Abstract
Chronic hypoxia is associated with altered pulmonary vasoreactivity, and it has been suggested that an increased response to voltage-dependent vasodilators may relate to enhanced Ca++entry via voltage-dependent channels, secondary to depolarization. Few studies have been performed on small pulmonary arteries, and it is unknown whether they are depolarized after chronic hypoxia. We examined the resting membrane potential, and the actions of voltage-dependent (verapamil, levcromakalim) and -independent (isoproterenol, forskolin, papaverine) vasodilators in small (∼300 μm internal diameter) pulmonary arteries from chronically hypoxic rats. The resting membrane potential was more positive in arteries after chronic hypoxia (control: −60 ± 0.5 mV; hypoxic: −54.4 ± 1.1 mV; P < .01), and this was reflected by a shift to the left of the response curves for K+ and 4-aminopyridine. In arteries constricted with prostaglandin F2α the response to verapamil and levcromakalim was increased after chronic hypoxia, although maximum prostaglandin F2α-induced tension was unchanged, which implies a reduction in voltage-independent constrictor mechanisms. Although vasorelaxation to isoproterenol was depressed in arteries from hypoxic rats, forskolin-induced relaxation was enhanced substantially, and because the response to the phosphodiesterase inhibitor papaverine was unchanged, we suggest that this reflects an up-regulation of adenylate cyclase. In conclusion, chronic hypoxia resulted in a significant depolarization in small pulmonary arteries, but this may explain only partly the increased efficacy of voltage-dependent vasodilators. Whether the reduction in voltage-independent constrictor mechanisms is related to the apparent up-regulation of adenylate cyclase remains to be elucidated.
Footnotes
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Send reprint requests to: Dr. J.P.T. Ward, Department of Medicine, UMDS, St Thomas’ Campus, Lambeth Palace Road, London SE1 7EH, UK.
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↵1 Supported by the British Heart Foundation and the Wellcome Trust (grants 038048 and 043357).
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↵2 Present address: Department of Intensive Care, St Thomas’ Hospital, London SE1 7EH, UK.
- Abbreviations:
- 4-AP
- 4-aminopyridine
- ACh
- acetylcholine
- cAMP
- cyclic adenosine monophosphate
- cGMP
- cyclic guanosine monophosphate
- CH
- chronic hypoxic group
- HPV
- hypoxic pulmonary vasoconstriction
- KPSS
- physiological salt solution containing 75 mM [K+], equimolar substitution for NaCl
- l-NMMA
- NG-monomethyl-l-arginine
- NO
- nitric oxide
- PGF2α
- prostaglandin F2α
- PHT
- pulmonary hypertension
- PSS
- physiological salt solution
- RMP
- resting membrane potential
- RV
- right ventricle
- SNP
- sodium nitroprusside
- TEA
- tetraethylammonium
- Received September 23, 1997.
- Accepted February 4, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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