Angiotensin II type 2 receptor-mediated inhibition of norepinephrine release in isolated rat hearts.
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY(2008)
摘要
We investigated wheather endogenous and exogenous angiotensin II (Ang II) regulated norepinephrine (NE) release from cardiac sympathetic nerves via both Ang II type 2 receptors (AT(2)Rs) and Ang II type I receptors (AT(1)Rs). Using isolated rat hearts, sympathetic nerves were electrically stimulated. Ang II with PD-1233196 (AT(2)R antagonist) but not Ang II alone produced a significant increase in nerve stimulation-induced NE overflow, which was abolished by the addition of AT(1)R antagonist losartan. In contrast, NE overlfow was markedly decreased by losartan with or without Ang II. This decrease was abolished by the combination with PD-123319, nitric oxide (NO) synthase inhibitor N-G-nitro-L-arginine (NOARG), icatibant (bradykinin B-2 receptor antagonist), or PKSI-527 (kinino-genase inhibitor). CGP-42112A (AT(2)R agonist) suppressed nerve stimulation-induced NE overflow in the same way as the combination of Ang II NOARG, icatibant. or PKSI-527. There were significant increases in NOx (NO2/NO3) contents in coronary effluent under conditions where NE overlfow was suppressed. Ang II seems to function as an inhibitory modulator of cardiac noradrenergic neuro-transmission via AT(2)Rs and well-known, AT(1)R-mediated stimulatory actions. The inhibitory mechanism may involve local bradykinin production, its B-2 receptor activation, and NO as a downstream effector.
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关键词
angiotensin II,AT(2) receptor,sympathetic neurotransmission,norepinephrine,nitric oxide,bradykinin
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