Enhanced coronary vasoconstrictive response to serotonin subsides after removal of dietary cholesterol in atherosclerotic monkeys.

Abstract

Constriction in response to serotonin is enhanced in the coronary arteries of atherosclerotic monkeys. The main objective of the present study was to determine whether abnormal responses to serotonin in atherosclerosis are reversed following removal of dietary cholesterol. In addition, we examined the effect of an atherogenic diet and reduction in dietary cholesterol on vascular responses to activation of ATP-sensitive K + channels with aprikalim. Diameters of small coronary arteries were measured on the epicardial surface of the left ventricle in vivo by using stroboscopic illumination synchronized to the heart cycle to visually freeze the motion of the heart. Diameters were measured with a microscope-video system during topical application of two vasoconstrictor agonists, serotonin and the thromboxane mimetic U46619, and the vasodilator agonists aprikalim and nitroprusside. Responses V ascular responsiveness to several agonists is altered by atherosclerosis, 17 and coronary vasoconstrictor responses to serotonin are augmented in patients with atherosclerosis or unstable angina. 56 Coronary microvessels relax in response to serotonin in normal monkeys and constrict in atherosclerotic animals.8 Thus, vasomotor abnormalities of atherosclerosis extend to the coronary microcirculation despite an absence of morphological evidence of disease.8 " A critical question is whether abnormal vascular responses in the atherosclerotic coronary circulation can be restored to normal by reducing dietary cholesterol. Reduction of dietary cholesterol reduces the intimal area of arteries as lipids are reabsorbed from the vessel wall.1214 Fibrosis progresses within the artery, however, so that maximal vasodilator responses do not improve consistently. 13 Nevertheless, studies in the hindlimb and cerebral circulation suggest improvement in vascular function after regression of atherosclerosis, with restoration of endothelium-dependent relaxation 15 and reduction in abnormal vasoconstriction in response to serotonin. 1617 It is unclear whether reductions in dietary cholesterol restore vascular reactivity of the coronary circulation to normal. The major objective of the present study was to determine whether reduction were compared in normal (n=9), atherosclerotic (n=14; highcholesterol diet), and regression (n=8; high-cholesterol diet followed by normal diet) monkeys. Constriction of coronary arteries in response to serotonin was enhanced in monkeys on an atherogenic diet and was normal in regression monkeys. Vasoconstriction in response to U46619 and vasodilation in response to nitroprusside and aprikalim were not altered by atherosclerosis. Thus, abnormal vascular responses to serotonin in small coronary arteries of atherosclerotic monkeys without morphological evidence of disease can be reversed to normal by reducing dietary cholesterol. (Arterioscler Thromb. 1994;14:951-957.) Key Words • serotonin • U46619 • aprikalim • nitroprusside • coronary resistance of dietary cholesterol in atherosclerotic monkeys abolishes v...

Prevention of Coronary Hyperreactivity in Preatherogenic Menopausal Rhesus Monkeys by Transdermal Progesterone

“…37 Reducing dietary cholesterol reverses abnormal vascular responses to serotonin in atherosclerotic monkeys without structural CAD. 38 In conjunction with reabsorption of lipid from the arterial wall, these early functional improvements in vasoconstriction occur well before changes in the mass of the atherosclerotic lesion can be detected. 39 Similarly, despite little reduction in size of intimal lesions after regression of atherosclerosis, attenuation of carotid and ocular artery vasoconstrictor hyperresponsiveness to serotonin and platelet activation has been observed.…”

Role of Sex Differences and Effects of Endothelial NO Synthase Deficiency in Responses of Carotid Arteries to Serotonin

“…For example, atherosclerosis is associated with hyperresponsiveness to serotonin, which tends to be greater than that observed with other vasoconstrictors. 31,32 In previous studies from our laboratory, relaxation of coronary arteries to serotonin was impaired in genetically altered, hypercholesterolemic mice at a time when vasorelaxation to acetylcholine was still normal. 27 In the present study, sex differences in vascular responses were more easily detected with the use of serotonin compared with acetylcholine or U46619.…”

Hypercholesterolemia Impairs Transduction of Vasodilator Signals Derived From Ischemic Myocardium

“…There are some articles reporting that several agonists (acetylcholine, serotonin, a thromboxane analogue, endothelin, etc) produce enhanced constriction in coronary microvessels from hypercholesterolemic animals. 6,19,25,26 Because such augmented constriction has been reported in monkeys and pigs so far, it is not clear whether the enhanced constriction takes place in rabbit coronary microvessels. However, we cannot exclude the possibility that the enhanced constriction of coronary microvessels from hypercholesterolemia may have masked the ischemiainduced coronary dilation.…”