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Leptin is a 16-kDa peptide hormone that is primarily synthesized and secreted by adipose tissue. One of the major actions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake, elevation in temperature and energy expenditure. in addition, increasing evidence suggests that leptin, through both direct and indirect mechanisms, may play an important role in cardiovascular and renal regulation. Although the relevance of endogenous leptin needs further clarification, it appears to function as a pressure- and volume-regulating factor under conditions of health. However, in abnormal situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for direct renal, vascular and cardiac damage.

Leptin is a 16-kDa-peptide hormone that is primarily synthesized and secreted by adipose tissue. One of the major actions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake and elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect mechanisms, may play an important role in cardiovascular and renal regulation. While the relevance of endogenous leptin needs further clarification, it appears to function as a pressure and volume-regulating factor under conditions of health. However, in abnormal situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for direct renal, vascular, and cardiac damage.

The incidence and prevalence of obesity has risen markedly in the last decade, and this epidemic represents a serious health hazard with significant morbidity and mortality. Although hypertension is recognized as one of the most serious consequences of obesity, its pathophysiology remains incompletely understood. Contemporary research suggests that the recently discovered hormone leptin may represent a common link between these 2 pathologic conditions. Leptin is primarily synthesized and secreted by adipocytes. One of the major functions of this hormone is the control of energy balance. By binding to receptors in the hypothalamus, it reduces food intake and promotes elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect actions, may play an important role in cardiovascular and renal functions. Although the relevance of endogenous leptin needs further clarification for the control of renal sodium excretion and vascular tone, it appears to be a potential pressure and volume-regulating factor in normal situations. However, in conditions of chronic hyperleptinemia, such as obesity, leptin may function pathophysiologically for the development of hypertension as well as cardiac and renal disease. Thus, in addition to weight control, reduction of circulating leptin may confer cardiovascular and renal protective effects in patients with obesity-hypertension.

Previous investigations in normotensive animals have demonstrated a marked natriuretic and diuretic response following the acute administration of supraphysiologic doses of synthetic leptin. However, the importance of endogenous leptin in the regulation of renal sodium and water balance is not yet defined. This study examined the hemodynamic and renal excretory effects of circulating leptin blockade with a specific polyclonal antibody in groups of normotensive, chronically saline-loaded Sprague-Dawley rats. In the experimental group (n = 10), leptin antibody significantly decreased urinary sodium excretion and urinary flow by approximately 30% compared to the control rats (n = 10). Mean arterial pressure remained unchanged. Collectively, these results are interpreted to suggest that leptin is an important renal sodium-regulating factor under conditions of mild sodium and volume expansion.

Objective: Previous investigations have demonstrated that leptin promotes natriuresis with a renal tubular effect. However, the mechanisms involved in this response are unclear. The present study was designed to examine the hypothesis that the natriuretic response to leptin in normotensive Sprague-Dawley rats is regulated by nitric oxide (NO). Research Methods and Procedures: The hemodynamic and renal excretory effects of intravenous bolus administration of pharmacological doses of synthetic murine leptin were examined in groups of control Sprague-Dawley rats (n = 8), Sprague-Dawley rats treated for 4 days with the NO synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) (n = 8), and Sprague-Dawley rats treated for 4 days with l-NAME followed by acute treatment with sodium nitroprusside (n = 8). Results: In the control group (n = 8), an intravenous bolus of leptin, 400 μg/kg body weight, increased urinary sodium excretion 4- to 6-fold. In the Sprague-Dawley rats chronically administered l-NAME (n = 8), an intravenous bolus of 400 μg/kg of leptin did not increase sodium excretion. Acute sodium nitroprusside infusion to Sprague-Dawley rats chronically treated with l-NAME (n = 8) was associated with partial restoration of the sodium excretory response to leptin administration. Discussion: Collectively, these results are interpreted to suggest that the natriuretic and diuretic responses to leptin observed in the Sprague-Dawley rat require a functional NO system.

Leptin is a circulating polypeptide hormone produced by an adipocyte-specific gene. It regulates energy balance by binding to receptors in the hypothalamus, leading to alterations in food intake, temperature, and energy expenditure. More recent pharmacologic information suggests that this circulating hormone may play an important role in the regulation of body fluid volume and pressures through direct and indirect actions. Although the relevance of the endogenous leptin on cardiovascular and renal function is yet to be clearly determined, it seems to be a potential salt-regulating factor and may function pathophysiologically as a common link to obesity and hypertension.

Purpose: A local renin angiotensin (ANG) system has been identified in the bladder. To our knowledge little is known about this system. To define further the physiology of this system we performed this study.Materials and Methods: The circulating and bladder tissue concentrations of ANG I and ANG II were examined in anesthetized Sprague-Dawley female rats in estrus, diestrus or pregnancy. Each was given an intravenous bolus infusion of ANG I, the ANG converting enzyme inhibitor enalaprilat or saline.Results: The mean concentrations of ANG I and ANG II were markedly higher in bladder tissue than in whole blood at the highest levels in pregnancy. The concentration of ANG I and ANG II increased significantly in the bladder tissue and circulation after the ANG I infusion in estrus and diestrus. In pregnancy only circulatory ANG I increased, while circulatory ANG II, tissue ANG I and ANG II remained unchanged. Enalaprilat infusion was associated with an increased concentration of whole blood ANG I in all group...

Background: Earlier studies have indicated that the atrial natriuretic factor prohormone fragment 31-67 (Pro ANF31–67) has important effects for the promotion of sodium excretion and vasodilation in several animal species. However, the mechanisms for the natriuretic actions of Pro ANF31–67 are not completely defined. In the present study, the effects of synthetic Pro ANF31–67 on renin secretion were examined in sodium-depleted, anesthetized dogs with a single intact kidney (n = 5). Methods: After 3 20-minute control renal clearance periods, synthetic dog Pro ANF31–67 was given intrarenally at a sustained dose of 0.03 μg/kg/min for 3 20-minute experimental intervals, and after discontinuation of the peptide infusion, 3 final 20-minute recovery periods were determined. Results: Sustained intrarenal infusions of the Pro ANF31–67 produced striking decrements (p

Calcium channel blockers are used in the treatment of hypertension because of their ability to decrease peripheral vascular resistance. Recent research has suggested that these drugs also preserve or improve renal function in patients with essential hypertensive renal disease, diabetic renal disease, and in renal transplant recipients with or without cyclosporin therapy. In general, studies in both animal models and humans have demonstrated maintenance or reduction in renal vascular resistance, and preservation or enhancement of renal blood flow and glomerular filtration rate. In addition, calcium channel blockers appear to have a positive effect on renal haemodynamic function in the setting of diabetes mellitus; prospective trials have demonstrated reductions in urinary protein excretion in these patients. Current evidence suggests that calcium channel blockers are well-suited for the treatment of patients with hypertensive disease even in the presence of renal impairment.

A procedure for the collection, processing, extraction, separation, and measurement of renal tissue angiotensin II [ANG-(1-8)] is described. The arterial plasma and renal tissue concentrations of ANG-(1-8) were examined in anesthetized Sprague-Dawley male rats (10 to 12 weeks of age) given an intravenous saline infusion (group 1; n = 6), an intravenous bolus infusion of 0.5 microgram angiotensin I (group 2; n = 6), or an intravenous bolus of an angiotensin-converting enzyme inhibitor (group 3; n = 6). Plasma and renal tissue were collected at the peak mean arterial pressure (MAP) response. The mean (+/- SEM) concentration of ANG-(1-8) in the group given the saline vehicle was 12 +/- 2 fmol/mL in the plasma and 2.4 +/- 0.3 pmol/g in the renal tissue. The angiotensin I bolus significantly increased MAP by 40%. Following the angiotensin I infusion, at the time of peak MAP response, the concentration of the circulating and renal tissue ANG-(1-8) were 12-fold and twofold higher, respectively, compared with the saline vehicle. The angiotensin-converting enzyme inhibitor significantly decreased MAP by 10% and decreased the circulating and renal tissue ANG-(1-8) levels by 75% and 62.5%, respectively, compared with the saline vehicle. The rapid conversion of exogenous angiotensin I to ANG-(1-8) in renal tissue provides direct evidence that renal tissue can generate de novo ANG-(1-8) from a circulating precursor. Furthermore, plasma and renal tissue respond similarly to acute angiotensin-converting enzyme inhibition.

The effects of calcium antagonism on the development and progression of renal disease are controversial. To address this problem, studies were performed on young, uninephrectomized spontaneously hypertensive rats (SHRs) with the dihydropyridine calcium antagonist, manidipine, to assess its effect on the early pathogenesis of focal glomerulosclerosis. Male SHRs underwent uninephrectomy at age 10 to 11 weeks and were subsequently assigned to no treatment (control), a predetermined subvasodepressor (low) dose of manidipine (2.5 mg/kg body weight), or a predetermined antihypertensive (high) dose of manidipine (20 mg/kg body weight). All animals received a diet containing 0.4% sodium and 23% protein. Serial determinations of body weight, systolic tail cuff pressure, and 24-hour urinary excretion of creatinine, sodium, and protein (UprotV) were made at 1- to 6-week intervals, for a total treatment period of 12 weeks. In final experiments plasma was obtained for creatinine, angiotensin I, and angiotensin II determinations, and renal tissue was harvested for histologic and morphometric analysis. Compared with the untreated control, low-dose manidipine therapy had no effect on body weight, systolic blood pressure, creatinine clearance, UprotV, renal histologic findings, glomerular volume, or plasma angiotensin I or II concentrations. In contrast, high-dose manidipine therapy decreased systolic blood pressure from 194 ± 3 to 160 ± 4 mm Hg (p < 0.01). Creatinine clearance and UprotV were unchanged. Although body weight was not different, kidney weight was higher. However, mean glomerular volume was lower. More importantly, the prevalence of mesangial expansion with proliferation was lower: 6.7% (control) versus 2.8% (high-dose manidipine) (p < 0.01). Finally, plasma angiotensin I and angiotensin II concentrations did not differ. The composite data demonstrate that manidipine, given as an effective antihypertensive drug, protected the uninephrectomized SHR kidney from the early development of structural glomerular injury.

In addition to the classic circulating renin—angiotensin system, increasing evidence supports the existence of local tissue renin—angiotensin systems (vascular, cardiac, kidney, and brain) that appear to participate in cardiovascular homeostasis and in the pathogenesis of cardiovascular disorders via multiple autocrine and paracrine functions. Components of local systems have been detected in cardiovascular tissues. Studies with angiotensin-converting enzyme (ACE) inhibitors provide further evidence of the existence and importance of tissue renin—angiotensin systems. The blood pressure-lowering effect of quinapril, for example, correlated better with inhibition of tissue ACE (aorta) than with inhibition of plasma ACE. The effects of ACE inhibitors on local tissue renin—angiotensin systems (vascular in particular) may be the crucial determinant of response to treatment. Newer ACE inhibitors, such as quinapril, have favorable side effect profiles as well as apparent tissue specificity for the vascular renin—angiotensin system (and possibly other relevant cardiovascular tissue). Differentiation among ACE inhibitors should play an even more important role in the future for individualization of therapy.

Recent experimental studies suggest that the resistance state of the preglomerular and postglomerular capillary arterioles may determine if a particular class of antihypertensive agents will protect the kidney from hemodynamically mediated glomerular injury. This review discusses (1) the effects of angiotensin II on the renal microcirculation, (2) the pathophysiology of essential hypertensive renal disease, (3) the renal pharmacology of angiotensin-converting enzyme (ACE) inhibitors, and (4) the hypothesis that renal protection is dependent on control of systemic and glomerular hypertension.

The aging kidney undergoes hemodynamic changes characterized by reductions in glomerular filtration rate and effective renal plasma flow. These functional changes are associated with loss of renal mass related to changes in the intrarenal vasculature. The reduced glomerular filtration surface area and subsequent microcirculatory adaptations enhance the risk for development of renal diseases associated with systemic diseases. Hypertensive nephrosclerosis accounts for 26% of all end-stage renal disease in the United States; the median age of those affected is 67 years. Hemodynamic and structural changes observed in the essential hypertensive kidney suggest an accentuation of the physiologic aging process. Initially observed hemodynamic changes, which may be reversible with specific drug therapy, suggest that excessive production of angiotensin II plays a role. Progressive renal impairment may occur despite control of systemic hypertension. Renal protection appears to require the therapeutic normalization of both systemic and glomerular capillary pressures. The latter may depend on a drug's ability to attenuate the intrarenal effects of angiotensin II on the renal microcirculation. Drug classes with renal protective potential include angiotensin-converting enzyme inhibitors and calcium antagonists. However, long-term clinical trials are required to assess the potential advantages of specific drug therapies in preventing the development and/or progression of hypertensive arteriolar nephrosclerosis.

The incidence and prevalence of obesity and the metabolic syndrome have risen markedly in the past decade, representing a serious cardiovascular health hazard with significant morbidity and mortality. The etiology of the metabolic syndrome and its various pathogenic mechanisms are incompletely defined and under intense investigation. Contemporary research suggests that the adipocyte-derived hormone leptin may be an important factor linking obesity, the metabolic syndrome, and cardiovascular disorders. Although recent evidence indicates that under normal conditions leptin may be an important factor in regulating pressure and volume, during situations of chronic hyperleptinemia and leptin resistance, this hormone may function pathophysiologically for the development of hypertension and cardiac and renal diseases. Future research will determine if reduction of circulating leptin and/or blockade of its peripheral actions can confer cardiovascular and renal protection in hyperleptinemic patients with obesity and the metabolic syndrome.

Leptin is a recently isolated circulating peptide hormone that is primarily synthesized and secreted by adipocytes. One of the major functions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake, elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect actions, may play an important role in cardiovascular and renal functions. While the relevance of endogenous leptin needs further clarification, it appears to be a potential pressure- and volume-regulating factor, and may function pathophysiologically as a common link to obesity and hypertension.

Leptin is a recently isolated circulating peptide hormone that is primarily synthesized and secreted by the adipocytes. A major function of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake, as well as elevation in temperature and energy expenditure. In addition, increasing pharmacological evidence suggests that leptin, through its direct and indirect actions, may play an important role in cardiovascular and renal functions. While the relevance of endogenous leptin needs further clarification, it appears to be a potential pressure and volume regulating factor, and may function pathophysiological as a common link to obesity and hypertension.

Mammalian hearts contain a family of peptides with potent natriuretic, diuretic, and vasorelaxant actions. In addition to atrial natruretic peptide (ANP) and brain natriuretic peptide, recent studies in humans and animals have suggested that the N-terminal ANP prohormone fragment 31–67 may represent another adaptive mechanism to achieve body fluid homeostasis. Furthermore, these investigations have also suggested that via different mechanisms of action on target organisms, the C-terminal hormone ANP 99–126 and pro-ANP 31–67 may coordinate and contribute to the regulation of hemodynamic and renal function in pathophysiologic situations, such as heart failure.

It has been demonstrated previously that the atrial natriuretic factor prohormone fragment 31-67 (ProANF31-67) circulates in animals and possesses natriuretic and vasodilating actions. Although the plasma levels of the peptide are reportedly elevated in patients with high blood pressure, its role and actions in hypertension are unknown. In the present study, synthetic human ProANF31-67 was infused intravenously at doses of 0, 10, 30, and 100 ng/kg/min into respective groups of anesthetized normotensive and spontaneously hypertensive rats. Mean arterial pressure (MAP), urine flow rate (UV), and sodium excretion (UNaV) were measured during two consecutive 30-min periods. In both strains of rats, reductions in MAP with ProANF31-67 were similar in magnitude and dose-related. Sodium excretion responses to the peptide infusions also were remarkably similar in both normotensive and hypertensive rats, and the responses demonstrated 3- to 5-fold (P < 0.05) increments compared to control at the doses of 10 and 30 ng/kg/min. However, in the two strains of rats, attenuation of natriuresis occurred with the highest infusion dose of 100 ng/kg/min and was probably related to the large decreases in MAP of 17-23 mmHg at this dose of the peptide. The present results indicate the ProANF31-67 has important hemodynamic and renal effects in hypertension and may represent one compensatory mechanism involved in this disease.

The hemodynamic, hormonal, and renal excretory effects of intravenous bolus administration of synthetic murine leptin were examined in groups of anesthetized normotensive (Sprague-Dawley), hypertensive (spontaneously hypertensive), and both lean and obese Zucker rats. In the normotensive animals (n = 8) an intravenous bolus of 400 microgram/kg of leptin produced a significant six- to sevenfold elevation in sodium excretion compared with controls (n = 8). The onset of natriuresis was delayed for approximately 30-45 min. Mean arterial pressure (MAP), creatinine clearance, plasma renin activity (PRA), and plasma aldosterone concentration (PAC) remained unchanged. In contrast, the hypertensive rats were refractory to the natriuretic effects of leptin when infused either with 400 (n = 8) or 1,600 (n = 8) microgram/kg. Also in these animals MAP, creatinine clearance, PRA, and PAC were unmodified. Finally, whereas lean Zucker rats (n = 8) responded very similarly to the Sprague-Dawley animals, the natriuretic effect of the hormone was attenuated in the obese Zucker groups. At 400 microgram/kg (n = 8) no natriuresis was elicited, but at 1,600 microgram/kg (n = 8) a modest but significant two- to threefold increment in sodium excretion was observed in the obese rats. In both Zucker groups, MAP, creatinine clearance, PRA, and PAC were unchanged. Collectively, these results demonstrate a significant natriuretic effect of exogenous leptin in the normal rat and a blunted saluretic response in hypertension and obesity. It is suggested that leptin may be a potential salt-excretory factor in normal rats and may function pathophysiologically in obesity and hypertension.

To assess the effects of chronic dietary sodium restriction and blood pressure reduction on glomerular function and structure during the pathogenesis of hypertensive renal disease, experiments were conducted in uninephrectomized (UNX) spontaneously hypertensive rats (SHR) using the dihydropyridine calcium antagonist manidipine. Male SHRs underwent UNX at age 10–11 weeks and subsequently were assigned to one of four groups: sodium-replete (0.4%); sodium-replete and a predetermined antihypertensive dose of manidipine (20 mg/kg body weight); sodium-deplete (0.09%); and sodium-deplete and manidipine (20 mg/kg body weight). Twelve weeks later, renal morphologic and functional studies were performed. Sodium restriction had no significant effect on systolic blood pressure, but creatinine clearance and urinary protein excretion were decreased. Importantly, mean glomerular volume and the prevalence of mesangial expansion were lower with sodium restriction. This occurred in the presence of high concentrations of plasma and renal tissue angiotensin II. Manidipine significantly reduced systolic blood pressure in the sodium-replete and sodium-deplete UNX-SHRs. This therapy was not associated with significant changes in creatinine clearance and urinary protein excretion in the sodium-deplete or sodium-replete UNX-SHRs. The prevalence of mesangial expansion in the sodium-replete UNX-SHR was approximately 50% lower with manidipine. Plasma and renal tissue angiotensin II concentrations were not affected by the drug. In the sodium-deplete UNX-SHR, the prevalence of mesangial expansion was not reduced further by manidipine. However, plasma and renal tissue angiotensin II concentrations were increased significantly. Based on the results of this study, 1) in the sodium-replete UNX-SHR, the calcium antagonist manidipine, given as effective anti-hypertensive therapy, attenuates early glomerular injury without altering circulating or renal tissue angiotensin II; 2) sodium depletion, independent of blood pressure and stimulation of circulating and renal tissue angiotensin II, attenuates early glomerular injury after uninephrectomy; and 3) in sodium-deplete UNX-SHR, effective antihypertensive treatment with manidipine does not produce an additional reduction in early glomerular injury.

Calcium channel blockers are used in the treatment of hypertension because of their ability to decrease peripheral vascular resistance. Recent research has suggested that these drugs also preserve or improve renal function in patients with essential hypertensive renal disease or diabetic renal disease, and in renal transplant recipients with or without cyclosporin therapy. In general, studies in animal models of hypertension and in hypertensive humans have demonstrated reduction in renal vascular resistance, and preservation or enhancement of renal plasma flow and glomerular filtration rate. In addition, calcium channel blockers appear to have a positive effect on renal addition, calcium channel blockers appear to have a positive effect on renal haemodynamic function in the setting of diabetes mellitus; prospective trials have also demonstrated reductions in urinary protein excretion in these patients. Current evidence suggests that calcium channel blockers are well-suited for the treatment of patients with hypertensive disease even in the presence of renal impairment, a clinical scenario common in the elderly population.

Calcitonin gene-related peptide (CGRP) is a recently discovered neurotransmitter that is extensively localized in fibers innervating vascular and endocrine systems. CGRP possesses potent vasorelaxant effects, and a role for this peptide in the regional regulation of blood flow has been suggested. Although pharmacologic evidence indicates that the renal vasculature is very sensitive to CGRP, the physiologic actions of this peptide on the kidney have not yet been fully elucidated. This short review focuses on relevant experimental and clinical information of the direct and indirect effects of CGRP on renal function with an emphasis on hemodynamics, sodium excretion, and the renin-angiotensin system.

The methodology for the collection, extraction, separation and measurement of urinary angiotensin II [the octapeptide, ANG(1-8)] is described. To determine the origin of urinary ANG(1-8), mean arterial pressure, renal hemodynamics and the arterial, renal venous and urinary concentrations of ANG(1-8) were examined prior to and following the constant intra-arterial infusion of tritiated angiotensin II [3H-ANG(1-8)] in graded doses of 0.5, 2.0 and 2.5 ng/kg/min in 5 uninephrectomized, anesthetized female dogs. The infusion of 3H-ANG-(1-8) had no significant effect on mean arterial pressure, glomerular filtration rate, renal blood flow or urine flow rate. The mean concentration of ANG(1-8) in the urine was 3.7 fmol/ml. None or only trace amounts of 3H-ANG(1-8) were detected in the urine in spite of marked increases in renal arterial 3H-ANG(1-8) concentrations. These observations suggest that urinary ANG(1-8) was derived de novo from the intrarenal generation of angiotensin II. In addition, plasma and urinary concentrations of ANG(1-8) were assessed in patients with essential hypertension undergoing treatment with either a diuretic (n = 14) or an angiotensin-converting enzyme inhibitor (n = 14). Although the concentrations of plasma ANG(1-8) responded appropriately to the respective therapies, the urinary excretion of ANG(1-8) was not different following either therapy. These data suggest that ANG(1-8) collected from the urinary bladder may not occur in adequate concentrations to accurately assess the activity of the intrarenal renin-angiotensin system.

Sixteen essential hypertensive patients were entered into a protocol assessing the effect of Spirapril, an angiotensin-converting enzyme (ACE) inhibitor, on blood pressure, the renin-aldosterone system, and renal function. Specifically monitored before, during 6 weeks, and 6 months of Spirapril therapy were plasma renin activity, plasma aldosterone, serum ACE, the renal clearances of creatinine, inulin, and para-aminohippurate, and urinary albumin excretion. Blood pressure was well controlled. Spirapril stimulated plasma renin activity and suppressed ACE throughout the entire protocol. Renal clearances were unchanged. Renal vascular resistance was decreased. Urinary albumin excretion was decreased. The authors conclude that the ACE inhibitor, Spirapril, when used as an effective antihypertensive agent, preserves renal function, lowers renal vascular resistance, and decreases urinary albumin excretion.

It is unknown if the antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors reflects attenuation in the rate of progression of diabetic nephropathy. We report the results of a randomized, double-blind clinical trial designed to evaluate the longitudinal (18-month) effect of the ACE inhibitor, enalapril (5 to 40 mg/d), versus a placebo on 24-hour urinary protein excretion and on the rate of progression of renal disease in 33 patients with clinical diabetic nephropathy. Systemic blood pressure was controlled throughout the trial with conventional antihypertensive drugs. Glomerular filtration rate (GFR), determined by Tc 99m DTPA renal clearance, and urinary protein excretion were monitored at 3-month intervals. Enalapril, in contrast to placebo therapy, was associated with an initial (40%) and sustained (33%) decrease in urinary protein excretion. Patients randomized to both enalapril or placebo experienced mean decreases in GFR, from 1.01 mL/s/1.73 m 2 (61 mL/min/1.73 m 2 ) to 0.85 mL/s/1.73 m 2 (51 mL/min/1.73 m 2 ), and from 1.06 mL/s/1.73 m 2 (64 mL/min/1.73 m 2 ) to 0.97 mL/s/1.73 m 2 (58 mL/min/1.73 m 2 ), respectively. Eleven of 18 patients (61 %) randomized to enalapril, and 10 of 15 (66%) patients randomized to placebo, had a decrease in GFR; their rates of progression were −1.18 mL/min/1.73 m 2 /mo and −1.00 mL/min/1.73 m 2 /mo, respectively. In the absence of changes in blood pressure, the addition of an ACE inhibitor to patients with clinical diabetic nephropathy could not be shown to confer a unique renal protective effect. A prolonged decrease in 24-hour protein excretion could not be shown to predict attenuation in the progression of established clinical diabetic nephropathy.

Twelve hypertensive patients with moderately severe renal dysfunction were entered into a protocol to assess the blood pressure and renal effects of the sustained release calcium antagonist, nifedipine GITS (30 — 180 mg/d given once a day) administered for 5 weeks. Nifedipine GITS monotherapy effectively lowered blood pressure in 50% of the patients. Glomerular filtration rate and effective renal plasma flow were increased 18% and 20%, respectively. The filtration fraction and urinary protein excretion remained unchanged. Changes that were observed in renal junction were independent of the blood pressure responses of the patients; there was no correlation between the systemic and renal effect of nifedipine GITS monotherapy. Patients who had a poor systemic blood pressure response exhibited an increase in glomerular filtration rate (+11%) but had a decrease in effective renal plasma flow (-6%); patients who achieved a goal blood pressure response showed increases in both glomerular filtration rate (+35%) and effective renal plasma flow (+40%). These results show that nifedipine GITS monotherapy has the potential to improve renal function abnormalities that are encountered in hypertensive patients with renal disease; the improvement in renal function may be independent of their effect on systemic blood pressure.

This review focuses on the effects of calcium antagonists on renal function in hypertensive human subjects. Specifically assessed are the acute and chronic effects of diltiazem, verapamil, amlodipine, felodipine, isradipine, nicardipine, nifedipine, and nitrendipine on glomerular filtration rate; effective renal plasma flow/renal blood flow; renal vascular resistance; and urinary protein excretion. Among the calcium antagonists, only the dihydropyridine derivatives have been demonstrated consistently to acutely increase effective renal plasma flow/renal blood flow. The acute effects on glomerular filtration rate are variable. With respect to chronic therapy, many of the calcium antagonists have been reported to produce sustained increases in the effective renal plasma flow/renal blood flow and/or the glomerular filtration rate. Renal vascular resistance is reduced. Although calcium antagonists preserve or improve renal perfusion and glomerular filtration, long-term clinical trials are required to determine their potential therapeutic benefit to modify the natural course of hypertensive renal disease.

This study investigated the intrarenal metabolism of circulating angiotensin II. Mean arterial pressure (MAP), renal hemodynamics, and the arterial, renal venous, and renal tissue concentrations of the angiotensin octapeptide [ANG-(1–8)] were examined following the constant intra-arterial infusion of tritiated angiotensin II [( 3H]ANG-(1–8)] in graded doses of 0.5, 2.0, and 2.5 ng.kg-1.min-1 in five uninephrectomized, anesthetized female dogs. The infusion of [3H]ANG-(1–8) had no significant effect on MAP, glomerular filtration rate, renal blood flow, or urine flow rate. The mean degradation rate of intra-arterially infused [3H]ANG-(1–8) was 72%. The net renal venous plasma concentration of ANG-(1–8) was greater than that predicted from the degradation rate of [3H]ANG-(1–8). High concentrations of ANG-(1–8) were measurable in all renal tissues. However, [3H]ANG-(1–8) was not detectable in any renal tissue. These observations suggest that ANG-(1–8) in the renal venous effluent was derived, in part, de novo from intrarenal generation. Likewise, renal tissue ANG-(1–8) was derived de novo from intrarenal generation.

The natural course of essential hypertensive renal disease is characterized by a slowly progressive impairment of renal function. Initially, the changes are functional and reversible; however, structural changes gradually occur, leading to hypertensive nephrosclerosis. Similarities exist between the early functional hemodynamic changes observed in the essential hypertensive kidney and the physiologic renal effects of angiotensin II. To the degree that the initial functional changes are the result of excessive endogenous production of angiotensin II, interruption of the integrity of this humoral system could be expected to reverse the pathophysiologic sequence of events leading to hypertensive nephrosclerosis. This review focuses on the pathophysiology of the essential hypertensive kidney, the intrarenal effects of angiotensin II, and the acute and chronic effects of angiotensin converting enzyme (ACE) inhibition therapy on the essential hypertensive kidney. The data reviewed suggest that ACE inhibition therapy does reverse the initial functional hemodynamic changes observed in the essential hypertensive kidney and may protect the glomerulus from hemodynamically mediated injury.

The angiotensin II (AII) type 1 receptor antagonists represent a new pharmacologic class of drugs that are specifically designed to displace All from its type 1 receptor subtype. These drugs antagonize AII-induced biologic actions, including smooth-muscle contraction, sympathetic pressor mechanisms, and aldosterone release. Initial clinical trials suggest that these drugs are effective in the treatment of essential hypertension and hypertensive patients with intrinsic renal disease. Thus, they are the newest addition to the therapeutic armamentarium for the treatment of hypertensive diseases. We review the developmental history and pharmacology of the All type 1 receptor antagonists. We specifically discuss the following factors: mechanism(s) of action; members under clinical investigation; effects on renal function, salt and water excretion, and plasma renin activity, plasma All type 1, and plasma aldosterone concentrations; and efficacy and safety. Given the demonstrable benefits of All type 1 receptor blockade, these drugs should achieve broad utility in the treatment of hypertensive diseases. (Arch Intern Med. 1995;155:1361-1368)

Eighteen hypertensive patients underwent short-term (8 weeks) and long-term (6 months) assessment of renal function and body fluid composition following diltiazem monotherapy (240 to 480 mg/day). Diltiazem monotherapy effectively lowered blood pressure in 60% of patients at 8 weeks. In 12 of the 18 patients continued on diltiazem monotherapy for 6 months, good control of blood pressure was sustained. Glomerular filtration rate, effective renal plasma flow, filtration fraction, and renal vascular resistance were unchanged throughout the protocol period. In individuals with pretreatment glomerular filtration rates less than or equal to 80 ml/min/1.73m2, diltiazem monotherapy showed both short-term and long-term improvement in glomerular filtration rate (62%) and effective renal plasma flow (34%). Filtration fraction was unchanged, suggesting that the changes in glomerular filtration rate might be related to the attenuated intrarenal effects of angiotensin II and/or norepinephrine. No long-term effect was seen on salt and water excretion or body fluid composition.

Calcium antagonists may increase glomerular filtration rate and renal plasma flow by antagonizing the intrarenal effects of angiotensin II and/or norepinephrine. We prospectively studied the effects of amlodipine, a once-a-day dihydropyridine calcium channel antagonist, in 19 patients with essential hypertension. Studies were performed after 4 weeks of placebo and 6 weeks of amlodipine therapy, and included the assessment of systolic and diastolic BP, renal clearances of inulin and p-aminohippurate, and determination of body fluid composition. Systolic and diastolic BPs were reduced following 6 weeks of amlodipine monotherapy. In spite of significant decreases in mean arterial pressure, there were increases in inulin clearance (+ 13%), and p-aminohippurate clearance (+ 19%). Filtration fraction was not changed. Renal vascular resistance was decreased (-25%). Total blood volume, extracellular fluid volume, and total body water and body weight were not changed. We conclude that amlodipine therapy has the potential to reverse renal abnormalities encountered in the hypertensive state.

The renal effects of the calcium entry-blocking drugs diltiazem, nifedipine, nitrendipine, nicardipine and verapamil are reviewed. Although nifedipine may acutely increase plasma renin activity, most of the calcium entry blockers have no sustained effect on any of the components of the renin-angiotensin-aldosterone system. Although all of the calcium entry blockers effectively lower blood pressure, none adversely affects renal function: Glomerular filtration rate and effective renal plasma flow are maintained. Diltiazem may increase glomerular filtration rate via attenuation of the intrarenal effects of angiotensin II or norepinephrine. Although all of the calcium entry blockers acutely increase salt and water excretion, most of the calcium entry blockers have no clinically sustained effect on salt and water excretion; serum electrolytes, urinary sodium and potassium excretion, body fluid composition and body weight are usually unchanged. Calcium entry blockers can be expected to assume a prominent role in the treatment of hypertension because of their ability to lower blood pressure while preserving renal perfusion and function.

The renal effects of the calcium entry-blocking drugs diltiazem, nifedipine, verapamil and nitrendipine are reviewed. Although nifedipine stimulates plasma renin activity on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on any of the components of the renin-angiotensin-aldosterone system. Although all of the calcium entry blockers effectively lower blood pressure, none adversely affects renal function; glomerular filtration rate and effective renal plasma flow are maintained. Diltiazem may increase glomerular filtration rate via attenuation of the intrarenal effects of angiotensin II or norepinephrine. Although diltiazem and nifedipine increase salt and water excretion on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on salt and water excretion; serum electrolytes, urinary sodium and potassium excretion, body fluid composition and body weight are unchanged. Thus, calcium entry blockers can be expected to assume a prominent role in the treatment of hypertension because of their ability to lower blood pressure while preserving renal perfusion and function.

18 renovascular hypertensive patients were entered into a randomised, double-blind protocol to assess the safety and efficacy of enalapril (5 to 20 mg twice-daily) and hydrochlorothiazide (50 to 100 mg/day), versus triple-drug therapy employing hydrochlorothiazide (50 to 100 mg/day), timolol (10 to 30 mg twice-daily) and hydralazine (50 to 150 mg twice-daily). Specifically monitored were the effects of each drug regimen on blood pressure, plasma renin activity and angiotensin II, glomerular filtration rate by insulin clearance, and effective renal plasma flow by para-aminohippurate clearance. Results indicate that enalapril/hydrochlorothiazide was more effective than triple-drug therapy in lowering blood pressure. All patients on enalapril/hydrochlorothiazide had excellent control of blood pressure, and there were no adverse effects. In contrast, 50% of the patients on triple-drug therapy had either uncontrolled blood pressure or significant drug-related side effects. Patients who were uncontrolled or intolerant of triple-drug therapy were well controlled on enalapril/hydrochlorothiazide. Patients on enalapril/hydrochlorothiazide demonstrated stimulation of plasma renin activity with inhibition of plasma angiotensin II, indicating adherence with therapy. Therapy for both unilateral and bilateral renovascular hypertension with enalapril/hydrochlorothiazide did not result in reductions in either glomerular filtration rate or effective renal plasma flow, except in 1 patient with a functional solitary stenotic kidney. In contrast, triple-drug therapy was generally associated with modest reductions in glomerular filtration rate and effective renal plasma flow, with a severe reduction in glomerular filtration rate and effective renal plasma flow occurring in 1 patient with bilateral symmetrical renovascular disease. We conclude that the combination of enalapril and hydrochlorothiazide is a safer and more effective regimen, compared with triple-drug therapy, for the treatment of renovascular hypertension.

The effects of long-term triple drug therapy on renal function in patients with moderate to severe essential hypertension have not been evaluated systematically. We prospectively studied fifteen male patients with moderate to severe essential hypertension receiving triple drug therapy (metolazone, atenolol or betaxolol, and minoxidil) for 16 weeks. Supplemental potassium was prescribed in an attempt to maintain serum potassium above 3.5 mEq/liter. Systemic blood pressure was well controlled with this regimen. However, glomerular filtration rate (assessed by inulin clearance), effective renal plasma flow (assessed by paraaminohippurate clearance), and renal blood flow were reduced. Filtration fraction and renal vascular resistance were not significantly altered. Plasma renin activity remained stimulated throughout the protocol. Weight gain occurred, and serum potassium remained low. These results suggest that triple drug therapy employing a diuretic, beta-adrenergic antagonist, and a potent vasodilator is effective therapy for controlling moderate to severe systemic hypertension. However this antihypertensive regimen may be associated with a decrement in renal function.

Thirty-nine hypertensive patients were entered into a randomized, double-blind protocol to assess the effects of enalapril (10-20 mg b.i.d.), or combined enalapril (10-20 mg b.i.d.) and hydrochlorothiazide (25-50 mg b.i.d.) therapy on renal function and hemodynamics. Enalapril, either alone or in combination with hydrochlorothiazide, effectively controlled blood pressure. In patients with an initial inulin clearance less than or equal to 80 ml/min/1.73 m2, inulin and p-aminohippurate clearances were markedly improved toward normal following either drug therapy. The filtration fraction was either unchanged (monotherapy) or increased (combination therapy), suggesting a direct glomerular effect of angiotensin-converting enzyme inhibition. Renal vascular resistance was decreased in all patients. These observations suggest that enalapril, either alone or in combination with a diuretic, has the potential to reverse renal function abnormalities encountered in the hypertensive state.

Although the calcium channel blocker diltiazem has been shown to be an effective antihypertensive agent, its effect on renal function, salt and water excretion, and body fluid composition has not been well characterized in patients with primary hypertension. Therefore, these parameters were prospectively studied in 18 subjects with primary hypertension after placebo and 8 weeks of diltiazem monotherapy. Diltiazem monotherapy was confirmed to be an effective antihypertensive agent. Although mean arterial pressure was reduced from 121 to 108 mm Hg, diltiazem had no overall effect on glomerular filtration rate, renal plasma blood flow, salt and water excretion, or body fluid composition. Renal vascular resistance, however, was decreased. In subjects with pretreatment glomerular filtration rates of 80 ml/min/1.73 m2 or less, diltiazem therapy was associated with marked improvement in glomerular filtration rate (48%) and effective renal plasma flow (36%). Since the filtration fraction was unchanged, changes in glomerular filtration rate may have been related to the attenuated intrarenal effects of angiotensin II or norepinephrine, or both.

Tangier disease, or familial high-density lipoprotein deficiency, is an inherited disorder resulting in tissue deposition of excessive cholesterol esters. Although associated corneal clouding has been reported to produce little visual impairment, this patient with Tangier disease had corneal clouding, decreased corneal sensation, and cicatricial ectropion and experienced slowly progressive marked visual impairment. All ocular cases of Tangier disease are reviewed. Ectropion and incomplete eyelid closure may precede corneal clouding and should be recognized as signs associated with Tangier disease. The combination of exposure keratopathy and corneal infiltration can cause significant visual impairment.

This review focuses on the renal effects of the angiotensin converting enzyme inhibitors, captopril and enalapril. Emphasis is placed on the renal response to these drugs in patients with primary essential hypertension, and in hypertension accompanying renal parenchymal disease. Specifically reviewed are the renal function and hemodynamic, salt and water, body fluid composition, and urinary protein excretion responses. The interruption of the renin-angiotensin-aldosterone axis has the potential to produce a variety of favorable renal responses, including reduction of renal vascular resistance, enhancement of renal blood flow, enhancement of glomerular filtration rate, acute natriuresis, sustained diuresis, and a decrease in urinary protein excretion. Data in support of these potential renal perturbations are presented and discussed. The results suggest that the angiotensin converting enzyme inhibitors are important therapeutic agents in the treatment of hypertensive disease, in that they may modify pathophysiologic renal abnormalities encountered in this disease state.

Enalapril (at a mean dose of 25 mg), a potent, long-acting angiotensin converting enzyme inhibitor, was prescribed in combination with hydrochlorothiazide (at a mean dose of 64 mg) for 96 weeks in 11 patients with essential hypertension who had pretreatment (placebo) glomerular filtration rates of less than 80 ml/minute/1.73 m 2 . Blood pressure was well controlled. After 56 weeks of therapy, glomerular filtration rate (assessed by inulin clearance) increased 55 percent and effective renal plasma flow (assessed by para-aminohippurate clearance) increased by 32 percent; these increases were sustained through the 96 weeks of therapy. Furthermore, gains in renal function were sustained without adversely affecting 24-hour urinary protein excretion, sodium excretion, or body fluid composition. These results suggest that enalapril, in combination with hydrochlorothiazide, has the pharmacologic capability to favorably modify a primary pathophysiologic characteristic of essential hypertension by decreasing renal vascular and mesangial tone.

Nine hypertensive patients with mild to moderate renal dysfunction were entered into a protocol to assess the blood pressure, humoral and renal effects of the angiotensin converting enzyme inhibitor, Benazepril (CGS14824A, 2 to 20 mg twice daily) in patients with hypertension and moderate renal insufficiency (mean creatinine clearance 56 ml/min/1.73 m2). Specifically monitored, prior to and following 12 weeks of Benazepril monotherapy, were plasma renin activity and plasma aldosterone, the clearances of creatinine, Tc99m-diethylenetriaminepentaacetic acid (TC99m-DTPA) and para-amino-hippurate, and the 24-hour urinary excretion of protein. Blood pressure was well controlled. Plasma renin activity was stimulated, and plasma aldosterone was suppressed. Mean serum potassium increased from 3.9 to 4.2 mEq/L. Benazepril monotherapy had no adverse renal hemodynamic effect. Benazepril appears to be an effective antihypertensive agent in hypertensive patients with moderately impaired renal function.

The effects of betaxolol, a long-acting, lipid-soluble, cardioselective, beta-adrenergic antagonist on renal function have not been previously reported. The present study was designed to prospectively assess the acute and chronic antihypertensive, humoral, and renal response to betaxolol, administered once daily, to patients with essential hypertension. After a four-week placebo run-in period, 13 patients with essential hypertension were treated with betaxolol monotherapy for a total of eight months. Results indicate that blood pressure is reduced, and renal function remains stable. These findings are consistent with previous observations with other beta-adrenergic antagonists.

Effects of renal denervation on the sodium excretory actions of leptin in hypertensive rats. Background Previous studies from this laboratory have reported a marked attenuation of the renal responses to pharmacologic doses of synthetic murine leptin infused in the spontaneously hypertensive rat (SHR) model compared with normotensive Sprague-Dawley and lean Zucker rat models. Methods In the present study, the hemodynamic and renal excretory effects of an intravenous bolus administration of pharmacologic doses of synthetic murine leptin were examined in groups of anesthetized SHR with unilateral nephrectomy and renal denervation or sham-denervation of the remaining kidney. Results In the SHR with acute renal denervation ( N = 8), an intravenous bolus of 1600 μg/kg of leptin produced a significant twofold to fourfold elevation in sodium excretion but did not increase natriuresis in the sham-denervated group ( N = 6). Chronic renal denervation of one-week duration ( N = 8) was associated with qualitatively and quantitatively similar increases of sodium excretion in response to leptin administration. Mean arterial pressure remained unchanged in all groups after the administration of leptin. Conclusions Collectively, these results are interpreted to suggest that the blunted natriuretic and diuretic responses to leptin observed in the SHR with intact renal nerves may be partially explained by the antinatriuretic effect of an enhanced baseline efferent renal sympathetic activity and/or leptin's stimulation of the sympathetic nervous system.

Twenty-six essential hypertensive patients were entered into a protocol to assess the blood pressure and renal effects of the dihydropyridine calcium antagonist, nifedipine (30 to 120 mg/d given in divided dosage) administered for twelve weeks. Nifedipine monotherapy effectively lowered blood pressure. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were increased following short-term therapy (four weeks); however, there was no net change in GFR or ERPF (compared to placebo) following long-term therapy (12 weeks). Renal vascular resistance was reduced. The filtration fraction and urinary albumin excretion was unchanged throughout the 12-week protocol. We conclude that nifedipine monotherapy does not adversely effect renal function. Tolerance occurs to the initial renal vasodilator response; hyperfiltration and hyperperfusion do not persist.