Alterations in endothelium‐dependent hyperpolarization and relaxation in mesenteric arteries from streptozotocin‐induced diabetic rats

Abstract

1 The aim of this study was to determine whether endothelium-dependent hyperpolarization and relaxation are altered during experimental diabetes mellitus. Membrane potentials were recorded in mesenteric arteries from rats with streptozotocin-induced diabetes and age-matched controls. The resting membrane potentials were not signi®cantly di erent between control and diabetic mesenteric arteries (755.3+0.5 vs 755.6+0.4 mV). However, endothelium-dependent hyperpolarization produced by acetylcholine (ACh; 10 78 ± 10 75 M) was signi®cantly diminished in amplitude in diabetic arteries compared with that in controls (maximum 710.4+1.1 vs 717.2+0.8 mV). Furthermore, the hyperpolarizing responses of diabetic arteries were more transient. 2 ACh-induced hyperpolarization observed in control and diabetic arteries remained unaltered even after treatment with 3610 74 M N G -nitro-L-arginine (L-NOARG), 10 75 M indomethacin or 60 u ml 71 superoxide dismutase. 3 Endothelium-dependent hyperpolarization with 10 76 M A23187, a calcium ionophore, was also decreased in diabetic arteries compared to controls (78.3+1.4 vs 718.0+1.9 mV). However, endothelium-independent hyperpolarizing responses to 10 76 M pinacidil, a potassium channel opener, were similar in control and diabetic arteries (720.0+1.4 vs 719.2+1.1 mV). 4 The altered endothelium-dependent hyperpolarizations in diabetic arteries were almost completely prevented by insulin therapy. Endothelium-dependent relaxations by ACh in the presence of 10 74 M L-NOARG and 10 75 M indomethacin in diabetic arteries were also reduced and more transient compared to controls. 5 These data indicate that endothelium-dependent hyperpolarization is reduced by diabetes, and this would, in part, account for the impaired endothelium-dependent relaxations in mesenteric arteries from diabetic rats.

Endothelial dysfunction in diabetes

“…These ®ndings suggest that distinct mechanisms may mediate the impaired response to endothelium-independent agonists. Interestingly, a selectively decreased responsiveness to ATPoperated potassium channel openers has been reported by several authors (Cameron & Cotter, 1992;Mayhan & Faraci, 1993;Crijns et al, 1998), although a preserved response was noted in other studies (Fukao et al, 1997;De Vriese et al, 1999).…”

“…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.…”

“…Impaired ACh-induced relaxation with normal responses to bradykinin has been reported in isolated resistance vessels from patients with type I diabetes (McNally et al, 1994), in the forearm circulation of type II diabetes patients (Gazis et al, 1999) and in mesenteric and hindlimb arteries of streptozotocin (STZ)-rats (Lash & Bohlen, 1991;Taylor et al, 1995), suggesting an abnormality at the level of the G-proteins. However, several other studies found equally suppressed responses to di erent endothelium-dependent agonists (Heygate et al, 1995;Fulton et al, 1996;Costa e Forti & Fonteles, 1998;Mayhan & Patel, 1995;1998;Mayhan, 1997) or impaired relaxation to the calcium-ionophore A23187 (Oyama et al, 1986;Durante et al, 1988;Cameron & Cotter, 1992;Fukao et al, 1997), making a disturbance of receptors or receptor-coupled mechanisms unlikely as a common mechanism of endothelial dysfunction.…”

“…In the absence of speci®c inhibitors of EDHF, most of the current evidence is inevitably indirect. Decreased ACh-induced hyperpolarization and NO synthase-and cyclo-oxygenase-resistant relaxation were observed in isolated mesenteric arteries (Fukao et al, 1997). In the Langendor perfused heart , in the isolated perfused kidney as well as in the renal microcirculation in vivo (De Vriese et al, 1999), the NO synthase-and cyclooxygenase-resistant vasodilatation to bradykinin or ACh was profoundly impaired.…”

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

“…Endothelium-dependent hyperpolarization and the component of the relaxation to acetylcholine that is independent of NO synthase and cyclooxygenase are decreased in isolated mesenteric arteries from diabetic rats [31]. Other authors observed a more pronounced impairment of the acetylcholine-induced relaxations when NO synthase and cyclooxygenase were blocked in isolated mesenteric arteries [32] or a decreased NO synthase-resistant acetylcholine-induced relaxation in isolated renal arteries of diabetic rats [33] but they did not relate their findings to an impaired EDHF-mediated influence.…”