Sympathoinhibitory and depressor effects of amlodipine in spontaneously hypertensive rats

The authors examined whether central actions contribute to the hypotensive effects of peripherally administered amlodipine, a lipophilic dihydropyridine with slow onset and long duration of action. After 5 to 6 weeks of high (8%, H-Na) or regular (0.6%, R-Na) salt intake, changes in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were recorded at rest and in response to intravenous (iv) and intracerebroventricular (icv) injection, and prolonged iv infusion of amlodipine, in conscious spontaneously hypertensive rats (SHR). Iv injection of amlodipine at 50 to 100 mug/kg decreased MAP but increased RSNA and HR in a dose-related manner. In contrast, icv injection of amlodipine at 10 to 50 mug/kg caused parallel decreases in MAP, RSNA, and HR. Iv infusion of amlodipine at 50 mug/kg per hour for 3 hours followed by 100 mug/kg per hour for 2 hours also decreased in parallel RSNA, MAP, and HR. Maximal decreases in RSNA, MAP, and HR in response to icv injection and iv infusion were significantly larger in SHR on H-Na versus R-Na. All responses lasted at least 1 hour following iv and icv injection, or after the termination of iv infusion of amlodipine. These data suggest that in SHR during prolonged iv infusion, amlodipine appears to cross the blood-brain barrier, block brain L-type Ca2+ channels, and decrease sympathetic outflow and thereby BP. Central actions may prevail during iv infusion of amlodipine at low rates, and the decrease in BP is associated with sympathoinhibition. High salt intake markedly enhances its sympathoinhibitory action, likely through central mechanisms.