Euhydric hypercapnia increases vasoreactivity of rat pulmonary arteries via HCO-3 transport and depolarisation

Objective: To examine whether altered PCO2 or HCO3- at normal pH potentiate agonist-induced vasoconstriction of small pulmonary arteries, and if so to determine the mechanism. Methods: Small intrapulmonary arteries (IPA) from rats were mounted on a myograph and PGF(2alpha) (3 muM)-induced tension recorded before and 40 min after replacing normal bath solution (5% CO2, 24 mM [HCO3-], pH 7.4) with one containing either normal [HCO3-] (24 mM) gassed with 10% CO2 (pH 7.12; hypercapnic acidosis) or high [HCO3-] (48 mM) gassed with 10% CO2 (pH 7.4; euhydric hypercapnia). Results: Hypercapnic acidosis had no significant effect on the response of IPA to PGF(2alpha). Euhydric hypercapnia however caused a substantial similar to5.5-fold potentiation of the response (n=17, p<0.001) in the majority of preparations, whilst 20% of IPA (11 of 58) developed a slow spontaneous vasoconstriction after similar to20 min. No equivalent responses to euhydric hypercapnia were observed in either mesenteric or renal arteries. Both the potentiation of PGF(2alpha)-induced vasoconstriction and the spontaneous vasoconstriction in IPA were inhibited by the L-type channel blocker diltiazem (10 muM). The potentiation was also suppressed by DIDS, an inhibitor of anion transporters, removal of extracellular Na+, and anthracene-9-carboxylic acid (A9C; 200 muM), reported to inhibit Ca2+-activated Cl- channels. Inhibition of nitric oxide synthase with L-NAME (100 [muM) did not prevent potentiation. Depolarisation with 20 mM [K] mimicked the effect of euhydric hypercapnia in that it also potentiated the response to PGF(2alpha). (>sixfold, n=6). Conclusions: Euhydric hypercapnia increases vasoreactivity of IPA, but not mesenteric or renal arteries, via a mechanism involving Na+-dependent HCO3- transport, activation of Ca2+-dependent Cl- channels, and subsequent depolarisation. These results may have consequences for patients with CO2-retaining chronic respiratory disease where plasma [HCO3-] is raised following renal compensation, and could explain the increased propensity to pulmonary hypertension and increased mortality in such patients. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.