Garry P. Reams

Renal effects of leptin in normotensive, hypertensive, and obese rats.

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 μg/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 ∼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) μg/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 μg/kg ( n = 8) no natriuresis was elicited, but at 1,600 μg/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.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.

Short- and long-term effects of calcium entry blockers on the kidney

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.

Effects of calcium entry blockers on renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion and body fluid composition

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.

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.

Renal effects of diltiazem in primary hypertension.

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.

Amlodipine Therapy Corrects Renal Abnormalities Encountered in the Hypertensive State

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.

Obesity-hypertension: emerging concepts in pathophysiology and treatment.

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.

Long-term renal effects of diltiazem in essential hypertension

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.

Renal effects of angiotensin converting enzyme inhibitors in hypertension

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.

Role of leptin in the regulation of body fluid volume and pressures.

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.