Normoksik ve Pulmoner Hipertansif Sıçanlarda İntermedin'in (IMD/AM2) Pulmoner Vasküler Yatağa Etkilerinin İncelenmesi

Abstract

Telli, G., Investigation The Role Of Intermedin/Adrenomedullin2 (IMD/AM2) On Pulmonary Vascular Bed In Normoxic and Pulmonary Hypertensive Rats, Hacettepe University Faculty of Pharmacy Department of Pharmacology Doctor of Philosophy Thesis, Ankara, 2017. In our study, we investigated the mechanism of the relaxation responses of IMD/AM2 in the rat main pulmonary artery. Another aim of the study is to evaluate the vasodilator effect of IMD/AM2 on pulmonary vascular bed in rats with secondary pulmonary hypertension (PH). CGRP8-37 (10-6M), L-NAME (10-4M), ODQ (10-5M), SQ22536 (10-4M), H89 (10-6M), TEA (10-2M), iberiotoxin (3x10-7M) and verapamil (10-5M) inhibited IMD/AM2 relaxation responses in rat main PA. The IMD/AM2 responses were also inhibited in the endothelium damaged PA, in the absence of Ca+2 and in the PA’s precontracted with 60 mM K+. There were no changes in the responses with the incubation of PA’s AM22-52, 4-aminopiridin (3x10-3M), glibenklamid (10-5M), apamin (3x10-7M) and TRAM-34 (10-5M), La+3 (10-4M). In experiments for changes in intracellular [Ca + 2] levels were investigated, [Ca+ 2] levels were increased with IMD/AM2 administration. These increases were inhibited with iberiotoxin (3x10-7M) and verapamil (10-5M) but there were no changes with La+3 (10-4M) incubation. IMD/AM2 induced relaxation in the main PAs and caused vasodilatation in resistance pulmonary arteries in pulmonary hypertensive rats. These responses were inhibited by L-NAME (10-4M). According to these results, it is thought that IMD/AM2 effects via CGRP receptors and sAMP-PKA pathways; the relaxation is endothelium-dependent and NO mediated. NO is released after increase of intracellular [Ca+2] with the activation of large-conductance calcium-activated K+ channels and L-type Ca+2 channels. IMD/AM2 produced important vasodilatation in the pulmonary vascular bed in PH suggests that IMD/AM2 may be evaluated as a therapeutic target in PH.