Role of Nitric Oxide in alpha-Melanocyte-Stimulating Hormone-Induced Hypotension in the Nucleus Tractus Solitarii of the Spontaneously Hypertensive Rats

摘要

Pro-opiomelanocortin(POMC)is expressed in the nucleus tractus solitarii(NTS)of the brainstem,where nitric oxide(NO)plays an important role in cardiovascular regulation.The POMC-derived neuropeptides and their receptors are important regulators of energy homeostasis and cardiovascular functions in the central nervous system.In this study,we investigated the cardiovascular effect of alpha-melanocyte-stimulating hormone(alpha-MSH),a POMC-derived neuropeptide,and its relationship with NO pathway in the NTS of spontaneously hypertensive rats(SHR).Unilateral microinjection of a-MSH(0.3-300 pmol)into the NTS resulted in a dose-dependent hypotension and bradycardia in urethane-anesthetized SHR.The a-MSH-induced hypotension was abolished by pretreatment with the antagonist of melanocortin-3/4 receptor(MC-3/4R),Ac-Nle-c[Asp-His-D-Nal(2')-Arg-Trp-Lys]-NH2(SHU9119).Blockade of cAMP/pro-tein kinase A(PKA),the downstream effector of melanocortin receptors,by previous injection of N-[2-(4-bromocinnamylami-no)ethyl]-5-isoquinoline(H89)also ablated the cardiovascular effect of alpha-MSH.To elucidate the role of NO pathway in alpha-MSH-evoked hypotension,pretreatment with N~(omega)-nitro-L-ar-ginine methyl ester,a universal inhibitor of nitric-oxide synthase(NOS),partially reversed the depressor and bradycardic effects of alpha-MSH.Furthermore,previous application of the inducible NOS(iNOS)inhibitor,aminoguanidine,but not the neuronal NOS inhibitor,7-nitroindazole,attenuated the cardiovascular effect of alpha-MSH.Histological analysis revealed the colocaliza-tion of MC-4R,but not MC-3R,with iNOS in the NTS of SHR.In summary,intra-NTS injection of alpha-MSH induces hypotension and bradycardia of SHR via MC-4R signaling,which activates cAMP/PKA and iNOS.