Mechanism of contractile dysfunction induced by serotonin in coronary artery in spontaneously hypertensive rats

Hypertension is one of the risk factors for coronary heart disease. The present study investigated the mechanism of contractile dysfunction induced by serotonin (5-HT) in coronary artery in spontaneously hypertensive rats (SHRs). Coronary arteries were isolated form SHRs and Wistar rats. Arterial ring contraction was measured using a multi myograph system. Intracellular calcium concentration was measured with a Ca 2+ probe fluo-4/AM in vascular smooth muscle cells (VSMCs) isolated from coronary arteries. Signaling pathway–related proteins were assayed by western blotting. A 5-HT 2A receptor blocker, sarpogrelate, completely eliminated coronary artery contraction induced by 5-HT. PLCβ inhibitor U73122 also significantly inhibited the response to 5-HT. Compared with the Wistar rats, serotonin (5-HT)– and CaCl 2 -induced coronary vasoconstriction in the SHRs was significantly reduced. Rho-associated protein kinase inhibitor Y27632, PKC inhibitor rottlerin, and l -type calcium channel blocker nifedipine inhibited the 5-HT-induced coronary artery contraction in a dose-dependent manner in SHRs and Wistar rats. However, the inhibitory effects were reduced in SHRs. In addition, store-operated Ca 2+ (SOC) induced an obvious Ca 2+ influx in coronary arterial smooth muscle cells, whereas SOC-mediated contraction was very slight in coronary arteries. At the same time, it was found that 5-HT 2A R, IP 3 R, and Cav1.2 protein expression and PKCδ activity were decreased, and STIM1 and Orai1 were increased in VSMCs from coronary arteries of SHRs compared with Wistar rats. These results implicate calcium-handling dysfunction mediated by the 5-HT 2A receptor and downstream signaling pathway might lead to a reduction in 5-HT-induced contraction in SHR coronary arteries.