Hypercholesterolemia contributes to the progression of atherosclerosis, coronary heart disease, and hypertension in humans. Normotensive hypercholesterolemic patients develop cardiac (leftventricular) concentric remodeling by unknown mechanisms. We used the cholesterol-fed guinea pig to examine the effects of hypercholesterolemia on cardiovascular homeostatic mechanisms. Guinea pigs that consumed a 1% dietary cholesterol regimen for 13 weeks developed cardiac concentric remodeling of the left ventricle, which was characterized by an increase in relative left ventricular wall thickness without an increase in left ventricular mass. Fractional shortening, a determinant of cardiac contractility, was unchanged. The baroreceptor reflex (BR) modulates mean arterial pressure by regulating sympathetic and parasympathetic discharge to the heart and vasculature. BR activity was impaired in hypercholesterolemic guinea pigs although these animals were normotensive. The gain and sensitivity of the BR were markedly diminished. A loss of BR activity in guinea pigs with cholesterol-induced cardiac concentric remodeling may be attributed to many mechanisms involved in autonomic regulation. Our studies determined that hyperholesterolemia may disrupt central processing of baroafferent function, and causes both down-regulation of cardiac -adrenoceptors and elevations in intrinsic heart rate. Systemic injections of the 5-HT3 receptor agonist phenylbiguanide, elicit Bezold-Jarisch reflex (BJR)- mediated falls in heart rate and mean arterial blood pressure. The BJR responses elicited by phenylbiguanide in conscious control and cholesterol-fed guinea pigs were due primarily to increases in cardiovagal drive. The BJR responses elicited by phenylbiguanide were reduced in hypercholesterolemic animals perhaps by down-regulation of 5-HT3 receptors rather than diminished central/efferent processing of the BJR reflex. We also obtained evidence that hypercholesterolemia markedly affects the rate of desensitization/resensitization of 5-HT3 receptors and that endogenous nitrosyl factors in vagal afferents of the rat regulate the rate of desensitization/resensitization of 5-HT3 receptors on vagal afferents mediating the BJR. Finally, we found that endothelium-dependent relaxation was reduced in cholesterol-fed guinea pigs via the reduced potency of endothelium-derived L-S-nitrosocysteine and that these guinea pigs have diminished vesicular stores of L-S-nitrosocysteine. Keywords: Hypercholesterolemia, concentric cardiac remodeling, echocardiography, cardiac morphology, baroreceptor heart rate reflex, Bezold-Jarisch reflex, endothelium-derived relaxing factors, nitric oxide, S-nitrosothiols.