Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2

Abstract

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.

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin - induced diabetic rats is restored by 5-methyltetrahydrofolate

“…These studies and our results contrast with observations that an overproduction of endothelium-derived vasoconstrictors, such as prostanoids, accounts for the impaired endothelium-dependent relaxations in diabetic blood vessels [12,13]. The existence of such an action of vasoconstrictor prostanoids in the kidney is not supported by our study, inasmuch as cyclooxygenase-inhibition did not restore the blunted relaxations observed in the diabetic animals.…”

“…The majority of the studies were done in large conduit arteries such as the aorta and the endothelial dysfunction was generally attributed to a reduced production or increased inactivation of NO [7±11] or to an overproduction of endothelium-derived vasoconstrictors, opposing the effects of NO [12,13]. These studies have, however, limited relevance to the alterations in the microcirculation and in the local control of tissue perfusion occurring in diabetes.…”

Endothelial dysfunction in diabetes

“…in pial arterioles of diabetic rats in vivo (Mayhan et al, 1991) and in diabetic isolated aorta (Shimizu et al, 1993;Tesfamariam et al, 1989). Similar mechanisms may play a role after in vitro exposure of rabbit aorta to high glucose concentrations (Tesfamariam et al, 1990).…”

“…These EDCFs are thought to be released together with the EDRFs and oppose their e ects on the smooth muscle cells. The impaired relaxations are restored by non-speci®c cyclo-oxygenase blockade and prostanoid TP receptor antagonists, but not by thromboxane A 2 synthase blockers, suggesting that the culprit is a prostaglandin endoperoxide (Tesfamariam et al, 1989;Mayhan et al, 1991;Shimizu et al, 1993). On the other hand, cyclooxygenase inhibition did not restore impaired endotheliumdependent relaxations in isolated mesenteric arteries (Taylor et al, 1992;Diederich et al, 1994;Fukao et al, 1997), in the isolated perfused heart and kidney Fulton et al, 1996) and in the renal microcirculation in vivo (De Vriese et al, 1999), indicating that vasoactive prostanoids do not play an important contributory role to the endothelial dysfunction in these vascular beds.…”

Retinal vascular fractals predict long-term microvascular complications in type 1 diabetes mellitus: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987)

“…Several endothelium-generated vasoconstrictors are produced in abnormally high amounts in diabetes, the main one being endothelin-1 [25]. At the same time, impaired production of nitric oxide (a vasodilator) is observed in endothelial dysfunction [26].…”