Smooth muscles from spastic coronary artery segments show hypercontractility to histamine

Abstract

An animal model of coronary spasm was produced in Göttingen miniature pigs by a selective endothelial denudation of the coronary artery. Five months after the denudation, intracoronary bolus administration of 10 micrograms/kg histamine reduced the luminal diameter angiographically by 57 +/- 16 and 17 +/- 10% (P less than 0.01) in the previously denuded and contralateral control coronary arteries. Muscle fibers of 0.08-0.1 mm wide were prepared from circumferential bundles of the medial smooth muscle in the spastic and nonspastic coronary arteries. Upward shifts of either dose-tonic contraction relationships in Ca2(+)-containing solution or dose-monophasic contraction relationships in Ca2(+)-free solution were noted in muscle fibers taken from the spastic site compared with those from the nonspastic site with no difference between the mean effective dose values. After skinning the muscle fibers with saponin, there was no significant difference in the Ca2+ concentration-tension relationships between the two fibers. These findings suggest that an increased number of histaminergic receptors and/or augmentation of signal transduction, but not Ca2+ sensitivity of the contractile proteins in the medial smooth muscle cells, cause histamine-induced coronary hypercontraction.

Preserved endothelium-dependent vasodilation at the vasospastic site in patients with variant angina.

“…These results suggest not only that endothelial dysfunction is not prerequisite to coronary vasospasm, but also that acetylcholine-induced vasospasm results primarily from augmented vasoconstriction of vascular smooth muscle to acetylcholine. The results are consistent with our previous works in miniature pigs with coronary artery spasm (16)(17)(18)(19)(20). In this animal model of coronary vasospasm, vascular smooth muscle from the spastic segments show markedly augmented responses to histamine and serotonin as compared to those ofthe nonspastic segments.…”

“…Thus, provocation of vasospasm by acetylcholine may result from enhanced vasoconstricting responses of vascular smooth muscle but may not be related to endothelial dysfunction. In fact, the previous studies in our laboratory in miniature pigs have indicated that smooth muscle at the spastic site demonstrates markedly enhanced responses to vasoconstricting agents such as histamine or serotonin (16)(17)(18)(19)(20). It also has been shown that atherosclerosis not only impairs endothelium-dependent vasodilation (10, 1 1), but also augments the constrictive responses of vascular smooth muscle to vasoactive agents (1,2,21).…”

Role of protein kinase C-mediated pathway in the pathogenesis of coronary artery spasm in a swine model.

“…In our swine model, smooth muscle contraction to autacoids (serotonin and histamine) is augmented, endothelium-dependent relaxations to the autacoids are reduced,8'9 and calcium sensitivity of the contractile proteins in smooth muscle per se is not augmented at the spastic site. 10 Thus, the key mechanism(s) for smooth muscle hyperconstriction appears to exist in the signal transduction pathway at a level between receptors and the contractile proteins.…”

Coronary Artery Spasm, Part II Basic Aspects

“…If endothelial dysfunction plays a primary role in the pathogenesis of coronary spasm, then the prevalence and severity of endothelial dysfunction in the coronary artery would be greater and/or more frequent in Japanese patients with vasospastic angina than in Caucasian counterparts, which however may not be the case. Contractility of coronary VSMC is indeed augmented at the spastic coronary segment in a patient with variant angina (Yokoyama et al 1990) and as mentioned later in detail, in the porcine models of coronary artery spasm (Satoh et al 1990;Katsumata et al 1997). Furthermore, it has been recently demonstrated in the new porcine model that VSMC hypercontraction plays a primary role while endothelial vasodilator function is fairly well preserved both in vivo and in vitro (Miyata et al 1999).…”

“…However, the vasocontracting response to increasing concentrations of Ca 2+ is unaltered in saponin-induced skinned smooth muscle from spastic coronary artery in the porcine model with endothelium removal and high-cholesterol feeding (Satoh et al 1990). Subsequently, it was also reported that the vasocontractory response to increasing concentrations of Ca 2+ is unaltered in aortic smooth muscle from Watanabe hereditary hyperlipidemic rabbits as compared with normal rabbits (Miwa et al 1994).…”