Cardiovascular effects of LY134046, an inhibitor of norepinephrine N-methyltransferase, in spontaneously hypertensive rats
Hahn, R.A.; Fuller, R.W.; Hemrick-Luecke, S.K.
Journal of Pharmacology and Experimental Therapeutics 226(1): 39-45
1983
ISSN/ISBN: 0022-3565 PMID: 6864549 Document Number: 213157
The cardiovascular activity of LY134046, an inhibitor of norepinephrine N-methyltransferase (NMT), was determined in anesthetized spontaneously hypertensive rats (SHR). Acute i.p. administration of 10 and 20 mg/kg of LY134046 produced minimal cardiovascular alterations, whereas 40 mg/kg resulted in a sustained decrease in mean arterial blood pressure and cardiac rate. The hypotension and bradycardia were rapid in onset and occurred at times when brain NMT activity was markedly inhibited. Brain concentrations of epinephrine were not decreased significantly at very early times when the pressure and rate effects of LY134046 were already maximal. The acute cardiovascular activities of LY134046 were not altered significantly by pretreatment of SHR with phentolamine, propranolol or atropine and LY134046 lowered cardiac rate of pithed SHR. Acute or chronic administration of LY134046 did not antagonize vasoconstrictor responses induced by sympathetic nerve stimulation or exogenous norepinephrine. LY134046 apparently does not interact with adrenergic or cholinergic receptors and neurogenic tone is not required for its hypotensive and bradycardiac effects. Chronic i.p. administration of LY134046 (40 mg/kg per day) produced prolonged and substantial inhibition of hypothalamic and brain stem NMT activity resulting in depletion of central epinephrine. Hypothalamic and brain stem concentrations of norepinephrine and dopamine were increased during chronic treatment of SHR with LY134046. In spite of chronic inhibition of central NMT and depletion of brain epinephrine, base-line mean arterial blood pressure and cardiac rate of SHR treated with LY134046 were not significantly different from those of control SHR injected with saline. Chronic treatment with LY134046 did not result in tolerance to its central biochemical effects or acute cardiovascular activities. That epinephrine-forming neurons are involved in the central regulation of cardiovascular function is not supported because the hypotension and bradycardia resulting from acute administration of LY134046 occurred before any substantial decrease in hypothalamic epinephrine concentration and chronic inhibition of central NMT and depletion of epinephrine resulted in insignificant alterations of base-line cardiovascular parameters.