Sensitization of isolated canine coronary arteries to calcium ions after exposure to cholesterol.

Abstract

The abundance of membrane cholesterol is an important determinant of the functional properties of biomembranes. To determine whether arterial smooth muscle acquires altered contractile properties in a high cholesterol environment, isolated canine coronary arteries were exposed to cholesterol in stable aqueous solution. Cholesterol, 10(-12) to 10(-10) M, was an efficacious vasoconstrictor, as maximum contractions equaled those obtained with 15 mM KCl. Antiadrenergic interventions, including chemical sympathectomy in vivo with 6-hydroxydopamine and alpha- and beta-adrenergic blockade with phentolamine and L-propranolol (both 10(-6 M), did not significantly attenuate the contractions. However, responses to cholesterol were abolished completely by (+/-)-verapamil (10(-6) M). Cholesterol in picomolar concentration enhanced the constrictor effects of CaCl2 and KCl, both in the presence and absence of alpha- and beta-adrenergic blockade. Increases in tone in response to graded elevations in the CaCl2 concentration (0-2 mM) were augmented up to 1.5-fold by 10(-12) M cholesterol (P less than 0.01). Results indicate that cholesterol sensitizes isolated coronary arteries to external Ca2+ by a nonadrenergic mechanism. The findings are consistent with the hypothesis that acquisition of membrane cholesterol may alter the contractile properties of coronary arterial smooth muscle, a phenomenon that could play a role in the pathophysiology of atherosclerotic heart disease.

Supersensitivity of Atherosclerotic Rabbit Aorta to Ergonovine

“…Results demonstrate that isolated aortae from rabbits fed a high-cholesterol diet are supersensitive to the constrictor effects of ergonovine. This finding is in agreement with previous studies (12,13) indicating that changes in the lipid environment of vascular smooth muscle may alter arterial contractility.…”

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

“…17 Hypercholesterolemia, however, may be a significant factor in the diminished response to norepinephrine, since the vasoconstrictor response to norepinephrine was reduced in both the WHHL rabbit aortas and the hypercholesterolemic NZW rabbit aortas. Yokoyama and Henry 6 have previously shown that cholesterol added to the tissue baths augmented the responses of isolated arteries to the vasoconstrictor effects of CaCI 2 and KCI. The present study failed to demonstrate an increased response to KCI in aortic rings from WHHL rabbits compared with NZW rabbits.…”

“…Other investigators have suggested that hypercholesterotemia per se may augment the reactivity of blood vessels. 6 In the present investigation, we hypothesized that augmented vasoconstrictor responses occur in blood vessels obtained from hypercholesterolemic animals that are prone to devebp atherosclerosis.In these studies, we used the Watanabe heritable hyperiipidemic (WHHL) rabbit. 7 * Homozygous WHHL rabbtts produced by serial inbreeding have plasma cholesterol concentrations of 500 to 950 mg/dl, develop grossly visible aortic atherosclerosis by 5 months of age, 8 -1011 and have decreased numbers of functioning low density lipoprotein (LDL) receptors in several tissues.…”

“…Other investigators have suggested that hypercholesterotemia per se may augment the reactivity of blood vessels. 6 In the present investigation, we hypothesized that augmented vasoconstrictor responses occur in blood vessels obtained from hypercholesterolemic animals that are prone to devebp atherosclerosis.…”

Endothelial Function and Coronary Spastic Angina

“…Recently, Shimokawa and his colleagues reported that protein kinase C and Rho-kinase activity are augmented in coronary smooth muscle in animal models of coronary spasm (36). Thus, coronary spasm may also be caused by hypercontraction of coronary smooth muscle in response to an increase of intracellular calcium ions (41,42). Calcium antagonists, which can block the entry of calcium ions into the cell, are highly effective in suppressing coronary spasm (43).…”