STUDY ON THE VASCULAR EFFECTS OF CHRONIC ADMINISTRATION OF TWO SULFONYLUREAS, CHLORPROPAMIDE AND GLIBENCLAMIDE, ON THE HEALTHY RAT THORACIC AORTA

Diabetes mellitus is one of the most common endocrine disorders with increasing prevalence. Cardiovascular complications are among the major causes of death in diabetic patients. Type II diabetes mellitus is generally treated with sulfonylureas. There are controversial reports regarding adverse cardiovascular effects of these drugs. Also evidence exists about differences in side effects between first and second generation sulfonylureas. Thus, an experimental and prospective study was performed. In this study, the vascular effects of two sulfonylureas belonging to the first(chlorpropamide) and second generation(glibenclamide) were investigated in healthy male rats. Healthy rats were treated with chlorpropamide(8mg/kg/day i.p.) and glibenclamide(0.285mg/kg/day i.p.) for one- and two-month periods and the response of isolated aortic rings to phenylephrine, acetylcholine and isosorbide dinitrate were then examined and compared to control. The results showed that chlopropamide pretreatment after two months caused a significant reduction in contractile response to phenylephrine. Moreover, a significant increase in endothelium-dependent relaxation in response to ACh was also observed after a two-month period of pretreatment with chlorpropamide. Such changes were not observed after one month administration so it appears that these changes are time dependent. Glibenclamide did not cause such changes after one-or two-month pretreatment. Calculated EC50s for either phenylephrine or ACh did not differ in test groups compared to control. So it is suggested that changes in the characteristics of smooth muscle alpha-1 adrenoceptors or endothelial muscarinic receptors may not be involved in the observed responses. The alpha-1 adrenoceptor-induced vasocontriction appears to be caused both by the release of intracellular Ca2+ and by the transmembranous influx of extracellular Ca2+. It has been demonstrated that glibenclamide may interfere with Ca2+ influx which in turn affects intracellular Ca2+ levels in arterial smooth muscle, leading to reduction to muscle contractility. Inhibitory effect of glibenclamide in the protein kinase-C mediated contractile mechanism has also been suggested. The observed effect of chlorpropamide on phenylephrine-induced contraction can be attributed to such mechanisms and a longer pretreatment may be needed for glibenclamide to show its inhibitory effect on contractile response to phenylephrine. On the other hand, it has been shown that sulfonylureas may stimulate the proliferation of endothelial cells from large vessels. There may be a difference between chlorpropamide and glibenclamide in the time needed to cause such an effect. Also, it is possible that vascular effects of chlorpropamide are due, at least in part, to changes in the post-receptor cellular components which are involved in signal transduction. Results obtained in this study indicate that up to two months pretreatment with chlorpropamide and glibenclamide in healthy rats did not affect the aortic function in such a way to contribute to hypertension.