Role of NO-synthases and cyclooxygenases in the hyperreactivity of male rabbit carotid artery to testosterone under experimental diabetes.
Cardiovascular disease is the major cause of morbidity and mortality in diabetic patients, which in turn is also associated with low levels of serum testosterone. The working hypothesis was that diabetes might modify the mechanisms involved in the vascular actions of testosterone in isolated rabbit carotid arteries. Testosterone (10(-8)-3x10(-4)M) induced a concentration-dependent relaxation of precontracted carotid arteries, which was higher in diabetic than in control rabbits. In control rabbits neither endothelium removal nor the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine (l-NOArg, 10(-5)M) modified the relaxant action of testosterone, and the cyclooxygenase (COX) inhibitor indomethacin (10(-5)M) enhanced this relaxation. In contrast, in diabetic rabbits endothelium removal, l-NOArg (10(-5)M) or indomethacin (10(-5)M) inhibited the testosterone induced relaxation. In arteries from diabetic rabbits, eNOS, iNOS and COX-2 expression and testosterone induced release of prostacyclin resulted enhanced in comparison with arteries from control rabbits. Testosterone (10(-4)M) strongly inhibited CaCl(2) (10(-5)-3x10(-2)M) concentration-related contractions of the carotid artery both in control and diabetic rabbits. These results suggest that testosterone relaxes the rabbit carotid artery by blocking the extracellular calcium entry. Diabetes enhances the vasodilator response of the rabbit carotid artery to testosterone by a mechanism that at least includes an increased modulatory activity of the endothelial nitric oxide and an augmented release of COX-2 vasodilator, prostacyclin rather than the absence of COX-1 vasoconstrictor, thromboxane A(2). The hypotestosteronemia observed in diabetic rabbits could be a consequence of the increased expression of iNOS and could contribute to the hyperreactivity of the rabbit carotid artery to testosterone.
Marrachelli
Vannina G
VG
Departamento de Fisiología, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain.
Miranda
Francisco J
FJ
Centeno
José M
JM
Salom
Juan B
JB
Torregrosa
Germán
G
Jover-Mengual
Teresa
T
Pérez
Antonio M
AM
Moro
Maria A
MA
Alborch
Enrique
E
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D018999:Charybdotoxin / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology; D011464:Epoprostenol / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011817:Rabbits; D013739:Testosterone / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D001786:Blood Glucose; D016861:Cyclooxygenase Inhibitors; D026902:Potassium Channel Blockers; D018999:Charybdotoxin; D019335:Nitroarginine; D001030:Apamin; D009569:Nitric Oxide; D013739:Testosterone; D013928:Thromboxane A2; D011464:Epoprostenol; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051546:Cyclooxygenase 2; D011188:Potassium; D002118:Calcium; D007213:Indomethacin