Effect of diabetes on endothelium-dependent and -independent relaxation in resistance arteries obtained from rat

A Kun, A Varró, JG Papp, J Pataricza. University of Szeged, Department of Pharmacology and Pharmacotherapy, H-6720, Hungary

Impaired endothelium-dependent and –independent vasodilations are underlying the development of cardiovascular complications in diabetes mellitus. Recent evidences suggest that penile vascular dysfunction may be considered as a marker of systemic vascular disorder. The purpose of the present study was to investigate 1) the involvement of endothelium-dependent and -independent relaxations in the development of diabetic vascular dysfunction and 2) whether penile vasculature is affected prior to mesenteric or coronary arteries in diabetes.

Diabetes was induced by a single intraperitoneal injection of streptozotocin (60 mg/kg) in male Sprague Dawley rats (body weights: 269±4g and 278±6g in control and diabetic group, respectively). Three months after the rats developed diabetes (body weights: 472±13g and 253±11g in control and diabetic group, respectively), penile intracavernous artery (ICA), mesenteric artery (MA) and left anterior descendent coronary artery (LAD) preparations were isolated from male control and diabetic rats (23-24 weeks of age) and were mounted in microvascular myograph for isometric tension recordings. Differences between concentration–response relationships, mean pD2 (calculated as -log EC 50 ) and magnitude of responses were analysed using two-way analysis of variance or t-test.

In control ICA and MA preparations (n=5-5), the acetylcholine (ACh, 10-9 – 10-6 M) induced endothelium-dependent vasodilatations were decreased by 56% and 12%, respectively (p<0.05), while in LAD preparations (n=4) were totally abolished in the presence of L-NAME (3x10-4 M) and Indomethacin (10-5 M), nitric oxide synthase and cyclooxygenase enzyme inhibitors, respectively. In diabetic ICA (n=6-7) and LAD (n=4) preparations, ACh-evoked relaxations were not changed either in the absence or presence of L-NAME and Indomethacin, compared to the control values. In contrast to these arteries, in diabetic MA (n=6) the dose-response curve for ACh-induced vasodilation was significantly rightward-shifted without a change in the maximum (pD2 values: 8.3±0.1 and 6.7±0.2 in control MA and diabetic MA, respectively, p<0.005) and, incubation with L-NAME and Indomethacin abolished the ACh-evoked vasorelaxation. The endothelium-independent vasodilator, sodium nitroprusside (SNP, 10-9 – 10-6 M) -induced relaxations were decreased in diabetic ICA and MA by 18 and 10%, respectively (p<0.05), but not in LAD preparations, compared to control values (n=4-5).

The present findings demonstrate the contribution of both nitric oxide/prostanoid and endothelium derived hyperpolarizing factors to ACh-evoked vasorelaxation in ICA and MA but not in LAD arteries. Our results show a decreased effect of SNP, an endothelium-independent vasodilator, in diabetic ICA and MA but not in LAD preparations. This suggests the development of penile and mesenteric vascular dysfunction before coronary artery function becomes affected.