LY134046 

LY134046 is an inhibitor of norepinephrine N-methyltransferase (NMT). Its cardiovascular activity was studied in anesthetized spontaneously hypertensive rats (SHR). Acute intraperitoneal injection of 10 and 20 mg/kg of LY134046 caused minimal cardiovascular changes, while 40 mg/kg resulted in a sustained decrease in mean arterial blood pressure and heart rate. This hypotension and bradycardia occurred rapidly and occurred when brain NMT activity was significantly inhibited. However, norepinephrine concentrations in rat brains were not significantly reduced at the time when LY134046-induced blood pressure and heart rate effects were maximal. The acute cardiovascular activity of LY134046 was not significantly affected by pretreatment of SHR with phentolamine, propranolol, or atropine, and LY134046 reduced heart rate in suspended SHR. In addition, acute or chronic administration of LY134046 did not antagonize the vasoconstrictor responses induced by sympathetic nerve stimulation or exogenous norepinephrine. These observations suggest that LY134046 does not interact with adrenergic or cholinergic receptors and that its hypotensive and bradycardic effects do not require neurogenic tension. Chronic intraperitoneal administration of LY134046 (40 mg/kg/day) resulted in a sustained and significant inhibition of hypothalamic and brainstem NMT activity, leading to central norepinephrine depletion. During chronic treatment, norepinephrine and dopamine concentrations increased in the brainstem and hypothalamus of SHR. Despite chronic inhibition of central NMT and norepinephrine depletion, cardiovascular parameters in SHR treated groups were not significantly different from those in saline-injected controls. Chronic treatment with LY134046 did not result in tolerance to its central biochemical effects or acute cardiovascular activity. The present study does not support the idea that norepinephrine-producing neurons are involved in the central regulation of cardiovascular function, because the hypotension and bradycardia induced by acute administration of LY134046 occurred before a significant decrease in hypothalamic norepinephrine concentrations, whereas chronic inhibition of central NMT and depletion of norepinephrine resulted in minimal changes in baseline cardiovascular parameters.

216.11

C₁₀H₁₁Cl₂N

71274-97-0

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• [1]. Cardiovascular effects of LY134046, an inhibitor of norepinephrine N-methyltransferase, in spontaneously hypertensive rats.