Influence of pretone agents on calcium release and influx pathways during HPV

Abstract

Hypoxic pulmonary vasoconstriction (HPV) is the response of small pulmonary arteries to acute moderate hypoxia. Although HPV has been extensively investigated, the underlying mechanisms and their relative contributions are still largely controversial, possibly due to differences in experimental conditions. However, there is wide agreement that Ca2+ release from the SR and influx of extracellular Ca2+ are crucial for the development of HPV. We have therefore investigated the contribution of these pathways to HPV with PGF2α and high K+ as pretone agents in isolated rat small pulmonary arteries mounted on a small vessel myograph. In vessels preconstricted with PGF2αphase 1 of HPV was not significantly altered by inhibition of ryanodine receptors with dantrolene (50 μM) and ryanodine (100 μM) or by the TRPC modulator flufenamic acid (FFA, 2 μM), but blocked by store depletion with low ryanodine (1 μM) and caffeine (10 mM), inhibition of store-operated Ca2+ entry with 2-APB (75 μM) and Ca2+ substitution with 4 mM Sr2+. Combined treatment of 2-APB with diltiazem (10 μM) blocked phase 1 significantly. Phase 2 was greatly inhibited by dantrolene, ryanodine (100 μM), 2-APB, 2-APB + diltiazem and Sr2+, but not altered by low ryanodine or FFA. However, when vessels were preconstricted with K+, dantrolene and 2-APB did not attenuate, Ca2+ substitution with Sr2+ inhibited and FFA (2 μM) increased HPV. We therefore conclude that the pathways involved in the development of HPV are dependent on the pretone agent used. It is highly likely that at least some of the discrepancies of earlier studies may be due to differences in the experimental conditions used. Sponsored by the BHF