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.
Vanková
Marie
M
Department of Asthma, Allergy and Respiratory Science, GKT School of Medicine, Guy's Hospital Campus, London SE1 1UL, UK.
Snetkov
Vladimir A
VA
Knock
Greg A
GA
Aaronson
Philip I
PI
Ward
Jeremy P T
JP
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001158:Arteries; D001639:Bicarbonates / Q000378:metabolism*; D001692:Biological Transport; D018118:Chloride Channels / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D006935:Hypercapnia / Q000378:metabolism*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011652:Pulmonary Circulation; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000873:Anthracenes; D001639:Bicarbonates; D018118:Chloride Channels; D007473:Ion Channels; D014662:Vasoconstrictor Agents; C010030:9-anthroic acid; D012964:Sodium; D019001:Nitric Oxide Synthase; D004110:Diltiazem; D015232:Dinoprostone; D000086:Acetazolamide; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D019331:NG-Nitroarginine Methyl Ester