Selective blockade of serotonin 5-HT2A receptor increases coronary blood flow via augmented cardiac nitric oxide release through 5-HT1B receptor in hypoperfused canine hearts.
Serotonin (5-hydroxytryptamine [5-HT]), which induces vasoconstriction via 5-HT2A receptors in smooth muscle cells and vasodilation through activating nitric oxide (NO) synthase (NOS) via 5-HT1B receptors in endothelial cells, possesses divergent effects on regulating vascular tone. These facts lead us to consider that sarpogrelate, a 5-HT2A receptor blocker, may increase coronary blood flow (CBF) via either attenuation of vasoconstriction through 5-HT2A receptor blockade or augmentation of vasodilation by relative stimulation of NOS through 5-HT1B receptor and we tested this hypothesis in ischemic canine hearts. In open chest dogs, coronary perfusion pressure was reduced so that CBF was decreased to 33% of the baseline and kept constant. Thereafter, sarpogrelate was infused selectively into the left anterior descending artery with and without either an inhibitor of NOS (NG-nitro-L-arginine methyl ester (L-NAME)) or a 5-HT1B receptor antagonist (GR55562). An intracoronary administration of sarpogrelate increased CBF (34.0 +/- 4.0 to 44.5 +/- 4.4 ml/100 g/min, P < 0.05), along with the cardiac NOx release (3.2 +/- 0.6 to 6.8 +/- 1.2 nmol/ml, P < 0.05). The increases in both CBF and NOx by sarpogrelate were completely blunted by the co-administration of either L-NAME or GR55562. Interestingly, sarpogrelate increased the cardiac serotonin release (-4.8 +/- 3.2 vs. 22.1 +/- 1.5 ng/ml, P < 0.05, respectively) in the hypoperfused heart. Immunohistochemical analysis showed that sarpogrelate induced serotonin production in ischemic cardiac myocytes. These results suggest that sarpogrelate increases CBF via augmented cardiac NO production through 5-HT1B receptor activation along with the blockade of 5-HT2A receptors. The increase in cardiac release of serotonin may increase NO production in the ischemic heart.
Fujita
Masashi
M
Division of Cardiology, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Minamino
Tetsuo
T
Sanada
Shoji
S
Asanuma
Hiroshi
H
Hirata
Akio
A
Ogita
Hisakazu
H
Okada
Ken-ichiro
K
Tsukamoto
Osamu
O
Takashima
Seiji
S
Tomoike
Hitonobu
H
Node
Koichi
K
Hori
Masatsugu
M
Kitakaze
Masafumi
M
D000818:Animals; D004285:Dogs; D006321:Heart / Q000187:drug effects*; D007150:Immunohistochemistry; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000097:blood*; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D012701:Serotonin / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D058830:Serotonin 5-HT2 Receptor Antagonists; D013386:Succinates / Q000494:pharmacology*; D013997:Time Factors
D044302:Receptor, Serotonin, 5-HT1B; D058830:Serotonin 5-HT2 Receptor Antagonists; D013386:Succinates; C064294:sarpogrelate; D009569:Nitric Oxide; D012701:Serotonin