Exogenous aldosterone antagonizes distal tubular effects of calcium entry blocker felodipine

Abstract

Calcium entry blockers, such as felodipine, increase natriuresis without increasing kaliuresis. Since these drugs acutely increase plasma renin activity without a concomitant change of aldosterone, inhibition of such stimulated aldosterone release might explain the absence of kaliuresis. In a randomized crossover study in 12 male volunteers, we compared the effects of simultaneously administered exogenous aldosterone and felodipine with the effects of either felodipine or aldosterone alone. Felodipine infusion decreased blood pressure, increased renal plasma flow, and induced natriuresis without kaliuresis. Aldosterone alone reduced sodium excretion and increased potassium excretion without influencing hemodynamics. Addition of aldosterone to felodipine attenuated its natriuretic effect and induced a kaliuresis, which clearly exceeded the rise of potassium excretion during aldosterone alone [delta% fractional excretion of K+ +42 +/- 12 with felodipine+aldosterone and +7 +/- 8% with aldosterone alone; means +/- SE, P < 0.02]. Our data suggest that felodipine-mediated inhibition of stimulated aldosterone release is essential for the absence of kaliuresis with felodipine. In addition, the pronounced kaliuresis with aldosterone during felodipine is in keeping with increased distal sodium delivery due to a proximal tubular action of felodipine.

Metoclopramide stimulates kaliuresis during felodipine without affecting its natriuresis.

“…However, the attenuation of the natriuretic effect of low doses of CEBs could easily be explained by the metoclopramide-induced large increase of PAC, which might have attenuated the natriuresis with felodipine comparable to the attenuation of natriuresis in our study with exogenous aldosterone and felodipine. 13 This possibility is further supported by the results of the present study in which metoclopramide attenuated the felodipine-mediated decrease of distal and not of proximal tubular sodium reabsorption. In the setting of elevated PAC during metoclopramide infusion, felodipine induced an immediate increase of potassium excretion.…”

“…In a previous study, 13 we demonstrated that adding exogenous aldosterone to a felodipine infusion resulted in a major increase of potassium excretion that was more pronounced than with aldosterone alone. However, definite conclusions could not be drawn because PAC levels were relatively high (>2.5 nmol/L).…”

“…Metoclopramide also increases plasma aldosterone concentration (PAC) 21 and thus enabled us to study the relation between CEB-induced natriuresis, endogenous aldosterone, and potassium excretion. In our previous study with exogenous aldosterone, 13 this infusion resulted in a relatively high PAC above 2.5 nmol/L. We therefore questioned whether an increase of endogenous aldosterone within the normal physiological range would also increase potassium excretion during CEB-mediated natriuresis.…”

“…We have previously demonstrated that simultaneous administration of exogenous aldosterone and felodipine was followed by a large increase of kaliuresis. 13 Therefore, the attenuation of potassium excretion during calcium entry blockade might be explained by the well-known CEB-mediated inhibition of aldosterone release. Dopamine exerts its biological effects through occupation of the type 1 and type 2 receptor subtypes (DA, and DA 2 ).…”

Importance of Proximal Tubular Fluid Output in Regulating Long-Term Urinary Sodium Excretion in Health and Disease

“…Ca 2+ entry blockers lead to afferent arteriolar vasodilatation, increased renal blood flow, and increased GFR [42]. In addition, these drugs directly inhibit proximal and distal Na + reabsorption [43, 44, 45, 46]. …”