Renal effects of prostaglandins have been widely investigated in anesthetized animals, but in contrast only few studies have been devoted to healthy and diseased humans. Recently, both prostacyclin and a stable analog of PGE1, misoprostol, have been available for therapeutic purposes in clinical conditions associated with peripheral or renal vasoconstriction; however, the renal effects have not been defined. We have therefore studied the acute renal effects of PGI2 5 ng.kg/min intravenously and of misoprostol, a stable PGE1 analogue, 400 micrograms orally in two groups of respectively 8 and 12 healthy supine subjects on normal sodium diet using sodium, lithium, inulin, PAH and neutral dextran clearances. PGI2 induced a slight natriuretic effect, a systemic and renal vasodilation with a decrease in mean arterial pressure from 85.3 +/- 1.1 to 80.2 +/- 1.6 mm Hg (P < 0.01) and in renal vascular resistance from 94 +/- 6 to 75 +/- 5 mm Hg.min/ml (P < 0.001). GFR did not change whereas fractional clearance of dextran decreased over the 34 to 48 A radius range. Applying these changes on a hydrodynamic model of filtration of macromolecules through water-filled pores, we calculated that PGI2 decreased the glomerular transcapillary pressure gradient from 35 +/- 1 to 32 +/- 1 mm Hg (P < 0.001), decreased nonsignificantly the ultrafiltration coefficient Kf and did not affect the membrane parameters r0 and omega 0. Misoprostol had no natriuretic effect, induced slight renal vasoconstriction and moderate decrease in GFR from 124 +/- 9 to 114 +/- 10 ml/min.1.73 m2 (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
The acute renal effects of neutral endopeptidase 24.11 (E-24.11) inhibition induced by a single oral dose of sinorphan (100 mg) were investigated in 10 healthy normotensive subjects on normal sodium diet. Sinorphan inhibited 90% of E-24.11 activity and increased plasma atrial natriuretic peptide (ANP) and urinary guanosine 3',5'-cyclic monophosphate (cGMP) by 70 and 100%, respectively. Sinorphan increased urinary sodium output by 50% (P < 0.001) and decreased fractional distal reabsorption by 4% (P < 0.01). Sinorphan increased glomerular filtration rate (GFR) and filtration fraction by 10% 1 h after administration and decreased renal plasma flow by 10%. Mean arterial pressure, renal vascular resistance, plasma aldosterone concentration, and renin activity were unmodified. Sinorphan decreased fractional clearance of neutral dextrans over the 34- to 52-A radius range. Applying the changes along with a hydrodynamic isopore with shunt model, sinorphan significantly increased capillary pressure gradient (delta P; 39 +/- 1 vs. 34 +/- 1 mmHg; P < 0.01), whereas ultrafiltration coefficient was unchanged. In conclusion, endopeptidase inhibition increased endogenous plasma ANP and cGMP generation and induced natriuresis through both an increase in filtered load and a decrease in distal tubular reabsorption of sodium. Sinorphan increases GFR, filtration fraction, and delta P, probably through an increase in efferent over afferent arteriolar resistance ratio.
Renal haemodynamics, sodium excretion, and free-water clearance were evaluated at baseline and after acute frusemide administration in nine moderately volume-expanded healthy volunteers receiving a single administration of either 750 mg lithium carbonate or placebo. Lithium plasma concentration under 0.29 mmol/l exerted no significant effect on renal haemodynamics, on absolute, fractional, or cumulative sodium excretion, or on free-water and chloride clearances at baseline or after frusemide administration. Despite previous volume expansion and presumably depressed proximal reabsorption, frusemide decreased the fractional reabsorption of lithium significantly, suggesting that a small but significant part of lithium may be reabsorbed in the thick ascending limb of Henle's loop. By contrast, frusemide did not change renal haemodynamics or plasma renin activity. Using combined free-water and lithium clearances at baseline and after frusemide administration, fractional reabsorption of sodium in the (FRTAL) was calculated as delta CH2O/CLi, where delta CH2O, the difference in free water clearance before minus after frusemide, is taken as an index of sodium reabsorption in the thick ascending limb, and lithium clearance as an estimation of sodium delivery to the thick ascending limb. FRTAL was calculated in these volume-expanded subjects to lie from 11% to 20% depending on whether some lithium is assumed to be in the thick ascending limb.
In 13 normotensive subjects on a normal sodium diet, we studied hormonal, blood pressure, and renal vascular changes and dextran sieving profiles induced by infusion of exogenous angiotensin II (Ang II) (5 ng • kg"'• min"'), during baseline conditions and after 5 days of administration of the angiotensin converting enzyme inhibitor cilazapril. Cilazapril induced a renal vasodilative effect without affecting supine blood pressure and glomerular filtration rate. Fractional dextran clearances were significantly decreased for dextran of effective radius ranging from 3.0 to 4.0 nm. This shift was primarily related to an increase in glomerular capillary plasma flow, because no change was observed in the transcapillary glomerular pressure gradient, the ultrafiltration coefficient, or the membrane parameters. Ang II elicited a slight pressor response accompanied by hormonal, antinatriuretic, and renal hemodynamic changes that were similar during and before short-term angiotensin converting enzyme inhibition. Dextran sieving curves were unchanged by a low dose of Ang II. However, the transcapillary glomerular pressure gradient and the ultrafiltration coefficient were computed to increase by 19.4% and to decrease by 44.2%, respectively, whereas membrane parameters were unaffected. When superimposed onto short-term angiotensin converting enzyme inhibition, glomerular response to this unique dose of Ang II was similar to that induced by Ang II alone.
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