McN-A-343 increases renal sympathetic nerve activity and blood pressure by a muscarinic and a non-muscarinic mechanism in the rat.

Abstract

1. Intravenous administration of the putative M1 muscarinic agonist McN-A-343 to conscious rats evokes an increase in mean arterial pressure (MAP) which can be blocked by muscarinic receptor antagonists. The present study was undertaken to evaluate the increase in MAP and renal sympathetic nerve activity (RSNA) evoked by intravenous administration of McN-A-343 to urethane-anaesthetized rats. 2. McN-A-343 (0.1-0.3 mg kg-1) evoked a concurrent increase in MAP and RSNA which could be inhibited by the nonselective muscarinic receptor antagonist methylatropine or the selective M1 muscarinic receptor antagonist telenzepine. Administration of higher doses of McN-A-343 (0.3-1.2 mg kg-1) in the presence of muscarinic receptor blockade evoked brief bursts in RSNA accompanied by increases in MAP. 3. The increases in MAP, but not the increases in RSNA, evoked by all doses of McN-A-343 could be attenuated by the selective alpha 1-adrenoceptor antagonist prazosin. Adding the selective alpha 2-adrenoceptor antagonist yohimbine to prazosin did not further inhibit the pressor response to the low doses of McN-A-343. 4. The irreversible alpha-adrenoceptor and NPY receptor antagonist benextramine also attenuated the pressor response evoked by the low doses of McN-A-343 but not the increases in RSNA. However, when combined with muscarinic receptor blockade, benextramine completely inhibited the brief bursts in RSNA, and thus also the increases in MAP, evoked by the high doses of McN-A-343. 5. The pressor response remaining after the administration of high doses of McN-A-343 to rats pretreated with prazosin and methylatropine was inhibited by treatment with alpha,beta-methylene ATP. 6. These results show that McN-A-343 evokes increases in RSNA by muscarinic and non-muscarinic mechanisms. Furthermore, the subsequent increase in MAP is primarily dependent upon activation of vascular alpha 1-adrenoceptors, but may also involve activation of P2 alpha receptors.