CENTRAL STIMULATION OF RENIN SECRETION THROUGH SEROTONERGIC, NONCARDIOVASCULAR MECHANISMS

The aims of the study were to determine; (1) whether activation of ser otonin (5-HT) receptors in the brain increases renin secretion, and (2 ) whether the hypertensive effects of a 5-HT agonist and 5-HT releaser obscure their ability to stimulate renin release. Various drugs that increase serotonergic neuro-transmission can activate the secretion of renin from the kidneys. Many of these drugs can also elevate blood pr essure. Changes in blood pressure can alter renin secretion by activat ing renal baroreceptor mechanisms, so that a decrease in profusion pre ssure will increase renin secretion and vice versa. To address the fir st objective, the 5-HT agonist RU 24969 (0, 10, 100 and 200 mu g/kg) a nd the 5-HT releaser p-chloroamphetamine (0, 50, 500 and 1,000 mu g/kg ) were injected intracerebroventriculary (ICV) at doses lower than tho se that are peripherally effective. ICV injection of RU 24969 dose-dep endently increased plasma levels of renin. ICV injection of the 5-HT2A /5-HT2C antagonist LY53857 (50 mu g/kg)inhibited the renin response to peripherally injected RU 24969 (0, 1, 5 and 10 mg/kg i.p.), suggestin g that 5-HT2A/5-HT2C receptors in the brain mediate the effect of peri pherally injected RU 24969 on renin secretion. In contrast, ICV inject ion of p-chloroamphetamine decreased renin secretion. To determine whe ther hypertensive actions could account for the differences between RU 24969 and p-chloroamphetamine, we measured the effects of both p-chol oroamphetamine and RU 24969 on blood pressure and heart rate. ICV inje ction of p-chloroamphetamine (1,000 mu g/kg) produced a large rise of 44 mm Hg at 2 min and 25 mm Hg at 5 min after injection, while ICV inj ection of RU 24969 (200 mu/kg) caused a slower and smaller blood press ure elevation of 18 mm Hg at 5 min after injection. To determine wheth er the hypertensive effects of both RU 24969 and p-chloroamphetamine c ould mask their effects on renin secretion, rats were pretreated with the alpha(1) antagonist prazosin. Administration of prazosin (1 mg/kg s.c), which prevents the hypertensive effects of p-chloroamphetamine, exposed a stimulatory effect of ICV-injected p-chloroamphetamine (500 mu g/kg) on renin secretion and potentiated the effect of RU 24969 (5 mg/kg i.p.) on renin release. In conclusion, these data suggest that b oth RU 24969 and p-chloroamphetamine increase renin secretion through central 5-HT receptors, and that these effects are partially obscured by their hypertensive actions.