calcimycin and Hypertension--Renovascular

Coronary endothelial dysfunction is associated with an increase in cardiac events. Hypercholesterolemia (HC) and hypertension (HT) are both associated with endothelial dysfunction, and their coexistence is associated with an increased incidence of cardiac events in epidemiological studies. However, pathogenic mechanisms are poorly understood. Here we studied the effects of coexisting HC and HT on coronary endothelial function.. Four groups of pigs were studied after 12 weeks of a normal diet (n=9), a 2% HC diet (n=9), HT (achieved by unilateral renal artery stenosis, n=8), or HC+HT (n=6). Coronary endothelial function was tested, in epicardial arteries and arterioles, by using organ chamber techniques. Oxidative stress was measured in coronary artery tissue. Vasodilatory response to bradykinin and calcium ionophore was significantly impaired in animals with HC+HT compared with each risk factor alone (P<0.05 for both). In animals with coexistent HC and HT, the increase in oxidative stress was more pronounced compared with each risk factor alone (P<0.05). Furthermore, chronic antioxidant supplementation significantly improved coronary artery vasoreactivity.. These results suggest that HC and HT have a synergistic deleterious effect on coronary endothelial function, associated with increased oxidative stress. This interaction may contribute to the increased incidence of coronary heart disease and cardiac events seen when HC and HT coexist.

Topics: Animals; Antioxidants; Ascorbic Acid; Bradykinin; Calcimycin; Coronary Artery Disease; Coronary Vessels; Cyclic GMP; Diet, Atherogenic; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Hypercholesterolemia; Hypertension, Renovascular; Lipids; Nitric Oxide; Nitroprusside; Oxidative Stress; Renal Artery Obstruction; Renin; Substance P; Swine; Vasodilator Agents; Vitamin E

Previous studies have shown that hypertension causes endothelial dysfunction. To study the influence of exogenous nitric oxide(NO) on endothelial dysfunction produced by hypertension, we administered a non-depressor dose of nipradilol to two-kidney, one-clip renovascular hypertensive rats(2K1C). Sprague-Dawley rats underwent either sham surgery(G-1) or clipping of the left renal artery. From day seven, 2K1C were randomized into 3 groups, placebo treatment(G-2), nipradilol treatment(G-3,) and propranolol treatment(G-4). Urinary NO2- + NO3-(NOx) excretion (UNOx V) was measured 4 weeks after clipping, and then, acetylcholine(Ach), A23187, or sodium nitroprusside(SNP)-induced relaxation were measured in the aorta. Blood pressure was increased in G-2, G-3, and G-4 compared to G-1. UNOx V was lower in G-2, G-3, and G-4 compared to G-1, but UNOx V was higher in G-3 compared to G-2 and G-4. Although Ach or A23187-induced relaxation was significantly decreased in isolated artery from G-2, G-3, and G-4 compared with those from G-1. Ach- or A23187-induced relaxation was improved in G-3. SNP-induced relaxation did not differ among the 4 groups. These results suggest that exogenous NO from nipradilol reduces the endothelial dysfunction caused by hypertension without changing the blood pressure.

Topics: Acetylcholine; Animals; Blood Pressure; Calcimycin; Disease Models, Animal; Endothelium, Vascular; Hypertension, Renovascular; In Vitro Techniques; Male; Nitric Oxide; Nitric Oxide Donors; Propanolamines; Rats; Rats, Wistar; Vasodilation

Hypertension is an established risk factor for atherosclerosis, a disease that is important in the pathophysiology of vein graft failure. Hypertension can also alter arterial vasoreactivity. The vasomotor function and histologic characteristics of autogenous vein grafts in hypertensive rabbits were assessed in this study. Hypertension was induced in 13 male New Zealand white rabbits by use of the Goldblatt one clip two kidney method. The right carotid artery was divided and bypassed with the reversed right external jugular vein 7 days later in these animals and in 13 normotensive controls. Blood pressure and renal function were assessed serially, and all the grafts were harvested after 28 days. Three grafts in each group were examined by light microscopy. The responses of the remaining grafts to norepinephrine, histamine, serotonin, and angiotensin II were determined in vitro under isometric tension. Endothelium-dependent relaxation to acetylcholine and calcium ionophore (A23187) was assessed in precontracted grafts. The mean arterial pressure was significantly increased after the Goldblatt procedure was performed. Intimal hyperplasia was observed in both groups, but the grafts in the hypertensive groups showed increased adventitial and medial fibrosis and a reduced number of vasa vasora. The grafts in the hypertensive rabbits were hypersensitive to all agonists as indicated by a significant reduction in their median effective dose values, and their maximal responses to all agonists were also significantly reduced. No graft relaxed in response to acetylcholine, and whereas precontracted grafts in normotensive rabbits had a maximal relaxation of 24% +/- 6% of precontraction with A23187, this was absent in the grafts in the hypertensive rabbits. The results suggest that angiotensin-induced hypertension may adversely affect vein graft patency by inducing hypersensitivity to physiologically important agonists and reducing the effect of receptor-independent endothelium-derived relaxation on vasomotor tone.

Topics: Acetylcholine; Angiotensin II; Animals; Blood Pressure; Calcimycin; Carotid Arteries; Graft Survival; Histamine; Hypertension, Renovascular; In Vitro Techniques; Jugular Veins; Male; Norepinephrine; Oxyhemoglobins; Rabbits; Serotonin; Vasoconstriction; Veins