RESUMO
The aim of the present study was to examine the effects of atrial natriuretic peptide (ANP) on the responses to coronary artery occlusion. In chloralose-urethane anaesthetised mongrel dogs either saline (controls) or human synthetic ANP was infused intravenously (10 microg kg(-1) + 0.1 microg kg(-1) min(-1)), starting 30 min before and continuing 10 min during a 25 min occlusion of the left anterior descending coronary artery (LAD). ANP infusion resulted in a fall in mean arterial blood pressure (by 17 +/- 2 mmHg, p < 0.05), a transient (max. at 5 min) increase in coronary blood flow (by 24 +/- 5 ml min(-1), p < 0.05), and a reduction in coronary vascular resistance (by 0.27 +/- 0.05 mmHg ml(-1), p < 0.05). When the LAD coronary artery was occluded, there was a less marked elevation in left ventricular end-diastolic pressure (LVEDP) in the ANP-treated dogs than in the controls (9.0 +/- 0.9 versus 12.2 +/- 0.8 mmHg, p < 0.05). Compared to the controls, ANP reduced the number of ventricular premature beats (VPBs, 26 +/- 12 versus 416 +/- 87, p < 0.05), the number of episodes of ventricular tachycardia per dogs (VT, 0.7 +/- 0.3 versus 12.4 +/- 4.2, p < 0.05), and the incidences of VT (45% versus 100%, p < 0.05) and ventricular fibrillation (VF 18% versus 57%, p < 0.05) during occlusion. Reperfusion of the ischaemic myocardium at the end of the occlusion period led to VF in all the control dogs (survival from the combined ischaemia-reperfusion insult was therefore 0%), but VF following reperfusion was much less in the dogs given ANP (survival 64%; p < 0.05). The severity of myocardial ischaemia, as assessed from changes in the epicardial ST-segment and the degree of inhomogeneity, was significantly less marked in dogs given ANP. We conclude that ANP protects the myocardium from the consequences of myocardial ischaemia resulting from acute coronary artery occlusion and reperfusion in anaesthetized dogs.
Assuntos
Fator Natriurético Atrial/uso terapêutico , Doença das Coronárias/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Isquemia Miocárdica/prevenção & controle , Análise de Variância , Animais , Fator Natriurético Atrial/administração & dosagem , Doença das Coronárias/complicações , Cães , Feminino , Infusões Intravenosas , Masculino , Isquemia Miocárdica/etiologia , Reperfusão MiocárdicaRESUMO
The effects of the intracoronary administration of isosorbide-2-mononitrate (ISMN; 3 microg kg(-1) min(-1)), a major metabolite of isosorbide dinitrate, were examined in chloralose-urethane anaesthetized dogs before and during a 25 min, acute occlusion of the left anterior descending coronary artery. The only significant haemodynamic effects of ISMN administration were a slight (-11 +/- 2 mmHg) decrease in arterial blood pressure and a decrease (< 12%) in diastolic coronary vascular resistance. Coronary occlusion in the presence of ISMN led to a markedly reduced incidence and severity of ventricular arrhythmias compared to those in control, saline-infused dogs. There were fewer ectopic beats (62 +/- 35 versus 202 +/- 72; p < 0.05), a lower incidence (25% versus 75%; p < 0.05) and number of episodes (0.7 +/- 0.4 versus 4.3 +/- 2.1; p < 0.05) of ventricular tachycardia and fewer dogs fibrillated during the ischaemic period (17% versus 82%; p < 0.05). More dogs given ISMN survived the combined ischaemia-reperfusion insult (50% versus 0%; p < 0.05). Changes in ST-segment elevation (recorded by epicardial electrodes) and in the degree of inhomogeneity of electrical activation within the ischaemic area were much less pronounced throughout the occlusion period in dogs given ISMN. These results add weight to the hypothesis that the previously reported antiarrhythmic effects of ischaemic preconditioning, and of the intracoronary administration of nicorandil, involve nitric oxide.
Assuntos
Dinitrato de Isossorbida/análogos & derivados , Isquemia Miocárdica/tratamento farmacológico , Animais , Doença das Coronárias/complicações , Cães , Feminino , Hemodinâmica/efeitos dos fármacos , Dinitrato de Isossorbida/farmacologia , Masculino , Isquemia Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/complicações , Índice de Gravidade de Doença , Fibrilação Ventricular/tratamento farmacológico , Fibrilação Ventricular/etiologiaRESUMO
The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. A 1 h infusion of Z13752A (128 microgram kg(-1) min(-1) intravenously) decreased arterial blood pressure (by 11+/-3%; P<0. 05) and increased coronary blood flow (by 12+/-4%, P<0.05). There were no other significant haemodynamic changes. Z13752A inhibited both NEP and ACE enzymes both in dog plasma and in tissue (lung ACE; kidney NEP). Pressor responses to angiotensin I in vivo were inhibited and systemic vasodilator responses to bradykinin were potentiated. When the left anterior descending coronary artery was occluded for 25 min, Z13752A markedly reduced the severity of the resultant ventricular arrhythmias. No ventricular fibrillation (VF) occurred (compared to 7/16 in the controls; P<0.05), and ventricular tachycardia (VT) was reduced (VT in 2/9 dogs treated with Z13752A cp. 16/16 of controls; episodes of VT 0.2+/-0.1 c.p. 10.7+/-3.3; P<0. 05). Reperfusion of the ischaemic myocardium led to VF in all control dogs but occurred less frequently in dogs given Z13752A (survival from the combined ischaemia-reperfusion insult 67% c.p. 0% in controls; P<0.05). Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg(-1), i.v.) a selective antagonist of bradykinin at B(2) receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls. We conclude that this ACE/NEP inhibitor is effective at reducing the consequences of coronary artery occlusion in this canine model and that this protection is primarily due to potentiation of released bradykinin. British Journal of Pharmacology (2000) 129, 671 - 680
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Arteriopatias Oclusivas/fisiopatologia , Bradicinina/farmacologia , Doença das Coronárias/fisiopatologia , Neprilisina/antagonistas & inibidores , Fenilalanina/análogos & derivados , Antagonistas Adrenérgicos beta/farmacologia , Angiotensina I/farmacologia , Angiotensina II/farmacologia , Animais , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/enzimologia , Arritmias Cardíacas/etiologia , Arteriopatias Oclusivas/tratamento farmacológico , Arteriopatias Oclusivas/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/análogos & derivados , Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/enzimologia , Cães , Relação Dose-Resposta a Droga , Feminino , Rim/efeitos dos fármacos , Rim/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Masculino , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/enzimologia , Isquemia Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/etiologia , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/metabolismo , Fenilalanina/farmacologiaRESUMO
Bacterial endotoxin reduces the severity of ventricular arrhythmias which occur when a coronary artery is occluded several hours later. We have now examined in anaesthetised dogs the effects on ischaemia and reperfusion-induced arrhythmias, of a non-toxic derivative component of the endotoxin molecule of the lipid-A (monophosphoryl lipid-A). This was given intravenously, in doses of 10 and 100 microg kg(-1), 24 h prior to coronary artery occlusion. Arrhythmia severity was markedly reduced by monophosphoryl lipid-A. During ischaemia, ventricular premature beats were reduced from 315+/-84 in the vehicle controls to 89+/-60 (with the lower dose of monophosphoryl lipid-A) and 53+/-23 (P<0.05) with the higher dose. The incidence of ventricular tachycardia was reduced from 75% to 25% (P<0.05) and 31% (P<0.05), and the number of episodes of ventricular tachycardia from 13.4+/-4.9 per dog to 1.1+/-1.1 (P<0.05) and 1. 2+/-0.9 (P<0.05) after doses of 10 and 100 microg kg(-1), respectively. The incidence of ventricular fibrillation during occlusion and reperfusion in the control group was 96% (15/16), i.e., only 6% (1/16) dogs survived the combined ischaemia-reperfusion insult. Monophosphoryl lipid-A (100 microg kg(-1)) significantly reduced the incidence of occlusion-induced ventricular fibrillation (from 50% to 7%; P<0.05), and increased survival following reperfusion to 54% (P<0.05). Monophosphoryl lipid-A also significantly reduced ischaemia severity as assessed from ST-segment elevation recorded from epicardial electrodes as well as the degree of inhomogeneity of electrical activation within the ischaemia area. There were no haemodynamic differences prior to coronary occlusion between vehicle controls and monophosphoryl lipid-A-treated dogs. These results demonstrate that monophosphoryl lipid-A reduces arrhythmia severity 24 h after administration. Although the precise mechanisms are still unclear, there is some evidence that nitric oxide and prostanoids (most likely prostacyclin) may be involved because the dual inhibition of nitric oxide synthase and cyclooxygenase enzymes by administration of aminoguanidine and meclofenamate abolished the marked antiarrhythmic protection resulted from monophosphoryl lipid-A treatment 24 h previously.