Interaction of rapid nongenomic cardiovascular aldosterone effects with the adrenergic system.
Interactions between the renin-angiotensin-aldosterone system and the adrenergic system are complex and have mainly been attributed to angiotensin II, with knowledge about aldosterone action much less advanced. Only recently has evidence been forthcoming that aldosterone blunts the baroreceptor reflex and lowers heart rate variability in humans. Both effects point to an adrenergic-like action of aldosterone. It has been proposed that this blunting of baroreceptor sensitivity is mediated nongenomically and that nongenomic aldosterone action itself is modulated by the adrenergic system. The aim of the present study was to prove the hypothesis of an interaction between the autonomic nervous system and rapid, nongenomic aldosterone effects. We conducted a randomized, double blind, 8-fold cross-over trial on 18 healthy male volunteers. After pretreatment with the beta-blocking agent esmolol, the beta-agonist dobutamine, the alpha(1)-agonist phenylephrine, or placebo, placebo (0.9% NaCl) or aldosterone (0.5 mg) was injected. After aldosterone injection the peak plasma levels were supraphysiological, reaching nanomolar concentrations. Primary target variables were differences in changes in mean arterial blood pressure, systemic vascular resistance, and cardiac output depending on the pretreatment. Cardiovascular parameters were measured by impedance cardiography during the maintained infusion of the adrenergic modulators for 45 min. Comparing pretreatments, diverse acute, and thus nongenomic, effects of aldosterone on mean arterial blood pressure were observed. After esmolol pretreatment, aldosterone caused an increase in mean arterial blood pressure by 4.1%, whereas after dobutamine pretreatment mean arterial blood pressure decreased by 1.6%, and the difference was statistically significant (P < 0.01). These effects were significant (P < 0.005) for the first 12 min, underlining their nongenomic nature. Our data support the hypothesis that aldosterone, via nongenomic mechanisms, has diverse effects on the cardiovascular system that depend on the preexisting adrenergic state. Furthermore, aldosterone blunts the blood pressure-lowering effect of the beta-blocking agent esmolol by a nongenomic mechanism.
Schmidt
B M
BM
Institute of Clinical Pharmacology, University Hospital of Mannheim, Faculty for Clinical Medicine Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Georgens
A C
AC
Martin
N
N
Tillmann
H C
HC
Feuring
M
M
Christ
M
M
Wehling
M
M
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D000450:Aldosterone / Q000097:blood* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002302:Cardiac Output / Q000187:drug effects; D003404:Creatinine / Q000652:urine; D018592:Cross-Over Studies; D004280:Dobutamine / Q000494:pharmacology; D004311:Double-Blind Method; D004573:Electrolytes / Q000652:urine; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D010919:Placebos; D011412:Propanolamines / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D014508:Urea / Q000652:urine; D014655:Vascular Resistance / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004573:Electrolytes; D010919:Placebos; D011412:Propanolamines; D010656:Phenylephrine; D004280:Dobutamine; D000450:Aldosterone; D014508:Urea; D003404:Creatinine; C036604:esmolol