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Roles of Endothelin-1 and Urotensin-II in Vascular Dysfunction of Type II Diabetic Patients: an in vitro and in vivo study – Salahaddin University-Erbil (SUE)

Roles of Endothelin-1 and Urotensin-II in Vascular Dysfunction of Type II Diabetic Patients: an in vitro and in vivo study

SUMMARY

The current research was designed to investigate the cellular mechanisms of the two most powerful vasoconstrictors; Endothelin-I (ET-1) and Urotensin-II (UII), and their incorporation in diabetes mellitus type II disease (T2DM) in patients undergoing coronary artery bypass graft surgery (CABG), as well as, measuring their levels beside enzymes and related metabolites.

Two main parts were carried out in this study; a case control study and the in vitro study that confirms each other’s results. In case control study, 73 individuals were participated, aged 40-60 years old (35 volunteers without diabetes (15 females and 20 males) and a body mass index BMI of ≤ 25 and 38 patients with T2DM (20 females and 18 males) and a BMI of ≥ 25), then each groups serum ET-I, UII, insulin, assymetric dimethylearginine (ADMA), and dimethylarginine dimethylaminohydrolase (DDAH) were measured instantly. Moreover, anthropometric criteria were measured including, Height, weight, waist circumference (WC), BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and estimated glomerular filtration rate (eGFR). The homeostatic model assessment for insulin resistance (HOMA-IR) was used to determine whether or not a person has experience T2DM. Furthermore, many biochemical criteria were measured in accordance with the study requirements

Correlation test between ET-I as a dependent variable with independent variables exhibits a positive correlation of ET-I with all studied parameters except for insulin, total cholesterol, high density lipoprotein-cholesterol (HDL-C), LDL-C, urea and alkaline phosphatase (ALP). Furthermore, correlation between UII as a dependent variable with independent variables also shows a positive correlation of UII with all studied parameters except HDL-C, LDL-C and serum insulin. Height, HDL-C are negatively and non-significantly correlated with UII whereas, insulin sensitivity represented by QUICKI is negatively and significantly correlated with UII. Multiple regression analysis for ET-I with the independent variables nominate hemoglobin A1C (HbA1C), UII, HOMA-IR, BMI, and MAP as good biomarkers for ET-I increase in T2DM patients. Moreover, results from stepwise multiple regression analysis for UII with all the studied parameters, show all of BMI, SBP, ET-I, and HbA1C as markers for increase of UII in T2DM individuals.

The second part of this study is in vitro study; it involves isolated segments of saphenous veins harvested from patients undergoing CABG surgery, they are divided into two parallel sets of groups; the T2DM group and non-DM group. Both groups undergo many pharmacological treatments using organ bath apparatus.

This part of the study interested in the determination of the physiological roles of potassium channel blockers, endothelium derived hyperpolarizing factor (EDHF) inhibitors, Ca2+ channel blocker, ET-I antagonists, and many enzyme inhibitors and their roles in the modulation of saphenous veins    vascular responses to ET-I dose response curve (DRC) induced contraction

The isolated saphenous veins incubated with potassium channel blockers that includes the following blockers or inhibitors, tetraethylammonium (TEA), a non-selective calcium-activated potassium channel blocker (KCa2+), charybdotoxin (CTN), big and intermediate conductance calcium-activated potassium channels (BKCa2+ and IKCa2+) blocker, barium chloride (BaCl2), delay inward rectifier potassium channels Kir blocker, clotrimazole, an IKCa2+ blocker, glibenclamide, adenosine triphosphates-sensitive potassium channels (KATP) blocker, 4-aminopyridines (4-AP), voltage sensitive potassium channels (KV) channel blocker.Then cumulative doses of ET-I were applied to each group.

           Other signaling pathways have also  been investigated through incubation of saphenous veins with nefidipine, L- type  Ca2+ channels blocker and through EDHF inhibitors that include, L-nitro-arginine methyl ester (L-NAME), an irreversible endothelial nitric oxide synthase (eNOS) inhibitor, indomethacin, a non-selective cyclooxygenase (COX) inhibitor, methylene blue (MB), a non-selective soluble guanylate cyclase (sGC) inhibitor. ET-I antagonists includes, BQ-123, a selective ET-1 receptor type-A (ETAR) blocker, BQ788, a selective ET-I receptor type-B (ETBR) blocker. The enzyme blockers include, RO 31-8220, a protein kinas C (PKC) inhibitor, oxypurinol, a xanthine oxidase (XO) inhibitor, tiron, superoxide anion (O2.-) scavenger, Apocynin, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, rotenone, mitochondrial electron transport chain inhibitor. Then cumulative doses of ET-I were applied to each group.

Another set of experiment was run by applying ET-I cumulative doses in isolated saphenous veins that are rendered endothelial dysfunction (ED) by denudation of endothelial layer in T2DM and non-DM groups. The maximum responses (Emax) to ET-1 were higher in endothelial denuded group but the potency of the drug (pD2) didn’t change comparing to the non-DM group in Emax and potency, while the Emax and the pD2 were higher non-significantly comparing to T2DM group.

Preincubation of saphenous vein with BQ788, increased the Emax of ET-1 significantly while decreased the pD2 significantly in non-DM group. In T2DM group the Emax of ET-1 is abolished significantly while decreased the pD2 non-significantly. BQ123 on the other hand decreased the Emax of ET-1 and decreases the pD2 non-significantly in non-DM groups. Moreover, the Emax of ET-1 did not affect while the pD2 decreased significantly in T2DM group.

Another important finding in this study was that potassium channels blockers reverses vascular responses noticeably and decreases ET-1 efficacy and pD2 with an exception in TEA that significantly augments the Emax of ET-I without changing the pD2. However, in T2DM groups, both BaCl2 and CTN exhibited unchanged Emax of ET-1.

The Emax of ET-1 were not only affected by potassium channel blockers, but also by Ca2+ channel blockers; nefidipine, decreases the pD2 of ET-1 non-significantly while decreased the Emax of ET-1 significantly; moreover, in ED induced T2DM, the pD2 increased significantly while the Emax of ET-1 did not change. L-NAME and indomethacin increased the Emax of ET-1 significantly while the pD2 decreased significantly, in contrast to MB, that abolished the Emax of ET-1 significantly and decreases the pD2 non-significantly in non-DM groups.

Furthermore, the Emax of ET-1 abolished using RO 31-8220, oxypurinol, tiron, apocynin, and rotenone while the pD2 reduced significantly using RO 31-8220 and tiron in non-DM groups. In T2DM, the efficacy abolished significantly by RO 31-8220, oxypurinol and rotenone while it is increased significantly by tiron and apocynin. Additionally, the pD2 of ET-1 decreased significantly by apocynin.

The present study, for the first time, highlighted that ED potentiated the vascular responses to ET-I and modulated potassium channels and EDHF contributions to vascular actions of ET-1. The present study also uncovered that enzymatic inhibitors and antioxidants pathways might synergistically share the peptide vasomotor actions. These findings provide some pharmacological tools for modulating the peptide behavior, in particular, under pathological conditions.