This study describes the effect of variable oxygen supply on relaxing responses induced by αCGRP and adrenomedullin (AM) on isolated pig coronary arteries in vitro. Organ culture during normoxia (21% O2) and hypoxia (5% O2) induced a significant leftward shift of the AM concentration-response curves compared to 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 (10M) on AM-induced vasorelaxation in fresh vessels (apparent pKB = 7.4 ± 0.1) was absent during hypoxic organ culture. TheRAMP1/Calcitonin like receptor (CLR) mRNA ratio was reduced and RAMP2/CLR mRNA ratio increased during hypoxic and normoxic organ culture compared to fresh vessels. Hypoxic organ culture for 24h - 72h potentiated the AM induced vasorelaxation via an AM22-52 sensitive receptor but attenuated the vasorelaxant effect of CGRP via 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.
Journal of Cardiovascular Pharmacology, 2014, Vol 63, Issue 1, p. 58-67