Role of nitric oxide in alpha-melanocyte-stimulating hormone-induced hypotension in the nucleus tractus solitarii of the spontaneously hypertensive rats.

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 alpha- MSH ( 0.3 - 300 pmol) into the NTS resulted in a dose- dependent hypotension and bradycardia in urethane- anesthetized SHR. The alpha- MSH- induced hypotension was abolished by pretreatment with the antagonist of melanocortin- 3/ 4 receptor ( MC- 3/ 4R), Ac- Nle- c[ Asp- His- DNal( 2')- Arg- Trp- Lys]- NH2 ( SHU9119). Blockade of cAMP/ protein kinase A ( PKA), the downstream effector of melanocortin receptors, by previous injection of N-[ 2-( 4- bromocinnamylamino) 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- arginine 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 colocalization 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.