PT  - JOURNAL ARTICLE
AU  - Ming-Hong Tai
AU  - Wen-Tsan Weng
AU  - Wan-Chen Lo
AU  - Julie Y. H. Chan
AU  - Che-Jen Lin
AU  - Hing-Chung Lam
AU  - Ching-Jiunn Tseng
TI  - Role of Nitric Oxide in α-Melanocyte-Stimulating Hormone-Induced Hypotension in the Nucleus Tractus Solitarii of the Spontaneously Hypertensive Rats
AID  - 10.1124/jpet.106.118299
DP  - 2007 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 455--461
VI  - 321
IP  - 2
4099  - http://jpet.aspetjournals.org/content/321/2/455.short
4100  - http://jpet.aspetjournals.org/content/321/2/455.full
SO  - J Pharmacol Exp Ther2007 May 01; 321
AB  - 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 α-melanocyte-stimulating hormone (α-MSH), a POMC-derived neuropeptide, and its relationship with NO pathway in the NTS of spontaneously hypertensive rats (SHR). Unilateral microinjection of α-MSH (0.3–300 pmol) into the NTS resulted in a dose-dependent hypotension and bradycardia in urethane-anesthetized SHR. The α-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 α-MSH. To elucidate the role of NO pathway in α-MSH-evoked hypotension, pretreatment with Nω-nitro-l-arginine methyl ester, a universal inhibitor of nitric-oxide synthase (NOS), partially reversed the depressor and bradycardic effects of α-MSH. Furthermore, previous application of the inducible NOS (iNOS) inhibitor, aminoguanidine, but not the neuronal NOS inhibitor, 7-nitroindazole, attenuated the cardiovascular effect of α-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 α-MSH induces hypotension and bradycardia of SHR via MC-4R signaling, which activates cAMP/PKA and iNOS. The American Society for Pharmacology and Experimental Therapeutics