Verapamil suppresses atherosclerosis in cholesterol-fed rabbits

Abstract

The effect of verapamil, a drug that reduces the concentration of intracellular calcium, on atherogenesis was evaluated in rabbits fed a cholesterol-rich diet for 10 weeks. Ten rabbits received oral verapamil, 8 mg/kg daily; eight received the same oral dose and 0.5 mg/kg daily subcutaneously; nine received oral lanthanum, 35 mg/kg daily, and nine were controls. Over the 10 week period, all groups had average serum cholesterol levels greater than 1,500 mg/dl (normal = 90 +/- 63 mg/dl). At the end of the experiment, the aortas were removed, opened and stained for lipid with Sudan IV. The extent of atherosclerosis was determined by planimetry. The group receiving oral and parenteral verapamil had significantly less atherosclerosis (25 +/- 26% of total intimal area; mean +/- standard deviation), as compared with the controls (73 +/- 24%). Reduction of atherosclerosis with oral verapamil (51 +/- 22%) and lanthanum (59 +/- 31) was not statistically significant. Indexes of contractility in isolated right ventricular papillary muscles (developed tension at maximal length [Lmax] and maximal velocity of shortening [Vmax]) were reduced in the group treated with oral and parenteral verapamil, but not in the others. It is concluded that verapamil suppresses the development of atherosclerosis in rabbits fed a cholesterol-rich diet.

Verapamil enhances receptor-mediated endocytosis of low density lipoproteins by aortic cells in culture.

“…During the past few years, attenuation of the development of experimental atherosclerosis by calcium antagonists has been reported. 8 - 10 The Ca + + channel blockers, nifedipine 11 and verapamil, 12 have been shown to suppress atherogenesis in cholesterol-fed rabbits, while aortic, but not intramural, coronary atherosclerosis was affected by diltiazem and flunarizine. 13 In all of these studies, the degree of atherosclerosis was determined morphologically by staining the total aortic intima for lipid with Sudan IV.…”

No effect of nifedipine on atherogenesis in cholesterol-fed rabbits.

“…Figure 3 shows typical curves of the specific activity in plasma of free cholesterol, of esterified cholesterol, and of protein from the time of injection until the aorta was removed. The ratio between the specific activity of free cholesterol and the specific activity of esterified cholesterol was much higher for 3 H than for 14 C during the entire period. This is a condition for the solution of Equations (1) and (2).…”

“…A similar lack of effect on concentration of plasma lipoproteins was found in cholesterol-fed rabbits treated with verapamil. 3 Esterified cholesterol in the intima and inner media is considered a sensitive marker of atherosclerotic lesions in rabbits, since it only occurs in the aortic tissue after the rabbits have been hypercholesterolemic for several weeks. 8 Neither in the intima-media layer of the proximal thoracic aorta, a region with high cholesterol concentration, nor in the intima-media layer of the distal thoracic aorta, a region with low cholesterol concentration, did nifedipine influence the accumulation of esterified and free cholesterol (Table 1).…”

“…Plasma labeled in vivo with 3 H and 14 C-cholesterol and serum proteins labeled in vivo with 3 H-leucine were injected intravenously into 24 rabbits 4 to 6 hours before sacrifice. The doubly labeled lipoproteins were obtained from four donor rabbits, each intravenously injected with 4.0 mCi of 1a,2a(n)-3 Hcholesterol (Amersham) in alcoholic saline, and at the same time fed 0.4 mCi of 4-14 C-cholesterol (Amersham).…”

Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. I. Characterization of cellular lipid metabolism.

“…1 " 8 In addition, some of these drugs have been shown to exert antiatherogenic effects in animals with dietary hypercholesterolemia. 9 " 20 However, two groups of Investigators did not find antiatherogenic effects in cholesterol-fed rabbits. 21 ' a The reason Watanabe rabbits did not respond favorably to nifedipine 23 is not yet clear, but these studies should be repeated in larger groups of animals.…”