Role of EDHF in Potentiation of ACh‐induced Relaxation of Aorta in Male UC Davis Type 2 Diabetes Mellitus (UCD‐T2DM) Rat: Sex Specific Responses

The UC Davis type 2 diabetes mellitus (UCD‐T2DM) Rat is a validated model of T2D that exhibits an etiology more similar to human disease than other rodent models. In spite of being a validated model, there are no published data on the vascular function in this model. We investigated whether vascular reactivity is altered, and if sex differences exist in aortic endothelial function in the UCD‐T2DM rats. We also examined the potential changes in the relative contributions of endothelium‐derived relaxing factors in modulating aortic reactivity of UCD‐T2DM. Endothelium‐dependent vasodilation (EDV) to acetylcholine (ACh, 10 −8 to 10 −5 M) was measured in aortic rings pre‐contracted with phenylephrine (PE, 2μM) before and after pretreatment with indomethacin (Indo; 10 μM), a cyclooxygenase (COX) inhibitor, Indo plus ODQ (10 μM), an inhibitor of soluble guanylyl cyclase (sGC) and ultimately following incubation with Indo, ODQ and L‐NNA (100 μM), a nonselective NO synthase (NOS) inhibitor. Endothelium‐independent vasodilation to sodium nitroprusside (SNP, 10 −9 to 10 −5 M) was assessed in endothelium‐denuded rings pre‐contracted with PE (2μM). Furthermore, constrictor response curves to PE (10 −8 to 10 −5 M) were also generated. The contribution of K + to ACh‐induced relaxation was assessed in male animals by obtaining the concentration response curves to ACh before and after treatment with TRAM‐34 (1μM), an intermediate‐conductance Ca 2+ activated K + (IK Ca ) channel inhibitor; apamin (1 μM), a small‐conductance Ca 2+ activated K + (SK Ca ) channel inhibitor. Moreover, the expression of K+ channels were evaluated in aortic tissues. Diabetes significantly impaired relaxation responses to ACh and SNP in aortic rings from female UCD‐T2DM Rats, however, potentiated the relaxation in males. The responsiveness to PE was significantly enhanced in diabetic groups, regardless of sex. Blocking of COX, sGC and NOS completely abolished the relaxation response to ACh in all of experimental groups except for the diabetic male rats, indicating the presence of endothelium‐dependent hyperpolarizing factor (EDHF)‐type relaxation in this group. To further study the contribution of EDHF in diabetic males, ACh‐induced relaxation was measured before and after TRAM 34 or Apamin in male tissues. Incubation of male aortic rings with TRAM 34, but not Apamin, significantly blunted the relaxation responses to ACh only in diabetic group. Accordingly, the level of expression of IKca channels was significantly higher in diabetic males than that in controls. These data, for the first time, show that the vascular function in aortic rings of UCD‐T2DM is altered in both sexes. It also suggests that an increased contribution of EDHF, specifically IKca channel, plays a role in potentiated relaxation responses to ACh in male UCD‐T2DM rats. Support or Funding Information Supported by NHLBI This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .