Johan Persson1, Peter Morsing, Per-Olof Grände. 1. Department of Physiological Sciences, University of Lund and University Hospital of Lund, Lund, Sweden. Johan.Persson@mphy.lu.se
Abstract
BACKGROUND: Vasopeptidase inhibition is a new antihypertensive approach combining inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), but severe oedema, mainly angio-oedema, has been reported. As ACE and NEP catalyse degradation of the permeability-increasing peptide bradykinin, and NEP also catalyses degradation of permeability-increasing peptides such as atrial natriuretic peptide, substance P, endothelin-1 and angiotensin II, vasopeptidase inhibition may increase microvascular permeability. OBJECTIVE: To analyse the effects of vasopeptidase inhibition on permeability. DESIGN: The study was performed on the autoperfused cat calf skeletal muscle, evaluating the effects on fluid and protein permeability of a clinically relevant dose of the vasopeptidase inhibitor, omapatrilat. The effects were compared with those of the vehicle, of selective ACE and NEP inhibition, and of omapatrilat during bradykinin receptor blockade. METHODS: Effects on fluid permeability were determined with a capillary filtration coefficient (CFC) technique, and effects on protein permeability were assessed from changes in the osmotic reflection coefficient for albumin. RESULTS: After 1.5 h of intravenous infusion of omapatrilat (0.35 mg/kg per hour), mean arterial pressure was reduced from 114 mmHg to 86 mmHg (P < 0.01) and skeletal muscle vascular resistance was reduced from 14.5 peripheral resistance units (PRU) to 11.5 PRU (P < 0.05). CFC was increased by 22% (P < 0.01) and the reflection coefficient was decreased by 17% (P < 0.01). Infusion of vehicle had no effects. Inhibition of NEP increased permeability without affecting blood pressure, whereas ACE inhibition decreased blood pressure without affecting permeability. The increase in permeability associated with omapatrilat was reduced by bradykinin blockade. CONCLUSIONS: A clinically relevant antihypertensive dose of omapatrilat reduces vascular resistance and increases fluid and protein permeability, the permeability effect more by inhibition of NEP than by inhibition of ACE, by a mechanism involving bradykinin.
BACKGROUND: Vasopeptidase inhibition is a new antihypertensive approach combining inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), but severe oedema, mainly angio-oedema, has been reported. As ACE and NEP catalyse degradation of the permeability-increasing peptide bradykinin, and NEP also catalyses degradation of permeability-increasing peptides such as atrial natriuretic peptide, substance P, endothelin-1 and angiotensin II, vasopeptidase inhibition may increase microvascular permeability. OBJECTIVE: To analyse the effects of vasopeptidase inhibition on permeability. DESIGN: The study was performed on the autoperfused cat calf skeletal muscle, evaluating the effects on fluid and protein permeability of a clinically relevant dose of the vasopeptidase inhibitor, omapatrilat. The effects were compared with those of the vehicle, of selective ACE and NEP inhibition, and of omapatrilat during bradykinin receptor blockade. METHODS: Effects on fluid permeability were determined with a capillary filtration coefficient (CFC) technique, and effects on protein permeability were assessed from changes in the osmotic reflection coefficient for albumin. RESULTS: After 1.5 h of intravenous infusion of omapatrilat (0.35 mg/kg per hour), mean arterial pressure was reduced from 114 mmHg to 86 mmHg (P < 0.01) and skeletal muscle vascular resistance was reduced from 14.5 peripheral resistance units (PRU) to 11.5 PRU (P < 0.05). CFC was increased by 22% (P < 0.01) and the reflection coefficient was decreased by 17% (P < 0.01). Infusion of vehicle had no effects. Inhibition of NEP increased permeability without affecting blood pressure, whereas ACE inhibition decreased blood pressure without affecting permeability. The increase in permeability associated with omapatrilat was reduced by bradykinin blockade. CONCLUSIONS: A clinically relevant antihypertensive dose of omapatrilat reduces vascular resistance and increases fluid and protein permeability, the permeability effect more by inhibition of NEP than by inhibition of ACE, by a mechanism involving bradykinin.
Authors: Rhéure Alves-Lopes; Augusto C Montezano; Karla B Neves; Adam Harvey; Francisco J Rios; Dominik S Skiba; Lauren B Arendse; Tomasz J Guzik; Delyth Graham; Marko Poglitsch; Edward Sturrock; Rhian M Touyz Journal: Hypertension Date: 2021-07-26 Impact factor: 10.190