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 release is enhanced. We investigated the possibility that this is due in part to alterations in activation of either release-inhibiting alpha 2-adrenoceptors or release-enhancing angiotensin II (AII) receptors at postganglionic sympathetic nerve endings. CHF was induced in rabbits by adriamycin [1 mg/kg intravenously (i.v.), twice weekly for 8 weeks] and was characterized by reduced cardiac output (CO) and enhanced norepinephrine (NE) release rate in pentobarbital-anesthetized rabbits. After pithing and stimulation of the spinal sympathetic outflow, there was no difference in NE release rate between the two groups, suggesting that the enhanced NE release rate observed in adriamycin-treated anesthetized rabbits was of central origin. The alpha 2-adrenoceptor-blocking drug yohimbine (1 mg/kg, i.v.) enhanced NE release rate, which is an indication of feedback inhibition of NE release through presynaptic alpha 2-adrenoceptors. In anesthetized rabbits, this effect of yohimbine was greater in adriamycin-treated than in vehicle-treated animals. However, in pithed rabbits with electrically stimulated sympathetic outflow, there was no difference in the facilitative effect of yohimbine between the two groups, suggesting that inhibitory presynaptic alpha 2-adrenoceptors are activated to a greater extent in heart failure due to the increased transmitter release. Removing inhibitory alpha 2-adrenoceptor input has a functional consequence in that yohimbine increased heart rate (HR) in adriamycin-treated but not in vehicle-treated anesthetized 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.(ABSTRACT TRUNCATED AT 250 WORDS)