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.