Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2.
Endothelium-dependent relaxations and vasoactive prostanoid production caused by acetylcholine were determined in the aortas of rabbits with diabetes mellitus induced by alloxan. Aortas of diabetic rabbits, contracted submaximally by phenylephrine, showed significantly decreased endothelium-dependent relaxations induced by acetylcholine compared with the aortas of normal rabbits. Indomethacin, a cyclooxygenase inhibitor, and SQ 29548, a prostaglandin H2-thromboxane A2 (PGH2-TxA2) receptor antagonist, normalized the sensitivity of diabetic aortas to acetylcholine, whereas these agents had no effect on the response of normal aortas. The relaxations in response to a nonreceptor-mediated endothelium-dependent vasodilator, A23187, and an endothelium-independent vasodilator, sodium nitroprusside, were not different between normal and diabetic aortas. Acetylcholine also caused contractions of resting aortic rings with endothelium from diabetic, but not normal rabbits; these contractions were inhibited by indomethacin. Synthesis of TxA2, measured as immunoreactive TxB2, was significantly increased in diabetic aortic segments only when the endothelium was present. These results suggest that in the diabetic state, the endothelium releases a major vasoconstrictor cyclooxygenase product that either directly counteracts the relaxation caused by or selectively interferes with the release of endothelium-derived relaxing factor(s) induced by cholinergic receptor stimulation. The vasoconstrictor is most likely TxA2 or possibly its precursor, PGH2.
Tesfamariam
B
B
Department of Clinical Research, Boston University Medical Center, Massachusetts 02118.
Jakubowski
J A
JA
Cohen
R A
RA
D000109:Acetylcholine / Q000494:pharmacology; D000496:Alloxan; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D008297:Male; D011449:Prostaglandin Endoperoxides / Q000502:physiology*; D011463:Prostaglandins H / Q000502:physiology*; D011817:Rabbits; D011863:Radioimmunoassay; D013928:Thromboxane A2 / Q000502:physiology*; D014661:Vasoconstriction; D014664:Vasodilation
D001095:Arachidonic Acids; D011449:Prostaglandin Endoperoxides; D011463:Prostaglandins H; D016718:Arachidonic Acid; D013928:Thromboxane A2; D000496:Alloxan; D000109:Acetylcholine