Autoregulation Of Glomerular Filtration Rate Research Articles

New concepts in the physiopathology of hypertension. Purinergic receptors

Hypertension is a major risk of morbidity and mortality in patients when it is uncontrolled. In spite of improved therapies currently available for blood pressure control, their complications are far away from being accomplished. Therefore, chronic renal failure is frequently observed in hypertensive patients. Thus, insights on mechanisms that may contribute to arterial pressure control should be studied to prevent life-threatening cardiovascular disorders. Purinergic receptors have been recognized in the physiopathology of hypertension; this review summarizes their participation in the renal abnormalities of the kidney in hypertension. Several studies have suggested the activation of renal purinergic receptors under an elevated interstitial ATP milieu as a fundamental pathway that leads to generation and maintained hypertension. Elevated ATP concentration alters fundamental mechanisms involved in the long-term control of blood pressure such as pressure natriuresis, autoregulation of glomerular filtration rate and renal blood flow, as well as increased tubule-glomerular feedback responses, overall, these alterations decrease sodium excretion; in addition, the expression of ATP receptors is modified. Under a genetical background, ATP induces the production of vasoactive compounds, decreases renal function and induces tubulointerstitial injury before glomerular damage. Simultaneously, a deleterious interaction between angiotensin II and purinergic receptors lead to the progression of renal damage.

Integration of purinergic and angiotensin II receptor function in renal vascular responses and renal injury in angiotensin II-dependent hypertension.

Glomerular arteriolar vasoconstriction and tubulointerstitial injury are observed before glomerular damage occurs in models of hypertension. High interstitial ATP concentrations, caused by the increase in arterial pressure, alter renal mechanisms involved in the long-term control of blood pressure, autoregulation of glomerular filtration rate and blood flow, tubuloglomerular feedback (TGF) responses, and sodium excretion. Elevated ATP concentrations and augmented expression of P2X receptors have been demonstrated under a genetic background or induction of hypertension with vasoconstrictor peptides. In addition to the alterations of the microcirculation in the hypertensive kidney, the vascular actions of elevated intrarenal angiotensin II levels may be mitigated by the administration of broad purinergic P2 antagonists or specific P2Y12, P2X1, and P2X7 receptor antagonists. Furthermore, the prevention of tubulointerstitial infiltration with immunosuppressor compounds reduces the development of salt-sensitive hypertension, indicating that tubulointerstitial inflammation is essential for the development and maintenance of hypertension. Inflammatory cells also express abundant purinergic receptors, and their activation by ATP induces cytokine and growth factor release that in turn contributes to augment tubulointerstitial inflammation. Collectively, the evidence suggests a pathophysiological activation of purinergic P2 receptors in angiotensin-dependent hypertension. Coexistent increases in intrarenal angiotensin II and activates Ang II AT1 receptors, which interacts with over-activated purinergic receptors in a complex manner, suggesting convergence of their post-receptor signaling processes.

Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys.

Renal expression of klotho is reduced in hypertension. Experiments were performed to examine whether exogenous klotho protein supplementation ameliorates pressure natriuresis in early phase of hypertension, using stroke-prone spontaneously hypertensive rats (sp-SHR). The interactions between klotho protein and renal renin-Ang (angiotensin) system were examined with immunoprecipitation and cell culture methods. Uninephrectomy was performed in sp-SHRs to induce nephrosclerosis, and they were treated with exogenous klotho protein or vehicle. Exogenous klotho protein supplementation to sp-SHR decreased blood pressure, renal Ang II levels, AGT (angiotensinogen) expression, HIF (hypoxia-inducible factor)-1α abundance, and medullary fibronectin levels, with increased renal klotho expression and serum and urine klotho levels. Klotho supplementation also reduced kidney weight, renal phosphorylated Akt, and mTOR (mammalian target of rapamycin) abundance. Furthermore, klotho supplementation restored renal autoregulation of glomerular filtration rate and enhanced pressure-induced natriuresis in sp-SHR. Klotho protein bound to AT1R (Ang II type-1 receptor) and decreased the presence of AT1R on HK-2 (human proximal tubular) cells, attenuating inositol triphosphate generation. Klotho protein suppressed Ang II-induced increments of AGT expression in HK-2 cells. Collectively, the present data demonstrate that klotho binds with the AT1R to suppress Ang signal transduction, participating in inactivating renal renin-Ang system. Our results also suggest that exogenous klotho supplementation represses Akt-mTOR signaling to reduce renal hypertrophy and restore the autoregulatory ability of glomerular filtration rate in uninephrectomized sp-SHRs. Finally, the present findings implicate that klotho supplementation inhibits HIF-1α pathway and medullary fibrosis, contributing to enhancements of pressure natriuresis and reduction in blood pressure.

Abstract P419: Klotho Ameliorate Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys

Recent data indicate that klotho interacts with the renin-angiotensin system (RAS). However, the effects of klotho protein supplementation on hypertensive renal injury have not been examined yet. First, the in vivo experiments were performed using spontaneously hypertensive rats (SHR). To elucidate in vivo observations, the in vitro studies were carried out to examine the interactions between klotho protein and angiotensin type-1 (AT1) receptor with immunoprecipitation and cell culture (HK-2 cell) methods. Uninephrectomized SHRs were treated with exogenous klotho protein or vehicle. Exogenous klotho protein supplementation to uninephrectomized SHRs decreased blood pressure, renal angiotensin II levels, angiotensinogen expression, HIF-1α abundance, and medullary fibronectin with increased renal klotho expression and serum and urine klotho levels. Klotho supplementation also reduced kidney weight, renal phosphorylated Akt and mTOR abundance. Furthermore, klotho supplementation restored renal autoregulation of glomerular filtration rate and renal plasma flow, and improved pressure-induced natriuresis in SHR. Klotho protein bound to AT1 receptors without affecting the bindings of angiotensin II to AT1 receptor. Klotho decreased the presence of AT1 receptors on HK-2 cells, attenuating inositol triphosphate generation. Angiotensin II elevated angiotensinogen expression in HK-2 cells, and klotho protein suppressed angiotensin II-induced increases in angiotensinogen expression. Of note, although angiotensin II improves glomerular autoregulatory ability especially at lower pressure range, angiotensin II impairs pressure-induced natriuresis. Collectively, the present data demonstrate that klotho binds with the AT1 receptors to suppress angiotensin signal transduction and inactivate the renal RAS. In addition, our results suggest that exogenous klotho supplementation suppresses Akt-mTOR signaling to decline renal hypertrophy and restores renal autoregulatory ability in uninephrectomized SHRs. Finally, the present findings implicate that klotho supplementation inhibits HIF-1α pathway to suppress medullary fibrosis, presumably involved in improvements of pressure-natriuresis and reduction in blood pressure.

Case Scenario: Hemodynamic Management of Postoperative Acute Kidney Injury

Case Scenario: Hemodynamic Management of Postoperative Acute Kidney Injury

Elucidating mechanisms underlying altered renal autoregulation in diabetes

Previous studies have reported that high-salt intake paradoxically activates tubuloglomerular feedback (TGF) in type 1 diabetes. Using Zucker lean (ZL) and diabetic fatty (ZDF) rats on normal and high-salt diets, renal hemodynamics and the renin-angiotensin system (RAS) were characterized. On normal salt diet, glomerular filtration rate (GFR) was higher in ZDF than ZL rats. Autoregulation of GFR was less efficient and lithium clearance was lower in ZDF rats than ZL rats. Salt load reduced GFR in ZDF rats with restoration of lithium clearance and partial improvement in autoregulatory index (AI). The administration of 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine-1 receptor antagonist to ZDF rats on a high-salt diet abolished the improvement of AI in GFR. However, this effect was seen by neither (Cx40)GAP27 nor (Cx37,43)GAP27, which inhibits connexin (Cx) 40 or Cx37. Renal ANG II was higher in ZDF than ZL rats on normal salt diet, but the difference was eliminated by a salt load. The present data provide the first demonstration for a salt paradox in type 2 diabetes and implicate that in addition to Cx alterations, an enhanced proximal reabsorption attenuates TGF, underlying glomerular hyperfiltration and RAS activation. These data suggest that a high-salt diet standardizes distal delivery in diabetes, suppressing the RAS, and improving GFR autoregulation and hyperfiltration through adenosine.

Role of cytochromeP-450 metabolites in the regulation of renal function and blood pressure in 2-kidney 1-clip hypertensive rats

Alterations in renal function contribute to Goldblatt two-kidney, one-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P-450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while that of 20-hydroxyeicosatetraenoic acids (20-HETE) is increased in this model. We utilized the inhibitor of soluble epoxide hydrolase cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) and HET-0016, the inhibitor of 20-HETE production, to study the role of EETs and 20-HETE in the regulation of renal function. Chronic c-AUCB treatment significantly decreased systolic blood pressure (SBP) (133 ± 1 vs. 163 ± 3 mmHg) and increased sodium excretion (1.23 ± 0.10 vs. 0.59 ± 0.03 mmol/day) in 2K1C rats. HET-0016 did not affect SBP and sodium excretion. In acute experiments, renal blood flow (RBF) was decreased in 2K1C rats (5.0 ± 0.2 vs. 6.9 ± 0.2 ml·min(-1)·g(-1)). c-AUCB normalized RBF in 2K1C rats (6.5 ± 0.6 ml·min(-1)·g(-1)). HET-0016 also increased RBF in 2K1C rats (5.8 ± 0.2 ml·min(-1)·g(-1)). Although RBF and glomerular filtration rate (GFR) remained stable in normotensive rats during renal arterial pressure (RAP) reductions, both were significantly reduced at 100 mmHg RAP in 2K1C rats. c-AUCB did not improve autoregulation but increased RBF at all RAPs and shifted the pressure-natriuresis curve to the left. HET-0016-treated 2K1C rats exhibited impaired autoregulation of RBF and GFR. Our data indicate that c-AUCB displays antihypertensive properties in 2K1C hypertension that are mediated by an improvement of RBF and pressure natriuresis. While HET-0016 enhanced RBF, its anti-natriuretic effect likely prevented it from producing a blood pressure-lowering effect in the 2K1C model.

Autoregulation of glomerular filtration rate during spironolactone treatment in hypertensive patients with type 1 diabetes: a randomized crossover trial

Autoregulation of GFR, i.e. maintenance of relative constancy of GFR despite variations in mean arterial pressure (MAP) >80 mmHg, is impaired in diabetic kidney disease; furthermore, some antihypertensive drugs may jeopardize autoregulation. The aim of our study was to establish if spironolactone affects the ability to autoregulate GFR. Sixteen hypertensive type 1 diabetic patients with persistent normoalbuminuria (presumed normal autoregulation) completed this randomized, double-masked, crossover trial. After a 4-week wash-out period, patients received spironolactone 25 mg o.d. and matched placebo for 4 weeks in random order. After each treatment period, the ability to autoregulate GFR was determined by measuring GFR ((51)Cr-EDTA clearance) before (basal) and after acute blood pressure reduction by intravenous injection of clonidine. During placebo, the mean (SE) basal GFR was 115 (5) ml/min/1.73 m(2) and the BP was 146 (4)/81 (2) mmHg corresponding to a MAP of 103 (2) mmHg. Spironolactone did not significantly reduce GFR or BP. Injection of clonidine induced a significant reduction in the MAP of 17 (2) and 19 (1) mmHg during placebo and spironolactone treatment, respectively, and an overall reduction in GFR of 11 and 15 ml/min/1.73 m(2) (both comparisons NS between treatment periods). Signs of impaired autoregulation were present in nine patients during placebo and in nine patients during spironolactone treatment. Relative changes in GFR on placebo treatment correlated with diabetes duration (R = 0.67, P < 0.01) but were not related to duration of hypertension, baseline BP, GFR, HbA1c or to changes in BP. Spironolactone did not change the overall ability to autoregulate GFR in 16 hypertensive type 1 diabetic patients with normoalbuminuria. Our data are suggestive that the ability to autoregulate GFR is gradually impaired with increasing diabetes duration, a phenomenon not previously described in normoalbuminuric patients.

Rationale and Strategies for Early Detection and Management of Diabetic Kidney Disease

Rationale and Strategies for Early Detection and Management of Diabetic Kidney Disease

The magic mountain or death in Venice: chronic hypoxia may alleviate oxidative stress in the kidney

Chronic hypoxia, as induced by simulated high altitude at 5500 m, seems to have astonishing beneficial effects when it comes to oxidative stress. In this issue of The Journal of Physiology, Yang et al. (2007) induced lipopolysaccharide-induced oxidative stress (LPS-OS) in rats maintained at sea level and in rats being kept for 15 days in an altitude chamber. This is an original way of preconditioning the kidney. Renal preconditioning is an area of increasing interest. It refers to the prospect of rendering the kidney resistant to subsequent injury by a prior insult manoeuvre. Ischaemic preconditioning of the kidney has been commonly used and provides protection against a subsequent ischaemic attack. Several candidates that could potentially serve as mediators of preconditioning have been identified. Yang et al. (2007) focus on the formation of superoxide by two major oxidative enzymes, NAD(P)H oxidase and xanthine oxidase, and the authors examine two antioxidative superoxide dismutase isoforms, Cu/ZnSOD and MnSOD. The impact of chronic hypoxia on the outcome of LPS-OS on renal haemodynamics and excretory functions was remarkably clear. Non-preconditioned rats (sea level) responded to LPS-OS with pronounced reduction of renal blood flow (RBF) and glomerular filtration rate (GFR). In contrast, RBF and GFR in preconditioned rats (altitude chamber) were far less impaired. Moreover, urine and sodium excretion were significantly reduced in the rats kept at sea level, whereas this drop was not found in the rats housed in high altitude chambers. The reasons for the differences may be of pre-renal origin, since mean arterial blood pressure drops by roughly 30 mmHg in the sea level group, whereas the pressure drop in the preconditioned animals was only roughly 10 mmHg. Autoregulation of RBF and GFR may not be as pronounced as normal (Flemming et al. 2001) in this setting, and therefore these measures may drop in response to decreases in perfusion pressure. Moreover, diuresis as well as natriuresis are extremely pressure dependent (Seeliger et al. 2001). A pre-renal origin of LPS-OS has been suggested before. Cohen et al. (2001) showed that haemodynamic changes after LPS-OS are only found in vivo, not in the isolated perfused kidney. However, in the highlighted study by Yang et al. evidence is provided for additional intrarenal effects of LPS-OS. It seems that lipopolysaccharides cause cytokine release via Toll-like receptor 4 (TLR4) (Cunningham et al. 2004), a receptor exclusively located in the kidney. Not only is TLR4 restricted to the kidney, it is also known to stimulate tumour necrosis factor-α, and interleukin-β production, resulting in NAD(P)H-oxidase generated superoxide (Li et al. 2002). Indeed, Yang et al. could demonstrate increased renal superoxide formation by LPS-OS along with augmented tumour necrosis factor-α, and interleukin-β levels. Maintenance of rats under hypoxic conditions for 15 days prior to the LPS-OS challenge effectively blunted the changes in this chain of effects. Moreover increases in antioxidative enzymes, such as Cu/ZnSOD, MnSOD and catalase, may further contribute to the beneficial effects of high altitude, as shown in the study reviewed. Taken together, the findings of Yang et al. provide a detailed picture of how chronic hypoxia may precondition the kidney to better cope with LPS-OS. When considering that hypoxia also stimulates erythropoietin synthesis, more possible routes of renal preconditioning appear likely. Erythropoietin is well known as a potent mediator of preconditioning in the brain and heart (Dawson, 2002; Baker, 2005). Lately it has been suggested that erythropoietin is also involved in the preconditioning of the kidney (Sharples & Yaqoob, 2006).

Making sense of the sensor: Mysteries of the macula densa

Increases in luminal NaCl concentration at the macula densa (MD), the sensing element, activate tubuloglomerular feedback (TGF). MD cell volume increases when increments are isosmotic and shrinks if osmolality increases. This interesting finding introduces additional complexity to the role of the MD in TGF.

Nonlinear interactions in renal blood flow regulation

We have developed a model of tubuloglomerular feedback (TGF) and the myogenic mechanism in afferent arterioles to understand how the two mechanisms are coupled. This paper presents the model. The tubular model predicts pressure, flow, and NaCl concentration as functions of time and tubular length in a compliant tubule that reabsorbs NaCl and water; boundary conditions are glomerular filtration rate (GFR), a nonlinear outflow resistance, and initial NaCl concentration. The glomerular model calculates GFR from a change in protein concentration using estimates of capillary hydrostatic pressure, tubular hydrostatic pressure, and plasma flow rate. The arteriolar model predicts fraction of open K channels, intracellular Ca concentration (Ca(i)), potential difference, rate of actin-myosin cross bridge formation, force of contraction, and length of elastic elements, and was solved for two arteriolar segments, identical except for the strength of TGF input, with a third, fixed resistance segment representing prearteriolar vessels. The two arteriolar segments are electrically coupled. The arteriolar, glomerular, and tubular models are linked; TGF modulates arteriolar circumference, which determines vascular resistance and glomerular capillary pressure. The model couples TGF input to voltage-gated Ca channels. It predicts autoregulation of GFR and renal blood flow, matches experimental measures of tubular pressure and macula densa NaCl concentration, and predicts TGF-induced oscillations and a faster smaller vasomotor oscillation. There are nonlinear interactions between TGF and the myogenic mechanism, which include the modulation of the frequency and amplitude of the myogenic oscillation by TGF. The prediction of modulation is confirmed in a companion study (28).

Blood pressure maintenance in NHE3-deficient mice with transgenic expression of NHE3 in small intestine

NHE3 Na(+)/H(+) exchanger knockout (Nhe3(-/-)) mice have severe absorptive deficits in the kidney proximal tubule and intestinal tract. The resulting hypovolemia has confounded efforts to carefully evaluate the specific effects of NHE3 deficiency on kidney function. Development of mice with transgenic expression of NHE3 in the small intestine (tgNhe3(-/-)) has allowed us to analyze the role of renal NHE3 in overall maintenance of blood pressure, pressure natriuresis, and autoregulation of both glomerular filtration rate (GFR) and renal blood flow (RBF). Ambulatory blood pressure, measured by telemetry, was lower in tgNhe3(-/-) mice than in wild-type controls (tgNhe3(+/+)) when the mice were maintained on a normal NaCl diet but was normalized when they were provided with a high NaCl intake. Furthermore, administration of the AT1-receptor blocker losartan showed that circulating ANG II plays a major role in maintaining blood pressure in tgNhe3(-/-) mice fed normal NaCl but not in those receiving high NaCl. Clearance studies revealed a blunted pressure-natriuresis response in tgNhe3(-/-) mice at lower blood pressures but a robust response at higher blood pressures. Autoregulation of GFR and RBF was normal in tgNhe3(-/-) mice. These results show that dietary NaCl loading normalizes blood pressure in awake tgNhe3(-/-) mice and that alterations in NHE3 activity are not essential for normal autoregulation of GFR and RBF. Furthermore, the data strongly support the hypothesis that NHE3 plays an important role in the diuretic and natriuretic responses to increases in blood pressure but also show that mechanisms not involving NHE3 mediate pressure natriuresis in the higher range of blood pressures studied.

Angiotensin receptor blockers in diabetic nephropathy: renal and cardiovascular end points

The activity of the renin-angiotensin-aldosterone system (RAAS) is elevated both in the circulation and in the renal tissue of diabetic and nondiabetic nephropathies. The increased RAAS activity plays an important role in the hemodynamic and nonhemodynamic pathogenetic mechanisms involved in kidney disease. Previous studies have demonstrated that albuminuria is not only a marker of glomerular lesions, but also a progression promoter, and finally a powerful predictor of the long-term beneficial effect of blood pressure-lowering therapy. Randomized crossover and parallel blind studies in patients with diabetic nephropathy have demonstrated that angiotensin II receptor blockers (ARB) induce favorable changes in systemic blood pressure, renal hemodynamics, and proteinuria similar to those induced by angiotensin-converting enzyme (ACE) inhibition. Studies have revealed the optimal renoprotective dose for some ARBs; however, additional dose titration studies are urgently needed to obtain the maximum benefit of this valuable new class of compounds. The combination of ARB and ACE inhibition is well tolerated and even more effective than monotherapy in reducing systemic blood pressure and albuminuria in diabetic nephropathy. In addition, dual RAAS blockade is safe and well tolerated. Impaired autoregulation of glomerular filtration rate (GFR); demonstrated with some blood pressure-lowering agents implies disturbances in the downstream transmission of the systemic blood pressure into the glomerulus, leading to capillary hypertension or hypotension depending of the level of blood pressure. ARB does not interfere with GFR autoregulation in hypertensive diabetic patients. In contrast to previous observational studies with ACE inhibition, long-term treatment with ARB has similar beneficial renoprotective effect on progression of diabetic kidney disease in hypertensive diabetic patients with ACE II and DD genotypes. ARB can prevent/delay development of diabetic nephropathy independently of its beneficial blood pressure-lowering effect in patients with type 2 diabetes and microalbuminuria. Recently, two landmark studies led to the following conclusion: “Losartan and Irbesartan conferred significant renal benefit in patients with type 2 diabetes and nephropathy. This protection is independent of the reduction in blood pressure it causes. The ARB is generally safe and well tolerated.” A recent metaanalysis indicates that ARBs reduce cardiovascular events mainly because of reduction in first hospitalization for congestive heart failure in hypertensive type 2 diabetic patients with albuminuria. The studies mentioned here suggest that ARB represents a beneficial treatment of hypertension and proteinuria in incipient and overt diabetic nephropathy.

Invited Lecture

Acquired and Inherited Forms of Ouabain‐Induced Hypertension: Significance and Relationship to Other Models. John M. Hamlyn. Department of Physiology, School of Medicine, University of Maryland, 655 West Baltimore, Baltimore, MD, USA.The etiology of essential hypertension remains an enigma—a mix of multiple environmental and genetic factors. In 1989, we described an endogenous inhibitor of the sodium pump in the human circulation and in 1991 identified the inhibitor as ouabain or a closely related isomer. Clinical studies showed that endogenous “ouabain” (EO) circulated in elevated amounts in a surprisingly large portion of patients with essential hypertension and that the relationship of EO with pressure was as significant as age. Causality was suggested subsequently by two sets of observations. First, blood pressure and plasma EO returned to normal following removal of the adrenal gland in patients with primary aldosteronism and other adrenal adenomas. Second, the prolonged infusion of ouabain in normal outbred rats induced sustained hypertension (OHR). As various animal models have provided insight into the mechanisms of hypertension, we bred rats for their resistance (BOR) or sensitivity (BOS) to the hypertensionogenic effect of ouabain. The strains were initiated simultaneously in 1992 from an F0 generation comprised of 80 normotensive outbred Sprague Dawley rats (40m, 40f, HSD, Indianapolis). Each member of the F0 generation received a maximally pressor dose of ouabain delivered over 5 weeks via osmotic pumps. Blood pressures were measured at baseline, during infusion, and 2 weeks following pump removal (week 7) using tail cuff plethysmography. Among the F0, 64 animals (∼85%) developed sustained hypertension while 12 (15%) showed little or no rise in either SBP or MBP. The increase in BP induced by ouabain was >1 S.D. above the group mean response in 13 animals (6m, 7f) and >1 S.D. below the mean in 16 animals (5m, 11f). BP in all animals was normal by week 7. Two breeding pairs of F0 OS and OR were chosen and, using a similar selection method and selective inbreeding, multiple stable generations were obtained. By the F3 generation, the BOS and BOR phenotypes were completely segregated while further inbreeding resulted in the appearance of spontaneous hypertension in BOS by week 6. This trait could not be selected against and became pronounced with further inbreeding. In OHR, hypertension was reversible, and characterized by elevated ouabain in the circulation, kidney, hypothalamus and anterior pituitary. Tissue levels were strongly correlated with BP. In both BOS and OHR, hypertension could be prevented or reversed by ACE, AT2 antagonists, digoxin, or blockade of brain EO by antibody fragments. As increased sympathetic nerve activity appears to be crucial to ouabain dependent hypertension we studied short‐term (STP) and long‐term potentiation (LTP) in the isolated superior cervical ganglia (SCG). The time constants for the decay of both STP and LTP (tL) were increased in BOS and OHR and correlated with blood pressure. Captopril normalized blood pressure and tL in OHR. Thus, the duration of ganglionic LTP and blood pressure are tightly linked in acquired and inherited forms of ouabain‐dependent hypertension. Enhanced plasticity in sympathetic neurons appears to be a major factor contributing to the increase in peripheral sympathetic nerve activity (SNA) in ouabain‐dependent hypertension. Studies of the contractility of isolated renal arteries showed enhanced force production in OHR in response to depolarization and in kidneys, the autoregulation of glomerular filtration rate and renal blood flow was less efficient, Moreover, a rightward shift in the pressure natriuresis relationship was found in OHR, such that 25–30 mmHg higher renal perfusion pressure was necessary to excrete a sodium load. In the OHR and BOS models, the overall involvement of the central and peripheral nervous system, hormone profiles, renovascular abnormalities and pharmacological sensitivity appear to have striking parallels with the SHR. It is suggested that common overlapping mechanisms are likely to underlie the etiology of hypertension in these models.

The impact of glycaemic control on autoregulation of glomerular filtration rate in patients with non-insulin dependent diabetes

The ability of the kidney to maintain constancy of glomerular filtration rate (GFR) over a wide range of renal perfusion pressures is termed autoregulation. Defective autoregulation of GFR has been demonstrated in patients with diabetic and non-diabetic nephropathy and in streptozotocin diabetic rats during hyperglycaemia. Information on the potential impact of acute changes in glycaemic control on autoregulation of GFR in diabetic patients is lacking. Therefore the aim of our study was to evaluate the effect of acute lowering of blood pressure (BP) on GFR during normoglycaemia and hyperglycaemia. We investigated 14 (12m/2f) normoalbuminuric patients with non-insulin dependent diabetes (NIDDM). The patients were examined in random order on two separate days with blood glucose (BG)<10 mmol/L or with BG>15 mmol/L. GFR (single shot [51Cr] EDTA plasma clearance technique) was measured twice each day; first without clonidine (baseline) followed by intravenous injection of clonidine 100-150 microg. We measured BG (One Touch 2), and BP (Takeda TM2420) several times during each GFR measurement. Clonidine reduced mean arterial blood pressure with 20 (1.4) vs. 16 (1.2) mmHg (mean (SE)) with BG<10mmol/L and with BG>15 mmol/L, respectively (p=0.053). GFR diminished in average from 92 (3.1) to 86 (3.7) ml/min/1.73m2 with BG<10 mmol/L (p<0.05), and from 102 (4.1) to 98 (4.2) ml/min/1.73 m2 with BG> 15 mmol/L, NS. Mean difference between changes in GFR (95% confidence interval) between the examination with BG<10 mmol/L and with BG>15 mmol/L were 2.3 (-1.3 to 5.9) ml/min/1.73 m2 (NS). The mean BG during normoglycaemia was 6.9 (0.3) vs.16.9 (0.4) during hyperglycaemia. Our study suggests that acute changes in glycaemic control have no detectable effect on autoregulation of GFR in NIDDM patients. Hyperglycaemia enhances GFR.

Benidipine dilates both pre- and post-glomerular arteriole in the canine kidney.

The aim of the present study was to determine the effects of benidipine on renal function and whether benidipine may dilate the efferent arteriole as well as the afferent arteriole of the canine kidney. The effects of benidipine on the renal segmental vascular resistance were estimated using Gomez's formula with some modification. The renal hemodynamic action of benidipine was also compared with that of amlodipine. Intrarenal arterial injection of benidipine at a dose of 3 microg/kg resulted in a significant increase in renal blood flow (RBF), urine flow and urinary excretion of sodium, but not in glomerular filtration rate (GFR). Amlodipine at a dose of 300 microg/kg also increased RBF, urine flow and urinary excretion of sodium to a significant degree equivalent to that by benidipine. However, in contrast to benidipine, amlodipine significantly increased GFR. After the administration of benidipine, autoregulation of RBF and GFR was relatively maintained and the renal perfusion pressure (RPP)-RBF relation shifted upward; that is, RBFs at 75 and 50 mmHg were maintained at a higher level than those of the control. In contrast to benidipine, amlodipine diminished the autoregulation of RBF and GFR. RBFs at 75 and 50 mmHg were not different from those of the control. The afferent and efferent arteriolar resistance (Ra and Re) were calculated based on the RPP-RBF and RPP-GFR relations. Benidipine reduced both Ra and Re, but amlodipine selectively reduced Ra. Benidipine increased RBF but not GFR via the dilation of both afferent and efferent arterioles. Thus, benidipine has unique renal hemodynamic actions which differ from those by most calcium antagonists.

Impaired autoregulation of the glomerular filtration rate in patients with nondiabetic nephropathies

The ability of the kidney to maintain constancy of the glomerular filtration rate (GFR) over a wide range of renal perfusion pressures is termed autoregulation. Defective autoregulation of GFR has been demonstrated in diabetic nephropathy. Whether this is also the case in patients with nondiabetic nephropathies is not known. We investigated the effect of acute lowering of blood pressure (BP) on GFR in 16 (8 males and 8 females) albuminuric subjects suffering from different nondiabetic nephropathies and in 14 (7 males and 7 females) controls matched with respect to sex, age, BP, and baseline GFR. The subjects received in random order an intravenous injection of either clonidine (150 to 225 microg) or saline (0.154 mmol/liter) within two weeks. We measured GFR ([51Cr]-EDTA), albuminuria (enzyme-linked immunosorbent assay; ELISA), and BP (Takeda TM-2420). Clonidine induced similar reductions in mean arterial BP 17 (2) versus 19 (2) mm Hg [mean (SE)] in patients with nephropathy and in controls, respectively. GFR diminished in average from 89 (6) to 82 (5) ml/min/1.73 m2 (P < 0.05), and albuminuria declined from a geometric mean of 1218 (antilog SE 1.3) microg/min to 925 (1.3) in the patients with nondiabetic nephropathies (P < 0.05), whereas these variables remained unchanged in the control group. The mean difference between changes in GFR (95% confidence interval) between the nondiabetic macroalbuminuric and control subjects was 6.1 (-0.03 to 12.21) ml/min/1.73 m2 (P = 0.051). Our study suggests that albuminuric patients with nondiabetic nephropathies frequently suffer from impaired autoregulation of GFR.

Contribution of endothelin to renal vascular tone and autoregulation in the conscious dog.

Exogenous endothelin-1 (ET-1) is a strong vasoconstrictor in the canine kidney and causes a decrease in renal blood flow (RBF) by stimulating the ETA receptor subtype. The aim of the present study was to investigate the role of endogenously generated ET-1 in renal hemodynamics under physiological conditions. In six conscious foxhounds, the time course of the effects of the selective ETA receptor antagonist LU-135252 (10 mg/kg iv) on mean arterial blood pressure (MAP), heart rate (HR), RBF, and glomerular filtration rate (GFR), as well as its effects on renal autoregulation, were examined. LU-135252 increased RBF by 20% (from 270 +/- 21 to 323 +/- 41 ml/min, P < 0.05) and HR from 76 +/- 5 to 97 +/- 8 beats/min (P < 0. 05), but did not alter MAP, GFR, or autoregulation of RBF and GFR. Since a number of interactions between ET-1 and the renin-angiotensin system have been reported previously, experiments were repeated during angiotensin converting enzyme (ACE) inhibition by trandolaprilat (2 mg/kg iv). When ETA receptor blockade was combined with ACE inhibition, which by itself had no effects on renal hemodynamics, marked changes were observed: MAP decreased from 91 +/- 4 to 80 +/- 5 mmHg (P < 0.05), HR increased from 85 +/- 5 to 102 +/- 11 beats/min (P < 0.05), and RBF increased from 278 +/- 23 to 412 +/- 45 ml/min (P < 0.05). Despite a pronounced decrease in renal vascular resistance over the entire pressure range investigated (40-100 mmHg), the capacity of the kidneys to autoregulate RBF was not impaired. The GFR remained completely unaffected at all pressure levels. These results demonstrate that endogenously generated ET-1 contributes significantly to renal vascular tone but does not interfere with the mechanisms of renal autoregulation. If ETA receptors are blocked, then the vasoconstrictor effects of ET-1 in the kidney are compensated for to a large extent by an augmented influence of ANG II. Thus ET-1 and ANG II appear to constitute a major interrelated vasoconstrictor system in the control of RBF.

Excessive vasoconstriction after stress by the aging kidney: Inadequate prostaglandin modulation of increased endothelin activity

The adaptive capacity of the aging kidney to stimulation of the sympathetic nervous system, as induced by a 30-minute mental stress (MS), was assessed in 8 elderly healthy women (68 to 82 years of age) and compared with that of 8 younger women (24 to 40 years of age). The study encompassed 4 consecutive 30-minute periods (baseline, mental stress, recovery 1, and recovery 2). In the elderly subjects, baseline effective renal plasma flow (ERPF)(iodine 131-labeled hippurate clearance) was lower and glomerular filtration rate (GFR)(iodine 125-labeled iotholamate clearance) was proportionally less reduced than in the younger group; the filtration fraction (FF) was higher. The elderly group excreted more endothelin 1 (ET-1) ( P < .05), prostaglandin E 2 (PGE 2), and 6-keto-prostaglandin F 1α (6-keto PGF 1α)( P < .001 for both)(radioimmunoassay). Mental stress induced similar increases in blood pressure, heart rate, and plasma catecholamines in the 2 age groups, limited to the stimulation period. In the elderly group, mental stress caused a prolonged decrease in ERPF that reached its maximum 60 minutes after mental stress (−33%, P < .05), while GFR remained constant during the whole experiment, so that FF increased. In the younger subjects, renal hemodynamic changes were limited to the mental stress period. ET-1 increased during mental stress and the first recovery period in the elderly group (+50% and +25%, P < .05) as it did in the younger group, but the elderly group differed from the younger in that vasodilating prostaglandins increased only during mental stress. In conclusion, the aging kidney reacts to adrenergic stimulation with more-pronounced and -prolonged vasoconstriction that is probably caused by a defect in prostaglandin modulation of endothelin activity. Autoregulation of GFR is maintained at the expense of increased intraglomerular pressure.