Prostanoid release and constrictor responses to noradrenaline in the rat mesenteric vascular bed in non‐insulin‐dependent diabetes mellitus

Abstract

1. The administration of streptozotocin (STZ) to 2-day old rats induced a non-insulin-dependent diabetes mellitus (NIDDM)-like state, with mild hyperglycaemia and no alterations in body weight at the adult age. 2. In the isolated and perfused mesenteric vascular bed of NIDDM animals, the constrictor responses to either noradrenaline (NA) or potassium chloride (KCl) were not modified as compared with age-matched non-diabetic controls. 3. The reduction in NA contractions induced by the cyclooxygenase inhibitor, 10 microM indomethacin in the control group was absent in the NIDDM rats. 4. The increase in the NA-induced contractions caused by endothelium removal was suppressed by indomethacin in the controls but not in the NIDDM group. 5. The prostanoid release from the mesenteric vascular beds of NIDDM rats was markedly reduced as compared with non-diabetic controls. Noradrenaline increased production of the constrictor prostaglandin (PG) F2alpha in control but not in NIDDM rats. 6. In summary, these results show that in STZ-induced NIDDM rats, there is an impairment of the prostanoid production, as well as a suppression of the role of prostanoids in the contractile effects of NA in the mesenteric vascular bed. These alterations are more severe than those previously observed in a model of insulin-dependent diabetes mellitus (IDDM), in which hyperglycaemia and reduction of body weight were more marked. The conclusion is that, in these models of diabetes and in the preparation studied, vascular alterations and modifications of glycaemia and body weight are not closely related.

Reactive oxygen species mediate abnormal contractile response to sympathetic nerve stimulation and noradrenaline in the vas deferens of chronically diabetic rats: effects of in vivo treatment with antioxidants

“…The increased a-adrenergic responsiveness of diabetic vas deferens observed in this study, may be attributable to new receptor synthesis or activation of post-receptor events due to diabetesinduced neuropathy rather than an enhancement in a-adrenoceptor affinity, as the pD 2 for the contractile effects of noradrenaline was found to be unchanged. This is in agreement with the results of other groups [5,7,19]. The increased contractile responses of vas deferens from diabetic rats to phenylephrine, and the decreased responses to nerve stimulation in diabetic rats, has been explained with denervation-like supersensitivity in receptor-mediated processes [6].…”

Phenylephrine-induced vasoconstriction of the rat superior mesenteric artery is decreased after repeated swimming

“…This suggests that, in the presence of indomethacin, the synergistic interaction between locally produced vasoconstrictor prostanoids and phenylephrine may be blocked, resulting in a consequent reduction of the effects of phenylephrine. Moreover, the effects of indomethacin on the vascular responsiveness to phenylephrine were observed both in preparations with and without endothelium, supporting previous studies that demonstrated a synergistic participation of non-endothelial vasoconstrictor prostanoids in the contractile actions of norepinephrine in rat mesenteric arteries (Peredo, 2001;Peredo, 2003) and aorta (Lamb et al, 1994) and of phenylephrine in rat aorta (Connoly et al, 1998).…”

Effects of prostanoids on phenylephrine-induced contractions in the mesenteric vascular bed of rats with streptozotocin-induced diabetes mellitus

“…This fact suggests that phenylephrine may stimulate the production of vasoconstrictive prostanoids by smooth muscle in the MVB. Similar results were obtained by Manku and Horrobin, 1976, Peredo and Adler-Graschinsky, 2000, and Peredo, 2001. These investigators demonstrated that indomethacin reduced the vasoconstrictive effect of noradrenaline in the mesenteric arterial bed of rats and suggested that the constrictive effect of noradrenaline involves the participation of two different pathways of arachidonic acid metabolism, i.e., the cyclooxygenase pathway and the lipoxygenase pathway.…”

“…These data show that in diabetic animals phenylephrine is unable to release vasoconstrictive prostanoids from MVB smooth muscle and that this is the major mechanism explaining the difference in reactivity to this agent observed in diabetic rats. Using noradrenaline with an agonist, Peredo et al, 1999, Peredo, 2001 obtained similar data for rats with diabetes mellitus in two distinct models (STZ diabetic rats and rats with diabetes similar to the human type II). However, 8 weeks after STZ induction of diabetes, the vasoconstrictive effect of noradrenaline was again reduced by indomethacin perfusion.…”