The role of bradykinin and nitric oxide in the cardioprotective action of ACE inhibitors.
BACKGROUND
The angiotensin-converting enzyme inhibitor ramiprilat has been previously demonstrated to protect myocardium from ischemia/reperfusion injury. The objective of these investigations was to examine the roles of bradykinin, angiotensin II, and nitric oxide in the cardioprotective effects of ramiprilat.


METHODS
Anesthetized, open-chest rabbits were instrumented for production of myocardial ischemia (30 minutes) and subsequent reperfusion (120 minutes), after which myocardial infarct size was measured. Animals were treated intravenously with either saline solution, ramiprilat (50 micrograms/kg), the bradykinin2 receptor antagonist HOE 140 (1 microgram/kg), ramiprilat + HOE 140, angiotensin II (2.5 ng.kg-1.min-1), the angiotensin II receptor antagonist losartan (20 mg/kg), ramiprilat + angiotensin II, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (100 micrograms.kg-1.min-1), or ramiprilat + NG-nitro-L-arginine methyl ester.


RESULTS
Among all treatment groups myocardial infarct size was reduced significantly below saline control only by ramiprilat (-54%) and ramiprilat + angiotensin II (-37%). Pretreatment with HOE 140 or NG-nitro-L-arginine methyl ester abolished the cardioprotective effect of ramiprilat. Neither stimulation nor antagonism of angiotensin II receptors altered infarct size from the saline control level. Also, when isolated neonatal rat cardiomyocytes were exposed to hypoxia/reoxygenation, ramiprilat (100 mumol/L) and bradykinin (10 nmol/L) improved cell viability (approximately 60%), and the protective effect of both agents was reversed by administration of HOE 140 (10 mumol/L).


CONCLUSIONS
These results indicate that the in vivo cardioprotective effect of ramiprilat can be abolished by antagonizing bradykinin receptors or inhibiting nitric oxide synthase, and that the effect is not related to angiotensin II receptor activity. The potential bradykinin-sparing property of ramiprilat may promote increased bradykinin-stimulated nitric oxide production leading to cardioprotection. Part of the cardioprotective effects of ramiprilat/bradykinin/nitric oxide may occur locally as demonstrated by the in vitro results using isolated cardiomyocytes.
Hartman
J C
JC
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000804:Angiotensin II / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000502:physiology* / Q000627:therapeutic use; D065168:Bradykinin Receptor Antagonists; D006321:Heart / Q000187:drug effects*; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D019808:Losartan; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000628:therapy; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase; D011817:Rabbits; D017257:Ramipril / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011945:Receptors, Angiotensin / Q000187:drug effects; D018002:Receptors, Bradykinin / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use
D000319:Adrenergic beta-Antagonists; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D065168:Bradykinin Receptor Antagonists; D007093:Imidazoles; D011945:Receptors, Angiotensin; D018002:Receptors, Bradykinin; D013777:Tetrazoles; D000804:Angiotensin II; D009569:Nitric Oxide; C052549:ramiprilat; C065679:icatibant; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019808:Losartan; D017257:Ramipril; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester