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 PGF_2α (3 μM)-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_2α. Euhydric hypercapnia however caused a substantial ∼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 ∼20 min. No equivalent responses to euhydric hypercapnia were observed in either mesenteric or renal arteries. Both the potentiation of PGF_2α-induced vasoconstriction and the spontaneous vasoconstriction in IPA were inhibited by the L-type channel blocker diltiazem (10 μM). The potentiation was also suppressed by DIDS, an inhibitor of anion transporters, removal of extracellular Na⁺, and anthracene-9-carboxylic acid (A9C; 200 μM), reported to inhibit Ca²⁺-activated Cl⁻ channels. Inhibition of nitric oxide synthase with l-NAME (100 μM) did not prevent potentiation. Depolarisation with 20 mM [K⁺] mimicked the effect of euhydric hypercapnia in that it also potentiated the response to PGF_2α (>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.