Catecholamine-cyclic-AMP-Ca+-induced ventricular tachycardia in the intact pig heart.
Agents known to increase cAMP levels in the myocardium were infused subepicardially (focal infusion, 10 microliter/min) in open-chested pigs. Infusion of noradrenalin (NA), adrenalin (10(-5) M each) or isoproterenol (10(-6) M) in the presence of Ca2+ (2.5 . 10(-3) M) consistently produced ventricular tachycardia (VT) within 60 s. This tachycardia could be mimicked by electrical stimulation of the infusion area. The NA/CA2+-VT could be maintained for 30 min and was readily reversible after stopping the infusion. Infusion of N6, O2'-dibutyryl-cAMP or N6-monobutyryl-cAMP (5 . 10(-2) M each) produced long-lasting VT within 10-20 min. VT was also induced by infusion of 8-Br-cAMP (5 . 10(-2) M) together wit the phosphodiesterase inhibitor Ro 7-2956 (5 . 10(-4) M) while infusion of the components alone had no such effect. The NA/Ca2+-VT was abolished by calcium antagonists [isoptin, D 600 (10(-4) M each), MnCl2 (5 . 10(-4) M] and beta-adrenoceptor blocking agents [propranolol (10(-4) M), pindolol (10(-6) M)], but was not suppressed by tetrodotoxin (up to 10(-5) M). Infusion of 5 x 10(-2) M N6-monobutyryl-2'-deoxy-cAMP, 2.5 x 10(-3) M CaCl2/0.9% NaCl or 10(-1) M Na-butyrate did not precipitate VT. Tissue analysis showed that myocardial cAMP was increased at the infusion site when the NA/Ca2+-VT ensued. It is concluded that the catecholamine-cAMP-Ca2+ system may play an important role in the initiation and perpetuation of VT, possibly by producing automaticity in ventricular fibres via slow Ca2+ channels.
D015124:8-Bromo Cyclic Adenosine Monophosphate; D000818:Animals; D003994:Bucladesine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D002395:Catecholamines / Q000494:pharmacology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D013552:Swine; D013610:Tachycardia / Q000139:chemically induced*
D002395:Catecholamines; C002373:monobutyryl cyclic AMP; D015124:8-Bromo Cyclic Adenosine Monophosphate; C028955:N(6)-monobutyryl-2'-deoxycyclic adenosine monophosphate; D003994:Bucladesine; D000242:Cyclic AMP; D006152:Cyclic GMP; D007545:Isoproterenol; D002118:Calcium; D009638:Norepinephrine