Caffeine potentiates vasodilator-induced renin release.
Previous studies strongly suggest that adenosine receptors on juxtaglomerular cells function to restrain the secretion of renin induced by a variety of stimuli. The clinical significance of this is that caffeine, a widely consumed adenosine receptor antagonist, could augment renin release responses to diseases such as renovascular hypertension, liver cirrhosis and heart failure and to therapeutic maneuvers such as salt restriction, diuretics and vasodilators. Caffeine may be particularly troublesome in this regard because this methylxanthine has central nervous system effects and intracellular actions that also might contribute to the overall ability of caffeine to potentiate renin secretion. The purpose of this study was to document the effects of caffeine on renin release responses to a vasodilator and to investigate what mechanisms were responsible for any augmentation of vasodilator-induced renin secretion. Accordingly, we compared the effects of caffeine vs. 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX; a xanthine that we documented in this study not to significantly enter the brain or penetrate cell membranes) on base-line and hydralazine-induced renin release in both normal and beta adrenoceptor-blocked (propranolol, 15 mg/kg) rats. Both xanthines (at a dose of 10 mg/kg plus 150 micrograms/min) attenuated adenosine-mediated hypotension and bradycardia, and DPSPX was at least as effective as caffeine in antagonizing peripheral adenosine receptors. Caffeine and DPSPX increased base-line plasma renin activity to a similar extent regardless of whether the animals were pretreated with propranolol. In rats with an intact beta adrenergic system, caffeine, but not DPSPX, increased the renin release response to low-dose hydralazine (1 mg/kg). Although both xanthines augmented the renin release response to high-dose hydralazine (10 mg/kg), caffeine was more efficacious in this regard. In beta adrenoceptor-blocked rats, neither caffeine nor DPSPX augmented the renin release response to low-dose hydralazine, whereas both xanthines equally potentiated the renin release response to high-dose hydralazine. These data demonstrate that caffeine increases base-line renin release primarily by blocking peripheral (most likely renal), cell-surface adenosine receptors; however, caffeine potentiates vasodilator-induced renin secretion in part by blocking peripheral (most likely renal), cell-surface adenosine receptors and in part by additional central nervous system and/or intracellular mechanism(s) that involve the beta adrenergic system.
Tofovic
S P
SP
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Branch
K R
KR
Oliver
R D
RD
Magee
W D
WD
Jackson
E K
EK
D000241:Adenosine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004357:Drug Synergism; D006830:Hydralazine / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects*; D012083:Renin / Q000097:blood / Q000378:metabolism*; D014970:Xanthines / Q000097:blood / Q000494:pharmacology*
D011983:Receptors, Purinergic; D014970:Xanthines; D006830:Hydralazine; D002110:Caffeine; C053896:1,3-dipropyl-8-(4-sulfophenyl)xanthine; D012083:Renin; D000241:Adenosine