A-4, A TERTIARY AMINE ANALOG OF HC-3, LOWERS ARTERIAL-PRESSURE IN SPONTANEOUSLY HYPERTENSIVE RATS

The 4-methyl piperidine analog (A-4) of hemicholinium-3 is a tertiary amine. A-4, like hemicholinium-3, inhibits sodium-dependent, high-affi nity choline transport. The present study examined whether central cho linergic systems are involved in the expression of genetic hypertensio n. We examined the effects of i.v. and i.c.v. administration of A-4 in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto r ats (WKY; control). Basal mean arterial pressure and heart rate values werel 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 mu mol /kg) evoked a dose-dependent decrease in MAP in SHR, but not in WKY. T he maximal decrease in MAP was 18 +/- 6 mm Hg (P < .01) in SHR. Depres sor responses appeared within 1 min and reached maximum within 10 min. The reductions in MAP were not associated with reductions in peripher al vascular resistances, suggesting that the hypotension was due to a reduction in cardiac output. The i.c.v. injection of A-4 (100 mu mol/r at) 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 du e to peripheral vasodilation. This dose was ineffective when given i.v . in either strain. A-4-induced decreases in MAP were accompanied by s ignificant tachycardia, which was maximal within 3 min of injection. T hese studies demonstrate that A-4 lowers MAP in SHR, but not in WKY. T he rapid onset of hypotension in SHR after A-4 administration suggests that there is rapid turnover of brain acetylcholine which may be dire ctly involved in maintaining elevated arterial pressure in SHR.