Effects of serotonin-receptor blockade on angioplasty-induced vasospasm in an atherosclerotic rabbit model.

Abstract

Vasospasm occurs both in patients and animal models after angioplasty and may be associated with early closure of the dilated vessel. To investigate the mechanism of angioplasty-induced vasospasm, the effect of serotonin-receptor blockade with two serotonin? (SJ antagonists, LY53857 and sergolexole, was examined in rabbits with focal femoral artery atherosclerosis. In preliminary studies, local infusion of 1-100 /ig serotonin caused significant femoral artery vasoconstriction (p<0.05) in both normal and atherosclerotic rabbits. There was no significant difference in the degree of vasoconstriction induced by equal doses of serotonin in normal and atherosclerotic animals. Infusion of 10 fig serotonin produced a 23 ±5% decrease in luminal diameter in atherosclerotic femoral arteries. This was blocked by pretreatment with both S 2 inhibitors given separately in different animals before serotonin infusion (/?< 0.002). In contrast, LY53857 (sergolexole was not tested) had no significant effect on phenylephrineinduced vasoconstriction, confirming its specificity as an S^-receptor antagonist Balloon angioplasty of atherosclerotic vessels caused a significant increase in vessel diameter at the angioplasty site (45% increase from baseline diameter, p<0.05). This was associated with significant luminal narrowing both proximal (21% redaction from baseline, p<0.05) and distal (17% reduction from baseline, p<0.03) to the angioplasty site. These proximal and distal changes are most likely due to vasospasm, as there was no histological evidence of thrombus or dissection at these sites to explain the luminal narrowing. Pretreatment of animals with 10 mg LY53857 or 20 mg sergolexole blocked the proximal vasospasm (2.6±0.4 before versus 2.2±0.1 mm after angioplasty for LY53857, 2.1 ±0.4 before versus 2.1 ±0.4 mm after angioplasty for sergolexole; p=NS). Treatment with 20 mg LY53857 inhibited both proximal (2J±0.1 before versus 2.2±0.2 mm after angioplasty, p=NS) and distal (1.7±0.1 before versus 1.6±0.2 mm after angioplasty, p=NS) vasospasm after angioplasty. Proximal (2.3 ±0.5 before versus 2.5±0.3 mm after) and distal (1.7±0.2 before versus 1.7±0.4 mm after) vasospasm was also prevented by pretreatment with 40 mg sergolexole. We conclude that 1) serotonin-induced vasoconstriction in normal and atherosclerotic rabbit femoral arteries is mediated in part by Sj receptors since it can be blocked by the specific antagonists LY53857 and sergolexole; 2) the specificity of LY53857 action is confirmed by its lack of inhibition of <x-adrenergic-mediated vasoconstriction by phenylephrine infusion; and 3) S 2 -receptor blockade inhibits angioplastyinduced vasospasm, suggesting that it may also be mediated by serotonin, perhaps released by platelets activated at the site of balloon angioplasty. Thus, this study suggests that S 2 -receptor antagonists may be useful in preventing arterial spasm after angioplasty. (Arteriosclerosis and Thrombosis 1991;ll:770-783) T he mechanism of acute closure after angioplasty is not definitely known. There i...

Roles of Serotonin in Atherothrombosis and Related Diseases

“…In systemic arterial smooth muscle, 5-HT induces contractions only at sites of endothelial damage where platelet aggregation occurs, and this effect is antagonized by 5-HT 2 receptor antagonists (Sigal et al, 1991). Serotonin also amplifies the effects of other vasoconstrictors, such as histamine, angiotensin II, prostaglandin F 2 , and noradrenaline (O'Rourke et al, 2006).…”

“…Functional analyses of the roles of 5-HT in the cardiovascular system using 5-HT 2A receptor knockout mice have not been performed. Several studies performed before the discovery of specific and/or selective 5-HT 2A receptor antagonists indicated that 5-HT 2 receptor blockers inhibit angioplasty-induced vasospasm and microvascular constriction following atherosclerotic plaque rupture in atherosclerotic rabbit models (Sigal et al, 1991;Taylor et al, 2004).…”

Platelet-induced vascular smooth muscle cell proliferation is modulated by the growth amplification factors serotonin and adenosine diphosphate.

“…After balloon angioplasty of atherosclerotic femoral arteries in rabbits, coronary spasm occurs that is prevented by serotonin antagonists. 42 High concentrations of serotonin have been measured in the coronary sinus following angioplasty in patients with atherosclerotic coronary artery lesions. 43 Therefore, angioplasty and other acute vascular events appear to release serotonin from platelets that may reach concentrations in local vascular tissue comparable to those used in our in vitro experiments.…”

Potentiation of the vasospastic response to angioplasty by pretreatment with fluoxetine. A study in the atherosclerotic rabbit.

“…Ten micrograms of serotonin, a dose previously shown to produce significant vasoconstriction, was given as a bolus injection through the catheter. 22 Angiography was repeated 5 minutes later to assess the effect of the infusion on angiographic luminal diameter. Angiography was repeated 45 minutes after administration of the serotonin to confirm that angiographic dimensions had returned to baseline.…”

“…receptor antagonists can prevent angioplasty-induced vasospasm both proximal and distal to the treated site. 22 This suggests that serotonin released from activated platelets at the site of balloon angioplasty may be an important mediator of angioplasty-induced vasospasm.…”