A study in the rat of the renal actions of nitrendipine and diltiazem on the adrenergic regulation of calcium and sodium reabsorption

Abstract

1In pentobarbitone-anaesthetized rats, intravenous administration of diltiazem at 5 g kg-' min -' did not change blood pressure or renal blood flow but increased glomerular filtration rate by approximately 16%, urine flow by 85%, calcium excretion by 151% and absolute and fractional sodium excretions by 100% and 69%, respectively. A similar pattern of responses was obtained in renally denervated animals, except that calcium excretion did not change statistically. Diltiazem given at 20 pg kg'1 min-' into renally innervated and denervated groups of animals depressed blood pressure between 15-17 mmHg but had no effect on renal haemodynamic or tubular function. 2 Nitrendipine administered at 0.5 ig kg-' min-' to renally innervated and denervated animals significantly depressed blood pressure in intact animals by 6 mmHg and in both groups did not change renal haemodynamics but caused similar increases in urine flow ofbetween 79-98%, calcium excretion of between 87 and 125%, absolute sodium excretion of between 108 and 140% and fractional sodium excretion of between 83 and 170%. Infusion of nitrendipine at 1.0 jig kg-' min' into intact or renally denervated animals decreased blood pressure by 18-20 mmHg and increased urine flow by 84-111 %, calcium excretion by 85%, absolute sodium excretion by 81-137% and fractional sodium excretion by 52-102%. 3 Stimulation of the renal nerves at low frequencies (0.8 to 1.5 Hz) caused minimal changes in renal haemodynamics but decreased urine flow by 27%, calcium excretion by 35%, absolute and fractional sodium excretions 32% and 36%, respectively. In different groups of animals given either diltiazem at 20 pg kg-I min' or nitrendipine at 0.5 pg kg'-min' or 1.0 fg kg'-min' , a similar degree of renal nerve stimulation caused an identical pattern of excretory responses of similar magnitude to those obtained in the absence of drug. 4 The calciuretic, diuretic and natriuretic activities of diltiazem and nitrendipine were not dependent on renal nerves and probably represented a direct action on the tubular reabsorptive processes of these ions. The renal nerve-induced increases in tubular calcium and sodium reabsorption indicate that these a-adrenoceptor-mediated responses are not dependent on the inward movement of calcium

A study of the action of amlodipine on adrenergically regulated sodium handling by the kidney in normotensive and hypertensive rats

“…It is likely that the post-receptor mechanisms depend on the mobilisation of intracellular rather than extracellular calcium. These findings are similar to those previously reported (Herod & Johns, 1985;Johns & Manitius 1986b) in which diltiazem, nifedipine and nitrendipine were all incapable of blocking the ability of the renal nerves to cause an antinatriuresis and antidiuresis.…”

“…It was also evident that the basal level of both sodium and water output became greater as the infusion rate of amlodipine was increased which appeared to be a dose-related event in both the normotensive and spontaneously hypertensive rats. This natriuretic and diuretic action of calcium channel blocking drugs has been consistently reported in normotensive rats (Brown & Churchill, 1983;Johns, 1985;Johns & Manitius, 1986b) and was also described following felodipine administration to spontaneously hypertensive rats (Nordlander et al, 1985). The mechanisms underlying this effect are not clear, as convincing evidence of an inhibition of tubular reabsorptive processes for sodium at specific sites along the nephron has not been produced (Johns, 1988).…”

“…Van Zwieten and coworkers (1985) contend that X2-adrenoceptor-mediated responses are primarily inhibited by the calcium channel blocking drugs, while Vanhoutte & Rimele (1982) have proposed that their inhibition of effector responses is dependent on the degree of functional specialization of the neuro-effector junction at particular tissues. As regards neuro-transmission at the renal nerve-epithelial cell junctions of the renal tubule, evidence to date has shown that the calcium channel blocking drugs have no action at this site (Herod & Johns, 1985;Johns & Manitius, 1986b).…”

Effects of diltiazem on plasma uric acid level and renal uric acid excretion in rats.

“…On the other hand, increased responses in GFR (7,8) and renal blood flow (9, 10, 11) to diltiazem have been reported, but the effect of Ca channel blockers on renal hemodynamics appears to vary depending on the experimental conditions (12). In the present study, GFR tended to increase after diltiazem administration, and obvious changes in blood pressure and renal blood flow were seen; that is, a transient fall in blood pressure and a long lasting decrease in renal blood flow.…”

“…However, continuous intravenous infusion of diltiazem, at a dose which had no effect on renal blood flow, showed a diuretic and antiuricosuric effect (data not shown). Furthermore, there have been several studies on the direct action of diltiazem on tubular water and sodium transport using dogs (9) and rats (7,8). Therefore, the mechanisms of the action of diltiazem on renal uric acid excretion may involve not only changes in renal hemody namics but also a direct effect on the tubular transport.…”