Fall In Renal Plasma Flow Research Articles

Gender and the Renal Nitric Oxide Synthase System in Healthy Humans

It is widely known that men with kidney disease progress to ESRD at a much greater rate than do women. The mechanism for these gender differences is not clear, but reduced availability of nitric oxide is thought to contribute to the age-related decline in renal plasma flow observed in both healthy men and women. Animal models suggest that the renal vasculature of men may be significantly more dependent on nitric oxide than that of women. Renal plasma flow response to the nonspecific nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L-NAME) was measured by para-aminohippurate clearance technique in 21 healthy, normotensive (8 male, 13 female) individuals in balance on a high-salt diet. There were striking differences between the genders in the renal hemodynamic response to L-NAME according to age, a difference that remained even after adjustment for other significant covariates. In men, the fall in renal plasma flow induced by L-NAME increased remarkably with increasing age. In women, there was no influence of age on the renovascular response to L-NAME. Neither age nor gender predicted the mean arterial pressure response to L-NAME. The renal vasculature of men becomes more dependent on nitric oxide with age compared with that of women, suggesting that any renal disease that interferes with nitric oxide production may, over time, cause existent kidney damage to progress more quickly in men relative to women.

Impact of Telmisartan Versus Ramipril on Renal Endothelial Function in Patients With Hypertension and Type 2 Diabetes

One of the earliest signs of vascular change is endothelial dysfunction, which is also known to provoke albuminuria and to predict cardiovascular prognosis. The aim of this study was to analyze the effects of renin-angiotensin system (RAS) blockade on renal endothelial function. In a multicenter, prospective, double-blind, forced-titration, randomized study, 96 patients with type 2 diabetes, hypertension, glomerular filtration rate >80 ml/min, and normo- or microalbuminuria were treated once daily with 40/80 mg telmisartan or 5/10 mg ramipril for 9 weeks. The mean +/- SE fall in renal plasma flow (RPF) in response to intravenous N(G)-monomethyl-L-arginine (L-NMMA), reflecting the magnitude of nitric oxide (NO) activity, increased with telmisartan from 71.9 +/- 9.0 ml/min before therapy to 105.2 +/- 9.7 ml/min at the end of treatment (P < 0.001). With ramipril, RPF response to L-NMMA increased from 60.1 +/- 12.2 to 87.8 +/- 9.2 ml/min (P = 0.018). The adjusted difference between treatments was -17.1 +/- 13.7 ml/min (P = 0.214). In accordance, telmisartan increased RPF at rest (i.e., without L-NMMA) from 652.0 +/- 27.0 to 696.1 +/- 31.0 ml/min (P = 0.047), whereas ramipril produced no significant changes in RPF. The more the basal NO activity improved, the greater was the vasodilatory effect on renal vasculature (r = 0.47, P < 0.001). In patients with type 2 diabetes, telmisartan and ramipril both increased NO activity of the renal endothelium significantly, which in turn may support the preservation of cardiovascular and renal function.

Cardiorenal abnormalities associated with high sodium intake: correction by spironolactone in rats

Reversal by the mineralocorticoid receptor antagonist spironolactone on cardiac and renal abnormalities, associated with long-term (since weaning) administration of a high (2 and 8% NaCl chow, HS2 and HS8) sodium diet, was assessed in Sprague-Dawley rats. At the age of 5 mo, spironolactone (20 or 100 mg/kg, gavage) or placebo were given for 14 days to HS2 and HS8 rats. A group fed a regular diet (0.8% NaCl, NS) remained untreated. High sodium intake had no detectable effect on blood pressure; however, cardiac mass index and cross-sectional area of the carotid artery, as well as albuminuria, were increased only in the HS8 group compared with the control group on NS diet. In addition, a marked reduction in glomerular filtration rate (by 40%), associated with a nonproportional fall in renal plasma flow (thus resulting in a decrease in filtration fraction), was observed only in the HS8 group. No change in cardiac and renal fibrosis was detected. Production of the reactive oxygen species (ROS) by aortic tissue was increased in HS8 rats, whereas ROS production by the heart was unaffected. Only the high dose of spironolactone was effective, as it markedly reversed the cardiac hypertrophy and renal hypofiltration associated with the HS8 feeding. The changes were observed in the absence of any effect on systemic blood pressure and production of ROS. These observations favor aldosterone's role in the deleterious effects of marked and prolonged increases in sodium intake.

Maintenance and recovery stages of postischemic acute renal failure in humans

Postischemic injury in 38 recipients of 7-day-old cadaveric renal allografts was classified into sustained (n = 15) or recovering (n = 23) acute renal failure (ARF) according to the prevailing inulin clearance. Recipients of long-standing allografts that functioned optimally (n = 16) and living transplant donors undergoing nephrectomy (n = 10) served as functional and structural controls, respectively. A combination of physiological and morphometric techniques were used to evaluate glomerular filtration rate and its determinants 1-3 h after reperfusion and again on day 7 to elucidate the mechanism for persistent hypofiltration in ARF that is sustained. Glomerular filtration rate in the sustained ARF group on day 7 was depressed by 90% (mean +/- SD); the corresponding fall in renal plasma flow was proportionately less. Neither plasma oncotic pressure nor the single-nephron ultrafiltration coefficient differed between the sustained ARF and the control group, however. A model of glomerular ultrafiltration and a sensitivity analysis were used to compute the prevailing transcapillary hydraulic pressure gradient (DeltaP), the only remaining determinant of DeltaP. This revealed that DeltaP varied between 27 and 28 mmHg in sustained ARF and 32-38 mmHg in recovering ARF on day 7 vs. 47-54 mmHg in controls. Sustained ARF was associated with persistent tubular dilatation. We conclude that depression of DeltaP, perhaps due partially to elevated tubule pressure, is the predominant cause of hypofiltration in the maintenance stage of ARF that is sustained for 7 days.

Renal perfusion and function in healthy African Americans

Despite their increased risk of nephropathy, remarkably little is known about renal perfusion and function in healthy African Americans. We enrolled 32 healthy African Americans and compared renal perfusion and function in 82 age-matched healthy Caucasians. Studies were performed on a diet containing 200 mmol of sodium and 100 mmol of potassium per day. In a separate study of 28 subjects, 10 African American and 18 Caucasians, the contribution of the renin-angiotensin system was assessed by measuring renal hemodynamic responses to angiotension II (Ang II) and captopril. Although glomerular filtration rate (GFR) was similar, renal plasma flow (RPF) was significantly less in age-matched African Americans (568 +/- 18) than Caucasians (620 +/- 13 mL/min/1.73 m(2), P = 0.0063). After captopril, African Americans had a sevenfold greater vasodilator response and a rise in RPF (35.3 +/- 4.9 vs. 4.9 +/- 12.4 mL/min/1.73 m(2) in African Americans and Caucasians, respectively, P < 0.028). Ang II administration caused a significantly smaller vasoconstrictor response in African Americans (Ang II-induced fall in RPF, -97 +/- 18 vs. -150 +/- 9 mL/min/1.73 m(2), P = 0.05), and angiotensin-converting enzyme (ACE) inhibition enhanced the response to Ang II in African Americans significantly. A reduction in RPF, blunting of the renal vascular response to Ang II, and an accentuated renal vasodilator response to captopril, which in turn corrects the blunting of responsiveness to Ang II, all suggest activation of the renin system in apparently healthy African Americans. As PRA was identical in Caucasians and African Americans, the findings suggest that it is the intrarenal-renin system that is activated in African Americans. This difference in normal control mechanisms could predispose to nephropathy.

Renal function and oxygen consumption during bacteraemia and endotoxaemia in rats.

The hypothesis that renal failure during septic shock may occur as a result of hypoxia-related cell dysfunction was investigated in two rat models of distributive shock. Pentobarbitone-anaesthetized rats received either a bolus (1 ml) of living Escherichia coli bacteria (hospital-acquired strain, 1 x 10(9) CFU/ml; BA-group, n = 7), or a 1-h infusion of endotoxin (E. coli O127.B8: 8 mg/kg; ET-group, n = 7), or saline to serve as time matched controls (C-group, n = 7). Urine flow in the BA- and ET-group reached a nadir at 1 h, but thereafter increased and reached values higher than control at 3 h. At this time point, renal oxygen delivery had decreased, in the BA-group mainly due to a fall in arterial oxygen content and in the ET-group to a fall in renal plasma flow (clearance of 131I-hippurate). However, renal oxygen extraction had significantly increased, by 31% in the BA and by 59% in the ET group, while renal oxygen consumption remained the same. Net tubular sodium reabsorption had decreased by 55% in the BA and by 25% in the ET group, due to a fall in glomerular filtration rate (clearance of creatinine). Hence, an excess oxygen consumption was found which was caused neither by an increased renal glucose release nor by the presence of an increased number of leukocytes stuck in the glomeruli. Renal tubular cells showed normal morphology. An indication that proximal tubular function in the BA and ET group remained largely intact were normal ATP levels, absence of urinary glucose, and a normal fractional excretion of sodium. However, since urine flow had increased in shocked rats at 3 h, water appeared selectively lost. Our data indicate that in rat models of septic shock renal failure is not caused by cortical hypoxia or a shortage of cellular energy supply.

Sensitivity of the segmental renal arterioles to angiotensin II in the aging rat

With advancing age the old rat kidney becomes tonically vasoconstricted by endogenous angiotensin II (ANGII) (C. Baylis. Am. J. Kid. Dis., 22 (1993) 842). The present study was designed to investigate the sensitivity of the cortical glomerular microvasculature of the old rat kidney (19–22 months of age) to exogenous ANGII, using the in vivo micropuncture technique. In the baseline state, glomerular blood pressure ( P GC) in old male rats was higher compared to young rats (4–5 months of age). During exogenous ANGII infusion (40 ng/kg/min), a significant rise in arterial blood pressure and renal vasoconstriction occurred in both young and old rats. In young rats, the ANGII induced fall in renal plasma flow (RPF) and glomerular plasma flow ( Q A) was accompanied by a rise in P GC and thus the glomerular hydrostatic pressure gradient, with little change in K f. Therefore, the glomerular filtration rate (GFR) and single nephron GFR (SNGFR) were unchanged by ANGII infusion in young rats. In old rats, RPF and Q A fell, a rise occurred in P GC and also a fall was seen in the glomerular capillary ultrafiltration coefficient ( K f), thus GFR and SNGFR fell significantly. The magnitude of the pressor and renal vasoconstriction response to ANGII were not affected by age; of interest, ANGII increased preglomerular and efferent arteriolar resistance ( R A, R E) and P GC by similar amounts in young and old rats. SNGFR was reduced in old rats, due to the marked ANGII-induced decline in K f. Neither absolute nor fractional proximal reabsorption were affected by ANGII infusion in either young or old rats. By 19–22 months of age, old rats had much more injured glomeruli than young rats. These data demonstrate that the afferent and efferent arterioles had similar sensitivity to exogenous pressor dose of ANGII in both young and old rats, but K f was more sensitive to ANGII in old rats leading to a significant fall in SNGFR.

Enalapril attenuates the renal hemodynamic effect of acetazolamide in patients with diabetes mellitus: possible implications for tubuloglomerular feedback.

Acetazolamide (ACTZ), a carbonic anhydrase inhibitor, causes a fall in renal plasma flow and glomerular filtration (GFR). It is generally believed that the tubuloglomerular feedback (TGF) mechanism is responsible. This study examined whether, in patients with diabetes mellitus, the renal hemodynamic response to ACTZ is intact and whether the angiotensin-converting enzyme inhibitor, enalapril, which would be expected to block TGF, attenuates this response to ACTZ. Six men with insulin-dependent diabetes mellitus lived in a clinical research center for 8 weeks and received enalapril 5-15 mg/day from the third through sixth week. At 2, 6 and 8 weeks p-aminohippurate (PAH) and inulin clearances were performed over eleven 30-min periods. ACTZ (150 mg) was given intravenously after 180 min. In both the pre- and postenalapril studies, PAH clearance fell after ACTZ administration (-60 +/- 15 and -66 +/- 20 ml/min/l1.73 m2, respectively, p < 0.05 for each study). In contrast, with enalapril treatment PAH clearance after ACTZ tended to rise (29 +/- 12 ml/ min/1.73 m2, p = 0.07). GFR after ACTZ fell during the pre- and postenalapril studies (-19 +/- 3 and -13 +/- 1 ml/min/1.73 m2, respectively, p < 0.05 for each study) but not with enalapril treatment (-6 +/- 3 ml/min/1.73 m2). After ACTZ was administered, estimated renal vascular resistance rose during both the pre- and postenalapril studies (p < 0.05 and p < 0.01, respectively) and fell with enalapril treatment (p < 0.05). These data indicate that enalapril alters the renal hemodynamic effects of ACTZ in patients with diabetes mellitus, possibly by inhibiting tubuloglomerular feedback.

Responses to converting enzyme and renin inhibition. Role of angiotensin II in humans.

We compared the renal vascular responses to angiotensin converting enzyme inhibition and renin inhibition to assess the influence of angiotensin II (Ang II). We examined the renal and endocrine responses to the renin inhibitor enalkiren, to captopril, and to placebo in nine healthy and nine hypertensive men on a 10-mmol sodium diet. Ang II was infused to assess effects of the agents on renal and adrenal responsiveness to Ang II. Plasma Ang II concentration was suppressed similarly with enalkiren and captopril--an identical level of blockade was achieved. Although renal plasma flow was stable during placebo, a substantial rise was seen with both enalkiren (+133 +/- 26 mL/min per 1.73 m2) and captopril (+99.4 +/- 22.6). There was remarkable intrasubject concordance between the renal plasma flow responses to renin inhibition and converting enzyme inhibition (r = .90, P < .004). The vasodilator response to both agents correlated inversely with the fall in renal plasma flow induced by Ang II alone (r = -.66, P < .05). Both agents significantly enhanced the renal vascular response to Ang II (P = .01), and, furthermore, the renal vasodilator response to captopril predicted the potentiation of the renal plasma flow response to Ang II after either agent (enalkiren: r = .91, P < .001; captopril: r = .56, P < .05). Concordance of the maximal renal plasma flow response to the two agents appeared in the hypertensive men as well. Our results indicate that the acute renal response to captopril largely reflects a reduction in Ang II formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium channel blockers protect transplant patients from cyclosporine-induced daily renal hypoperfusion

Renal toxicity, possibly due to vasoconstriction and vascular injury, is the most relevant side-effect of chronic cyclosporine (CsA) therapy given to prevent graft rejection. In kidney transplant recipients each oral dose of CsA is invariably followed by a transient reduction in renal plasma flow (RPF) and glomerular filtration rate (GFR) that results from a form of acute reversible hypoperfusion. We sought to determine whether the Ca2+ channel blocker, lacidipine, prevented CsA-associated renal hypoperfusion in these patients. Parallel studies on CsA pharmacokinetics, renal function parameters (GFR and RPF), as inulin and p-aminohippurate (PAH) clearances, respectively, and urinary excretion of the vasoconstrictor endothelin in 10 consecutive renal transplant patients given CsA as a part of their immunosuppressive therapy were performed. Patients were studied at different time intervals after CsA alone, CsA and lacidipine (4 mg/day), and again seven days after lacidipine withdrawal. In all patients basal RPF and GFR declined on average 51% (139.3 +/- 20.7 ml/min/1.73 m2) and 50% (32.5 +/- 5.8 ml/min/1.73 m2), respectively, two to four hours after maximum blood CsA concentration was reached. As blood levels of CsA returned to trough, both parameters progressively increased to baseline. Lacidipine administration completely prevented the fall in RPF (pre-CsA: 277.1 +/- 23.6; 6 hr post-CsA: 304.5 +/- 31.1 ml/min/1.73 m2) and GFR (pre-CsA: 66.6 +/- 8.1; 6 hr post-CsA: 70.1 +/- 9.8 ml/min/1.73 m2). When lacidipine treatment was discontinued the abnormal RPF and GFR response to CsA administration was again observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of thromboxane A2 receptor antagonism on amphotericin B-induced renal vasoconstriction in the rat

Amphotericin B (AmB) is the drug of choice for most systemic fungal infections, but doses are frequently reduced because of nephrotoxicity. We investigated the role of thromboxane as a mediator for this nephrotoxicity. Vehicle or amphotericin (0.60 mg/kg) was infused into the left renal artery in four groups of rats, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Group 1 received vehicle for 90 min. Group 2 received vehicle followed by a 30 minute AmB infusion which caused a significant and reversible fall in the RPF and GFR. Group 3 received vehicle followed by AmB infusion, but were infused with a bolus of ibuprofen (20mg/kg) 45 minutes before AmB. This group exhibited an insignificant attenuation in the fall in RPF and GFR. Group 4 received vehicle followed by AmB, but were infused with a bolus and continuous infusion of the thromboxane receptor antagonist SQ29,548. This group demonstrated an attenuation in the fall in RPF and a significant decrease in GFR compared to AmB control rats. In addition, the rat glomeruli were incubated with AmB (4ugm/ml). Supernatant levels of thromboxane B 2 were significantly elevated in the presence of AmB vs buffer alone. We conclude that the reduction in RPF and GFR observed with AmB infusion in the rat is partially mediated by release of thromboxane.

Glomerular and tubular antinatriuretic actions of low-dose angiotensin II infusion in man

The aim was to study the physiological effects of angiotensin II upon the glomerular and tubular handling of sodium. Healthy volunteers were examined before and during infusion with either low-dose angiotensin II (n = 11) or placebo (n = 13). Lithium clearance was used to estimate the segmental tubular reabsorption of sodium. During infusion with angiotensin II a sustained and marked fall in renal plasma flow was observed. The glomerular filtration rate (GFR) decreased to a minor extent so that the filtration fraction increased during angiotensin II infusion. Angiotensin II caused an extensive and instantaneous fall in both urinary flow and urinary sodium excretion. Proximal absolute reabsorption of sodium was unchanged despite the fall in GFR, showing that proximal fractional reabsorption was enhanced by angiotensin II. Distal absolute reabsorption was decreased during the entire period of angiotensin II infusion. However, when the distal reabsorption was related to the delivery of sodium from the proximal tubules, distal fractional reabsorption in fact increased after 30 min angiotensin II infusion. None of the measured parameters changed during infusion with placebo. A significant increase in plasma aldosterone was observed 30 min after the start of the angiotensin II infusion. Plasma atrial natriuretic peptide did not change during infusion with either angiotensin II or placebo. We conclude that physiological increments in angiotensin II affect glomerular haemodynamics and cause a marked antinatriuresis in man. The antinatriuretic effect of angiotensin II is caused initially by a combination of a decrease in the GFR and an increase in proximal fractional sodium reabsorption, and later by the enhanced distal fractional reabsorption of sodium.

Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney.

These studies were conducted in the conscious, chronically catheterized rat to determine whether the endothelial derived relaxing factor (EDRF) controls renal function in the normal state. Administration of the EDRF synthesis inhibitors N-monomethyl-L-arginine (NMA; 100 mg/kg body weight) or N-nitro-L-arginine methylester (NAME; 10 mg/kg body wt) led to a large, sustained rise in blood pressure, a large rise in renal vascular resistance, a fall in renal plasma flow, a relatively slight reduction in glomerular filtration rate, and a consequent rise in filtration fraction. In addition, a marked natriuresis occurred because of a reduction in the fractional reabsorption of sodium. In separate studies, a continuous infusion of excess L-arginine (300 mg/kg body wt bolus followed by 50 mg/kg body wt per min) attenuated the NMA- or NAME-induced rise in blood pressure and reversed the renal hemodynamic effects such that a significant rise in renal plasma flow was seen. L-Arginine alone produced a selective renal vasodilation and large increases in sodium excretion. These observations support earlier suggestions that tonic release of EDRF controls the basal blood pressure and also show that renal function in the normal unstressed rat is markedly influenced by EDRF. These studies suggest that, in addition to controlling renal plasma flow, EDRF may have other, complex actions at the glomerulus. The natriuresis seen after acute inhibition of EDRF with NMA or NAME was probably the result of a pressure natriuretic response to the abrupt rise in blood pressure and also, perhaps, reflects removal of an EDRF influence to directly enhance sodium reabsorption somewhere in the nephron.

Ca&lt;sup&gt;2+&lt;/sup&gt; Antagonists and db-cAMP Sustain a Rise in Renal Blood Flow Induced by Acetylcholine in Indomethacin-Treated Dogs

Renal arterial infusion of acetylcholine (ACh) in the dog normally produces a sustained rise in sodium excretion (UNaV) and in renal plasma flow (RPF). When prostaglandin (PG) synthesis is inhibited, ACh induces only a transient increase in UNaV and RPF followed by a progressive decline in UNaV and RPF, and a rise in renin secretory rate (RSR). Renal arterial infusion of PGE2 but not a vasodilator such as bradykinin restored the response to ACh to normal in indomethacin (Indo)-treated dogs. During renal arterial infusion of dibutyryl cyclic AMP (6 mg/min), ACh also produced a sustained increase in UNaV and RPF despite an inhibition of PG synthesis by Indo. Renal arterial infusion of verapamil (60 micrograms/min) or diltiazem (60 micrograms/min) also prevented the subsequent fall in RPF when ACh was infused; RSR, however, did not show a rise. The results suggest that synthesis of PGE2 with stimulation of cAMP is required for sustained ACh action. When PGE synthesis is inhibited, ACh may produce renal vasoconstriction by increasing intracellular Ca2+ concentration. The partial effect of calcium channel blockers suggests that release of calcium from intracellular stores as well as calcium entry may mediate the response.

EFFECTS OF Nva2-CYCLOSPORINE ON GLOMERULAR FILTRATION RATE AND RENAL BLOOD FLOW IN THE RAT1

The effects of Nva2-cyclosporine on glomerular filtration and renal blood flow in rats were studied and compared with those of cyclosporine. An infusion of Nva2-cyclosporine (20 mg/kg) caused a 53% fall in glomerular filtration rate (1.0 +/- 0.08 to 0.47 +/- 0.09; P less than 0.001) and renal plasma flow (3.2 +/- 0.4 to 1.6 +/- 0.4; P less than 0.005). Nva2-cyclosporine when infused in a dose of 10 mg/kg caused a nearly identical fall in inulin clearance and renal plasma flow. By comparison an infusion of cyclosporine (20 mg/kg) caused a 50% decrease in inulin clearance and a fall in renal plasma flow from 2.6 +/- 0.3 to 0.9 +/- 0.3. Nva2-cyclosporine or cyclosporine was given chronically in a dose of 20 mg/kg intraperitoneally for seven days. Cyclosporine produced a 27% fall in creatinine clearance, whereas Nva2-cyclosporine produced a 19% decrease in creatinine clearance (NS). These studies suggest that Nva2-cyclosporine has adverse effects on renal blood flow and glomerular filtration rate similar to those seen with cyclosporine.

The effects of atrial natriuretic peptide on whole-kidney and proximal straight tubular function in the rabbit.

The mechanisms by which atrial natriuretic peptide (ANP) produces a diuresis and natriuresis remain unclear. It has been suggested that the major if not sole mediator of ANP's renal effects is a hemodynamically induced increase in glomerular filtration rate (GFR). Data from clearance studies in anesthetized rabbits demonstrate that ANP administration can produce a significant increase in absolute and percentage sodium excretion (42.0 +/- 5.9----64.6 +/- 10.2 mu eq/min, P less than 0.01, and 1.97 +/- 0.28----3.12 +/- 0.35%, P less than 0.001, respectively) without increasing GFR (16.8 +/- 2.1----16.1 +/- 2.5 cc/min, P greater than 0.30). The natriuresis occurred despite a fall in renal plasma flow (RPF) (56.7 +/- 7.0----44.5 +/- 9.4 cc/min, P less than 0.01), a rise in filtration fraction (0.33 +/- 0.01----0.46 +/- 0.05, P less than 0.01), and an unchanged filtered load of sodium (2.28 +/- 0.27----2.16 +/- 0.32 mu eq/min, P greater than 0.10). Isolated tubular microperfusion studies demonstrated that ANP, present as a 10(-9) M concentration in the solution bathing perfused proximal straight tubules (PST), did not affect fluid flux (Jv) (0.38 +/- 0.07----0.41 +/- 0.07 nl/mm/min, P greater than 0.30) or phosphate reabsorption (Jp) (1.50 +/- 0.5----1.38 +/- 0.36 pmole/mm/min, P greater than 0.50). When ANP was infused into rabbits prior to harvesting the PSTs for isolated tubular microperfusion and the results were compared to tubules taken from control animals, there was again no effect on Jv (0.37 +/- 0.05 vs 0.42 +/- 0.05 nl/mm/min, P greater than 0.50) or Jp (2.41 +/- 0.27 vs 2.42 +/- 0.44 pmole/mm/min, P greater than 0.90). These findings suggest that ANP can inhibit sodium transport without increasing whole-kidney GFR or RPF, but does not directly inhibit transport in the proximal straight tubule.

Renal Hemodynamic Effects of Tertatolol in Essential Hypertension

Tertatolol, a new beta-blocker, and propranolol, considered a reference beta-blocker, were given orally (5 and 160 mg slow release, respectively) for 15 days to two groups of patients with essential hypertension in order to compare their effects on renal hemodynamics. Systolic and diastolic blood pressure, heart rate, and erect plasma renin activity fell significantly in both groups while prostaglandin E2 urinary excretion was unchanged. Tertatolol administration produced increases in glomerular filtration rate, as shown by inulin clearance (+8.9%; p = 0.038) and renal plasma flow, as shown by paraaminohippurate clearance (+13.0%; p = 0.007). In contrast, propranolol administration resulted in a slight decrease in glomerular filtration rate (-2.8%; not significant) and a fall in renal plasma flow (-13.4%; p less than 0.001). Comparison between both treatments showed that glomerular filtration rate and renal plasma flow were higher in the patients treated with tertatolol than in those treated with propranolol whereas filtration fraction was lower, which suggests that tertatolol causes a vasodilation of the glomerular afferent arteriole. These results demonstrate that in contrast to propranolol (160 mg), and despite both drugs exhibiting a comparable antihypertensive activity, tertatolol (5 mg) does not alter but even improves renal perfusion in hypertensive patients.

On the mechanism of renal vasoconstriction induced by acetylcholine in indomethacin-treated dogs.

Renal arterial infusion of acetylcholine (ACh) in control dogs produced a natriuresis and diuresis and an increase in renal plasma flow (RPF) without a change in glomerular filtration rate (GFR) or in renin secretory rate (RSR). In dogs pretreated with indomethacin (Indo), an inhibitor of prostaglandin synthetase, renal arterial infusion of ACh first produced a rise, then a decline in urine flow, sodium excretion (UNaV) and GFR that was accompanied by a progressive fall in RPF and a progressive rise in RSR. The rise in RSR was potentiated by renal arterial infusion of an alpha-adrenergic receptor blocker, phenoxybenzamine (Phenoxy), and attenuated, but not completely abolished, by beta-adrenergic receptor blockade with propranolol (Prop). Chemical denervation with reserpine alone, or in combination with chronic surgical renal denervation, failed to prevent the fall in RPF, GFR and UNaV and the rise in RSR produced by ACh in Indo-treated dogs. Renal arterial infusion of Phenoxy and intravenous infusion of Prop, alone or in combination with renal arterial infusion of an angiotensin II antagonist, saralasin, failed to maintain the vasodilatory, diuretic and natriuretic effects of ACh in Indo-treated dogs. Elimination of endogenous vasopressin by hypophysectomy also failed to prevent the vasoconstriction induced by ACh in Indo-treated dogs. The results suggest that ACh produced renal vasoconstriction in Indo-treated dogs by mechanism(s) other than an increase in renal adrenergetic activity or an increase in the activity of the renin-angiotensin system. The results also suggest that the vasoconstriction was independent of vasopresin.

Transient renal dysfunction during initial inhibition of converting enzyme in congestive heart failure.

Treatment with captopril in resistant normotensive congestive heart failure is associated with a pronounced reduction in blood pressure, particularly after the first dose. The effects of this reduction on renal function were assessed in 10 patients at the beginning of and during chronic treatment (at one week and three months). Renal plasma flow and glomerular filtration rates were measured by isotope clearance during water diuresis. The first dose of captopril (25 mg) led to a pronounced fall in renal plasma flow and glomerular filtration rates together with a decrease in mean arterial pressure; this fall correlated with baseline plasma renin activity. These changes were paralleled by decreases in water and sodium excretion. In contrast, by the end of the first week of treatment a similar fall in mean arterial pressure occurred together with a pronounced increase in renal plasma flow; the glomerular filtration rate was maintained and there was no decrease in water and sodium excretion. This new response pattern recurred after three months of treatment. The difference in response at different stages of treatment may reflect the balance between the different mechanisms influencing kidney dynamics in heart failure and their alteration by converting enzyme inhibition. The sustained increase in renal plasma flow during chronic treatment with captopril may account for the continued control of heart failure in these patients.

ROENTGENOGRAPHIC CONTRAST MEDIUM (RCM)-INDUCED RENAL VASOCONSTRICTION

Contrast media, and other hypertonic solutions, have been shown to induce renal vasoconstriction, but their influence on acute changes in FF and GFR have not been assessed. All known vasoactive agents that reduce renal blood flow (RBF), such as norepinephrine (NEPI), reduce GFR and increase FF. We compared intrarenal bolus injections of RCM (4 cc meglumine/sodium diatrizoate 76%, 1650 mOsm/kg) and NEPI, (3–10 μg) on RBF (electromagnetic flowmeter) and GFR (Tc 99m DTPA extraction) in dogs. To assess GFR transients, a pump was used with a rapid, simultaneous renal venous and arterial sampling at 15 second intervals. NEPI induced a fall in renal plasma flow (RPF) (69 ± 14 vs. 16 ± 3 ml/min) and the expected rise in FF (0.36 ± .04 vs. 0.42 ± 0.07). RCM induced a fall in RPF (102 ± 5 vs. 79 ± 10 ml/min) and an unanticipated fall in FF (0.32 ± 0.01 vs. .18 ± 0.02). The fall in FF post RCM reflected a larger and more sustained fall in GFR (33 ± 2 vs. 14 ± 2 ml/min; -Δ 19 ml/min) than post NEPI (20 ± 5 vs. 6 ± 2 ml/min; -Δ 14 ml/min). To examine the role of intrarenal pressures on RBF and FF, acute changes in renal length (L), ureteral pressure (UP) and wedged interlobar venous pressure (VP) were measured following intrarenal bolus injections of RCM and NEPI. Whereas NEPI produced decreases in L, UP, and VP, the RCM-induced vasoconstriction was associated with increases in these parameters. The RCM-induced increases in L, UP, and VP must reflect osmotic forces. The fall in FF probably reflects Starling forces in the glomerular capillaries, with osmotic transients dominating: the same forces may well be responsible for the vascular responses to RCM, and may contribute to RCM-induced acute renal failure.