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-D-Nal(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 Nomega-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.
Tai
Ming-Hong
MH
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, and Graduate Institute of Biochemistry, Kaohsiung Medical University, 386 Ta-Chung 1st Road, Kaohsiung 813, Taiwan.
Weng
Wen-Tsan
WT
Lo
Wan-Chen
WC
Chan
Julie Y H
JY
Lin
Che-Jen
CJ
Lam
Hing-Chung
HC
Tseng
Ching-Jiunn
CJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008845:Microinjections; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D044105:Receptor, Melanocortin, Type 4 / Q000032:analysis / Q000502:physiology; D015398:Signal Transduction; D017552:Solitary Nucleus / Q000187:drug effects* / Q000502:physiology; D000521:alpha-MSH / Q000494:pharmacology*
D044105:Receptor, Melanocortin, Type 4; D009569:Nitric Oxide; D000521:alpha-MSH; D017868:Cyclic AMP-Dependent Protein Kinases; D019331:NG-Nitroarginine Methyl Ester