Mechanisms of U46619- and 5-HT-induced contraction of bovine pulmonary arteries: role of chloride ions.
OBJECTIVE
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.


METHODS
Endothelium-intact ring segments of BPA were mounted in Krebs/Henseleit buffer (37 degrees C) under a tension of 2g and gassed with 95%O(2)/5%CO(2).


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
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.
Alapati
V R
VR
Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK.
McKenzie
C
C
Blair
A
A
Kenny
D
D
MacDonald
A
A
Shaw
A M
AM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D018118:Chloride Channels / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D018490:Serotonin Agents / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases
D015220:Calcium Channels; D018118:Chloride Channels; D002712:Chlorides; D047908:Intracellular Signaling Peptides and Proteins; D018490:Serotonin Agents; D014662:Vasoconstrictor Agents; D012701:Serotonin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D002118:Calcium