The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; A primary protective role for bradykinin

Mohamed Ali Rastegar, Francesco Marchini, Gabrielle Morazzoni, A. Végh, J. Papp, J. Parratt

Research output: Contribution to journalArticle

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Abstract

1. The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. 2. A 1 h infusion of Z13752A (128 μg 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. 3. 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. 4. 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). 5. 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). 6. Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. 7. 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. 8. 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.

Original languageEnglish
Pages (from-to)671-680
Number of pages10
JournalBritish Journal of Pharmacology
Volume129
Issue number4
Publication statusPublished - 2000

Fingerprint

Coronary Occlusion
Bradykinin
Angiotensin-Converting Enzyme Inhibitors
Coronary Vessels
Dogs
Ventricular Tachycardia
Reperfusion
Ischemia
Ventricular Fibrillation
Z13752A
Angiotensin I
Vasodilator Agents
Canidae
Cardiac Arrhythmias
Myocardium
Arterial Pressure
Hemodynamics
Kidney
Lung
Enzymes

Keywords

  • Anaesthetized dogs
  • Bradykinin
  • Combined ACE/NEP inhibition
  • Myocardial ischaemia
  • Ventricular arrhythmias
  • Z13752A

ASJC Scopus subject areas

  • Pharmacology

Cite this

The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; A primary protective role for bradykinin. / Rastegar, Mohamed Ali; Marchini, Francesco; Morazzoni, Gabrielle; Végh, A.; Papp, J.; Parratt, J.

In: British Journal of Pharmacology, Vol. 129, No. 4, 2000, p. 671-680.

Research output: Contribution to journalArticle

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T1 - The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; A primary protective role for bradykinin

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AU - Végh, A.

AU - Papp, J.

AU - Parratt, J.

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N2 - 1. The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. 2. A 1 h infusion of Z13752A (128 μg 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. 3. 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. 4. 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). 5. 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). 6. Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. 7. 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. 8. 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.

AB - 1. The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. 2. A 1 h infusion of Z13752A (128 μg 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. 3. 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. 4. 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). 5. 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). 6. Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. 7. 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. 8. 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.

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