Modulation of renin secretion by atrial natriuretic factor prohormone fragment 31-67.

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 microg/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<0.05) in renin secretion, from a control value of 1418 +/- 243 to 401 +/- 223 ng of angiotensin I/min. This 66% fall in renin secretion was associated with significant (P < 0.05) increases in creatinine clearance (40%), renal blood flow (8%), urine flow (50%), and sodium excretion (17%). CONCLUSIONS: It is suggested that this inhibition of renin secretion was mediated, at least in part, in response to a ProANF31-67-induced increment in the sodium load delivered to the macula densa. An interaction of the peptide with the renal vascular receptor for suppression of renin release is also possible. ProANF31-67 may represent an important hormonal mechanism involved in the regulation of body-fluid balance.

Hemodynamic and renal effects of ProANF31-67 in hypertensive rats.

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 angiotensin II type 1 receptor antagonists. A new class of antihypertensive drugs.

The angiotensin II (AII) type 1 receptor antagonists represent a new pharmacologic class of drugs that are specifically designed to displace AII 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 AII 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 AII type 1, and plasma aldosterone concentrations; and efficacy and safety. Given the demonstrable benefits of AII type 1 receptor blockade, these drugs should achieve broad utility in the treatment of hypertensive diseases.

Effects of losartan on the renin-angiotensin-aldosterone axis in essential hypertension.

Twelve essential hypertensive patients were entered into a prospective study assessing the effect of losartan, a non-peptide specific angiotensin II receptor antagonist, on blood pressure, the renin-angiotensin-aldosterone axis and renal function. Specifically monitored prior to and following 12 weeks of therapy at 6 (peak) and 24 (trough) h after dosing, were blood pressure, plasma renin activity (PRA), plasma aldosterone, and plasma angiotensin II (Ang II), creatinine clearance and urinary albumin excretion (UAE). In this small sample of hypertensive patients, losartan monotherapy and losartan-hydrochlorothiazide (HCTZ) combination therapy were associated with modest reductions in systolic, diastolic and mean arterial BPs; significant changes were observed only at the peak dosing interval. Losartan, given as either monotherapy or combination therapy, was associated with an increase in the 'trough' values of PRA; significant changes in the 'trough' values of plasma Ang II and plasma aldosterone were not observed. In contrast, PRA and plasma Ang II were stimulated, and plasma aldosterone was depressed, 6 h after dosing. There were significant negative correlations between both PRA and plasma Ang II reactivity (difference between PRA or plasma Ang II values obtained 6 h after placebo dosing and 6 h after drug dosing) and the change in systolic, diastolic and mean arterial BPs. Of interest, losartan/HCTZ combination therapy was associated with a decrease in the creatinine clearance; UAE was not significantly altered. Losartan appears to be an effective anti-hypertensive agent in patients with mild to moderate hypertension. Its peak BP effect appears to be at the dosing interval corresponding to pharmacological blockade of angiotensin II receptors. Furthermore, this anti-hypertensive agent may be more efficacious in patients with a reactive renin-angiotensin system.

Do calcium channel blockers have renal protective effects?

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.

Renin-angiotensin system and myocardial fibrosis in hypertension: regulation of the myocardial collagen matrix.

The cardiac interstitium is composed of non-myocyte cells embedded in a highly organized extracellular matrix containing a three-dimensional collagen network which serves to maintain the architecture of the myocardium and determines myocardial stiffness. In hypertensive heart disease, a heterogeneity in myocardial structure, created by the altered behaviour of cardiac fibroblasts responsible for collagen synthesis and degradation, can explain the appearance of diastolic and ultimately systolic dysfunction of the left ventricle. In vivo, circulating and myocardial renin-angiotensin systems (RAS) were found to be involved in the regulation of the structural remodelling of the cardiac interstitium. In vitro, in cultured adult rat cardiac fibroblasts, angiotensin II was shown to stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation. In the SHR-model of primary hypertension, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness, due to interstitial fibrosis, could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.

Calcium channel blockers: do they offer renal protection?

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 cyclosporine 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.

Short- and long-term effects of spirapril on renal hemodynamics in patients with essential hypertension.

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.

An evaluation of the renal protective effect of manidipine in the uninephrectomized spontaneously hypertensive rat.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized, double-blind, placebo-controlled trial to evaluate the effect of enalapril in patients with clinical diabetic nephropathy.

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 Tc99mDTPA 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 m2 (61 mL/min/1.73 m2) to 0.85 mL/s/1.73 m2 (51 mL/min/1.73 m2), and from 1.06 mL/s/1.73 m2 (64 mL/min/1.73 m2) to 0.97 mL/s/1.73 m2 (58 mL/min/1.73 m2), 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 m2/mo and -1.00 mL/min/1.73 m2/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.

Angiotensin-converting enzyme in renal and cerebral tissue and implications for successful blood pressure management.

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.

ACE inhibitors in renal disease.

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 hypertensive kidney: pathophysiology and therapeutic options.

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 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.

Hypertension with co-existing renal disease.

It is generally accepted that treatment of systemic hypertension protects the kidney from haemodynamically-mediated injury. However, renal function may deteriorate during traditional antihypertensive therapy. Currently, hypertensive nephrosclerosis accounts for approximately 26% of all end-stage renal disease (ESRD) in the United States. Furthermore, in spite of aggressive treatment of hypertension, there is no evidence of a reduction in the incidence of hypertensive nephrosclerosis as a cause of ESRD. A current hypothesis states that renal protection is dependent on control of systemic hypertension (when present), and control of glomerular hypertension (when present). Since angiotensin II is a potent vasoconstrictor of the postglomerular capillary bed, which increases glomerular capillary pressure, it is attractive to hypothesize that drug therapies which can interrupt the intrarenal generation of angiotensin II (ACE inhibitors), or drug therapies which may attenuate the intrarenal actions of angiotensin II (calcium antagonists), may be renal protective. ACE inhibitors do control both systemic and glomerular hypertension. Calcium antagonists do control systemic hypertension; they may control glomerular hypertension. Long-term clinical trials in hypertensive patients, comparing the renal effects of ACE inhibitors with other antihypertensive drug classes (including calcium antagonists), have not been reported. It remains to be determined if the potential differing effects of antihypertensive drug classes on the renal microcirculation do, or do not, translate into differing renal protective advantages to patients at risk for the development and/or progression of renal disease.

Renal protection in essential hypertension: how do angiotensin-converting enzyme inhibitors compare with calcium antagonists?

By interrupting the integrity of the systemic and renal renin-angiotensin system, angiotensin-converting enzyme inhibitors have been shown, experimentally, to preferentially reduce postglomerular capillary arteriolar resistance, to reduce glomerular capillary pressure, and to increase the ultrafiltration coefficient. Under normal physiological conditions, angiotensin-converting enzyme inhibitors have little effect on glomerular filtration rate; however, they increase effective renal plasma flow at renal perfusion pressures within the normal autoregulatory range and renal vascular resistance is decreased. In contrast, calcium antagonists have been shown, experimentally, to preferentially reduce preglomerular capillary arteriolar resistance. Their effects on angiotensin II and postglomerular capillary arteriolar resistance (hence, glomerular capillary pressure and the ultrafiltration coefficient) are controversial. Under normal physiological conditions, calcium antagonists increase both glomerular filtration rate and effective renal plasma flow at renal perfusion pressures within the normal autoregulatory range and renal vascular resistance is decreased. In patients with essential hypertension, studies have demonstrated that angiotensin-converting enzyme inhibitors (as predicted) sustain glomerular filtration rate, increase effective renal plasma flow, and decrease renal vascular resistance. However, essential hypertensive patients with impaired glomerular filtration rate may demonstrate marked improvement in both glomerular filtration rate and effective renal plasma flow. Calcium antagonists (as predicted) may increase both glomerular filtration rate and effective renal plasma flow (at high renal perfusion pressures) and may decrease renal vascular resistance. Calcium antagonists may also improve both glomerular filtration rate and effective renal plasma flow in patients with impaired glomerular filtration rate. Long-term clinical trials comparing the renal effects of angiotensin-converting enzyme inhibitors with those of calcium antagonists in essential hypertensive patients have not been reported. It remains to be determined if the potentially different effects of these two classes of antihypertensive drugs on the renal microcirculation do or do not translate into different renal protective advantages to patients at risk for the development and/or progression of hypertensive nephrosclerosis.

Effects of calcium antagonists on the hypertensive kidney.

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.

Acute and chronic effects of angiotensin converting enzyme inhibitors on the essential hypertensive kidney.

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.

Renal protection with calcium antagonism in essential hypertension.

The natural history of uncontrolled essential hypertension, with respect to renal function, is characterized by a progressive rise in renal vascular resistance, a progressive fall in effective renal plasma flow, and a progressive fall in glomerular filtration rate. Sustained effective antihypertensive therapy may reverse this pathophysiological sequence, preventing the development of arteriolar nephrosclerosis. It is unknown whether such a therapeutic benefit is a nonspecific response to controlling systemic hypertension, or is dependent on controlling both systemic and glomerular hypertension. Recent experimental evidence indicates that the control of systemic blood pressure may not necessarily be associated with control of glomerular capillary hypertension. The renal effects of calcium antagonists in essential hypertensive patients are only now being characterized. We have demonstrated that diltiazem, amlodipine, and nifedipine monotherapies enhance glomerular filtration rate and effective renal plasma flow, and lower renal vascular resistance. Although calcium antagonists attenuate the intrarenal effects of norepinephrine and angiotensin II, the precise mechanism(s) by which these drugs reverse the functional renal abnormalities in the essential hypertensive state, and by which they may attenuate the progression of hypertensive renal disease, are unknown. It is our hypothesis that renal protection requires normalization of both systemic and glomerular capillary pressure. Calcium antagonists have the ability to control systemic hypertension. If they can be demonstrated experimentally to reduce both pre- and post-glomerular capillary resistances (i.e. maintain a normal glomerular capillary pressure), they can be expected to provide long-term renal protection.

The effect of triple drug therapy on renal function in patients with essential 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.