Impaired endothelium‐dependent relaxation in isolated resistance arteries of spontaneously diabetic rats

Abstract

1 Previous studies have shown that endothelium-dependent relaxation in the aorta of spontaneously diabetic bio bred rats (BB) is impaired. 2 We have investigated noradrenaline (NA) contractility, endothelium-dependent acetylcholine (ACh) and bradykinin (BK) relaxation, and endothelium-independent sodium nitroprusside (SNP) relaxation in mesenteric resistance arteries of recent onset BB rats and established insulin treated BB rats, compared to their age-matched non diabetic controls. 3 There was no significant difference in the maximum contractile response or sensitivity to noradrenaline in either of the diabetic groups compared to their age-matched controls. 4 Incubation with the nitric oxide synthetase inhibitor NG-nitro-L-arginine (L-NOARG) resulted in a significant increase in maximum contractile response to noradrenaline in the recent onset age-matched control group (P<0.05). Analysis of the whole dose-response curve (using ANOVA for repeated measures with paired t test) showed a significant left-ward shift following the addition of L-NOARG (P<0.001). A similar but less marked shift (P<0.01) was evident in vessels from recent onset diabetics. An overall shift in both sensitivity and maximum response was also evident in the age-matched non diabetic controls of the insulin-treated group (P<0.05). However, by contrast, there was no significant change in sensitivity in the insulin-treated diabetic rats. 5 ACh-induced endothelium-dependent relaxation was significantly impaired in the recent onset diabetic rats compared to their age-matched controls (47 ± 11% versus 92 ± 2%, P<0.05, n = 6), and in the insulin treated diabetic rats (34±5% versus 75 + 6%, P< 0.05, n = 6). The relaxation responses to BK also were significantly impaired in the diabetic rats compared to their age-matched controls (recent onset: 20+3% versus 72±7%, P<0.05, n=6; insulin treated: 12+9% versus 68+7%, P<0.05, n=7). 6 Incubation with either the nitric oxide synthetase substrate, L-arginine, or the free radical scavenging enzyme superoxide dismutase (150 jml1') failed to improve the attenuated response of acetylcholineinduced relaxation in the diabetic vessels. 7 Endothelium-dependent relaxation mediated by ACh and BK was significantly attenuated in both the diabetic and control vessels after incubation with L-NOARG. 8 Pretreatment with a cyclo-oxygenase inhibitor, indomethacin, significantly enhanced the relaxation to ACh in both the recent onset and insulin treated diabetic rats (42+10%, n=7 versus 64±7%, n=7, P<0.05, and 40±5%, n=7 versus 65+9%, n=6, P<0.05). 9 Following endothelium removal, there was a marked impairment in endothelium-dependent relaxation responses to ACh and BK in both the diabetic and control vessels. 10 Incubation with the thromboxane A2 receptor antagonist SQ29548, did not significantly improve the ACh endothelium-dependent relaxation response in the diabetic vessels. 11 Endothelium-independent relaxation to sodium nitroprusside was significantly impaired in the first group of diabetic vessels studied; however, subse...

Oxygen‐derived free radicals mediate endothelium‐dependent contractions in femoral arteries of rats with streptozotocin‐induced diabetes

“…Oxygen-derived free radicals play an important role in the occurrence of endothelium-dependent contractions in the basilar artery of the dog and the aorta of the spontaneously hypertensive rat Katusic et al, 1993;Yang et al, 2003aYang et al, , 2004aTang et al, 2007). Previous studies from our laboratory demonstrate that the calcium ionophore A23187 induces greater endothelium-dependent contractions in the femoral artery of diabetic rats than those of normoglycaemic animal (Shi et al, 2007), exemplifying the endothelial dysfunction caused by diabetes (Pieper and Gross, 1988;Heygate et al, 1995;Makimattila et al, 1996;Pieper et al, 1997;Vallejo et al, 2000). This prompted the investigation of the role of oxygen-derived free radicals in the endothelium-derived contracting factor-mediated responses of the femoral artery of rats with STZ-induced diabetes.…”

“…The effect of STZ-induced diabetes on nitric oxidemediated vasodilatation is still controversial; it has been reported as normal in the aorta (Head et al, 1987;Harris and MacLeod, 1988;Mulhern and Docherty, 1989), mesenteric artery (Harris and MacLeod, 1988) and femoral artery (Wigg et al, 2001), as blunted in aorta (Pieper et al, 1997;Vallejo et al, 2000), mesenteric artery (Heygate et al, 1995;Vallejo et al, 2000;Shi et al, 2007) and femoral artery (Shi et al, 2006) or augmented in aorta (Altan et al, 1989). The production of vasoconstrictor prostaglandins is augmented in diabetic animals (aorta , renal artery (Pflueger et al, 1999) and femoral artery (Shi et al, 2007)).…”

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

“…Production of superoxide anion inactivates NO (Marshall et al, 1988;Rubanyi & Vanhoutte, 1986;Kobayashi & Kamata, 2001) and dismutation of free radicals has generally (Pieper et al, 1996;Hattori et al, 1991;Kamata & Kobayashi, 1996) but not always (Heygate et al, 1995) been found to improve impaired endothelium-dependent relaxation in experimental models of diabetes. Indeed, we recently reported that NO is metabolized by O 2 7 to NO 3…”

Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: Role of insulin and C‐peptide

“…There is now substantial evidence that endotheliumdependent vasodilation is abnormal in both conduit and resistance arteries of chemically induced experimental diabetic animals [Mayhan, 1989;Pieper and Gross, 1990;Mayhan et al, 1991;Diederich et al, 1994;Rosen et al, 1995;Taylor et al, 1995]. In two genetic models of IDDM, a similar impaired relaxation has been documented in the aorta [Durante et al, 1988;Pieper et al, 1996] and mesenteric arteries [Heygate et al, 1995;Lindsay et al, 1997] of diabetes-prone BB/W or BB/E rats. Similar results are reported for aorta and mesenteric arteries [Miyata et al, 1993] of the diabetes-prone WBN/Kob rat.…”