COMPARATIVE EFFECTS OF ENDOTHELIN AND NEUROTENSIN ON INTRINSIC CARDIAC NEURONS IN-SITU

Studies were performed on anesthetized dogs to determine whether the p eptides endothelin and neurotensin influence intrinsic cardiac neurons in situ and, if so, whether intrinsic cardiac neurons sensitive to th ese peptides are involved in cardiac regulation. Endothelin-1 (0.1 ml, 100 nM), which has high affinity for ET(A) endothelin receptors, when administered to a population of right atrial neurons via their region al arterial blood supply increased neuronal activity (+173%), heart ra te (+18%), as well as right (62%) and left ventricular (14%) intramyoc ardial systolic pressures in 12 dogs so tested. When the selective ET( B) endothelin receptor agonist BQ-3020 (0.1 ml, 100 nM) was applied to these neurons their activity increased (+119%) in 10 of 12 dogs teste d, as did right (56%) and left (12%) ventricular intramyocardial systo lic pressures. Neuronal and cardiac responses were induced by BQ-3020, but not by endothelin-1, in the presence of a selective ET(A) recepto r antagonist (BQ-610). When a greater dose of endothelin-1 (0.1 ml, 10 mu M) was administered to right atrial neurons in four separate dogs, alterations in neuronal activity were accompanied by ventricular arrh ythmias that progressed to ventricular fibrillation. In contrast, when neurotensin (0.1 ml, 10 mu M) was administered into their regional ar terial blood supply intrinsic cardiac neurons were excited without car diac variables being affected. These data indicate that: 1) mammalian intrinsic cardiac neurons are sensitive to endothelin and neurotensin; 2) endothelin-sensitive intrinsic cardiac neurons possess ET(A) and E T(B) receptors; 3) cardiac indices are enhanced when intrinsic cardiac neurons sensitive to endothelin, not neurotensin, become activated.