SPINAL MUSCARINIC CHOLINERGIC AND NITRIC-OXIDE SYSTEMS IN CARDIOVASCULAR REGULATION

Pharmacological activation of muscarinic receptors located in the thor acic spinal cord evokes a marked increase in blood pressure and heart rate. We have previously demonstrated that the cardiovascular response to stimulation of spinal cord muscarinic cholinergic receptors is dep endent upon a pharmacologically described ascending spine-bulbar pathw ay. The purpose of the study was to determine whether the blood pressu re and heart rate responses to intrathecal (i.t.) injection of the mus carinic cholinergic receptor agonist carbachol are mediated by a local nitric oxide (NO)-generating system. Freely moving rats were previous ly prepared with chronic indwelling i.t. and intra-arterial catheters. Both the presser and tachycardic responses produced by i.t. injection of carbachol were inhibited in a dose-dependent manner by i.t. pre-tr eatment with the NO synthase inhibitor N-omega-Nitro-L-arginine methyl ester (L-NAME). To confirm the site of action of the drugs employed in conscious rats, a separate group of rats was anesthetized, and using surgical procedures previously developed in this laboratory, drug dist ribution was limited specifically to the lower thoracic spinal cord. W hen carbachol was administered by i.t. injection and localized to the lower thoracic area, muscarinic cholinergic receptor stimulation again produced a marked presser response, but without the accompanying tach ycardia. The ability of N-omega-Nitro-L-arginine methylester (L-NAME) to inhibit the presser response to carbachol in conscious rats was con firmed in anesthetized rats, although higher doses of L-NAME than thos e employed in conscious rats were required. L-NAME-induced inhibition of the carbachol-evoked presser response was reversed by the L-, but n ot the D-isomer, of arginine, Moreover, i.t. pre-treatment with Methyl ene blue, that interferes with NO production and function, effectively inhibited the expression of the presser response to i.t. injection of carbachol. The 'anti-muscarinic' action of L-NAME was not due to a di rect interaction with spinal muscarinic receptors, as L-NAME did not s ignificantly displace [H-3]methyl-scopolamine from spinal cord membran es in vitro. The results of this study support the hypothesis that spi nal muscarinic cholinergic receptors participate in a sympathoexcitato ry pathway that interacts either directly or indirectly with a local N O-generating system involved in the regulation of blood pressure.