Role of EDRFs in aortic and mesenteric arterial function of the UC Davis Type 2 Diabetic Mellitus (UCD-T2DM) male rats
European Heart Journal
Several studies have shown vascular dysfunction in diabetic rats, however, there is no data on the vascular function of UC Davis type 2 diabetes Mellitus (UCD-T2DM) rats. UCD-T2DM is a novel but validated model of type 2 diabetes (T2D) which more closely resembles the pathophysiology of diabetes in humans. The aim of this study was to determine whether aortic or mesenteric arterial function were altered in UCD-T2DM male rats. Specifically, we determined the responses to endothelium-dependent vasodilator and vasoconstrictor in this model. We also studied the relative contribution of endothelium-derived relaxing factors (EDRFs) in modulating vascular reactivity of aorta or mesenteric artery (MA) in UCD-T2DM male rats.
Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh) was measured in rat aorta or MA pre-contracted with phenylephrine (PE). Particularly, EDV to ACh were measured before and after pretreatment with indomethacin (indo, cyclooxygenase inhibitor), ODQ (soluble guanylate cyclase inhibitor), L-NNA (nitric oxide synthase (NOS) inhibitor), TRAM-34 (IKca blocker), or Apamin (SKca blocker). Constrictor response curves to PE were also generated in both aorta and MA. Furthermore, the protein expression of IK channels were determined using Western blotting.
We demonstrated that EDV to ACh was impaired in MA, while potentiated in the aortic rings of UCD-T2DM rats. In diabetic MA, the importance of endothelium-derived hyperpolarizing factor (EDHF) in ACh-induced relaxation was decreased, while the contribution of nitric oxide (NO) was enhanced. On the other hand, in diabetic aorta, the relative contribution of EDHF in relaxation responses to ACh was significantly enhanced (as measured by ACh response which was insensitive to indo, ODQ and L-NNA).
The incubation of aorta or MA with TRAM-34 blunted the relaxation responses to ACh in both control and diabetic groups. However, the inhibitory effects of TRAM 34 on ACh responses were more prominent in arteries taken from UCD-T2DM groups compared to those in controls. By contrast, ACh responses were not affected following incubation of aorta or MA with Apamin in either control or diabetic groups suggesting that SKca channels plays no role in EDHF-mediated relaxation in either vascular beds. Accordingly, the IKca expression level was significantly higher in aortic rings of diabetic group than in the controls.
The responsiveness to PE was significantly enhanced in the aortic rings of diabetic group, whereas in MA, diabetes did not alter the contractile responses to PE.
These data suggest that in MA of UCD-T2DM rats, the predisposition to vascular injury may be due to a shift away from EDHF, initially the major vasodilatory factor, toward a greater reliance on NO. However, in aorta, despite elevated contractile responses, ACh responses were enhanced. Increased contribution of NO-independent factors specifically IKca channel plays a role in potentiated responses to ACh in this model.
Graham, J. L.,
Stanhope, K. L.,
Havel, P. J.,
Role of EDRFs in aortic and mesenteric arterial function of the UC Davis Type 2 Diabetic Mellitus (UCD-T2DM) male rats.
European Heart Journal, 40(1),