Effect of clentiazem on arterial pressure and renal function in normotensive and hypertensive rats.

The present study evaluated the effects of a new benzothiazepine calcium channel antagonist, clentiazem, on arterial pressure and renal function in spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) and Munich-Wistar rats (MWR). Administration of clentiazem in doses from 1 to 20 micrograms/kg/min produced dose-dependent increases in sodium and water excretion in MWR, reaching maximum values of 292 and 376% of control, respectively, at the 20-micrograms/kg/min dose. Clentiazem (10 micrograms/kg/min) lowered arterial pressure by 16% and doubled glomerular filtration rate (GFR) in MWR. The rise in GFR was associated with an increase in glomerular capillary pressure of 16 mm Hg, produced by a combination of preglomerular vasodilation and efferent arteriolar vasoconstriction. In SHR, administration of clentiazem (10 micrograms/kg/min) lowered arterial pressure by 30 mm Hg and increased urine flow and sodium excretion by 137 and 200%, respectively. In WKY rats, the same dose of clentiazem decreased arterial pressure by only 10 mm Hg, whereas urine flow and sodium excretion increased 62 and 38%, respectively. A high dose of clentiazem (1 mg/kg bolus plus 1 mg/kg/hr infusion i.v.) lowered arterial pressure by 63 mm Hg in SHR. Renal vascular resistance fell by 39% and there was a 5-fold increase in sodium excretion. In WKY rats, the same dose of clentiazem reduced arterial pressure by 20 mm Hg, but it had no significant effect on sodium excretion. These results indicate that clentiazem increases sodium excretion and GFR in normotensive rats in part by preferentially dilating the renal preglomerular vasculature. This compound is also an antihypertensive agent that lowers arterial pressure and promotes sodium excretion in SHR.     

Role of renal sympathetic nerves in mediating hypoperfusion of renal cortical microcirculation in experimental congestive heart failure and acute extracellular fluid volume depletion.

To evaluate the pathophysiologic importance of renal nerves in regulating the renal vasomotor tone, we measured several parameters of renal cortical microcirculation before and after acute renal denervation (DNx) in the following three groups of anesthetized Munich-Wistar rats: (group 1) congestive heart failure after surgically induced myocardial infarction (n = 10), (group 2) acute extracellular fluid volume depletion after deprivation of drinking water for 48 h (n = 8), and (group 3) sham or nontreated controls (n = 6). In the myocardial-infarcted rats, DNx led to a uniform increase in glomerular plasma flow rate of, on average, 36%. Single nephron glomerular filtration rate of myocardial-infarcted rats also increased despite a reduction in glomerular capillary hydraulic pressure. These changes were associated with a fall in arteriolar resistances, particularly in the efferent arteriole. The glomerular capillary ultrafiltration coefficient rose in all but one myocardial-infarcted animal. A similar hemodynamic pattern was seen after DNx in water-deprived animals. In every water-deprived animal, glomerular plasma flow rate and single nephron GFR increased on average by 28 and 14%, respectively. Again, afferent and efferent arteriolar resistances decreased significantly. Furthermore, the ultrafiltration coefficient increased uniformly and substantially with DNx. To ascertain the potential importance of the interaction between the renal nerves and angiotensin II in these circumstances, we compared the renal cortical hemodynamics in additional groups of water-deprived rats (group 4) after DNx (n = 15), (group 5) during inhibition of angiotensin II with saralasin (n = 15), and (group 6) during treatment with both saralasin and DNx (n = 15). No appreciable difference was detected between group 4 vs. 6. In contrast, substantial differences were noted between group 5 vs. 6: on average, the glomerular plasma flow rate was 26% higher and the afferent and efferent arteriolar resistances 25% and 27% lower, respectively, in group 6. These observations provide direct evidence to indicate pathophysiologic importance of renal nerves in the profound intrarenal circulatory adjustments in prerenal circulatory impairment. The vasoconstrictive effects of renal nerves appear to be mediated in part by their stimulatory influence on angiotensin II release and their direct constrictor actions on pre- and post-glomerular vessels as well.     

An experimental model for studying the effects of uridine and inosine on renal circulation and function in the rat

Summary The effects of uridine and inosine on blood pressure, renal plasma flow (RPF), intrarenal blood distribution, glomerular filtration rate (GFR) and serum and urine electrolytes were investigated in the rat. Uridine constantly produced an elevation in blood pressure, an increase in RPF and an even greater rise in GFR, resulting in a significant increase in FF which was due to a prevalent constriction of the efferent arterioles. Inosine produced a short-lived pressor effect followed by a more prolonged fall of blood pressure. RPF and GFR increased significantly and to a similar extent so that there was no change in FF. It is suggested that these two substances may be involved in the vasomotor control of the kidneys.     

Therapeutic strategy for progressive renal disease

Renal disease constitutes an important determinant of cardiovascular disease. Although the mechanisms for the progression of renal impairment remain fully undetermined, available evidence indicate that renal glomerular hypertension is responsible in part for the development of renal injury. In renal disease, afferent arteriolar tone is reported to be reduced, while the augmented intrarenal angiotensin II serves to act as an efferent arteriolar constrictor, both of which result in an increase in glomerular capillary pressure. Angiotensin converting enzyme inhibitors (ACE-I) are established as the agent possessing both antihypertensive and renoprotective actions, which exert vasodilator action on efferent arterioles. Calcium antagonists are also reported to have salutary effect on renal disease, although their beneficial action varies depending on the antagonists used and the underlying disease. The use of calcium antagonists, however, is mandatory particularly under the circumstance where renal failure moderately to severely progresses and the ACE-I cannot be used.     

The effect of fenoldopam, a dopaminergic agonist, on renal hemodynamics

Fenoldopam, a dopaminergic agonist, was administered intravenously to 18 healthy male subjects in doses ranging from 0.025 to 1.0 microgram/kg/min for 2 hours. Three subjects were studied in a three-way crossover of fenoldopam at doses of 0.025, 0.10, and 0.50 microgram/kg/min. Fenoldopam decreased diastolic blood pressure and increased pulse rate without changing systolic blood pressure. Fenoldopam produced dose-related increases in para-aminohippuric acid clearance up to 75% at the 0.50 microgram/kg/min dose. This increase in renal blood flow was accompanied by increases in urine volume, water, and solute excretion; glomerular filtration rate was unchanged. Doses greater than 0.25 microgram/kg/min caused flushing and nasal congestion. The dopamine receptor antagonist metoclopramide (0.1 mg/kg/hr) did not block the systemic hemodynamic effects of fenoldopam but attenuated the increase in para-aminohippuric acid clearance. Fenoldopam plasma levels achieved steady state between 30 and 120 minutes after the start of the infusion and were linear with respect to infusion rate. Our findings show that intravenous fenoldopam causes systemic arteriolar vasodilation, accompanied by renal vasodilation and increased sodium excretion.     

Effect of sympathetic blocking agents on the antinatriuresis of reflex renal nerve stimulation.

To evaluate the effects of reflex renal sympathetic nerve stimulation on renal tubular sodium handling, clearance studies were performed in anesthetized dogs. With renal perfusion pressure held constant, baroreceptor reflex renal sympathetic nerve stimulation was produced by controlled arterial hemorrhage or carotid sinus perfusion. Significant decreases in urinary sodium excretion occurred in the presence of minor insignificant alterations in renal blood flow and no changes in glomerular filtration rate. Renal alpha adrenergic receptor blockade (phenoxybenzamine) or adrenergic blockade (guanethidine) completely reversed the fall in urinary sodium excretion; this could not be attributed to alterations in glomerular filtration rate or renal blood flow. These studies support the interpretation that adrenergic innervation of the renal tubules is involved in the regulation of renal tubular sodium reabsorption.     

Interaction of renal prostaglandins with the renin-angiotensin and renal adrenergic nervous systems in healthy subjects during dietary changes in sodium intake

In six healthy subjects the role of renal prostaglandins (PG) in modulating the actions of the renin-angiotensin and renal adrenergic nervous systems on renal function was investigated. During high dietary sodium intake (350 mmol/day) for 4 days no changes in urinary excretion of PGE2, PGF2 alpha, noradrenaline or adrenaline were noted, whereas plasma renin activity (PRA) and urinary aldosterone excretion were suppressed. After 4 days of low sodium intake (35 mmol/day) urinary excretion of PGE2, aldosterone and noradrenaline, as well as PRA, had significantly increased. Inhibition of PG synthesis with indomethacin (2 mg/kg body weight) had no effects on renal function on day 5 of high sodium intake. Despite suppression of PRA and urinary aldosterone, indomethacin significantly reduced p-aminohippurate (PAH) clearance, glomerular filtration rate (GFR) and urinary sodium excretion on day 5 of low sodium intake, when urinary noradrenaline excretion remained high. The results point to the crucial role of the renal adrenergic nervous system in controlling renal vascular resistance and sodium conservation in healthy subjects during low sodium intake, which is unmasked when renal PG synthesis is blocked by indomethacin. Enhanced renal PG synthesis during sodium restriction therefore not only attenuates the vascular and tubular effects of the renin-angiotensin system but, more importantly, also those of the highly stimulated renal adrenergic nervous system.     

Role for intrarenal adenosine in the renal hemodynamic response to contrast media

The intrarenal injection of contrast media results in a transient fall in renal blood flow (RBF) and a decrease in glomerular filtration rate (GFR). These effects are enhanced by dietary sodium restriction and attenuated by sodium loading. A similar sodium-dependent response of RBF and GFR occurs with the intrarenal injection of adenosine. In view of these similarities, we sought to determine whether endogenous adenosine is involved in the renal hemodynamic response to contrast media. The intrarenal injection of contrast media (meglumine-Na diatrizoate, 76%) in six sodium-depleted, anesthetized dogs resulted in a 17% +/- 4% decrease in RBF and a 31% +/- 5% decrease in GFR. The infusion of the adenosine receptor antagonist, theophylline (5 mumol/min), reduced the decrease in RBF to 6% +/- 2% and in GFR to 12% +/- 3% of control values. During the intrarenal infusion of dipyridamole (24 micrograms/kg/min), a potentiator of adenosine through its action to inhibit the cellular uptake of nucleosides, the hemodynamic response to contrast media was greater; RBF fell 25% +/- 4% and GFR fell 44% +/- 7%. In addition, the urinary excretion of endogenous adenosine increased after the injection of contrast media (388 +/- 79 vs. 830 +/- 231 nmol/min). In summary, the contrast media-induced fall in RBF and GFR was attenuated by theophylline and augmented by dipyridamole, and the administration of contrast media resulted in an increase in the excretion of endogenous adenosine. These results support the hypothesis that endogenous adenosine is involved in the renal hemodynamic response to contrast media.     

Renal and cardiac function during α 1 -β-blockade in congestive heart failure

The kidney and the neurohormonal systems are essential in the pathogenesis of congestive heart failure (CHF) and the physiologic response. Routine treatment of moderate to severe CHF consists of diuretics, angiotensin-converting enzyme (ACE) inhibition and &#103 -blockade. The need for control of renal function during initiation of ACE-inhibition in patients with CHF is well known. The aim of this study was to investigate whether supplementation by a combined &#102 1 - &#103 -blockade to diuretics and ACE-inhibition might improve cardiac function without reducing renal function. Methods : Fourteen patients treated for moderate to severe CHF with diuretics and ACE inhibitors were investigated at baseline, after 4 months of maximum carvedilol treatment and after withdrawal of carvedilol. Results : Carvedilol lowered blood pressure and heart rate but increased left and right ventricular ejection fractions without changing cardiac output or pulmonary blood volume. At the same time, a minor fall was seen in glomerular filtration rate (GFR), but renal blood flow was unchanged and effective renal plasma flow slightly increased. Carvedilol also lowered the plasma levels of angiotensin II and aldosterone. All changes were reversed after withdrawal of carvedilol. Conclusions : Carvedilol augments ACE-inhibitor-induced vasodilation by lowering blood pressure, and angiotensin II beside reducing heart rate. The heart adapts to the haemodynamic alterations without changes in cardiac output and pulmonary blood volume. GFR is slightly lowered despite no changes in renal blood flow and a slight increase in effective renal plasma flow. The study emphasizes the need for control of renal function during treatment with carvedilol in patients with CHF.     

Renal and cardiac function during alpha1-beta-blockade in congestive heart failure

The kidney and the neurohormonal systems are essential in the pathogenesis of congestive heart failure (CHF) and the physiologic response. Routine treatment of moderate to severe CHF consists of diuretics, angiotensin-converting enzyme (ACE) inhibition and beta-blockade. The need for control of renal function during initiation of ACE-inhibition in patients with CHF is well known. The aim of this study was to investigate whether supplementation by a combined alpha1-beta-blockade to diuretics and ACE-inhibition might improve cardiac function without reducing renal function. METHODS: Fourteen patients treated for moderate to severe CHF with diuretics and ACE inhibitors were investigated at baseline, after 4 months of maximum carvedilol treatment and after withdrawal of carvedilol. RESULTS: Carvedilol lowered blood pressure and heart rate but increased left and right ventricular ejection fractions without changing cardiac output or pulmonary blood volume. At the same time, a minor fall was seen in glomerular filtration rate (GFR). but renal blood flow was unchanged and effective renal plasma flow slightly increased. Carvedilol also lowered the plasma levels of angiotensin II and aldosterone. All changes were reversed after withdrawal of carvedilol. CONCLUSIONS: Carvedilol augments ACE-inhibitor-induced vasodilation by lowering blood pressure, and angiotensin II beside reducing heart rate. The heart adapts to the haemodynamic alterations without changes in cardiac output and pulmonary blood volume. GFR is slightly lowered despite no changes in renal blood flow and a slight increase in effective renal plasma flow. The study emphasizes the need for control of renal function during treatment with carvedilol in patients with CHF.     

Therapeutic strategy for the treatment with hypertensive renal injury

Hypertension constitutes a pivotal determinant of the progression of renal disease, which would raise the risk for cardiovascular events. From the standpoint of renal micro-circulation, correction of glomerular hypertension could retard the development of renal injury, which is attainable by the reduction in renal efferent arteriolar resistance as well as systemic blood pressure. Although both ACE inhibitors and angiotensin receptor blockers are established as a tool for improving glomerular hypertension, whether calcium antagonists ameliorate this abnormality remains unclear. However, recent clinical trials including ALLHAT and INSIGHT demonstrate a beneficial action of amlodipine and nifedipine on the development of renal injury. Therefore, calcium antagonists can be used not only as a first line drug, but also as add-on therapy that could potentiate the hypotensive action of underlying medication.     

Effects of Felodipine on the dog kidney: a lithium clearance study.

This study was performed in order to investigate the possible influence of sympathetic nerve activity on the effects of the dihydropyridine calcium antagonist felodipine on absolute and fractional reabsorption rates of sodium and water in proximal and distal tubular segments in the dog kidney. Clearance of 51Cr-EDTA was used as a measure of glomerular filtration rate (GFR). GFR, urinary excretion rates of sodium and water, and lithium clearance (C-Li) were used for assessing the absolute and fractional tubular reabsorption rates. Felodipine infusion into the right renal artery increased renal vascular conductance (renal blood flow divided by renal arteriovenous pressure gradient) significantly (by 9%) while GFR remained unchanged. Calculated absolute proximal reabsorption rates remained unchanged while distal sodium reabsorption rate increased significantly from 2.1 +/- 0.3 to 2.7 +/- 0.4 mmol min-1. Sodium clearance (C-Na) increased from 0.22 +/- 0.08 to 0.40 +/- 0.07 ml min-1. The alpha-adrenergic blockade with phentolamine did not affect renal haemodynamic or excretory variables, nor did it influence the haemodynamic response to felodipine. After alpha-adrenergic blockade felodipine caused an increase in C-Na from 0.28 +/- 0.06 ml min-1 to 0.63 +/- 0.04 ml min-1, which was significantly greater than that measured after felodipine alone. The distal load (C-Li) was not significantly different from that obtained after felodipine alone, but distal sodium reabsorption rate increased less significantly after alpha-adrenergic blockade. The results suggest that felodipine, by its effect on tubular flow and/or composition, activates local alpha-adrenergic reflex mechanism(s), which stimulates distal sodium reabsorption, thereby attenuating the natriuretic effect.     

Role of the renal nerves in modulating renin release during pressure reduction at the feline kidney

Experiments were undertaken in pentobarbitone-anaesthetized cats to determine how reflex activation of the renal nerves altered the responsiveness of the kidney to release renin during reductions in renal perfusion pressure. Reflex activation of the renal nerves was achieved by reducing carotid sinus perfusion pressure by 30 mmHg, which increased systemic blood pressure. During this period renal perfusion pressure was regulated at control levels and neither renal blood flow nor glomerular filtration rate changed, but there was a significant decrease in sodium excretion and increase in renin secretion. Renal denervation abolished both these latter responses. Renal perfusion pressure reduction, by 25-30 mmHg, had no effect on renal blood flow or glomerular filtration rate but significantly decreased sodium excretion and increased renin secretion. Simultaneous reduction of carotid sinus and renal perfusion pressures had no effect on renal blood flow or glomerular filtration rate, decreased sodium excretion, and the magnitude of the increase in renin secretion was significantly greater than that obtained with reduction in renal perfusion pressure alone. Renal denervation abolished the increase in renin secretion during these manoeuvres. During atenolol administration, renal haemodynamics and sodium excretion responses to renal pressure reduction were similar to those obtained in the absence of the drug. Renin secretion was increased, but significantly less than in the absence of atenolol. Simultaneous carotid sinus and renal pressure reductions during atenolol administration had no effect on renal haemodynamics, reduced sodium excretion and increased renin secretion, the magnitude of which was significantly greater than that recorded with only renal pressure reduction in the presence of atenolol. Direct electrical stimulation of the renal nerves, at frequencies which caused a 5-10% reduction in renal blood flow, did not change glomerular filtration rate, decreased sodium excretion by 30% and increased the rate of renin secretion twofold. In the presence of atenolol, such renal nerve stimulation reduced renal blood flow to the same degree, did not change filtration rate, decreased sodium excretion by 37% but did not change renin secretion. These results show that the magnitude of the release of renin in response to renal pressure reduction is dependent on activity within the renal nerves, being blunted after denervation, and enhanced during reflex activation of the renal nerves.     

Interaction between renal prostaglandins and angiotensin II in controlling glomerular filtration in the dog

Although previous studies suggest that the renal vasoconstrictor effects of angiotensin II (ANG II) are normally confined to the efferent arterioles, the mechanisms that prevent ANG II from constricting preglomerular vessels are still unclear. In the present study, the role of prostaglandins (PG) in protecting preglomerular vessels from ANG II constriction was examined in dogs with normal or non-filtering kidneys in which ANG II formation was blocked with captopril and renal artery pressure was servo-controlled at 75-80 mmHg. Before PG blockade (n = 6), ANG II infusion (20 ng min-1 kg-1) decreased renal blood flow (RBF) by 54 +/- 4%, but did not change glomerular filtration rate (GFR) significantly. After PG blockade (n = 6), ANG II infusion decreased GFR by 37 +/- 7% and RBF by 56 +/- 6%, while increasing calculated preglomerular resistance much more than before PG blockade. In another group of dogs, secondary changes in renal resistances, due to tubuloglomerular feedback, were prevented by occluding the ureter during mannitol diuresis until glomerular filtration ceased. After inhibition of tubuloglomerular feedback in non-filtering kidneys (n = 7), ANG II decreased RBF by 40 +/- 3% and increased glomerular hydrostatic pressure, estimated from stop-flow ureteral pressure and plasma colloid osmotic pressure, by 8.7 +/- 1.7 mmHg. Postglomerular resistance increased by 91 +/- 12% while preglomerular resistance was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tubuloglomerular Feedback NONLINEAR RELATION BETWEEN GLOMERULAR HYDROSTATIC PRESSURE AND LOOP OF HENLE PERFUSION RATE

The present experiments were performed to quantify the effect of changes in distal tubular sodium delivery on glomerular flow dynamics both below and above the normal physiologic range. Glomerular capillary pressure as derived from the tubular stop flow pressure was assessed while the loop of Henle of the same nephron was perfused with varying flow rates. During Ringer perfusion no change of glomerular capillary pressure was observed when flow was increased from 0 to 13 nl/min. Further increasing flow to 27 nl/min was associated with a reduction of glomerular hydrostatic pressure by an average of 7.0+/-4.4 cm H(2)O (+/-SD). During perfusion at a rate of 43 nl/min glomerular pressure was decreased by a mean of 10.5+/-4.0 cm H(2)O. Changing the flow rate in small steps revealed that a significant reduction of capillary pressure was found when increasing the flow rate from 13 to 21 nl/min and that the maximum response was reached at 32 nl/min. No effect of perfusion rate changes on glomerular capillary pressure was observed when 300 mM mannitol was used as perfusion fluid. These results imply that a nonlinear relationship exists between end-proximal flow rate and glomerular capillary pressure. It is suggested that during deviations of distal sodium delivery into a positive direction filtration rate is intrarenally regulated probably by prevalence of afferent arteriolar constriction. During reductions of distal sodium load intrarenal regulation is either abolished or it involves proportionate resistance changes of both afferent and efferent arterioles.     

Low-dose dopamine infusion in cirrhosis with refractory ascites

To investigate the effect of dopamine on the renal blood flow, five cirrhotic patients with refractory ascites but no hepatorenal syndrome were allocated to this study. Low-dose dopamine infusion at a rate of 2 micrograms/kg/min was undertaken at least for 24 hours. Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured by computerised nuclear scanning before and after dopamine infusion. The results revealed no difference in the changes of blood urea nitrogen, creatinine, creatinine clearance, blood pressure, pulse rate, serum sodium, serum aldosterone and GFR despite insignificant increases in urine output and urinary sodium excretion after dopamine infusion. However, ERBF values before and after dopamine infusion were 288-311, 208-267, 418-442, 246-270 and 262-396 ml/min in these five patients respectively and showed significant increase (p < 0.01). Our study revealed that low-dose dopamine infusion could increase ERPF in cirrhotic patients with refractory ascites.     

Intrarenal effects of ecadotril during acute volume expansion in dogs with congestive heart failure

Neutral endopeptidase 24.11 (NEP) inhibitors are known to have vascular, diuretic, and natriuretic effects that may be helpful in the treatment of congestive heart failure (CHF). Most NEP inhibitors may act principally through intrarenal mechanisms, which are not completely understood. The purpose of this study was to determine the principal renal effects of the NEP inhibitor ecadotril in dogs with progressive CHF induced by rapid ventricular pacing. Renal function was measured before, during, and after acute i.v. infusion of normal saline in a total of six dogs during normal cardiac function, early left ventricular dysfunction, and overt CHF. During overt CHF, each dog was treated with either ecadotril or placebo orally for 1 week. Parameters measured included glomerular filtration rate, renal blood flow, urine output, sodium clearance, sodium fractional excretion, and proximal and distal sodium reabsorption. Ecadotril treatment resulted in increased urine output, sodium clearance, and renal sodium excretion relative to placebo-treated controls. The principal intrarenal effect of ecadotril was decreased distal renal tubular sodium reabsorption. Both glomerular filtration rate and renal blood flow declined during overt CHF and were unaffected by ecadotril treatment. The results of this study are consistent with the principal action of ecadotril occurring by way of intrarenal events as opposed to changes in renal hemodynamics. The principal effect of ecadotril on distal tubular sodium reabsorption suggests that inhibition of NEP activity in the proximal renal tubules may allow increased binding of filtered atrial natriuretic peptide to natriuretic peptide receptor sites in the distal renal tubules and collecting ducts.     

Dual blockade of the renin-angiotensin system in diabetic nephropathy

OBJECTIVE: To review the literature concerning dual blockade of the renin-angiotensin system (RAS) with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) in diabetic nephrophathy. DATA SOURCES: MEDLINE (1998-September 2003), EMBASE (1998-September 2003), and International Pharmaceutical Abstracts (1998-September 2003) were used to access the literature. Search terms included angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diabetic nephropathy, dual blockade, renin-angiotensin system, and combination therapy. DATA SYNTHESIS: Monotherapy with an ACE inhibitor provides incomplete blockade of the RAS. Dual blockade of the RAS has been studied in approximately 300 patients with diabetic nephropathy. Recent randomized controlled studies suggest that dual blockade using an ACE inhibitor and an ARB in diabetic nephropathy is well tolerated and will provide an additional 11-43% reduction in albuminuria versus monotherapy. CONCLUSIONS: Dual blockade of the RAS using an ACE inhibitor and an ARB provide statistically significant reductions in albuminuria and blood pressure. Use of dual blockade is safe, but requires additional monitoring for hyperkalemia. Long-term studies are needed to determine whether the decrease in albuminuria will correlate with an actual improvement from overt proteinuria to microalbuminuria or a decreased incidence of end-stage renal disease in the overall diabetic population.     

Long-term effects of cyclosporine on renal function in organ transplant recipients

To evaluate whether cyclosporine nephrotoxicity is progressive, glomerular filtration rate and renal plasma flow were determined by isotopic techniques in 24 cyclosporine-treated organ transplant recipients (12 heart, 1 pancreas, and 11 kidney recipients). The cyclosporine group demonstrated reductions in glomerular filtration rate and renal plasma flow, with higher renal vascular resistance and mean arterial pressure as compared with an azathioprine-treated control group. However, longitudinal studies over a mean time period of 23 months in eight cyclosporine-treated renal transplant recipients showed renal function to remain stable. In the entire group of 24 cyclosporine-treated patients, longer duration of cyclosporine treatment was associated with decreased but stable glomerular filtration rate, increased renal plasma flow, decreased renal vascular resistance, and lower daily doses of cyclosporine. Evaluation of intrarenal resistances demonstrated a greater decrease in efferent than afferent arteriolar resistance, consistent with the fall in plasma renin activity that occurred with time. Short-term treatment of 12 patients with prazosin produced no beneficial effect on renal function, whereas treatment of nine patients with captopril produced a 20% increase in renal plasma flow, with a significant reduction in renal vascular resistance. We conclude that although cyclosporine treatment produces decreased renal function, the loss in renal function is not necessarily progressive. Treatment with captopril may improve the abnormal renal hemodynamics of cyclosporine-treated patients.     

Evidence for enhanced distal tubule sodium reabsorption in chronic salt-depleted dogs.

In order to assess the renal tubular site(s) at which sodium reabsorption is enhanced in chronic sodium-depletion, seven normal dogs, six salt-depleted dogs, and three normal dogs receiving aldosterone were studied during a steady-state water diuresis under Pentothal anesthesia and during progressive hypotonic saline diuresis. For both maintenance of the water diuresis and progressive hypotonic saline diuresis 0.45% NaCl was used. During the steady state water diuresis delivery of sodium to the diluting segment of the nephron as approximated by solute-free water clearance + sodium clearance/glomerular filtration rate (CH2O + CNa/GFR) was significantly lower in salt-depleted dogs compared to normal dogs with or without aldosterone. During progressive hypotonic saline infusion fractional free water excretion (CH2O/GFR) was similar in all three groups as CH2O + CNa/GFR increased up to 12-14 ml/min-100 ml GFR. Thereafter, CH2O/GFR continued to rise in virtually a straight line in salt-depleted dogs but leveled off in normal dogs with or without aldosterone. These data demonstrate that enhanced sodium reabsorption in the diluting segment of the nephron is an important determinant of the renal sodium retention in chronic extracellular volume contraction in dogs in addition to confirming the presence of increased proximal tubule sodium reabsorption in these animals.