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

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Philip Hasbak, Majid Sheykhzade, Søren Schifter, Lars Edvinsson

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.
Original languageEnglish
JournalJournal of Cardiovascular Pharmacology
Issue number1
Pages (from-to)58-67
Number of pages10
Publication statusPublished - Jan 2014

ID: 92540628