Supersensitivity of Atherosclerotic Rabbit Aorta to Ergonovine

Abstract

A B S T R A C T Patients with coronary vasospasm appear to be supersensitive to the coronary constrictor effects of ergonovine. To determine whether atherosclerosis alters arterial reactivity and sensitizes arteries to ergonovine, contractile responses of isolated aortae from control rabbits and from rabbits fed a highcholesterol diet were compared. Aortic strips were mounted in a myograph for the monitoring of isometric tension, equilibrated in oxygenated Krebs buffer, and exposed to graded concentrations of agonists and antagonists. The concentration-response relation for ergonovine in atherosclerotic arteries exhibited a markedly depressed constrictor threshold concentration (0.5 pM vs. 0.23 uM in controls), a significantly lowered one-half effective dose (ED50) value, and an augmented maximal response. Furthermore, atherosclerotic arteries showed similar, although less pronounced changes in the concentration-response relation for serotonin. In contrast, responses to 34 mM KC1 were virtually identical, and the concentration-response relation for phenylephrine were similar in the two groups. In control arteries, 0.1 ,M phentolamine and 0.1 ,M prazosin suppressed responses to 1 ,uM ergonovine by 71 and 90%, respectively. However, in atherosclerotic arteries a-blockers in the same concentration inhibited responses to 0.01 ,uM ergonovine by less than 10%. On the other hand, 0.1 ,uM cyproheptadine, a serotonergic antagonist, suppressed these responses by 82%. Thus, the supersensitivity to ergonovine appeared to be mediated predominantly by a serotonergic mechanism. These results indicate that smooth muscle in atherosclerotic arteries may be supersensitive to specific vasoconstricting stimuli, a change that might contribute to arterial dysfunction in vivo.

Effect of atherosclerosis on cerebral vascular responses to activation of leukocytes and platelets in monkeys.

“…An example of the response to PGE 2 is shown in Figure 5. PGE 2 in response to PGE2, but the response was variable ( Figure 6). PGE2 produced a marked reduction in blood flow to the retina and choroid of the eye in atherosclerotic animals (/?<0.05 versus control for retina and choroid) ( Figure 6).…”

Vasoconstrictor and vasodilator effects in normal and atherosclerotic conscious rabbits

“…The pressor response to all three agents was similarly enhanced in atherosclerotic animals suggesting a mechanism which does not discriminate between various agonists. Attempts have been made to clarify this hyperresponsiveness of arteriosclerotic vessels by experiments in vitro, but the results differed greatly depending on species and experimental conditions (Henry & Yokoyama, 1980;Godfraind & Miller, 1983;Kawachi et al, 1984;j / Ginsburg et al, 1984;Harrison et al, 1987). The defective endothelium-derived relaxing factor (EDRF) release in atherosclerotic vessels (Freiman et al, 1986;Jayakody et al, 1987a; (EDCF) or endothelin (Yanagisawa et al, 1988) as is found in hypertension or in regenerating endothelium (Luescher & Vanhoutte, 1986;Vanhoutte, 1987;Shimokawa et al, 1987 (Hof et al, 1987), for this purpose.…”

“…This has been shown both in experiments in vitro and in vivo. The enhancement of the vasoconstrictor effect of 5-hydroxytryptamine (5-HT) was among the first of such changes demonstrated experimentally (Henry & Yokoyama, 1980;Shimokawa et al, 1983;Kawachi et al, 1984). Acetylcholine (ACh)-induced relaxation is diminished in atherosclerotic vessels (Freiman et al, 1986, Habib et al, 1986Bossaller et al, 1987a) and this can also be demonstrated angiographically in patients (Ludmer et al, 1986).…”

Effect of hypercholesterolaemia on voltage-operated calcium channel currents in rabbit arterial smooth muscle cells

“…Some studies of cholesterol-fed rabbits have reported increased responses of isolated vessels to KCl 30,31 while others have not. [24][25][26][27] A study of WHHL rabbits did not find an increase in response to KCl. 28 These findings contrast with the consistent increase in reactivity and Ca 2+ influx seen in in vitro studies where isolated arteries or cells are exposed to cholesterol either in the form of liposomes 4,6,7 or as LDL-cholesterol.…”

“…In both cholesterol fed animals and WHHL rabbits responses to serotonin and serotonin receptor agonists have been consistently reported to be increased [24][25][26][27][28] and may be attributable to an increase in 5HT 2 receptor number. 29 In contrast responses to phenylephrine 24,26,28 have generally been reported to be unaffected or reduced. In the case of a depolarizing potassium solution (KCl), which would be expected to act largely or wholly via activation of voltage-operated calcium channels, the literature is contradictory.…”