Euhydric hypercapnia increases vasoreactivity of rat pulmonary arteries via HCO3- 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 PGF2alpha (3 microM)-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 PGF2alpha. Euhydric hypercapnia however caused a substantial approximately 5.5-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 approximately 20 min. No equivalent responses to euhydric hypercapnia were observed in either mesenteric or renal arteries. Both the potentiation of PGF2alpha-induced vasoconstriction and the spontaneous vasoconstriction in IPA were inhibited by the L-type channel blocker diltiazem (10 microM). The potentiation was also suppressed by DIDS, an inhibitor of anion transporters, removal of extracellular Na+, and anthracene-9-carboxylic acid (A9C; 200 microM), reported to inhibit Ca2+-activated Cl- channels. Inhibition of nitric oxide synthase with L-NAME (100 microM) 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.