Reduction Of Renal Perfusion Pressure Research Articles

Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L‐arginine and antioxidants

Nitric oxide (NO) and superoxide are considered to be regulatory in renal blood flow (RBF) autoregulation, and hence may contribute to development of hypertension. To extend our previous observations that dynamic NO release is impaired in the spontaneously hypertensive rat (SHR) we investigated, firstly, if superoxide dependency of RBF autoregulation is increased in SHR and, secondly, if the beneficial effect of perinatal supplementation in SHR is partly as a result of early correction of RBF autoregulation. We hypothesized that perinatal supplementation by restoring dynamic NO release and/or decreasing superoxide dependency and would improve life-long blood pressure regulation. Autoregulation was studied using stepwise reductions in renal perfusion pressure in anaesthetized male SHR, SHR perinatally supplemented with arginine and antioxidants (SHRsuppl) and Wistar-Kyoto (WKY), prior to and during i.v. Nomega-nitro-l-arginine (NO synthase inhibitor) or tempol (superoxide dismutase mimetic). Spontaneously hypertensive rat displayed a wider operating range of RBF autoregulation as compared with WKY (59 +/- 4 vs. 33 +/- 2 mmHg, respectively; P < 0.01). Perinatal supplementation in SHR decreased mean arterial pressure, renal vascular resistance and the operating range of RBF autoregulation (43 +/- 3 mmHg; P < 0.01). In addition autoregulation efficiency decreased. RBF autoregulation characteristics shifted towards those of normotensive WKY. However, dynamic NO release was still impaired and no clear differences in superoxide dependency in RBF autoregulation between groups was observed. Perinatal supplements shifted RBF autoregulation characteristics of SHR towards WKY, although capacity of the SHRsuppl kidney to modulate NO production to shear stress still seems impaired. The less strictly controlled RBF as observed in perinatally supplemented SHR could result in an improved long-term blood pressure control. This might partly underlie the beneficial effects of perinatal supplementation.

Na,K‐ATPase in the Plasma Membrane of the Rat Proximal Tubule is Increased by An Acute Reduction in Renal Perfusion Pressure

Increases in blood pressure inhibit sodium reabsorption in proximal tubule (Zhang, Y. et al., Am. J. Physiol. 274:C1090, 1998). Conversely, an acute decrease in renal perfusion pressure should stimulate sodium reabsorption. To test this hypothesis we placed a constricting ligature around the aorta between the renal arteries, and monitored perfusion pressure to kidneys above and below the constriction in anesthetized male Sprague-Dawley rats. Perfusion pressure to the left kidney was reduced to 69 ± 1mm Hg by tightening the ligature. Right renal perfusion pressure was 107 ± 4 mm Hg. Pressures were maintained constant for 10 min, after which the kidneys were flushed, excised, and the cortex dissected, minced, and sieved. The cell mixture was centrifuged and the proteins in the pellet biotinylated at pH 9.0. Membrane proteins were extracted, and biotinylated plasma membrane proteins isolated with immobilized streptavidin. Based on western blotting and densitometry, there was a 75% ± 35% (P< 0.03) increase in arbitrary units in the immunoblot signal from the alpha-subunit of Na, K-ATPase from kidneys subjected to the lower perfusion pressure compared to normal pressure. There was no difference observed in sham constricted controls (n=4). Since increased amounts of Na,K-ATPase in the plasma membrane should promote sodium reabsorption, our data suggest that acutely reduced renal perfusion results in increased proximal sodium reabsorption mediated by enhanced incorporation of Na,K-ATPase into the proximal plasma membrane. Supported by DK60752-01A1.

Renal Hemodynamic and Autoregulation Abnormalities in Type 2 Diabetic Rats at Prediabetic and Diabetic Stages

The mechanisms underlying the development and suppression of diabetic nephropathy are still not fully understood. Recent studies suggested that early angiotensin (Ang) II blockade might be an effective strategy for preventing the development of type 2 diabetic renal injury. 1) To examine the role of hemodynamics in the prediabetic stage, we determined the effect of the AT1 receptor antagonist (OLM; olmesartan 5mg/kg) on total (RBF), superficial (SBF), and deep renal cortical blood flow (DBF) in OLETF rats (Type 2 Diabetes rats) aged 11 weeks. Blood glucose levels were similar between OLETF and control LETO rats, while body weights were higher at this age in the OLETF rats. OLM caused a significant decrease in blood pressure of both groups, and no significant change in RBF. OLM significantly increased SBF of control LETO (from 594 ± 62 to 672 ± 71 PU; p<0.05), but had no significant effect on SBF in OLETF. In contrast, OLM had no effect on DBF in LETO, but improved DBF in OLETF (from 264 ± 37 to 309 ± 51 PU; p<0.05). 2) In OLETF at about 40 weeks age we assessed the effect of changes of renal perfusion pressure (RPP) on renal blood flow. Using a manual clamp on the abdominal aorta, we measured RBF, SBF and DBF in response to comparable reductions of RPP. Whereas SBF showed no significant change in both OLETF rats and LETO rats, DBF decreased significantly more in OLETF than LETO (OLETF 83.9 ± 1.7%, LETO 95.0 ± 3.4%, p<0.05). These findings strongly suggest the presence of abnormal renal hemodynamics, especially in the deep cortical region; OLM improved these abnormalities at the prediabetic stage.

Diagnosis and Management of Ischemic Nephropathy

Analysis of the Third National Health and Nutrition Examination Survey (1988 to 1994) suggests that chronic kidney disease (CKD) is a major public health problem (1). Approximately 11% of the US population has CKD. Roughly half have a GFR <60 ml/min per 1.73 m2 with or without kidney damage (stages 3 to 4), and half have exclusively kidney damage as manifested by microalbuminuria (stages 1 to 2) (2). It is widely recognized that the prevalence of stage 5 CKD is also increasing at a rapid rate, and it is estimated that the number of patients who have ESRD may reach 2.24 million by 2030 (3). Evidence to establish reduced GFR as an independent risk factor for cardiovascular disease (CVD) mortality has emerged. Analysis of data from several population-based epidemiologic studies (4,5) demonstrates poorer outcomes regarding stroke, myocardial infarction, and congestive heart failure (CHF) in patients with even mild compromise of kidney function. The morbidity of this group of patients constitutes an economic burden both directly in terms of resource utilization and indirectly through loss of productivity and impaired quality of life (2). Atherosclerotic renovascular disease (ARVD) can result in renovascular hypertension. However, ARVD is an increasingly recognized cause of CKD (6,7). In this article, we focus mainly on ARVD or renal artery stenosis (RAS) secondary to atherosclerosis as a cause of ischemic nephropathy. ARVD is a disease of aging, and several studies have shown its strong association with extrarenal atherosclerotic disease (8–10). Patients with ARVD seem to be at a much greater risk for cardiovascular death than for progressing to renal replacement therapy (11). Whether renal revascularization can benefit renal and cardiovascular outcomes has not been established. Atherosclerosis is the cause of approximately 90% of RAS in adults who are older …

Putting the Brakes on Renin Release

Modulation of renin release from juxtaglomerular cells is critical for appropriate adjustments of the cardiovascular and renal systems to internal and external stresses, and dysregulation of renin release participates in the pathophysiology of hypertension, vascular disease, heart failure, and chronic renal disease. This justifies investments in research to elucidate the fundamental mechanisms regulating renin release. These investments have yielded, and continue to yield, high returns, as exemplified by Schweda et al1 in this issue of Hypertension , showing that A1 receptors mediate high perfusion pressure–induced inhibition of renin release, whereas prostaglandins (PGs) participate in low perfusion pressure–mediated stimulation of renin release. The purpose of this commentary is to discuss how Schweda et al’s findings confirm and challenge present-day models of renin release. As comprehensively reviewed by Davis and Freeman2 and Keeton and Campbell,3 investigators recognized early on that three systems, namely the sympathetic nervous system, the macula densa apparatus, and the intrarenal baroreceptor, are the primary physiological mechanisms regulating renin release from juxtaglomerular cells. A key development was the recognition that the two most important biochemical accelerators of renin release are catecholamines (mediating sympathetically induced renin release) and PGI2 (mediating macula densa–induced and intrarenal baroreceptor–stimulated renin release).4 Subsequently, a third autocoid, adenosine (acting via A1 receptors), was proposed to serve as a molecular brake on renin release and thereby to moderate the effects of catecholamines and PGI2 on renin secretion.5 Because cAMP is a critical second messenger mediating the exocytosis of renin from juxtaglomerular cells, adenylyl cyclase unifies these concepts because β-adrenoceptors and PGI2 receptors accelerate, whereas A1 receptors brake the rate of cAMP production. The results reported by Schweda et al corroborate the accelerator/brake model of renin release because they report that PGs mediate stimulation of renin release …

Blood Pressure–Dependent Inhibition of Renin Secretion Requires A1 Adenosine Receptors

Renal perfusion pressure (RPP) regulates renin release with a reduction of RPP stimulating and an elevation inhibiting renin secretion. The precise sensing and effector mechanisms by which changes in arterial pressure are linked to the exocytosis of renin are not well-defined. The present experiments were designed to study the potential role of adenosine as a mediator of this renal baroreceptor mechanism. In isolated perfused mouse kidneys a stepwise reduction of RPP from 90 mm Hg to 65 and 40 mm Hg stimulated renin secretion rates (RSR) 1.4-fold and 3.6-fold, whereas stepwise elevations of RPP from 90 mm Hg to 115 and 140 mm Hg suppressed RSR to 64% or 40% of baseline. Inactivation of A1 adenosine receptors by either pharmacological blockade (DPCPX 1 micromol/L) or genetic deletion (A1AR(-/-) mice) did not modify the stimulation of renin release by a low RPP, but completely prevented the suppression of renin secretion by higher perfusion pressures. In vivo, the induction of arterial hypertension by either acute (single subcutaneous injection) or chronic (osmotic minipump for 72 hours) application of phenylephrine significantly reduced plasma renin concentration (PRC) in wild-type mice to approximately 40% of control, whereas it did not significantly affect PRC in A1AR(-/-) mice. Together these data demonstrate that A1 adenosine receptors are indispensable for the inhibition of renin secretion by an increase in blood pressure, suggesting that formation and action of adenosine is responsible for baroreceptor-mediated inhibition of renin release. In contrast, the stimulation of the renin system by a low blood pressure appears to follow different pathways.

Sandford Lloyd Skinner (1933–2005)

Sandford Lloyd (“Sandy”) Skinner, one of the pillars of the renin-angiotensin system, died on May 29, 2005, after a long illness. Sandy was a gentleman, scientist, teacher, and family man who touched the lives of the many who were fortunate to know him.⇓ Sandy was born in Clare, South Australia, on August 6, 1933. He graduated MBBS from The University of Adelaide in 1957. Following his medical studies, he researched the effects of vasoactive substances on the circulation and respiration of humans in the Department of Physiology, The University of Adelaide, for which he was awarded an MD degree in 1962. He also reported the artifactual elevation of plasma potassium levels during venepuncture.1 His first postdoctoral position during 1962–1963 was at the Cleveland Clinic working with Irvine Page and James McCubbin. This was the start of his life-long passion for the renin-angiotensin system. At the Cleveland Clinic he performed seminal studies demonstrating the role of the baroreceptor mechanism of control of renin release.2 Importantly, his studies demonstrated that renin release could be stimulated by reduction in renal perfusion pressure within the physiological range without significant change in renal blood flow, thus demonstrating that renin release was caused by a baroreceptor mechanism and not renal ischemia. He also showed that renal compression could stimulate renin release. These studies were important in showing that variation in renin release may have …

THE ‘BODY FLUID PRESSURE CONTROL SYSTEM’ RELIES ON THE RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM: BALANCE STUDIES IN FREELY MOVING DOGS

1. The physiological role of the 'renal body fluid pressure control system', including the intrarenal mechanism of 'pressure natriuresis', is uncertain. 2. Balance studies in freely moving dogs address the following questions: (i) what is the physiological contribution of pressure natriuresis to the control of total body sodium (TBS); (ii) to what extent is long-term mean arterial blood pressure (MABP) determined by TBS and total body water (TBW); and (iii) during Na accumulation, is Na stored in an osmotically inactive form? 3. Diurnal time-courses of Na excretion (U(Na)V) and MABP reveal no correlation. Spontaneous MABP changes do not affect U(Na)V. The long-term 20% reduction of renal perfusion pressure (RPP) results in Na retention via pressure-dependent stimulation of the renin-angiotensin-aldosterone system (RAAS), not via a pressure natriuresis mechanism. Prevention of pressure natriuresis does not result in ongoing Na retention when the RAAS is operative. The long-term 20% elevation of RPP induced by sustained TBS elevation facilitates Na excretion via pressure natriuresis, but does not restore TBS to normal. 4. Changes in TBW correlate well with changes in TBS (r(2) = 0.79). This correlation is even closer when concomitant changes in total body potassium are also considered (r(2) = 0.91). 5. With normal or elevated TBW, long-term MABP changes correlate well with TBW changes (r(2) = 0.69). At lowered TBW, no correlation is found. 6. In conclusion, the physiological role of pressure natriuresis is limited. Pressure natriuresis does not appear to be operative when RPP is changed from -20 to +10% and neurohumoral control of U(Na)V is unimpeded. Within this range, pressure-dependent changes in the RAAS mediate the effects of changes in RPP on U(Na)V. Pressure natriuresis may constitute a compensating mechanism under pathophysiological conditions of substantial elevation of RPP. A large portion of the long-term changes in MABP are attributable to changes in TBW. The notion of osmotically inactive Na storage during Na accumulation appears to be invalid.

Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP

Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the renin-angiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI2 in renovascular hypertension in vivo, employing mice lacking the PGI2 receptor (IP–/– mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP–/– mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP–/– mice than in WT mice. All these parameters were measured in mice lacking the four PGE2 receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI2 is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP–/– mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP–/– mice. These results indicate that PGI2 derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo.

Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP.

Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the renin-angiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI2 in renovascular hypertension in vivo, employing mice lacking the PGI2 receptor (IP-/- mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP-/- mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP-/- mice than in WT mice. All these parameters were measured in mice lacking the four PGE2 receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI2 is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP-/- mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP-/- mice. These results indicate that PGI2 derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo.

Blood flow-dependent changes in intrarenal nitric oxide levels during anesthesia with halothane or sevoflurane

We previously demonstrated that intrarenal nitric oxide (NO) levels and renal blood flow are reduced during halothane anesthesia. Studies were performed to determine if volatile anesthetics-induced reductions in renal NO levels are associated with blood flow changes. Halothane and sevoflurane at 0.8 and 2.4 Mac were administered by inhalation to dogs, and cGMP and NOx concentrations in the renal interstitial fluid were measured by a microdialysis method. Neither halothane nor sevoflurane at 0.8 Mac altered renal blood flow and renal interstitial cyclic guanosine monophosphate (cGMP) and NOx levels, but both anesthetics significantly decreased these values at 2.4 Mac. Using an adjustable aortic clamp, renal perfusion pressure was reduced in 2 steps without halothane and sevoflurane anesthesia. Renal blood flow as well as cGMP and NOx concentrations in the renal interstitial fluid were unchanged within the autoregulatory range, but significantly decreased below the autoregulatory range. Changes in cGMP and NOx concentrations in the renal interstitial fluid were highly correlated with renal blood flow changes during halothane or sevoflurane anesthesia, and during stepwise reductions in renal perfusion pressure. The results suggested that halothane- and sevoflurane-induced decreases in intrarenal NO levels result from reductions in blood flow.

ANG II-induced downregulation of RBF after a prolonged reduction of renal perfusion pressure is due to pre- and postglomerular constriction.

Previous experiments from our laboratory showed that longer-lasting reductions in renal perfusion pressure (RPP) are associated with a gradual decrease in renal blood flow (RBF) that can be abolished by clamping plasma ANG II concentration ([ANG II]). The aim of the present study was to investigate the mechanisms behind the RBF downregulation in halothane-anesthetized Sprague-Dawley rats during a 30-min reduction in RPP to 88 mmHg. During the 30 min of reduced RPP we also measured glomerular filtration rate (GFR), proximal tubular pressure (P(prox)), and proximal tubular flow rate (Q(LP)). Early distal tubular fluid conductivity was measured as an estimate of early distal [NaCl] ([NaCl](ED)), and changes in plasma renin concentration (PRC) over time were measured. During 30 min of reduced RPP, RBF decreased gradually from 6.5 +/- 0.3 to 6.0 +/- 0.3 ml/min after 5 min (NS) to 5.2 +/- 0.2 ml/min after 30 min (P < 0.05). This decrease occurred in parallel with a gradual increase in PRC from 38.2 +/- 11.0 x 10(-5) to 87.1 +/- 25.1 x 10(-5) Goldblatt units (GU)/ml after 5 min (P < 0.05) to 158.5 +/- 42.9 x 10(-5) GU/ml after 30 min (P < 0.01). GFR, P(prox), and [NaCl](ED) all decreased significantly after 5 min and remained low. Estimates of pre- and postglomerular resistances showed that the autoregulatory mechanisms initially dilated preglomerular vessels to maintain RBF and GFR. However, after 30 min of reduced RPP, both pre- and postglomerular resistance had increased. We conclude that the decrease in RBF over time is caused by increases in both pre- and postglomerular resistance due to rising plasma renin and ANG II concentrations.

NO mediates downregulation of RBF after a prolonged reduction of renal perfusion pressure in SHR.

The aim of the study was to investigate mechanisms underlying the downregulation of renal blood flow (RBF) after a prolonged reduction in renal perfusion pressure (RPP) in adult spontaneously hypertensive rats (SHR). We tested the effect on the RBF response of clamping plasma ANG II in sevoflurane-anesthetized SHR. We also tested the effect of general cyclooxygenase (COX) inhibition and inhibition of the inducible COX-2. Furthermore, we assessed the effect of clamping the nitric oxide (NO) system. A prolonged period (15 min) of reduced RPP induced a downregulation of RBF. This was unchanged after clamping of plasma ANG II concentrations, general COX inhibition, and specific inhibition of COX-2. In contrast, clamping the NO system diminished the ability of SHR to downregulate RBF to a lower level. The downregulation of RBF was not associated with a resetting of the lower limit of autoregulation in the control group, in the ANG II-clamped group, or the NO clamped group. However, general COX inhibition and specific COX-2 inhibition enabled downward resetting of the lower limit of autoregulation. In conclusion, in SHR the renin-angiotensin system does not appear to play a major role in the downregulation of RBF after prolonged reduction of RPP. This response appears to be mediated partly by the NO system. We hypothesize that, in SHR, lack of downward resetting of the lower limit of autoregulation in response to a prolonged lowering of RPP could be the result of increased COX-2-mediated production of vasoconstrictory prostaglandins.

Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury: studies on transgenic/knockout mice of adrenomedullin gene.

Adrenomedullin (AM) is a potent depressor peptide whose vascular action is suggested to involve nitric oxide (NO) release. To explore the role of endogenous AM in vascular and renal function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists AM(22-52) and CGRP(8-37) on the renal perfusion pressure (RPP) of kidneys isolated from AM transgenic (TG)/heterozygote knockout (KO) mice and wild-type littermates (WT). Furthermore, we evaluated the renal function and histology 24 hours after bilateral renal artery clamp for 45 minutes in TG, KO, and WT mice. Baseline RPP was significantly lower in TG than in KO and WT mice (KO 93.4+/-4.6, WT 85.8+/-4.2, TG 72.4+/-2.4 mm Hg [mean+/-SE], P<0.01). ACh and AM caused a dose-related reduction in RPP, but the degree of vasodilatation was smaller in TG than that in KO and WT (%DeltaRPP 10(-7) mol/L ACh: KO -48.1+/-3.9%, WT -57.5+/-5.6%, TG -22.8+/-4.8%, P<0.01), whereas N(G)-nitro-L-arginine methyl ester (L-NAME) caused greater vasoconstriction in TG (%DeltaRPP 10(-4) mol/L: KO 33.1+/-3.3%, WT 55.5+/-7.2%, TG 152.6+/-21.2%, P<0.01). Both AM antagonists increased RPP in TG to a greater extent compared with KO and WT mice (%DeltaRPP 10(-6) mol/L CGRP(8-37): KO 12.8+/-2.6%, WT 19.4+/-3.6%, TG 41.8+/-8.7%, P<0.01). In mice with ischemic kidneys, serum levels of urea nitrogen and renal damage scores showed smaller values in TG and greater values in KO mice (urea nitrogen: KO 104+/-5>WT 98+/-15>TG 38+/-7 mg/dL, P<0.05 each). Renal NO synthase activity was also greater in TG mice. However, the differences in serum urea nitrogen and renal damage scores among the 3 groups of mice were not observed in mice pretreated with L-NAME. In conclusion, AM antagonists increased renal vascular tone in WT as well as in TG, suggesting that endogenous AM plays a role in the physiological regulation of the vascular tone. AM is likely to protect renal tissues from ischemia/reperfusion injury through its NO releasing activity.

Blood flow-dependent changes in renal interstitial guanosine 3',5'-cyclic monophosphate in rabbits.

We examined responses of renal interstitial guanosine 3',5'-cyclic monophosphate (cGMP) to changes in renal perfusion pressure (RPP) within and below the range of renal blood flow (RBF) autoregulation. A microdialysis method was used to monitor renal cortical and medullary interstitial cGMP levels in anesthetized rabbits. RPP was reduced in two steps: from ambient pressure (89 +/- 3 mmHg) to 70 +/- 2 mmHg (step 1) and then to 48 +/- 3 mmHg (step 2). RBF was maintained in step 1 but was significantly decreased in step 2 from 2.94 +/- 0.23 to 1.47 +/- 0.08 ml x min(-1) x g(-1). Basal interstitial concentrations of cGMP were significantly lower in the cortex than in the medulla (12.1 +/- 1.4 and 19.9 +/- 0.4 nmol/l, respectively). Cortical and medullary cGMP did not change in step 1 but were significantly decreased in step 2, with significantly less reduction in cGMP concentrations in the medulla than in the cortex (-25 +/- 3 and -44 +/- 3%, respectively). Over this pressure range, changes in cortical and medullary cGMP were highly correlated with changes in RBF (r = 0.94, P < 0.005 for cortex; r = 0.82, P < 0.01 for medulla). Renal interstitial nitrate/nitrite was not changed in step 1 but was significantly decreased in step 2 (-38 +/- 2% in cortex and -20 +/- 2% in medulla). Nitric oxide synthase inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg bolus, 50 mg x kg(-1) x h(-1) i.v. infusion) significantly decreased RBF (by -46 +/- 4%) and interstitial concentrations of cGMP (-27 +/- 4% in cortex and -22 +/- 4% in medulla, respectively). During L-NAME treatment, renal interstitial concentrations of cGMP in the cortex and medulla were similarly not altered in step 1. However, L-NAME significantly attenuated cGMP responses to a reduction in RPP in step 2. These results indicate that acute changes in RBF result in alterations in nitric oxide-dependent renal interstitial cGMP levels, with differential effects in the medulla compared with the cortex.

Role of the renin-angiotensin system in regulation and autoregulation of renal blood flow.

The role for ANG II in renal blood flow (RBF) autoregulation is unsettled. The present study was designed to test the effect of clamping plasma ANG II concentrations ([ANG II]) by simultaneous infusion of the angiotensin-converting enzyme inhibitor captopril and ANG II on RBF autoregulation in halothane-anesthetized Sprague-Dawley rats. Autoregulation was defined as the RBF response to acute changes in renal perfusion pressure (RPP). Regulation was defined as changes in RBF during long-lasting changes in RPP. The results showed that a prolonged reduction of RPP reset the lower limit of autoregulation from 85 +/- 1 to 73 +/- 2 mmHg (P < 0.05) and regulated RBF to a lower level. Reduction of RPP to just above the lower limit of autoregulation (88 mmHg) induced regulation of RBF to a lower level within 10 min. Clamping [ANG II] per se reset the lower limit of autoregulation to 62 +/- 5 mmHg. In this case, reduction in RPP to 50 mmHg did not induce a downregulation of RBF. We conclude that ANG II plays an important role in the resetting of the autoregulation limits. The ability to regulate RBF to a new level as a response to changes in RPP also depends on changes in [ANG II].

Effect of renal perfusion pressure on renal function, renin release and renin and angiotensinogen gene expression in rats.

1. A study was undertaken to examine the influence of acute renal perfusion pressure (RPP) reduction on renin release, renal renin and angiotensinogen gene expression and the role played by angiotensin II in these responses. 2. In chloralose-urethane anaesthetised rats, reduction of RPP to 60 mmHg for 3 h in vehicle or losartan-treated (5 days at 10 mg kg-1 bis in die (b.i.d.)) rats decreased renal blood flow by 46 and 29 % (both P < 0.001), respectively, glomerular filtration rate by 45 and 57 % (both P < 0.001), respectively, and sodium excretion by 96 and 98 % (both P < 0.01). 3. Chloralose-urethane anaesthesia and surgery caused a rise in plasma renin activity but was associated with a suppression of renal renin (50 %, P < 0.01) and angiotensinogen (40 %, P < 0.05) gene expression. Following reduction of RPP to 60 mmHg for 3 h, plasma renin activity was increased more than 7-fold (P < 0.001) and renal renin gene expression about 2-fold (P < 0.05). 4. Chronic (5 days) blockade of angiotensin II receptors with losartan elevated plasma renin activity some 29-fold (P < 0.001) and caused a marked increase (30-fold, P < 0.05) in renal renin gene expression, compatible with angiotensin II exerting a negative feedback control on renin release and gene expression. Reduction of RPP to 60 mmHg for 3 h in these animals had little effect on renal renin gene expression. 5. From these findings it can be concluded that (a) chloralose-urethane anaesthesia and surgery had a stimulatory effect on renin release but suppressed basal levels of renal renin and angiotensinogen gene expression; (b) acute reduction of RPP for 3 h could stimulate renin gene expression in the renin producing cells; and (c) the negative feedback control of angiotensin II on renin release and synthesis which was evident following chronic losartan treatment was not apparent during short-term reduction of RPP.

Pressure-dependent renin release: effects of sodium intake and changes of total body sodium.

The impact of sodium intake and changes in total body sodium (TBS) for the setting of pressure-dependent renin release (PDRR) was studied in freely moving dogs. An aortic cuff allowed servo control of renal perfusion pressure (RPP) at preset values. Protocols were 1) high sodium intake (HSI), 2) low sodium intake (LSI), 3) TBS moderately increased (+3.1 mmol Na/kg body wt) by 20% reduction of RPP for 2-4 days, 4) large increase of TBS (+8.2) by combining protocol 3 with aldosterone infusion, and 5) TBS reduced (-3.1) by peritoneal dialyses. Twenty-four-hour time courses of arterial plasma renin activity (PRA) revealed that LSI increased PRA for the first 10 h only; afterward PRA did not differ between LSI and HSI. Reduced TBS increased PRA constantly, and the large increase of TBS constantly reduced PRA. PDRR stimulus-response curves (assessed 20 h after last sodium intake) revealed an exponential relationship in each protocol. PDRR was not changed by different sodium intake. Conversely, reduced TBS increased PDRR markedly, whereas the large increase of TBS suppressed it. Thus an inverse relationship between TBS and PRA, i.e., a TBS-dependent renin release, was found. This relationship was enhanced by decreasing RPP. This interplay between TBS-dependent renin release and PDRR allows the organism a differentiated reaction to changes in TBS and arterial pressure.

Effects of vasodilatory beta-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney.

The mechanisms for the vascular actions of vasodilatory beta-blockers remain undetermined. For some kinds of beta-blockers, the involvement of nitric oxide (NO) has been suggested. We studied the effects of vasodilatory beta-blockers on renal perfusion pressure (RPP) and NO release in the rat kidney. Infusion of bopindolol, celiprolol, and nebivolol caused a dose-dependent reduction in RPP and an increase in NO release (RPP: bopindolol 10(-6) mol/L, -23+/-2%; celiprolol 10(-4) mol/L, -27+/-2%; nebivolol 10(-5) mol/L, -35+/-3%; NO: bopindolol 10(-6) mol/L, +33+/-2; celiprolol 10(-4) mol/L, +41+/-2; nebivolol 10(-5) mol/L, +45+/-5 fmol. min-1. g kidney-1, mean+/-SEM). Metergoline (10(-6) mol/L), a 5-hydroxytryptamine (5-HT)1/2 antagonist, or NAN-190 (10(-6) mol/L), a 5-HT1A antagonist, almost completely abolished the vasorelaxation and NO release caused by bopindolol, celiprolol, and nebivolol. However, neither propranolol nor bisoprolol decreased RPP. Celiprolol and nebivolol caused vasodilation in the rat thoracic aorta, and it was markedly reduced by endothelial denudation, Nomega-nitro-L-arginine methyl ester (10(-4) mol/L), or NAN-190 (10(-6) mol/L). In deoxycorticosterone acetate-salt hypertensive rats, 4-week administration of celiprolol (50 mg. kg-1. d-1 IV) restored the responses regarding RPP and NO release to acetylcholine. These results suggest that several beta-blockers exert their vasodilatory action through the 5-HT1A receptor/NO pathway and that treatment with these beta-blockers may protect against endothelial injury in hypertension.

Kinins modulate the sodium-dependent autoregulation of renal medullary blood flow.

In the recent past it has become clear that the kallikrein-kinin system is closely intertwined with long-term blood pressure regulation. It was shown that a kinin B2 receptor blockade leads to a sodium-dependent rise in blood pressure. The underlying mechanisms of this phenomenon, however, remain unclear. The osmotic gradient of the renal medulla is a prerequisite for the preservation of volume and sodium by the kidney. We thus hypothesized, that a kinin dependent modulation of medullary blood flow accounts for the influence of sodium on blood pressure. In 39 urethane anaesthetized rats pressure dependent regulation of whole kidney blood flow and cortical and medullary blood flow were estimated via laser-Doppler flux by a stepwise reduction of renal perfusion pressure to 30 mm Hg. In controls (n = 15), a reduction in renal perfusion pressure to 30 mm Hg lead to a concomitant reduction in whole kidney blood flow (25 +/- 3% of baseline) and cortical laser-Doppler flux (36 +/- 5% of baseline). In contrast, medullary laser-Doppler flux decreased only to 79 +/- 8% of the baseline level. Providing a 2% sodium chloride solution as drinking water over 5 days (n = 12), resulted in a significantly lower capability to autoregulate medullary flow (50 +/- 6% of baseline, P < 0.05). Acute subcutaneous administration of Hoe 140, a bradykinin B2 receptor antagonist (300 micrograms/kg bwt), restored autoregulation of medullary flow to almost normal levels (93 +/- 12% of baseline, P < 0.01 versus high sodium diet alone, n = 12). Our results indicate that B2 receptor blockade restores the attenuated autoregulation of medullary Doppler flux during sodium enriched diet. This, suggests that the kinin dependent impact of sodium on blood pressure regulation is mediated by modulations of medullary blood flow autoregulation.