Mechanisms of U46619‐ and 5‐HT‐induced contraction of bovine pulmonary arteries: role of chloride ions

Background and purpose: Thromboxane A 2 and 5‐hydroxytryptamine (5‐HT) are implicated in pulmonary hypertension. The involvement of chloride, voltage‐operated calcium channels (VOCCs), store‐operated calcium channels (SOCCs) and the Rho kinase in the contractile response of bovine pulmonary arteries (BPA) to the thromboxane A 2 mimetic U46619 and 5‐HT was investigated. Experimental approach: Endothelium‐intact ring segments of BPA were mounted in Krebs/Henseleit buffer (37°C) under a tension of 2g and gassed with 95%O 2 /5%CO 2 . Key results: Depletion or removal of extracellular chloride, inhibition of chloride and SOCC, Na:K:2Cl, Cl/HCO 3 , Rho kinase inhibited contractions to U46619. Combining Rho kinase inhibition and chloride channel blockade (with NPPB) almost abolished the contractions to U46619. In contrast 5‐HT‐induced contraction was inhibited by verapamil and mibefradil. Depletion of stored calcium with caffeine almost abolished the response to U46619 but not 5‐HT. The contraction by the sarco(endo)plasmic reticulum Ca 2+ ‐ATPase inhibitor CPA was abolished by SOCC and chloride channel blockade (with NPPB) and by chloride depletion. Conclusions and implications: This study suggests that the contractile response of BPA to U46619 involves Rho kinase together with a chloride‐sensitive mechanism, which does not involve VOCC but may have a role in calcium release and calcium entry via SOCC. In contrast contraction of the BPA by 5‐HT appears to involve verapamil‐ and mibefradil‐sensitive VOCC. This study may indicate that the use of calcium channel blockers in the management of pulmonary hypertension may not always be effective and that Rho kinase and chloride channels may be targets for the development of new therapies. British Journal of Pharmacology (2007) 151 , 1224–1234; doi: 10.1038/sj.bjp.0707338