Impaired vascular sensitivity to nitric oxide in the coronary microvasculature after endotoxaemia.
1. The effects of endotoxaemia on coronary vasodilator responses to bradykinin (BK), sodium nitroprusside (SNP) and nicardipine were investigated in the rat isolated heart perfused at constant flow ex vivo. 2. Dose-dependent reductions in coronary perfusion pressure reaching a maximum of 56+/-3 and 57+/-5 mmHg were observed for BK and SNP respectively. The BK response was biphasic, consisting of a rapid dilator response that was insensitive to N(G)nitro-L-arginine methyl ester (L-NAME, 0.1 mM) and a second slower component whose duration was attenuated by L-NAME. 3. Hearts obtained from rats treated with endotoxin (2.5 mg kg(-1), i.p.) for 2 or 6 h had increased basal coronary perfusion pressure and reduced vasodilator responses to BK or SNP. Dilator responses to nicardipine were not affected by endotoxin treatment. In vitro perfusion of hearts from endotoxin-treated rats with L-NAME (0.1 mM) restored SNP responses to control values. 4. Treatment with dexamethasone (1 mg kg(-1)), 1 h before endotoxin did not alter the endotoxin-induced impairment of dilator responses to BK or SNP. 5. These results show that coronary microvascular responses are altered following endotoxin exposure. Endotoxin results in increased coronary microvascular tone despite induction of NO synthase and inhibits the dilator response to BK and SNP, vasodilators that act via the release of NO. Responses to SNP in endotoxin-treated hearts were restored to control values in the presence of L-NAME suggesting that enhanced endogenous NO synthesis might saturate guanylate cyclase resulting in reduced response to NO donors. The reduced response to vasodilators and increased coronary resistance might be important in determining the response of the coronary circulation to systemic inflammation and infection.
Bogle
R G
RG
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, UK.
McLean
P G
PG
Ahluwalia
A
A
Vallance
P
P
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000139:chemically induced; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D008070:Lipopolysaccharides / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009529:Nicardipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D004731:Endotoxins; D008070:Lipopolysaccharides; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D009529:Nicardipine; D001920:Bradykinin