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

Abstract

1 An investigation was undertaken to examine the effect of calcium channel blockade, induced by amlodipine, on the ability of the renal sympathetic nerves to cause an antidiuresis and antinatriuresis in normotensive Sprague Dawley and spontaneously hypertensive rats anaesthetized with pentobarbitone. 2 Low frequency renal nerve stimulation in normotensive rats, which did not change renal blood flow, caused a 15% reduction in glomerular filtration rate and was associated with falls in urine flow of 37%, absolute sodium excretion of 47%, and fractional sodium excretion of 38%. The magnitude of these renal excretory changes was unaffected by prior administration of amlodipine at either 200pgkg-1 plus 50pgkg-1h-l or 400pgkg-l plus 100l gkg-'h-l. Amlodipine given in the higher dose, decreased basal levels of blood pressure and increased basal urine flow and sodium excretion. 3 In spontaneously hypertensive rats, renal nerve stimulation minimally affected renal haemodynamics but decreased urine flow, absolute and fractional sodium excretion by 29%, 31% and 24%, respectively. 4 Similar renal nerve stimulation in spontaneously hypertensive rats given amlodipine at 200pgkg-1 plus 5O0 gkg-1h'-or 400 pgkg-1 plus 100lugkg-1h-1 caused minimal changes in renal haemodynamics and in the excretion of water and sodium. The higher dose of drug resulted in decreased blood pressure and increased basal rates of urine flow and sodium excretion. 5 These data show that in spontaneously hypertensive rats but not normotensive rats, calcium channel blockade inhibited the ability of the renal nerves to stimulate the reabsorptive processes for sodium at the renal tubule. This indicated that in spontaneous hypertension the post-receptor mechanisms had changed and become more dependent on the inward movement of calcium.

The α‐adrenoceptor mediating the tubular actions of the renal nerves in spontaneously hypertensive and stroke‐prone spontaneously hypertensive rats

“…Thus, Minneman (1989) has provided evidence that a,,-, but not a,,-adrenoceptors can be inhibited by the calcium channel blockers. Therefore, taking the present observations together with those of a previous report (Johns, 1988), one interpretation is that under normotensive conditions the aIBadrenoceptors mediate the action of the renal nerves at the level of the tubules, whereas in the spontaneously hypertensive rat aIA-adrenoceptors become involved.…”

“…The present findings provided further evidence that although renal a,adrenoceptor density may well be raised in the spontaneously hypertensive rat (Graham et al, 1982), there was preservation of aladrenoceptor mediation of the tubular effects of the renal nerves. However, in a previous report (Johns, 1988) it was apparent that these a,-adrenoceptors in the spontaneously hypertensive rat became susceptible to inhibition by the calcium channel blocking drugs. The reasons for this could be explained by the recent awareness that different subpopulations of a,-adrenoceptors can be defined.…”

“…It is possible that the increased content of a2-adrenoceptors could take over neuro-transmission normally requiring a,-adrenoceptors. In a recent report (Johns, 1988) it was found that the increase in tubular sodium reabsorption caused by low level renal nerve stimulation was inhibited by the calcium channel blocker amlodipine in the spontaneously hypertensive but not the normotensive rat. One possible explanation for this observation could be that the a,-adrenoceptor function was taken over by a,-adrenoceptors as this subtype is known to be sensitive to inhibition by the calcium channel blockers (van Zwieten et al, 1985), supporting the radioligand binding work of Graham et al (1982).…”

Amlodipine

“…In studies that examined possible mechanisms of the natriuretic effects of amlodipine, intravenous infusion of amlodipine in spontaneously hypertensive and normotensive rats produced natriuretic and diuretic effects without changes in renal blood flow, glomerular filtration rate, or proximal tubular resorption. Further investigations showed that in spontaneously hypertensive rats (but not normotensive rats), amlodipine inhibited the ability of renal nerves to stimulate the sodium resorption process at the renal tubule (29,30).…”

Normalization of pressure-natriuresis by nisoldipine in spontaneously hypertensive rats.

“…47 - 9 In addition, calcium channel blockers increase sodium excretion when administered acutely to hypertensive patients 8 - 9 or SHR, 10 -13 but they have little effect in normotensive animals. The mechanism by which calcium entry blockers alter renal function in hypertension remains obscure.…”