The 4-methyl piperidine analog (A-4) of hemicholinium-3 is a tertiary amine. A-4, like hemicholinium-3, inhibits sodium-dependent, high-affinity choline transport. The present study examined whether central cholinergic systems are involved in the expression of genetic hypertension. We examined the effects of i.v. and i.c.v. administration of A-4 in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY; control). Basal mean arterial pressure and heart rate values were 108 +/- 4 mm Hg and 370 +/- 5 bpm in WKY and 167 +/- 5 mm Hg and 337 +/- 13 bpm in SHR. The i.v. injection of A-4 (5, 10 and 20 mumol/kg) evoked a dose-dependent decrease in MAP in SHR, but not in WKY. The maximal decrease in MAP was 18 +/- 6 mm Hg (P < .01) in SHR. Depressor responses appeared within 1 min and reached maximum within 10 min. The reductions in MAP were not associated with reductions in peripheral vascular resistances, suggesting that the hypotension was due to a reduction in cardiac output. The i.c.v. injection of A-4 (100 nmol/rat) significantly decreased MAP in SHR (-23.8 +/- 2.4 mm Hg, P < .01), but not in WKY. The maximal decrease in MAP appeared within 1 min and reached maximum 10 min later. These falls in MAP were associated with falls in vascular resistances, suggesting that the hypotension was due to peripheral vasodilation. This dose was ineffective when given i.v. in either strain. A-4-induced decreases in MAP were accompanied by significant tachycardia, which was maximal within 3 min of injection. These studies demonstrate that A-4 lowers MAP in SHR, but not in WKY. The rapid onset of hypotension in SHR after A-4 administration suggests that there is rapid turnover of brain acetylcholine which may be directly involved in maintaining elevated arterial pressure in SHR.