Hypertension and Hypercholesterolemia: Biochemical and Pharmacological Studies in the Rabbit

[摘要] 1. Four groups of rabbits were set up to investigate the separate and combined effects of hypertension and hypercholesterolemia on a number of cardiovascular parameters, including in vivo vascular reactivity, phosphoinositide metabolism in aortic tissue, and platelet [Ca2+]i concentrations. The four groups were: a control group, a hypertensive group (perinephritis hypertension), a hypercholesterolemic group (0. 3% cholesterol diet), and a hypertensive-hypercholesterolemic group. 2. As the basic pharmacology of one of the agonists used in this work, endothelin, was poorly understood at the time these studies were planned, preliminary investigations into its effects in normotensive-normocholesterolemic animals were undertaken before embarking on the main project. In addition, some phosphoinositide studies were done using rat aorta. Endothelin-1 caused a dose-related increase in phosphoinositide hydrolysis in both rat and rabbit aorta. In rat aorta, endothelin-1-induced phosphoinositide hydrolysis increased with stimulation time for the first 30 minutes, and thereafter plateaued. The endothelin-stimulated effects were attenuated with endothelium removal, or with extracellular Ca2+ depletion. The endothelin-l-induced phosphoinositide hydrolysis was greater in rat aorta than in rabbit aorta. In vivo endothelin-1 caused a short-lived depressor response followed by a long-lasting pressor response in the rabbit. The pressor response was dose-related, and could be attenuated by the calcium antagonist nifedipine. 3. The imposition of perinephritis hypertension caused an increase of about 40 mmHg in mean arterial pressure in the operated rabbits, which stabilized after 6-7 weeks, while feeding a 0. 3% cholesterol diet induced a continual rise in plasma cholesterol levels in the rabbits, which reached 30 mmol/L after 4 months. In contrast to 0.3% cholesterol diet, perinephritis hypertension was a significant risk factor for cardiovascular deaths in the course of a 4-month study. There were significantly greater numbers of cardiovascular deaths in both the hypertensive and the hypertensive-hypercholesterolemic groups versus the control group (p= 0.038 and 0.009, respectively), but no significant difference between the hypercholesterolemic and the control group, or between the hypertensive-hypercholesterolemic and the hypertensive group. However, it is noteworthy that when the hypertensive-hypercholesterolemic group was compared to the hypertensive group, 0.3% cholesterol diet tended to augment the cardiovascular deaths in these hypertensive animals. 4. The imposition of perinephritis hypertension enhanced the pressor responses to angiotensin II, and endothelin-1, as well as the depressor responses to acetylcholine, isoproterenol, and nitroprusside at 2-3, 6-7, and 13-16 weeks of study. The differences tended to increase with the duration of hypertension for the pressor responses, but not for the depressor responses. The patterns of changes in the duration of hypertension differed from one pressor agonist to another, suggesting that structural changes in the vessel wall were not the sole explanation for enhanced vascular reactivity. Similar conclusions held for the depressor agonists. In contrast, the imposition of 0. 3% cholesterol diet had no effect on the in vivo vascular reactivity at any time point of the study, whether given to normotensive or hypertensive animals. 5. Neither perinephritis hypertension nor 0. 3% cholesterol diet caused any changes in the basal platelet [Ca2+] at the 17th week of study. 6. At the 18th week of study, perinephritis hypertension tended to enhance the noradrenaline-stimulated, but not the endothelin-stimulated phosphoinositide hydrolysis in rabbit aorta, but the difference was significant only at 10e-4 M noradrenaline for the hypertensive versus the control group. In contrast, 0.3% cholesterol feeding tended to decrease both noradrenaline- and endothelin-stimulated, phosphoinositide hydrolysis. The difference was significant at 10e-4 M noradrenaline for the hypercholesterolemic versus the control group, as well as for the hypertensive-hypercholesterolemic versus the hypertensive group, and at 10e-6 & 10e-5 M endothelin-1 for the hypertensive-hypercholesterolemic versus the hypertensive group. There was no difference in the basal [ 3H]-inositol phosphates formation between any experimental group and the control group, suggesting that neither perinephritis hypertension nor 0.3% cholesterol diet for 18 weeks altered the basal phosphoinositide metabolism in rabbit aorta. 7. Overall, in our study no significant additive effects of the two disease states were observed in any of the parameters examined. However, the number of biochemical responses, vessels and animals examined were limited, and further studies might identify sites of interaction between the two parameters.

[发布机构] University:University of Glasgow

[关键词] Biochemistry, Pharmacology, Physiology