KT3-671, an angiotensin AT1 receptor antagonist, attenuates vascular but not cardiac responses to sympathetic nerve stimulation in pithed rats

Abstract

Effects of KT3-671 on vascular and cardiac sympathetic neurotransmission were investigated in pithed rats. The pressor response to spinal stimulation (5 Hz) of the pithed rat without the adrenals was approximately 75% of that with the adrenals. Guanethidine (8 mg/kg, i.v.) decreased by about 76% the pressor response to sympathetic stimulation in the pithed rat with intact adrenals and the guanethidine-resistant response was almost completely abolished by bilateral adrenalectomy. Therefore, the following experiments were done using the pithed rat without the adrenals. KT3-671 (1-10 mg/kg, i.v.) as well as losartan (1-10 mg/kg, i.v.) inhibited dose-dependently the pressor response to sympathetic stimulation. KT3-671 was approximately four times more potent than losartan in inhibiting the pressor response. The two angiotensin II subtype 1 receptor antagonists (10 mg/kg, i.v.) did not affect the pressor response to exogenously administered norepinephrine. Neither KT3-671 nor losartan influenced the tachycardia induced by spinal stimulation and isoprenaline. Intravenous infusion of angiotensin II (100 ng/kg/min) did not affect both pressor and tachycardic responses to sympathetic stimulation. In conclusion, KT3-671 as well as losartan inhibits vascular but not cardiac sympathetic neurotransmission of the pithed rats, which may contribute to its overall antihypertensive efficacy.