Bradykinin B2 receptors activate Na+/H+ exchange in mIMCD-3 cells via Janus kinase 2 and Ca2+/calmodulin.

We used a cultured murine cell model of the inner medullary collecting duct (mIMCD-3 cells) to examine the regulation of the ubiquitous sodium-proton exchanger, Na+/H+ exchanger isoform 1 (NHE-1), by a prototypical G protein-coupled receptor, the bradykinin B2 receptor. Bradykinin rapidly activates NHE-1 in a concentration-dependent manner as assessed by proton microphysiometry of quiescent cells and by 2'-7'-bis[2-carboxymethyl]-5(6)-carboxyfluorescein fluorescence measuring the accelerated rate of pH(i) recovery from an imposed acid load. The activation of NHE-1 is blocked by inhibitors of the bradykinin B2 receptor, phospholipase C, Ca2+/calmodulin (CaM), and Janus kinase 2 (Jak2), but not by pertussis toxin or by inhibitors of protein kinase C and phosphatidylinositol 3'-kinase. Immunoprecipitation studies showed that bradykinin stimulates the assembly of a signal transduction complex that includes CaM, Jak2, and NHE-1. CaM appears to be a direct substrate for phosphorylation by Jak2 as measured by an in vitro kinase assay. We propose that Jak2 is a new indirect regulator of NHE-1 activity, which modulates the activity of NHE-1 by increasing the tyrosine phosphorylation of CaM and most likely by increasing the binding of CaM to NHE-1.

Effect of chronic bradykinin B2 receptor blockade on blood pressure of conscious Dahl salt-resistant rats.

1. In this study 3 protocols were utilized to determine the role of endogenous kinins in the resistance of the inbred Dahl (Rapp) salt-resistant (SR/Jr) rats to high salt diet-induced blood pressure elevation. 2. The bradykinin B2 receptor antagonist, Hoe 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) at doses of either 10-20 or 20-40 nmol day(-1) (subcutaneously (s.c), via osmotic minipumps, for either 1 or 3 weeks during a high (8%) salt diet) effectively blocked or attenuated the hypotensive responses to 100-1000 ng of bradykinin. 3. In the first protocol, 5 week old SR/Jr rats treated with Hoe 140 (10-20 nmol day(-1), n = 9, s.c., via osmotic minipumps) for 3 weeks and concomitantly fed high (8%) NaCl diet had significantly higher conscious tail cuff blood pressures (BPc) at 1 and 3 weeks when compared with rats treated with vehicle (0.9% NaCl, n = 6). The differences in BPc between the 2 groups were 13 mmHg (P < 0.001) after 1 week and 8 mmHg (P < 0.05) after 3 weeks of treatment. 4. In the second protocol, 5 week old SR/Jr rats were treated with Hoe 140 (20-40 nmol day(-1), n = 8, s.c., via osmotic minipumps) or vehicle (n = 8) for 3 weeks. During the first week of treatment the rats were fed normal (0.8%) NaCl diet. The rats were then switched to 8% NaCl for 2 remaining weeks of the protocol. The mean BPc of Hoe 140-treated rats was not significantly different from that of the vehicle-treated rats when fed 0.8% NaCl diet. In contrast, rats treated with Hoe 140 and concomitantly fed high (8%) NaCl diet had significantly increased BPc (123+/-2 vs 111 +/- 1 mmHg, P < 0.001 for the Hoe 140- and vehicle-treated rats, respectively). 5. In the third protocol, treatment with Hoe 140 (20 40 nmol day(-1), s.c., via osmotic minipumps) during high salt diet did not increase BPc in rats that were pre-exposed to the high salt diet for 2 weeks. 6. At the end of 3 weeks of study, blood pressure was measured via an arterial catheter during pentobarbitone-induced anaesthesia. Rats treated with Hoe 140 for 1 or 3 weeks had significantly lower mean arterial blood pressures than the vehicle-treated rats. 7. Our findings suggest that in SR/Jr rats, kinin activation of bradykinin B2 receptors at least partially contributes to early regulatory mechanisms that resist an increase in blood pressure following exposure to a high salt diet. The mechanism underlying the decreased blood pressure during pentobarbitone anaesthesia of SR/Jr rats chronically treated with Hoe 140 has yet to be elucidated.

Bradykinin B2 receptor antagonist increases chloride and water absorption in rat medullary collecting duct.

This study tested the hypothesis that intrarenal kinins play a regulatory role in electrolyte excretion by altering Cl- absorption in the collecting duct. We measured Cl- and insulin concentrations in tubular fluid samples obtained from medullary collecting ducts (MCD) of Dahl/Rapp salt-resistant (SR/ Jr) rats by microcatheterization of ducts of Bellini before and after treatment with the bradykinin receptor antagonist HOE-140. Tubular fluid was obtained from paired terminal inner medullary (t-IMCD) and outer medullary (OMCD) collecting duct sites of the left kidney. HOE-140 (n = 7) or vehicle (n = 5) was infused intravenously, and the collections were repeated. HOE-140 did not alter glomerular filtration rate but decreased urine flow rate (P < 0.05) and absolute and fractional Cl- excretion (P < 0.01). HOE-140 did not alter the fraction of filtered Cl- delivered (FDCl) to the OMCD but decreased FDCl to the t-IMCD from 2.3 +/- 0.3 to 1.3 +/- 0.3% (P < 0.05). The fraction of filtered Cl- absorbed per millimeter between the collection sites was increased from 0.2 +/- 0.1 to 0.6 +/- 0.1% (P < 0.05). Fractional absorption of water along the MCD was also increased (P < 0.05). No changes in excretory function or tubular Cl- or water absorption were observed in vehicle-treated rats. These studies show that kinin B2 receptor blockade enhances Cl- and water absorption in the MCD, a finding that supports a role of renal kinins in the regulation of NaCl and water excretion.

Calciphylaxis in chronic renal failure.

Calciphylaxis is a rare and life-threatening complication that is estimated to occur in 1% of patients with ESRD each year. Typically, extensive microvascular calcification and occlusion/thrombosis leads to violaceous skin lesions, which progress to nonhealing ulcers and sepsis. Secondary infection of skin lesions is common, often leading to sepsis and death. The lower extremities are predominantly involved (roughly 90% of patients). Patients with skin involvement over the trunk or proximal extremities have a poorer prognosis. Although most calciphylaxis patients have abnormalities of the calcium:phosphate axis or elevated levels of parathyroid hormone, these abnormalities do not appear to be fundamental to the pathophysiology of the disorder, and the etiology of calciphylaxis remains unclear. Recently, functional protein C deficiency has been hypothesized to cause a hypercoagulable state that could induce thrombosis in small vessels, with resulting skin ischemia, necrosis, and gangrene. The lack of understanding of the pathophysiology of the disease results in treatments that are equally unsatisfactory. Patients who undergo parathyroidectomy have a tendency to improve, but the prognosis for the disease is poor and mortality remains high.

Effect of dietary protein and enalapril on proximal tubular delivery and absorption of albumin in nephrotic rats.

In passive Heymann nephritis (PHN), angiotensin-converting enzyme inhibition (ACEI) or a low dietary protein intake decreases albuminuria (UAlbV). Although this reduction in albuminuria appears to result from an improvement in glomerular permselectivity, the effect of these treatments on albumin permeation and absorption by the nephron has not been clarified. This study used micropuncture techniques to examine the effect of these two treatments on albumin permeation (by measuring the delivery of albumin to the proximal tubule) and the tubular absorption of albumin. PHN rats (12-18 days after injection of FX1A) were switched from 23% to either 40% protein diet (HP), 40% protein diet and concomitantly treated with enalapril (40 mg.kg-1.day-1) (HPE), or to 8% (LP) protein diet for 4-6 days. Although left kidney glomerular filtration rate (GFR) did not differ among the groups, UAlbV from the left kidney in LP and HPE was only 20-40% of that observed for the HP group. In protocol 1, the fractional recovery of albumin (FRAlb) in urine was calculated following injection of artificial tubular fluid containing [14C]inulin and 125I-labeled albumin into the earliest identifiable proximal loops. There were no differences in FRAlb among the three groups. In protocol 2, timed quantitative collections of tubular fluid were obtained from proximal tubular loops. The rate of albumin delivery to the earliest accessible loops of the proximal tubule was significantly lower for the LP and HPE groups compared with the HP group. For each group, albumin concentration corrected for water absorption was not altered along the proximal tubule. The data indicate that alterations of dietary protein intake or ACEI treatment results in large changes in the delivery of albumin at the proximal tubule that could singularly account for the changes in urinary albumin excretion.

Role of kinins in the renal response to enalaprilat in normotensive and hypertensive rats.

This study examined the role of endogenous kinins in the alteration of renal hemodynamics induced by low-dose converting enzyme inhibition in hydropenic normotensive rats and in the nonclipped kidney of hydropenic two-kidney, one clip hypertensive rats. Infusion of a bradykinin B2 receptor antagonist (D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin, 1 or 10 micrograms.kg-1.min-1) did not alter renal function of normotensive rats. In a second series of experiments, infusion of enalaprilat at 0.1 mg.kg-1.h-1 increased renal blood flow (P < .01) and decreased renal vascular resistance (P < .01). The superimposition of the kinin antagonist at 1 micrograms.kg.min-1 during the enalaprilat infusion decreased renal blood flow to a value similar to the preenalaprilat baseline and significantly different from the mean of the two enalaprilat periods before and after the addition of the kinin antagonist--the "mean effect of enalaprilat." The decrease in renal blood flow induced by the kinin antagonist was associated with an increase in renal vascular resistance above the mean effect of enalaprilat (P < .025). In two-kidney, one clip hypertensive rats, systemic infusion of enalaprilat augmented the hemodynamics of the nonclipped kidney by a degree similar to that in normotensive rats. In contrast to normotensive rats, superimposition of the kinin antagonist did not alter the enalaprilat-induced change in blood flow or vascular resistance of the nonclipped kidney. The results of this study suggest that endogenous kinins contribute to the increased renal function induced by low-dose converting enzyme inhibition in hydropenic normotensive rats but appear to contribute less to the enalaprilat-induced alterations of renal function in the nonclipped kidney of two-kidney, one clip hypertensive rats.

Effects of chronic treatment with angiotensin converting enzyme inhibitor or an angiotensin receptor antagonist in two-kidney, one-clip hypertensive rats.

The effects of chronic angiotensin II (Ang II) receptor blockade (losartan) or converting enzyme inhibition (enalapril) on blood pressure (BP), urinary albumin excretion (Ualb V), renal histology and the hemodynamic and excretory function of the clipped and nonclipped kidneys were studied in two-kidney, one-clip (2-K 1-C) rats. One day after clipping the right renal artery, male Wistar rats were divided into three groups receiving: (1) losartan, 20 mg/kg/day (N = 7), (2) enalapril, 20 mg/kg/day (N = 8), or (3) no treatment (controls, N = 9) for three weeks. Both losartan and enalapril treatments maintained conscious BP at comparably lowered levels compared to control animals (116 +/- 6 mm Hg and 113 +/- 2 mm Hg vs. 188 +/- 11 mm Hg, respectively, P < 0.01). Treatment also prevented the increase in Ualb V, observed for the untreated group, three weeks after clipping (1.7 +/- 0.5 and 0.7 +/- 0.1 mg/24 hr vs. 17.8 +/- 7 mg/24 hr, respectively, P < 0.01). After three weeks of treatment, acute study of renal function during pentobarbital anesthesia revealed higher values of GFR and RPF and lowered vascular resistance for nonclipped kidneys from the losartan and enalapril groups compared to the corresponding kidneys from control animals. Despite the lower BP of both treated groups, clipped kidney GFR and RPF were unchanged compared to the control group. Ualb V for nonclipped kidneys from untreated rats was approximately 5- to 10-fold higher than in the nonclipped kidneys from the treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathophysiology of altered renal function in renal vascular hypertension.

It is now clear that specific angiotensin-dependent mechanisms contribute importantly to the pathophysiology of hypertension (HT) and altered renal function in models of two-kidney, one-clip (2-K, 1-C) HT in rats. The discovery of specific antagonists for angiotensin-converting enzyme and the newer angiotensin receptor and kinin receptor antagonists have allowed delineation of the contributions of these hormones to altered renal function in these models. The focus of interest in most of these studies has been the nonclipped kidney, which would be expected to ameliorate elevated blood pressure by exhibiting a pressure diuresis and natriuresis in the environment of systemic HT. Antagonism of the renin-angiotensin system in rat models of renal vascular HT indicates that the effects of angiotensin attenuate renal hemodynamic and excretory behavior, particularly in the nonclipped kidney. Furthermore, angiotensin attenuates the efficiency of autoregulation of renal hemodynamics in the nonclipped kidney. Function of the clipped kidney appears to be both angiotensin and perfusion pressure dependent. Evidence that inhibition of angiotensin reverses or improves these altered hemodynamic and excretory functions indicates that angiotensin may contribute importantly to the pathophysiology of HT in these models by altering or impairing the ability of the nonclipped or "normal" kidney to excrete sodium and volume. The precise roles of altered activity of vasodilator hormones to contribute to these alterations of renal function remains to be defined.

Thromboxane A2 receptor blockade improves renal function and histopathology in the post-obstructive kidney.

To elucidate the role of the vasoconstrictor thromboxane A2(TXA2) in post-obstructive nephropathy, we examined the effect of the TXA2 receptor antagonist GR32191(GR) on renal function and histopathology in the post-obstructed kidney (POK) in rats. Rats pre-treated with 3 or 6 mg/kg i.p. of GR prior to ureteral obstruction and maintained on b.i.d. doses of GR were compared to vehicle-treated and sham-operated controls. Renal hemodynamic, clearance and excretory function were assessed in each kidney following relief of 24 hours of unilateral ureteral obstruction. The histology of each kidney was evaluated. Mean clearances of inulin for the POK were significantly greater in the treated rats (0.42 +/- 0.06 ml/min at 6 mg/kg) than in controls (0.13 +/- 0.04 ml/min) and a dose-response effect was observed (P < 0.05). Paraaminohippurate clearance was increased by > 150% and renal vascular resistance was reduced by 50% in GR treated animals compared with controls (P < 0.05). Histopathologic findings in the untreated POK were typical of early obstruction. In the GR treated groups these changes were much less severe. These data support an important role for TXA2 in the pathogenesis of post-obstructive nephropathy.

Kinins as vasoactive peptides.

During the past year, a number of significant publications have provided data that clearly establish the basis for the important role of the tissue kallikrein-kinin system in cardiovascular control and renal function. These publications include a report of advances in techniques for system component measurement, reports of the localization of central bradykinin receptors and an alteration in the sensitivity of the central bradykinin system in hypertension, and a description of the effects of new kinin receptor antagonists on our understanding of endogenous and exogenous kinin-induced vasorelaxation and its possible alteration in hypertension. Several significant reports describe the potentiation of endogenous kinin action by kininase inhibitors and establish the important interaction between kininase activity and kinin control of blood pressure.

Tubuloglomerular feedback in one-kidney, one-clip hypertensive rats.

Previous studies have shown that hydropenic one-kidney, one-clip (1-K, 1-C) hypertensive HT rats exhibit impaired autoregulation of glomerular filtration rate (GFR) in response to reduced arterial perfusion pressure. We investigated the possible role of altered tubuloglomerular feedback (TGF) activity in this phenomenon. Uninephrectomized Wistar rats were studied acutely 3 weeks after placing silver clips (0.2 mm) on the renal artery. Experiments were performed in 1-K,1-C HT rats and in uninephrectomized control animals. TGF activity was assessed as changes in proximal tubule stop-flow pressure (SFP) in response to orthograde microperfusion from 0 to 80 nl/min into late proximal tubule segments. Only the highest perfusion rates (approximately 40 nl/min) into late proximal tubule segments resulted in maximal decreases in SFP, indicating a marked rightward shift of overall TGF activity in 1-K,1-C HT rats. Similar responses were observed in the uninephrectomized animals. In contrast, changes of SFP were observed at lower perfusion rates in normal animals and maximal responses were observed at perfusion rates of approximately 20 nl/min. These observations are consistent with the possibility that altered TGF activity contributes to impaired autoregulation of GFR in 1-K,1-C HT rats in response to reduced renal perfusion pressure. In response to treatment with i.v. captopril, the 1-K,1-C HT rats exhibited marked decreases in systemic arterial pressure associated with decreases in SFP and virtually complete inhibition of TGF activity. It is attractive to hypothesize that these alterations in TGF characteristics in the 1-K,1-C HT rats play a significant pathophysiologic role in the acute renal dysfunction observed in response to acute decreases of blood pressure during conditions of augmented angiotensin activity. Additional future studies will allow us to address the precise role for intrarenal angiotensin in these phenomena.

Influences of angiotensin on renal function in renal vascular hypertension.

The scope and the magnitude of the roles which angiotensin plays in the generation and maintenance of elevated blood pressure in models of renal vascular hypertension are continuing to expand. It is now clear that specific angiotensin dependent mechanisms contribute importantly to the pathophysiology of hypertension and altered renal function in models of two-kidney, one clip hypertension in rats. The generation of angiotensin in the local intrarenal environment of the kidney is a new and potentially important mechanism contributing to altered renal function in these models. Application of antagonists of the renin-angiotensin system to rat models of renal vascular hypertension indicate that the effects of angiotensin attenuate renal hemodynamic and excretory behavior, particularly in the nonclipped kidney. Further, angiotensin may attenuate the efficiency of autoregulation of renal hemodynamics in the nonclipped kidney. Evidence that inhibition of angiotensin reverses or improves these altered hemodynamic and excretory functions indicate that angiotensin may contribute importantly to the pathophysiology of hypertension in these models by altering or impairing the ability of the nonclipped or normal kidney to excrete sodium and volume.

Effects of verapamil and converting enzyme inhibition on bilateral renal function of two-kidney, one-clip hypertensive rats.

Experiments were conducted in two-kidney, one-clip renal vascular hypertensive rats (GHR) to assess the responses of each kidney to acute treatment with the antihypertensive calcium channel blocking agent verapamil in the presence and in the absence of converting enzyme inhibitor (CEI). One group of GHR (0.2 mm inner diam. clip 3 weeks before study) were examined during a control period, and during a second period of infusion of verapamil (600 micrograms h-1 kg-1). A second group of GHR were examined during a control period, during CEI (teprotide, 3 mg h-1 kg-1) infusion and during a third period of verapamil (600 micrograms h-1 kg-1) infusion superimposed on CEI infusion. Although systemic blood pressure (BP) decreased from 175 +/- 4 to 149 +/- 5 mmHg (mean +/- SEM) in response to verapamil alone, renal blood flow for non-clipped kidneys increased from 5.9 +/- 0.4 to 6.5 +/- 0.3 ml/min, indicating a 30% reduction of renal vascular resistance (P values less than or equal to 0.01; n = 9). Glomerular filtration rate (GFR) for non-clipped kidneys (n = 24) increased from 0.91 +/- 0.09 to 1.47 +/- 0.14 ml/min and filtration fraction increased from 0.32 +/- 0.04 to 0.47 +/- 0.03 (P values less than or equal to 0.05). Urine flow rate and absolute and fractional sodium excretion for non-clipped kidneys increased. GFR for clipped kidneys decreased during verapamil. Treatment with CEI alone resulted in nearly identical responses of BP and function of the non-clipped kidney, except filtration fraction was unchanged. The addition of verapamil to ongoing converting enzyme blockade tended to augment the increased GFR of the non-clipped kidney. Plasma renin activity (PRA) increased from 30 +/- 3 to 59 +/- 7 ng of angiotensin (ANG) I h-1 ml-1 with verapamil alone, a significantly larger increment than the increase of PRA from 27 +/- 5 to 39 +/- 9 ng of ANG I h-1 ml-1 in GHR subjected to comparable blood pressure reduction by mechanical aortic constriction. Verapamil resulted in many similar effects on renal function to those observed during blockade of converting enzyme. The increased filtration fraction observed in response to verapamil may be the result of vasodilatation of the afferent arteriole or of an increase in the glomerular ultrafiltration coefficient.

Effects of angiotensin inhibition and renal denervation in two-kidney, one clip hypertensive rats.

Neural and angiotensin-mediated influences that alter hemodynamic and excretory behavior of the nonclipped kidney of two-kidney, one clip hypertensive rats were assessed by sequential acute surgical denervation of the nonclipped kidney and intravenous infusion of converting enzyme inhibitor (SQ 20881), 3 mg/kg X hr. Normal and two-kidney, one clip hypertensive rats (0.2-mm silver clip on the right renal artery 3-4 weeks before study) were prepared to allow study of each kidney. Mean arterial blood pressure of two-kidney, one clip hypertensive rats fell significantly from control values of 149 +/- 6 to 135 +/- 6 mm Hg after denervation of the nonclipped kidney. Despite this decrease in arterial pressure, the nonclipped kidney exhibited significant increases in glomerular filtration rate (from 1.00 +/- 0.08 to 1.24 +/- 0.08 ml/min), sodium excretion (from 88 +/- 39 to 777 +/- 207 nEq/min), fractional sodium excretion (from 0.06 +/- 0.02 to 0.54 +/- 0.14%), and urine flow rate (from 3.7 +/- 0.5 to 8.2 +/- 1.1 microliter/min). A significant decrease in glomerular filtration rate (from 1.12 +/- 0.07 to 0.85 +/- 0.08 ml/min) with no change in excretory function was observed for the clipped kidney following denervation of the nonclipped kidney. Intravenous addition of converting enzyme inhibitor significantly increased renal blood flow (from 7.0 +/- 1.3 to 10.6 +/- 1.5 ml/min) and sodium excretion (from 777 +/- 207 to 1384 +/- 425 nEq/min) for the nonclipped kidney; blood pressure decreased from 135 +/- 6 to 123 +/- 4 mm Hg, and renal vascular resistance decreased significantly (from 22 +/- 3 to 13 +/- 2 mm Hg X min/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of potassium concentration on-line with an ion-specific electrode during hemodialysis.

Patients requiring hemodialysis for end-stage renal disease are vulnerable to wide fluctuations in plasma potassium concentration [K+]p. Dialysis of K+ can result in rapid and large changes of [K+]p and result in significant morbidity. Since blood is routinely diverted extracorporeally to the dialyzer, the measurement of [K+]p could be made 'on-line' in this circuit with an ion-selective electrode (ISE) with negligible additional risk. Valinomycin/tetraphenylborate embedded in polyvinylchloride (PVC) electrodes of high K:Na selectivity were manufactured in our laboratory. The electrodes were calibrated in vitro and placed in a T diverter tube upstream from the dialyzer. Intermittently small amounts of blood were diverted to flow past the electrode allowing measurement of the electrical potential developed between the ISE half cell and a Ag:AgCl electrode placed 4 mm from the valinomycin membrane which could be read as [K+]p ISE. Blood flowing through the T diverter was then collected in glass tubes for measurement of [K+]p by flame photometry. Forty-six comparative measurements were made for 6 patients who had given informed consent for study. Least squares regression analysis for all observations gave a correlation coefficient of 0.95 and a regression equation of y = 1.1 X -0.39. Only six samples were discrepant by 0.5 mmol/l, and all of these had [K+]p greater than 5.0 mmol/l where the ISE measurements were less precise. Although the correlation of the two techniques was less than perfect, the ISE shows potential utility for monitoring trends of [K+]p instantaneously during hemodialysis.

Pressure dependence of exaggerated natriuresis in two-kidney, one clip Goldblatt hypertensive rats.

This study evaluated the responses of each kidney of two-kidney, one clip Goldblatt hypertensive rats to acute volume loading to delineate the contribution of elevated perfusion pressure to the mechanisms of the exaggerated natriuresis in this model of hypertension. Eleven Goldblatt animals (0.2 mm clip 3 weeks prior to study) were studied at spontaneous blood pressure for each kidney's response to volume loading. In 11 other Goldblatt animals an aortic clamp between the renal arteries allowed reduction of perfusion pressure for the left, nonclipped kidney to normal levels. Ten normal rats served as controls. Renal function was examined during control periods and following the infusion of 3.5% body wt of 154 mM X liter-1 NaCl at 22.5 ml X hr-1. An exaggerated natriuresis was observed for the left, nonclipped kidney of the hypertensive Goldblatt rats, while the clipped kidney exhibited an attenuated natriuresis compared to either kidney of normal control rats. Reduction of perfusion pressure to the nonclipped kidney of Goldblatt animals to normal levels resulted in reduced clearance and excretory function before volume loading and attenuated its natriuretic response to levels less than those for the Goldblatt group at spontaneous, hypertensive blood pressure. The exaggerated natriuresis observed at hypertensive blood pressure was attributable to increases of filtered load of Na+ and reduced fractional absorption. These observations indicate that an exaggerated natriuresis occurs in the two-kidney, one clip Goldblatt hypertensive rat and that this phenomenon depends on the elevated renal perfusion pressure to the nonclipped kidney.

Evidence for angiotensin-stimulated proximal tubular fluid reabsorption in normotensive and hypertensive rats: effect of acute administration of captopril.

The effects of captopril on mean arterial blood pressure and proximal tubular fluid reabsorption (JV) were examined in anaesthetized normotensive rats and in the non-clipped kidneys of two-kidney, one-clip Goldblatt hypertensive rats. In the normotensive animals, captopril reduced arterial blood pressure from 121 +/- SD 9 to 106 +/- 10 mmHg and JV decreased from 3.78 +/- 0.45 to 2.57 +/- 0.58 X 10(-4) mm3 mm-2 s-1. Captopril had a greater effect on blood pressure in the hypertensive animals (172 +/- 17 reduced to 133 +/- 23 mmHg) although the decrease in JV from 3.62 +/- 0.12 to 2.40 +/- 0.40 was similar to that observed in normotensive animals. These results provide evidence that, in the anaesthetized rat, angiotensin II contributes to the maintenance of the rate of proximal fluid reabsorption. The magnitude of the angiotensin-stimulated component of proximal fluid absorption is similar in normotensive and two-kidney, one-clip Goldblatt hypertensive rats.

Angiotensin-dependent renal mechanisms in two-kidney, one-clip renal vascular hypertension.

Our understanding of the physiology of the renin-angiotensin system has advanced remarkably in the last decade as a result of the development of several pharmacologic agents that effectively block components of this humoral cascade. The use of these antagonists has also advanced our understanding of the contribution of the renin-angiotensin system to the development and maintenance of two-kidney, one-clip renal vascular hypertension. These antagonists have contributed greatly to the characterization of the systemic hemodynamic changes that occur in this model and, particularly, to the delineation of the behavior of the nonclipped kidney, a previously normal kidney that is subjected acutely to an environment of elevated systemic blood pressure and the input of a variety of other extrinsic influences. This kidney not only allows the blood pressure to increase and persist at elevated levels but appears to actively participate in the development and propagation of the hypertension. Although a variety of mechanisms impinge on the function of the nonclipped kidney in this model, the goal of this review is to analyze the behavior of this kidney and how its functional state is perturbed, primarily by the influence of angiotensin, which is believed to be delivered to it by the systemic circulation.