Hyperreactivity of coronary arterial smooth muscles in response to ergonovine from rabbits with hereditary hyperlipidemia.

Abstract

SUMMARY. This study was undertaken to examine the response to ergonovine, an agent used to provoke spastic constriction of large epicardial coronary arteries, to elucidate the, responsible underlying mechanism, and to determine the impact of endogenous hyperlipidemia on contractile properties of isolated vessels from different beds. The isolated arteries from both control and Watanabe hereditary hyperlipidemic rabbits (WHHL rabbits) were suspended for recording isometric force in oxygenated Krebs buffer and exposed to agonists and antagonists. In atherosclerotic aortas from WHHL rabbits, the concentration-response relations for ergonovine and serotonin exhibited a marked leftward shift with significantly depressed constrictor threshold concentration and lowered one-half maximally effective concentration values. In coronary arteries with no atherosclerotic lesions detectable macroscopically from WHHL rabbits, the concentrationresponse relations showed a leftward shift for ergonovine but not for serotonin. Coronary contraction evoked by ergonovine was remarkably inhibited by 0.1 tiu cyproheptadine and 0.3 /iM methysergide, serotonergic antagonists, in both groups. a-Adrenergic blockade with 0.1 JZM prazosin was effective in inhibiting ergonovine-induced contraction of aortas from control rabbits, but not that of atherosclerotic ones. The constrictor response to ergonovine of atherosclerotic aortas was inhibited by cyproheptadine. The responsiveness to ergonovine of both carotid and femoral arteries from WHHL rabbits with no sclerotic lesions, which was suppressed by prazosin was not different from that of control rabbits. In contrast, the concentration-response relations for phenylephrine in the four different types of arteries did not differ appreciably between the two groups, and the constrictor responses to 20 ITIM KG were virtually identical. Thus, aortas and coronary arteries exposed to endogenous hyperlipidemia appear to be hyperreactive to ergonovine mediated by a serotonergic mechanism. (Circ Res 53: 63-71, 1983)

Augmented vasoconstrictor responses to serotonin precede development of atherosclerosis in aorta of WHHL rabbit.

“…No differences in methacholine-induced relaxations were observed between control NZW and hypercholesterolemic NZW rabbits, indicating that, as with the serotonin responses, the condition of hypercholesterolemia alone does not explain the altered responses in aortas of 1-month-old WHHL rabbits. Verbeuren and coworkers 16 reported a reduced vasodilation with acetylchoiine in cholesterol-fed rabbits. They attributed this effect to intimal thickening and lipid accumulation producing a barrier that prevented the endothelial vasodilatory factor from reaching the smooth muscle.…”

“…These studies demonstrate selective augmentation of the contractile response to serotonin. Potentiated vasoconstrictor responses to serotonin have been reported in atherosclerotic aortas from 24-month-old WHHL rabbits 16 and from rabbits and monkeys chronically fed a high-cholesterol diet. 1718 Enhanced responses were also noted in the deenddthelialized canine coronary artery.…”

Impairment of Endothelium-Dependent Arterial Relaxation By High-Fat Feeding in ApoE-Deficient Mice

“…[3][4][5][6][7][8][9][10][11]12 In addition, hyperlipidemia and atherosclerosis can be associated with abnormal vasoconstrictor responses. [13][14][15][16][17] Reduced ␣-adrenergic contractile responses but increased serotonergic contractile responses were reported in hyperlipidemic rabbits. 11,12 On aortic rings mounted in organ chambers, oxidized LDL can mimic the arterial dysfunctions observed in dyslipidemic subjects, and 2 oxidized LDL derivatives, lysolecithins 18,19 and cholesterol oxides, 20 constitute potent inhibitors of the endotheliumdependent arterial relaxation through the inhibition of the nitric oxide release.…”

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.…”

“…23 Hypercholesterolaemia has also been shown to increase the reactivity of isolated arterial smooth muscle in vitro. 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.…”