The beneficial in vitro effects of lovastatin and chelerythrine on relaxatory response to acetylcholine in the perfused mesentric bed isolated from diabetic rats

• Published in: European journal of pharmacology Vol. 535; no. 1; pp. 228 - 233
• Main Authors: Fatehi-Hassanabad, Zahra, Imen-Shahidi, Mohsen, Fatehi, Mohammad, Farrokhfall, Khadijeh, Parsaeei, Heidar
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 27-03-2006; Elsevier
• Subjects: Acetylcholine - pharmacology; Alkaloids; Animals; Benzophenanthridines; Biological and medical sciences; Blood Glucose - metabolism; Blood Pressure; Body Weight; Chelerythrine; Diabetes; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Dose-Response Relationship, Drug; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelium; Enzyme Inhibitors - pharmacology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; In Vitro Techniques; Lovastatin; Lovastatin - pharmacology; Male; Medical sciences; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiopathology; Nitroprusside - pharmacology; Perfusion; Pharmacology. Drug treatments; Phenanthridines - pharmacology; Phenylephrine - pharmacology; Protein Kinase C - antagonists & inhibitors; Rat mesenteric bed; Rats; Rats, Wistar; Streptozotocin; Vasoconstriction - drug effects; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Rat mesenteric bed; Lovastatin; Diabetes; Streptozotocin; Chelerythrine; Endothelium; Endocrinopathy; Antineoplastic agent; Rat; Enzyme; Diabetes mellitus; Rodentia; Enzyme inhibitor; Statin derivative; In vitro; Vertebrata; Antibiotic; Mammalia; Animal; Neurotransmitter; Hydroxymethylglutaryl-CoA reductase; Acetylcholine; Oxidoreductases; Antilipemic agent
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2006.01.063

Diabetes mellitus is associated with an increased risk of cardiovascular disease. Endothelial dysfunction (i.e. decreased endothelium-dependent vasorelaxation) plays a key role in the pathogenesis of diabetic vascular disease. The present study was undertaken to determine whether diabetes induced by streptozotocin alters mesenteric responses to vasodilators and, if so, to study the acute in vitro effects of lovastatin and chelerythrine. Endothelial function was assessed in constantly perfused preparation removed from rats, 12
weeks after treatment with either saline or streptozotocin (45
mg/kg, intraperitoneally). In pre-contracted mesenteric beds (with 100
μM phenylephrine) removed from diabetic rats, the concentration response curve to acetylcholine, but not to sodium nitroprusside, was significantly reduced. Perfusion with lovastatin (10
μM for 20
min) or chelerythrine (1
μM for 20
min) significantly improved the acetylcholine-mediated relaxation in preparations removed from diabetic but not control rats. Pre-incubation of tissue with
N
G-nitro-
l-argenine methyl ester hydrochloride (10
μM for 20
min) inhibited the beneficial effect of lovastatin but not chelerythrine. Pre-treatment of tissue with indomethacin (10
μM for 20
min) did not modify the effects of lovastatin or chelerythrine on acetylcholine responses. The present results demonstrate that endothelial dysfunction induced by diabetes (in a resistant vasculature, such as rat mesenteric bed) may be improved by an acute exposure to either lovastatin or chelerythrine. Furthermore, our results suggest that the beneficial effect of lovastatin is mediated via the nitric oxide pathway.