). RBF remained constant during stepwise reduction of renal perfusion pressure from 120 to 100 mmHg in both sham males and females at 24 hours and 1 week, indicating intact autoregulation as reflected by autoregulatory index (ARI) between 0.1±0.0 and 0.2±0.1. IR led to impaired RBF autoregulation in males at 24 hours and 1 week, and in females at 24 hours as indicated by ARI between 0.8±0.1 and 1.1±0.2. Interestingly, autoregulation partially recovered in females at week 1 as indicated by ARI of 0.5. Preglomerular microvessels (PGMV) were collected for mRNA measurement (n=4–7 rats/each group). IR increased mRNA expression of p67phox in males at 24 hours (7.3±1.5 vs. 1.1±0.2 in sham, P&lt;0.05) and 1 week (2.2±0.3 vs. 1.0±0.1 in sham, P&lt;0.05). In contrast, IR elevated p67phox mRNA expression in females at 24 hours only (3.9±0.4 vs. 1.5±0.2 in sham, P&lt;0.05) but to a lesser degree compared to IR males (P&lt;0.05). The p47phox mRNA expression was elevated in IR males at 1 week (2±0.3 vs. 1.0±0.1 in sham, P&lt;0.05) but remained unchanged in IR females. IR also markedly increased mRNA expression of MCP‐1 in both male and female rats at 24 hours and 1 week (P&lt;0.05 vs respective sham). TGF‐β mRNA expression tends to increase in IR males at 24 hours and reached statistical significance at week 1 (2.5±0.2 vs 1.1±0.1 in sham, P&lt;0.05). TGF‐β was significantly elevated in IR females though still lower compared to IR males at week 1 (1.7±0.2 vs 2.5±0.2, P&lt;0.05). In conclusion, these results suggest that IR impairs RBF autoregulation in male and female rats which might be associated with activation of NOX, MCP‐1 and TGF‐β pathways in PGMV. Female rats have less kidney injury which might be attributed to less NOX expression in PGMV.Support or Funding InformationThis study was supported by grants from NIH (DK106500) to ZG, and NIH (DK044628 and HL095499) to EWI.

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.

Defective renal autoregulation in the chronic bile duct ligation model of liver failure.

Cirrhosis of the liver is often associated with an impairment of renal function that is usually not associated with consistent structural abnormalities of the renal parenchyma, but is thought to be the functional consequence of arterial underfilling and reduced arterial blood pressure. We have used the cirrhosis model of chronic bile duct ligation (BDL) to assess the response of renal blood flow to a change of blood pressure. We have measured renal haemodynamics in BDL rats. Three weeks after BDL, rats showed elevated levels of total bilirubin, AST, and ALT as well as reduced arterial blood pressure. Creatinine clearance was significantly reduced, and plasma creatinine and urea nitrogen were elevated. Renal blood flow at baseline blood pressure was significantly lower in the BDL group than in the sham group. Clamp-induced reductions of renal perfusion pressure caused significantly greater changes of renal blood flow in BDL than control rats. The autoregulatory index over a comparable blood pressure range averaged 0.28 ± 0.35 in control rats and 1.26 ± 0.6 in BDL rats (p = 0.0004) indicating impairment of renal autoregulation in liver cirrhosis. Tubuloglomerular feedback (TGF) responses were significantly attenuated in BDL rats, especially in the subnormal flow range. Impairment of renal blood flow autoregulation, to some extent mediated by reduced TGF-mediated vasodilatation, may contribute to the renal vascular constrictor state in liver cirrhosis by preventing the full dilatory response to the blood pressure reduction.

Snakes and Hypertension.

Inhibition of Angiotensin Conversion in Experimental Renovascular Hypertension. By Miller ED Jr, Samuels A, Haber E, and Barger AC. Science 1972; 177:1108-9. Reprinted with permission from AAAS.Constriction of the renal artery and controlled reduction of renal perfusion pressure is followed by a prompt increase in systemic renin activity and a concomitant rise in blood pressure in trained, unanesthetized dogs. The elevated blood pressure induced by the renal artery stenosis can be prevented by prior treatment with the nonapeptide Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro, which blocks conversion of angiotensin I to angiotensin II. Further, the nonapeptide can restore systemic pressure to normal in the early phase of renovascular hypertension. These results offer strong evidence that the renin- angiotensin system is responsible for the initiation of hypertension in the unilaterally nephrectomized dog with renal artery constriction.

ET B Receptors in High Salt Diet‐Induced Decline of Renal Autoregulation in Rats

High salt (HS) diet is linked to increased endothelin-1 (ET-1) and salt-dependent hypertension. Previous studies showed that HS treatment increased renal microvascular ETB receptor expression and impaired renal blood flow (RBF) autoregulation. We hypothesized that HS leads to a decline of renal autoregulation via activation of ETB receptors. RBF autoregulation was assessed in anesthetized ETB deficient (ETB) and intact control littermates (Con) rats fed normal salt (NS) or HS (8% NaCl) for 2 weeks. RBF was monitored using an ultrasonic flow probe and autoregulation was assessed during step-decrements of arterial pressure imposed using an aortic occluder placed between the two renal arteries. ETB deficient rats (n=6) exhibited significantly elevated baseline mean arterial pressure (MAP, 132±5 vs. 116±1 mmHg in Con+NS, n=8, P<0.05). HS did not change MAP in either group but significantly increased RBF in Con rats (n=8, 12.5±0.7 vs. 9.2±0.5 ml/min.gkw in Con+NS, P<0.05) while decreasing RBF in ETB rats (6.8±0.6 ml/min.gkw vs. Con+NS, P<0.05). HS led to attenuated autoregulation of RBF in Con rats. Decreasing renal perfusion pressure from ambient to 95 mmHg resulted in an 11±2% decrease in RBF in Con+HS versus a 3±1% in Con+NS (P<0.05). Accordingly, autoregulatory index (AI) was 0.63±0.08 in Con+HS versus 0.18±0.09 in Con+NS (P<0.05). In contrast, RBF remained fairly stable in ETB+NS and ETB+HS rats during a stepwise reduction of renal perfusion pressure from ambient to 95 mmHg. AI averaged 0.26±0.14 and 0.12±0.24, respectively, suggesting intact autoregulation in ETB deficient rats. These data suggest that HS leads to attenuated RBF autoregulation and increased RBF via ETB receptoractivation.

Influence of Renal Sympathetic Nerve Activity on Mean Arterial Pressure during Reduced Renal Perfusion Pressure

Renal sympathetic nerve activity (RSNA) has direct actions on the kidneys to affect renin secretion, tubular sodium reabsorption, and renal vascular resistance. As a result, the renal nerves influence blood volume and blood pressure regulation. To determine the quantitative influence of changes in RSNA on mean arterial pressure (MAP) during a unilateral reduction in renal perfusion pressure (RPP), we developed a mathematical model and simulated a study conducted by Mizelle et al. (Hypertension 1993;22:102–110). In response to a 12 day servo-controlled reduction in RPP of ~13 mmHg, Mizelle et al. reported a sustained reduction in Na+ excretion from the low pressure kidney, a persistent natriuresis from the contralateral side, an increase in MAP of ~ 3 mmHg and a modest increase in plasma renin activity. Similar responses occurred in the simulation. Additionally, the model indicated a sustained decrease in RSNA of ~ 5%. When RSNA was prevented from decreasing by clamping RSNA at normal levels, there was a 3–4 mmHg greater increase in MAP. Finally, to simulate a sympathoexcitatory effect of angiotensin II, RSNA was increased 10% during reduced RPP. This resulted in a 14 mmHg increase in MAP. These results provide quantitative insight into the potential influence of changes in RSNA on MAP during reduced RPP and suggest that sustained sympathoinhibition normally attenuates the severity of the hypertension. Supported by NSF EPSCoR 0903787

Renal hemodynamic responses to sustained suppression of central sympathetic outflow

Chronic electrical stimulation of the carotid baroreflex causes sustained reductions in blood pressure by suppression of sympathetic activity (SA). The role of SA in controlling renal hemodynamic responses to chronic reductions in renal perfusion pressure is unknown. Therefore, we compared renal and systemic hemodynamics in normotensive dogs in which blood pressure was lowered consecutively for 2 weeks by either baroreflex activation (BA, low SA) or calcium channel blockade with amlodipine, 5mg/kg/day, (CCB, high SA). Both interventions caused a similar sustained reduction in mean arterial pressure (MAP) by ~18 mmHg. Glomerular filtration rate (GFR) responses were as follows: BA CCB Control 67.8±3.3 65.0±2.0 Week 1 59.3±2.4* 62.4±3.0 Week 2 59.7±2.3* 63.7±2.5 Recovery 64.3±2.5 64.2±2.2 P&lt; 0.05 vs control GFR decreased by 10–15% during baroreflex activation while it was unchanged from control during CCB. Renal blood flow (RBF), measured continuously by ultrasound flow probes, decreased by 10–15% during baroreflex activation while its circadian pattern of variation was maintained. These data are consistent with the hypothesis that despite reduced MAP, sustained suppression of renal SA by BA chronically reduces Na+ reabsorption prior to the macula densa, initiating sustained preglomerular vasoconstriction, which results in lowering of GFR and RBF. As renal disease is commonly associated with hyperfiltration and glomerular hypertension, this effect may provide an additional benefit in hypertensive patients in which reductions in renal hyperfiltration are desirable.

Magnetic resonance elastography (MRE) detects medullary renal fibrosis

MRE is a noninvasive novel MRI modality that detects changes in tissue viscoelastic properties by imaging shear wave propagation. Renal artery stenosis (RAS) induces kidney fibrosis, yet we have previously shown that concomitant reductions in renal perfusion pressure mask an increase in cortical stiffness. We hypothesized that due to its lower vascular volume and turgor, change es in medullary elasticity in RAS would be detectable by MRE. MRE 3D elastograms were obtained in pigs after 10 weeks of RAS or matched controls (n=6 per group), and contrast‐enhanced computed tomography images obtained in the same pigs guided selection of MRE medullary regions of interest (Fig 1). Trichrome staining was used for computer‐aided quantification of medullary fibrosis ex‐vivo. The renal medulla was significantly more fibrotic (5.96±0.19 vs. 1.82±0.49%, p&lt;0.001) and stiffer (10.9±0.84 vs. 7.88±0.26 kPa, p&lt;0.05) in RAS compared to controls (Fig 1 and 2). The histological degree of medullary fibrosis directly correlated with MRE‐derived stiffness (R2=0.55, p&lt;0.05, Fig 3). This study therefore suggests that renal medullary MRE may be useful for detection of chronic kidney fibrosis in RAS.Grant Funding Source: NIH DK73608, HL77131, HL085307, and EB001981

Direct-Acting Vasodilators

KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Hydralazine and minoxidil act by dilating resistance arterioles, thus reducing peripheral resistance, with no dilating effect on the venous side of the circulation. • There is a baroreflex-mediated venoconstriction, resulting in an increase in venous return to the heart, along with a direct catecholamine-mediated positive inotropic and chronotropic stimulation of the heart. • Hydralazine therapy is usually combined with a sympathetic inhibitor to prevent expression of this reflex, as well as with a diuretic agent to prevent sodium retention caused by reduction in renal perfusion pressure. • Hydralazine is indicated in the long-term therapy of essential hypertension, in the short-term therapy of pregnancy-induced hypertension and eclampsia, and in the therapy of hypertensive crisis. • Adverse effects include the anticipated tachycardia, fluid retention, and headache, caused by the vasodilation, especially in the early days of therapy, but may frequently be prevented by the concomitant use of a β-blocker. • As with other drugs that are N-acetylated, there is a low risk of lupus-like syndrome with high doses and long-term use. • Because of the severity of adverse effects with minoxidil, its usage is limited to persons with severe hypertension unresponsive to other treatments. • Hirsutism, a common side effect of minoxidil, is particularly bothersome in women and reverses in a few months after discontinuation. • Sodium nitroprusside is used in the intensive care setting to lower pressure in hypertensive crisis or to treat severe left ventricular failure, particularly valuable when elevated pressure or severe left ventricular failure threatens the patient's survival. • Although nitrates have not achieved widespread use as antihypertensive agents, they are effective in producing sustained blood pressure (BP) reductions when added to other antihypertensive regimens.

Estrogen dependence of the renal vasodilatory effect of nicotine in rats: Role of α 7 nicotinic cholinergic receptor/eNOS signaling

Aims We recently reported that acute exposure to nicotine vasodilates the renal vasculature of male rats via facilitation of endothelial nitric oxide synthase (eNOS). In this study, we investigated whether this effect of nicotine is sexually dimorphic and the role of estrogen in modulating the nicotine effect. Main methods Nicotine-evoked vasodilation was evaluated in phenylephrine-preconstricted perfused kidneys obtained from male, proestrus female, ovariectomized (OVX) and estrogen-replaced OVX (OVXE 2) rats. Key findings Nicotine infusion (5 × 10 − 5 , 1 × 10 − 4 , and 5 × 10 − 4 M) produced greater concentration-dependent reductions in the renal perfusion pressure (RPP) in an isolated kidney from proestrus females than from males. Inhibition of NOS by N G-nitro- l-arginine abolished the nicotine-evoked reduction in RPP and abolished the gender difference in the nicotine effect. Nicotine vasodilation was also attenuated in kidneys isolated from OVX and diestrus rats, models characterized by reduced estrogen levels. Further, estrogen or l-arginine supplementation in OVX rats largely restored the renal vasodilatory response to nicotine. Estrogen receptor blockade by tamoxifen abrogated the enhanced nicotine-evoked vasodilation elicited by E 2 in OVX rats. The nitrite/nitrate levels and protein expressions of eNOS and α 7 nicotinic cholinergic receptor (α 7 nAChRs) were significantly higher in renal tissues of OVXE 2 compared with OVX rats, suggesting a facilitatory effect for E 2 on α 7 nAChRs/eNOS signaling. Significance Estrogen-dependent facilitation of NOS signaling mediates the enhanced vasodilator capacity of nicotine in the renal vasculature of female rats. Preliminary evidence also suggests a potential role for α 7 nAChRs in this estrogen-dependent phenomenon.

P2X1receptor blockade inhibits whole kidney autoregulation of renal blood flow in vivo

In vitro experiments demonstrate that P2X(1) receptor activation is important for normal afferent arteriolar autoregulatory behavior, but direct in vivo evidence for this relationship occurring in the whole kidney is unavailable. Experiments were performed to test the hypothesis that P2X(1) receptors are important for autoregulation of whole kidney blood flow. Renal blood flow (RBF) was measured in anesthetized male Sprague-Dawley rats before and during P2 receptor blockade with PPADS, P2X(1) receptor blockade with IP5I, or A(1) receptor blockade with DPCPX. Both P2X(1) and A(1) receptor stimulation with alpha,beta-methylene ATP and CPA, respectively, caused dose-dependent decreases in RBF. Administration of either PPADS or IP5I significantly blocked P2X(1) receptor stimulation. Likewise, administration of DPCPX significantly blocked A(1) receptor activation to CPA. Autoregulatory behavior was assessed by measuring RBF responses to reductions in renal perfusion pressure. In vehicle-infused rats, as pressure was decreased from 120 to 100 mmHg, there was no decrease in RBF. However, in either PPADS- or IP5I-infused rats, each decrease in pressure resulted in a significant decrease in RBF, demonstrating loss of autoregulatory ability. In DPCPX-infused rats, reductions in pressure did not cause significant reductions in RBF over the pressure range of 100-120 mmHg, but the autoregulatory curve tended to be steeper than vehicle-infused rats over the range of 80-100 mmHg, suggesting that A(1) receptors may influence RBF at lower pressures. These findings are consistent with in vitro data from afferent arterioles and support the hypothesis that P2X(1) receptor activation is important for whole kidney autoregulation in vivo.

The renin-angiotensin system and the third mechanism of renal blood flow autoregulation

Autoregulation of renal blood flow comprises three mechanisms: the myogenic response (MR), the tubuloglomerular feedback (TGF), and a third mechanism (3M). The nature of 3M is unknown; it may be related to hypotensive resetting of autoregulation that probably relies on pressure-dependent stimulation of the renin-angiotensin system (RAS). Thus we used a normotensive angiotensin II clamp in anesthetized rats and studied autoregulation 1) by slow ramp-shaped reductions in renal perfusion pressure (RPP) followed by ramp-shaped RPP restorations and 2) by means of the step response technique: after 30 s of either total or partial suprarenal aortic occlusion, a step increase in RPP was made and the response of renal vascular conductance analyzed to assess the mechanisms' strength and initial direction (vasodilation or constriction). The angiotensin clamp abolished the resetting of autoregulation during ramp-shaped RPP changes. Under control conditions, the initial TGF response was dilatory after total occlusions but constrictive after partial occlusions. The initial 3M response presented a mirror image to the TGF: it was constrictive after total but dilatory after partial occlusions. The angiotensin clamp suppressed the TGF and turned the initial 3M response following total occlusions into dilation. We conclude that 1) pressure-dependent RAS stimulation is a major cause behind hypotensive resetting of autoregulation, 2) TGF sensitivity strongly depends on pressure-dependent changes in RAS activity, 3) the 3M is modulated, but not mediated, by the RAS, and 4) the 3M acts as a counterbalance to the TGF and might possibly be related to the recently described connecting tubule glomerular feedback.

Roles of Insulin Receptor Substrates (IRS) in renal function and renal hemodynamics.

We have reported previously that renal hemodynamic abnormalities exist in the prediabetic stage of type II diabetic rats. At this stage these rats have insulin resistance. It is well known that insulin resistance is frequently associated with renal abnormalities, but the mechanism underlying this association has remained speculative. Although insulin is known to modify renal hemodynamics, little is known about the roles of insulin receptor substrates (IRS1, IRS2) in the renal actions of insulin. To address this issue, we investigated in wild type (WT), IRS1‐deficient (IRS1‐/‐), and IRS2‐deficient (IRS2‐/‐) mice. IRS2‐/‐ mice had elevated blood pressure and glucose level as expected. 24‐h urine collections revealed that creatinine clearance did not significantly differ between these groups. Fractional excretion of sodium was significantly lower in IRS1‐/‐ and IRS2‐/‐ compared to WT mice. Albuminuria was found in IRS1‐/‐ and IRS2‐/‐ groups. We assessed autoregulatory responses of total renal blood flow (RBF), and of superficial (SBF) and deep renal cortical blood flow (DBF) to stepwise reductions of renal perfusion pressure (RPP) induced by a manual clamp on the abdominal aorta. RBF, SBF and DBF fell significantly more in IRS1‐/‐ and IRS2‐/‐ than in WT mice. These results indicate that IRS plays a major role in the stimulation of renal functions and renal hemodynamics in type II diabetes.

Abnormal autoregulation and tubuloglomerular feedback in prediabetic and diabetic OLETF rats

The mechanisms underlying the development and prevention of diabetic nephropathy are still not fully understood. In the present study in the Otsuka Long-Evans Tokushima Fatty (OLETF) model of type 2 diabetic rats, we investigated whether renal hemodynamic abnormalities exist and whether they precede the onset of diabetes. Using OLETF rats in both prediabetic and diabetic stages, we assessed autoregulatory responses of total renal blood flow (RBF) and of superficial (SBF) and deep renal cortical (DBF) blood flow to stepwise reductions of renal perfusion pressure (RPP) induced by a manual clamp on the abdominal aorta. During clamp-induced reductions of RPP by 10 or 20 mmHg, RBF fell significantly more in OLETF rats than in lean control [Long-Evans Tokushima Otsuka (LETO)] rats. Whereas SBF showed no significant changes in either OLETF rats or LETO rats during mild clamping, DBF decreased significantly more in OLETF rats than LETO rats. Reduced autoregulatory efficiency in OLETF rats was observed in both prediabetic and diabetic stages. Micropuncture studies showed that tubuloglomerular feedback (TGF) responses of stop flow pressure are reduced in prediabetic (-7.3 vs. -25.7%) as well as in diabetic OLETF rats compared with LETO control rats (-4.4 vs. -18.8%). Renal corticotomy was performed to measure glomerular capillary pressure (Pgc) directly. Pgc of deep cortical glomeruli was higher than superficial glomerular Pgc in both strains of rats, but the difference was especially pronounced in OLETF rats (deep 78 +/- 2 vs. superficial 57 +/- 4 mmHg). This study demonstrates reduced autoregulatory adjustments and impaired TGF efficiency in prediabetic OLETF rats. Thus abnormal RBF regulation precedes the onset of diabetes and is especially pronounced in the deep cortical region.

Failure to upregulate the adenosine2Areceptor-epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl salt-sensitive rats

Adenosine-activated renovascular dilatation in Sprague-Dawley (SD) rats is mediated by stimulating adenosine(2A) receptors (A(2A)R), which is linked to epoxyeicosatrienoic acid (EET) synthesis. The A(2A)R-EET pathway is upregulated by high salt (HS) intake in normotensive SD rats. Because this pathway is antipressor, we examined the role of the A(2A)R-EET pathway in Dahl salt-sensitive (SS) rats. Male Dahl salt-resistant (SR) and SS rats were fed either HS (8.0% NaCl) or normal salt (NS; 0.4% NaCl) diet for 7 days. On day 8, isolated kidneys were perfused with Krebs-Henseleit buffer containing indomethacin and N(G)-nitro-l-arginine methyl ester and preconstricted with phenylephrine. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1-20 microg) elicited dose-dependent dilation in both Dahl SR and SS rats. Dahl SR rats fed a HS diet demonstrated a greater renal vasodilator response to 10 microg of 2-CA, as measured by the reduction in renal perfusion pressure, than that of Dahl SR rats fed a NS diet (-104 +/- 6 vs. -77 +/- 7 mmHg, respectively; P < 0.05). In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed NS or HS diet (96 +/- 6 vs. 104 +/- 13 mmHg in NS- and HS-fed rats, respectively). In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A(2A)R and the cytochrome P-450 2C23 and 2C11 epoxygenases, and elevated the renal efflux of EETs. Thus the Dahl SR rat is able to respond to HS intake by recruiting EET formation, whereas the Dahl SS rat appears to have exhausted its ability to increase EET synthesis above the levels observed on NS intake, and this inability of Dahl SS rats to upregulate the A(2A)R-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension.

Angiotensin II Type 2 Receptors and Nitric Oxide Sustain Oxygenation in the Clipped Kidney of Early Goldblatt Hypertensive Rats

Angiotensin-converting enzyme inhibitors (ACEIs) decrease the glomerular filtration rate and renal blood flow in the clipped kidneys of early 2-kidney, 1-clip Goldblatt hypertensive rats, but the consequences for oxygenation are unclear. We investigated the hypothesis that angiotensin II type 1 or angiotensin II type 2 receptors or NO synthase mediate renal oxygenation responses to ACEI. Three weeks after left renal artery clipping, kidney function, oxygen (O(2)) use, renal blood flow, renal cortical blood flow, and renal cortical oxygen tension (Po(2)) were measured after acute administration of an ACEI (enalaprilat) and after acute administration of ACEI following acute administration of an angiotensin II type 1 or angiotensin II type 2 receptor blocker (candesartan or PD-123,319) or an NO synthase blocker (N(G)-nitro-L-arginine methyl ester with control of renal perfusion pressure) and compared with mechanical reduction in renal perfusion pressure to the levels after ACEI. The basal renal cortical Po(2) of clipped kidneys was significantly lower than contralateral kidneys (35+/-1 versus 51+/-1 mm Hg; n=40 each). ACEI lowered renal venous Po(2), cortical Po(2), renal blood flow, glomerular filtration rate, and cortical blood flow and increased the renal vascular resistance in the clipped kidney, whereas mechanical reduction in renal perfusion pressure was ineffective. PD-123,319 and N(G)-nitro-L-arginine methyl ester, but not candesartan, reduced the Po(2) of clipped kidneys and blocked the fall in Po(2) with acute ACEI administration. In conclusion, oxygen availability in the clipped kidney is maintained by angiotensin II generation, angiotensin II type 2 receptors, and NO synthase. This discloses a novel mechanism whereby angiotensin can prevent hypoxia in a kidney challenged with a reduced perfusion pressure.