Ramiprilat attenuates the local release of noradrenaline in the ischemic myocardium.
The effects of the converting enzyme inhibitors ramiprilat and enalaprilat on ischemia-induced release of noradrenaline (NA) were examined in the isolated perfused rat heart, submitted to 30 min of total flow restriction followed by 5 min of reperfusion. Ramiprilat (2.6 nM-2.6 microM) caused a concentration-dependent decrease in the efflux of NA at reperfusion. The maximal effect (about 70% reduction) was observed at a concentration of 26 nM. In contrast, enalaprilat (10 nM-10 microM) caused no reduction in NA efflux until at a high concentration (10 microM, NA efflux reduced by about 20%). Moreover, the prodrugs ramipril and enalapril (added to the perfusion medium) were without any significant effects on ischemia-induced NA release. Both the angiotensin II receptor antagonist saralasin (0.1 microM) and bradykinin (0.1 and 1 nM) caused marked reductions in ischemic NA efflux. However, when indomethacin (10 microM) was added to the perfusion medium, the effects of bradykinin (1 nM) and ramiprilat (26 nM) on NA efflux were abolished. Likewise, in the presence of angiotensin II (0.1 microM) the effect of ramiprilat was no longer evident. The magnitude of cellular injury, expressed as efflux of creatine kinase during reperfusion, was reduced by bradykinin (0.1 and 1 nM) and by ramiprilat (by about 55% at 2.6 microM). It is concluded that ramiprilat, at therapeutically relevant concentrations, attenuates the ischemia-induced mobilization of NA via a reduction in local angiotensin II production and/or bradykinin degradation. The lack of effect of enalaprilat in this model may reflect differences between converting enzyme inhibitors regarding tissue accumulation or the potency of local enzyme inhibition.
Carlsson
L
L
Department of Pharmacology, University of Göteborg, Sweden.
Abrahamsson
T
T
D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003327:Coronary Disease / Q000378:metabolism*; D003402:Creatine Kinase / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D017257:Ramipril / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D012504:Saralasin / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D011758:Pyrroles; D000804:Angiotensin II; C052549:ramiprilat; D003402:Creatine Kinase; D012504:Saralasin; D017257:Ramipril; D001920:Bradykinin; D009638:Norepinephrine; D007213:Indomethacin