Different effects of the beta-adrenoceptor antagonists celiprolol and metoprolol on vascular structure and function in long-term type I diabetic rats.
An intriguing problem of diabetes mellitus is the development of generalized angiopathy and concomitant hypertension. However, there is still a controversy whether beta-adrenoceptor antagonists can be used as antihypertensive agents in diabetes. Four groups of rats were investigated: nondiabetic controls, diabetes mellitus, diabetes + celiprolol (250 mg/kg body weight/day), diabetes + metoprolol (125 mg/kg body weight/day) after 6 months. Diabetes was induced by i.v. streptozotocin injection. We examined vascular structure and function histologically and by an in vitro microvideoangiometry of isolated perfused mesenterium. Additionally, we investigated the effects of hyperglycemia and celiprolol on NO release in cultivated aortic endothelial cells and the effect of celiprolol on transendothelial paracellular permeability. Diabetes resulted in endothelial dysfunction, characterized by a reduced response to acetylcholine and L-N(G)-nitro-arginine and an unchanged response to sodium nitroprusside (SNP). These effects were significantly antagonized by celiprolol but were not influenced by metoprolol treatment. This was supported by the finding of typical vascular changes associated with diabetes like media thickening, reduced cardiac capillary/muscle fiber ratio, and glomerulosclerosis, which were significantly reduced by celiprolol but not influenced by metoprolol treatment. Ketonuria improved after celiprolol treatment, whereas blood glucose, lipids, and body weight were not different between the diabetic groups. In cultured cells, celiprolol did not induce direct NO release but reversed the impairment of stimulated NO release caused by hyperglycemia. Furthermore, celiprolol reduced endothelial paracellular permeability. We conclude that celiprolol can exert antiangiopathic effects in diabetic rats and that both beta-adrenoceptor antagonists did not aggravate diabetic angiopathy and metabolic derangement.
Institute of Pharmacology, University of Cologne, Germany.
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Olbrich
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Salameh
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Roesen
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Dhein
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001774:Blood Chemical Analysis; D001808:Blood Vessels / Q000033:anatomy & histology / Q000187:drug effects*; D017272:Celiprolol / Q000494:pharmacology*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology* / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D008790:Metoprolol / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000319:Adrenergic beta-Antagonists; D009569:Nitric Oxide; D017272:Celiprolol; D008790:Metoprolol