Intermedin/adrenomedullin‐2 (IMD/AM2) relaxes rat pulmonary arterial rings via protein kinase G (PKG) and BKCa channel dependent pathway: The effect of chronic hypoxia induced pulmonary hypertension

Abstract

Our previous results showed that when rat pulmonary arterial (PA) rings were precontracted with U‐46619 IMD relaxes PA rings in a nitric oxide and endothelial dependent manner. In this study the pulmonary vasorelaxant response (PVR) to IMD in PA was inhibited by cholera toxin, Rp‐8‐Br‐PET‐cGMPs and iberitoksin whereas rolipram, KT5720 and apamin were without effect. PVR to IMD was potentialized in the presence of sildenafile. In PA rings isolated from rats with pulmonary hypertension induced by chronic hypoxia (PHCH), PVR to both IMD and ACh response were diminished. In contrast, in the isolated, buffer‐perfused rat lungs with PHCH, the pulmonary vasodilator responses to IMD and ACh were not altered. In PA rings from rats with PHCH, the PVR to NS1619 decreased when compared to control rats. The present data suggest that cGMP‐induced PKG activation and promotion of hyperpolarization through BKCa is the major pathway for rIMD induced vasorelaxation in PA rings. CH may induce downregulation of BKCa channels in pulmonary arterial conductance segments whereas pulmonary resistance arterial segments may not be susceptible to similar changes by PHCH, it is possible other mechanisms such as selective upregulation of eNOS or downregulation in phosphodiesterase activity in response to CH in resistance arteries may explain the difference in vascular responsiveness.