MODULATION OF NOREPINEPHRINE RELEASE IN ADRIAMYCIN-INDUCED HEART-FAILURE IN RABBITS - ROLE OF PRESYNAPTIC ALPHA(2)-ADRENOCEPTORS AND PRESYNAPTIC ANGIOTENSIN-II RECEPTORS

In congestive heart failure (CHF), sympathetic neurotransmitter releas e is enhanced. We investigated the possibility that this is due in par t to alterations in activation of either release-inhibiting alpha(2)-a drenoceptors or release-enhancing angiotensin II (AII) receptors at po stganglionic sympathetic nerve endings. CHF was induced in rabbits by adriamycin [1 mg/kg intravenously (i.v.), twice weekly for 8 weeks] an d was characterized by reduced cardiac output (CO) and enhanced norepi nephrine (NE) release rate in pentobarbital-anesthetized rabbits. Afte r pithing and stimulation of the spinal sympathetic outflow, there was no difference in NE release rate between the two groups, suggesting t hat the enhanced NE release rate observed in adriamycin-treated anesth etized rabbits was of central origin. The alpha(2)-adrenoceptor-blocki ng drug yohimbine (1 mg/kg, i.v.) enhanced NE release rate, which is a n indication of feedback inhibition of NE release through presynaptic a,adrenoceptors. In anesthetized rabbits, this effect of yohimbine was greater in adriamycin-treated than in vehicle-treated animals. Howeve r, in pithed rabbits with electrically stimulated sympathetic outflow, there was no difference in the facilitative effect of yohimbine betwe en the two groups, suggesting that inhibitory presynaptic alpha(2)-adr enoceptors are activated to a greater extent in heart failure due to t he increased transmitter release. Removing inhibitory alpha(2)-adrenoc eptor input has a functional consequence in that yohimbine increased h eart rate (HR) in adriamycin-treated but not in vehicle-treated anesth etized rabbits. Captopril (1 mg/kg, i.v.) decreased NE release rate in pithed rabbits with stimulated sympathetic outflow but had no effect on NE release rate in anesthetized rabbits. However, since equihypoten sive infusion of sodium nitroprusside (SNP 7 mu g/kg/min i.v.) enhance d NE release rate in anesthetized rabbits, this reflex effect indicate s that captopril induced a relative reduction in NE release. These eff ects of captopril are an indication of endogenous AII facilitation of NE release, and this was not different in adriamycin-treated animals. Our results suggest that in adriamycin-induced heart failure in rabbit s the enhanced sympathetic transmitter release is substantially buffer ed by the presynaptic alpha(2)-adrenoceptor mechanism, which serves to protect organs such as heart from excess sympathetic stimulation. The vasoconstrictor and neuronal effects of AII appear to be unchanged in this model.