Pressor effect of the putative M(1) muscarinic receptor agonist McN-A-343 in the conscious rat

The putative M(1) muscarinic receptor agonist McN-A-343 evoked a dose-dependent increase in mean arterial pressure (MAP) when administered intravenously to conscious freely-moving rats pretreated with the ganglionic nicotinic receptor antagonist pentolinium. A tachycardia accompanied the increase in MAP which was blocked by the beta-adrenergic receptor antagonist propranolol. The increase in MAP was attenuated by the alpha(1)-adrenergic receptor antagonist prazosin combined with the alpha(2)-adrenergic receptor antagonist yohimbine. Adding propranolol to alpha-adrenergic receptor blockade uncovered a latent presser response. Replacing prazosin with benextramine (which blocks NPY in addition to alpha-adrenergic receptors) attenuated the presser response unmasked by propranolol. This attenuation was comparable to that provided by benextramine of the presser response to intravenous administration of NPY. Adrenal demedullation only slightly attenuated the presser response while having no effect on the tachycardia. The catecholamine depletor guanethidine greatly attenuated the McN-A-343-evoked increase in MAP and heart rate. The combination of adrenal demedullation and guanethidine did not further attenuate the increase in MAP but did provide better attenuation of the tachycardia than guanethidine alone. These results show that McN-A-343 evokes an increase in MAP and heart rate of conscious freely-moving rats primarily by causing the release of catecholamines, and possibly NPY, from sympathetic neurons with the adrenal glands playing a minor role.