Bradykinin-induced release of nitric oxide by the isolated perfused rat heart: importance of preformed pools of nitric oxide-containing factors.
OBJECTIVE
To study whether the vasorelaxant effect of bradykinin in the coronary vascular bed depends on the release of NO from preformed pools and/or de-novo synthesis of NO resulting from bradykinin-induced stimulation of NO synthase.


METHODS
Rat hearts were perfused according to Langendorff's method. Coronary flow was measured continuously. We constructed concentration-response curves for bradykinin and L-arginine under control conditions, after downregulation of NO synthase by exposing the heart to high concentrations (10 mmol/l) of NO and during chronic inhibition of NO synthase, obtained by perfusing the heart for 30 min with 0.1 mmol/l N(omega)-nitro-L-arginine methyl ester. The effect of acute inhibition of NO synthase was studied by infusing single submaximal doses of bradykinin and of L-arginine in the absence and presence of 0.1 mmol/l N(omega)-nitro-L-arginine methyl ester.


RESULTS
Coronary flow [baseline 9 +/- 2 ml/min (mean +/- SD)] increased to maximally 23 +/- 6 ml/min with bradykinin and to 16 +/- 4 ml/min with L-arginine. Maximal coronary flow, established as the maximal effect in response to NO, was 22 +/- 4 ml/min. Chronic inhibition of NO synthase reduced coronary flow to 4 +/- 1 ml/min. Coronary flow did not change after downregulation of NO synthase by NO. Neither downregulation nor acute inhibition of NO synthase affected the response to bradykinin, whereas chronic inhibition of NO synthase blocked the bradykinin-induced increase in coronary flow by > 90%. Administration of L-arginine no longer increased coronary flow under all tested conditions.


CONCLUSIONS
Preformed pools of NO-containing factors exist within the isolated perfused heart and bradykinin exerts its vasorelaxant effects at least in part by the mobilization of these preformed pools. These data may reconcile previous discrepancies about the (lack of) effect of NO synthase inhibitors on bradykinin-induced coronary vasodilatation.
Danser
A H
AH
Department of Pharmacology, Cardiovasculair Onderzoeksinstituut Erasmus Universiteit Rotterdam, The Netherlands. danser@farma.fgg.eur.nl
de Vries
R
R
Schoemaker
R G
RG
Saxena
P R
PR
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin