Factors modifying the early nondiuretic vascular effects of furosemide in man. The possible role of renal prostaglandins.

Abstract

Animal experiments have suggested that salt-balance, prostaglandin synthesis, and renal function are important determinants of the nondiuretic vascular effects of furosemide. To investigate the influence of these factors in humans, we studied 10 normal volunteers and five anephric patients. The volunteers were studied on three occasions: when on a 10 mEq/day sodium diet, on a 250 mEq/day sodium diet, and on a 10 mEq/day sodium diet with indomethacin, 200 mg/day. The anephric patients were studied immediately after dialysis. Plethysmographic methods were used to measure venous capacitance and blood flow in the calf before, and at 5, 10, and 15 minutes after furosemide, 80 mg, iv. Blood was obtained before and 15 minutes after furosemide for determination of plasma renin activity by radioimmunoassay and of plasma 6-keto-prostaglandin F1 alpha by chromatography-mass spectrometry. We found that furosemide significantly increased venous capacitance in the calf of the normal volunteers on a low salt diet. Indomethacin, high salt intake, or lack of renal function was sufficient to inhibit this effect. Plasma renin activity increased only in the group that had the increase in venous capacitance. Limb blood flow decreased gradually in the 15 minutes following administration of furosemide in the normal volunteers, regardless of salt balance or indomethacin, but remained unchanged in the anephric patients. Plasma 6-keto-prostaglandin F1 alpha was less than 30 pg/ml in all samples. Indomethacin concentration averaged 1.3 micrograms/ml in volunteers on the drug. To determine whether indomethacin, salt intake or renal function affected another venodilator, we studied an additional group of normal and uremic volunteers who received 0.6 mg nitroglycerin sublingually.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased blood pressure and vascular smooth muscle tone in mice lacking basolateral Na+-K+-2Cl−cotransporter

“…In addition to venodilation, several investigators have reported increases in blood pressure and vascular resistance (34, 52) after loop diuretic treatment. The reduction in contractility of isolated Nkcc1 Ϫ/Ϫ portal veins is consistent with the hypothesis that the increased venous compliance in response to loop diuretics is due to inhibition of NKCC1 in the vasculature; however, the results of several studies (5,16,23) suggest that these effects might also be due to the release of vasoactive compounds from the kidney. If the kidney is involved, then inhibition of NKCC1, which is expressed in the extraglomerular mesangium and the glomerular afferent arteriole (25), could contribute to this effect.…”

“…Additional studies will be needed to determine the extent of the deficit in vascular contractility, the ionic basis for this defect, and whether it is the major mechanism of the observed hypotension. Given the expression of NKCC1 in renin-secreting cells of the glomerular afferent arteriole, it seems possible that alterations in the secretion of vasoactive compounds from the kidney might, as suggested by others (5,16,23), account for some of observed vascular effects of loop diuretics in vivo. The reduction in excitatory amino acid release observed in Nkcc1 Ϫ/Ϫ astrocytes (49) suggests that neuronal mechanisms could also be involved.…”

The effects of propranolol and digoxin on the acute vascular responses to frusemide in normal man.

“…A high salt diet, pre-treatment with indomethacin and severely impaired renal function will prevent the acute venodilator effects of frusemide (Johnston et al, 1983a). In these situations acute frusemideinduced renin release and prostaglandin formation (PGE2, PGI2) are reduced.…”

Salt sensitivity of blood pressure in NKCC1-deficient mice

“…Vascular responses to blocking NKCC1 with loop diuretics include direct vasodilatation, indirect vasodilatation through mediation of vasorelaxing prostaglandins, and reductions in the contractile responses to vasoconstrictors such as norepinephrine and ANG II (11,15). A reduction of arterial blood pressure has been reported in NKCC1 Ϫ/Ϫ mice using the tail cuff method (19,26).…”