PHARMACOLOGICAL ANALYSIS OF AUTONOMIC INNERVATION OF THE RIGHT ATRIA OF RATS AND GUINEA-PIGS - DEMONSTRATION OF NONADRENERGIC NONCHOLINERGIC NERVES

Abstract

Transmural nerve stimulation (TNS) of the right atria in vitro produced positive and negative chronotropic responses in rats and guinea pigs. The negative component appeared only temporarily soon after the cessation of TNS and was usually masked by the positive component. The positive and negative chronotropic responses were accompanied by an increase and decrease in contractile force, respectively. Atenolol (3 .times. 10-6 M) decreased and atropine (10-6 M) potentiated the TNS-induced positive chronotropic response. In the presence of both atenolol and atropine, TNS accelerated the heart rate markedly in the right atria of guinea pigs and slightly in those of ras. TNS-induced acceleration of the heart rate was also observed in surgically sympathectomized or reserpine-pretreated (5 mg/kg/48 hr and 2.5 mg/kg/24 hr i.p.) right atrium, in which tyramine (up to 10-4 M) exerted no appreciable effect. Inasmuch as tetrodotoxin (10-6 M) almost abolished the TNS-induced chronotropic response, this atenolol- and atropine-resistant response is likely mediated by nonadrenergic noncholinergic (NANC) nerve(s). The NANC nerve-mediated positive chronotropic response was not affected by diphenhydramine (10-6 M), cimetidine (10-6 M), methysergide (10-6 M) and hexamethonium (3 .times. 10-6 M). The NANC nerve-mediated response was relatively slow at the onset yet long-lasting compared with adrenergic and cholinergic responses, suggesting that the neurotransmitter of the NANC nerve is a certain substance which may be inactivated more slowly than biogenic amines. Histochemical studies demonstrated the presence of vasoactive intestinal polypeptide-like and substance P-like immunoreactive nerves in the right atrium, as well as catecholamine-fluorescence and acetylcholinesterase-positive nerves. However, vasoactive intestinal polypeptide and substance P are unlikely to be the neurotransmitter(s) of NANC nerve(s) as vasoactive intestinal polypeptide and substance P showed only a little and no positive chronotropic effects, respectively. The results demonstrate the presence of NANC nerves as well as adrenergic and cholinergic nerves in the right atria of rats and guinea pigs.