Potentiated adrenomedullin-induced vasorelaxation during hypoxia in organ cultured porcine coronary arteries

TY - JOUR

T1 - Potentiated adrenomedullin-induced vasorelaxation during hypoxia in organ cultured porcine coronary arteries

AU - Hasbak, Philip

AU - Sheykhzade, Majid

AU - Schifter, Søren

AU - Edvinsson, Lars

PY - 2014/1

Y1 - 2014/1

N2 - This study describes the effect of variable oxygen supply on relaxing responses induced by α-calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. Organ culture during normoxia (21% of O2) and hypoxia (5% of O2) induced a significant leftward shift of the AM concentration-response curves compared with fresh vessels altering the pEC50 values from 6.9 ± 0.04 to 8.0 ± 0.04, whereas the potency (pEC50) of αCGRP was attenuated from 8.8 ± 0.04 to 7.6 ± 0.04. AM22-52 exerted significant antagonistic effect on AM-induced vasorelaxation in hypoxic and normoxic conditions (apparent pKB = 6.8-7.2), whereas no antagonistic effect was observed in fresh and hyperoxic (95%) organ cultured vessels. The antagonistic effect exerted by αCGRP8-37 (10-10 M) on αCGRP-induced vasodilatation in fresh vessels (derived from Schild plot pA2 = 7.4 ± 0.1) was unaltered during organ culture. The antagonistic effect exerted by αCGRP8-37 (10 M) on AM-induced vasorelaxation in fresh vessels (apparent pKB = 7.4 ± 0.1) was absent during hypoxic organ culture. The receptor activity-modifying proteins 1 (RAMP1)/calcitonin-like receptor (CLR) messenger RNA ratio was reduced and RAMP2/CLR messenger RNA ratio was increased during hypoxic and normoxic organ culture compared with fresh vessels. Hypoxic organ culture for 24-72 hours potentiated the AM-induced vasorelaxation through an AM22-52-sensitive receptor but attenuated the vasorelaxant effect of CGRP through the CGRP receptors. This could possibly be explained by relatively decreased levels of RAMP1, thus favoring RAMP2 + CLR complex (=AM receptor) formation during hypoxic organ culture.

AB - This study describes the effect of variable oxygen supply on relaxing responses induced by α-calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. Organ culture during normoxia (21% of O2) and hypoxia (5% of O2) induced a significant leftward shift of the AM concentration-response curves compared with fresh vessels altering the pEC50 values from 6.9 ± 0.04 to 8.0 ± 0.04, whereas the potency (pEC50) of αCGRP was attenuated from 8.8 ± 0.04 to 7.6 ± 0.04. AM22-52 exerted significant antagonistic effect on AM-induced vasorelaxation in hypoxic and normoxic conditions (apparent pKB = 6.8-7.2), whereas no antagonistic effect was observed in fresh and hyperoxic (95%) organ cultured vessels. The antagonistic effect exerted by αCGRP8-37 (10-10 M) on αCGRP-induced vasodilatation in fresh vessels (derived from Schild plot pA2 = 7.4 ± 0.1) was unaltered during organ culture. The antagonistic effect exerted by αCGRP8-37 (10 M) on AM-induced vasorelaxation in fresh vessels (apparent pKB = 7.4 ± 0.1) was absent during hypoxic organ culture. The receptor activity-modifying proteins 1 (RAMP1)/calcitonin-like receptor (CLR) messenger RNA ratio was reduced and RAMP2/CLR messenger RNA ratio was increased during hypoxic and normoxic organ culture compared with fresh vessels. Hypoxic organ culture for 24-72 hours potentiated the AM-induced vasorelaxation through an AM22-52-sensitive receptor but attenuated the vasorelaxant effect of CGRP through the CGRP receptors. This could possibly be explained by relatively decreased levels of RAMP1, thus favoring RAMP2 + CLR complex (=AM receptor) formation during hypoxic organ culture.

U2 - 10.1097/fjc.0000000000000025

DO - 10.1097/fjc.0000000000000025

M3 - Journal article

C2 - 24084221

SN - 0160-2446

VL - 63

SP - 58

EP - 67

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

IS - 1

ER -