Cristina Nuñez1, Victor M Victor2, Miguel Martí1, Pilar D'Ocon3. 1. Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Spain. 2. Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Spain; FISABIO-Hospital Universitario Doctor Peset, Av. Gaspar Aguilar 90, 46017 Valencia, Spain; Department of Physiology, University of Valencia, Valencia, Spain. 3. Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Spain. Electronic address: m.pilar.docon@uv.es.
Abstract
UNLABELLED: Our aim was to investigate the role played by endothelial nitric oxide (NO) during acute vascular response to hypoxia, as a modulator of both vascular tone (through guanylate cyclase (sGC) activation) and mitochondrial O2 consumption (through competitive inhibition of cytochrome-c-oxydase (CcO)). Organ bath experiments were performed and O2 consumption (Clark electrode) was determined in isolated aorta, mesenteric and pulmonary arteries of rats and eNOS-knockout mice. All pre-contracted vessels exhibited a triphasic hypoxic response consisting of an initial transient contraction (not observed in vessels from eNOS-knockout mice) followed by relaxation and subsequent sustained contraction. Removal of the endothelium, inhibition of eNOS (by L-NNA) and inhibition of sGC (by ODQ) abolished the initial contraction without altering the other two phases. The initial hypoxic contraction was observed in the presence of L-NNA+NO-donors. L-NNA and ODQ increases O2 consumption in hypoxic vessels and increases the arterial tone in normoxia but not in hypoxia. When L-NNA+mitochondrial inhibitors (cyanide, rotenone or myxothiazol) were added, the increase in tone was similar in normoxic and hypoxic vessels, which suggests that inhibition of the binding of NO to reduced CcO restored the action of NO on sGC. CONCLUSION: A complex equilibrium is established between NO, sGC and CcO in vessels in function of the concentration of O2: as O2 falls, NO inhibition of mitochondrial O2 consumption increases and activation of sGC decreases, thus promoting a rapid increase in tone in both pulmonary and systemic vessels, which is followed by the triggering of NO-independent vasodilator/vasoconstrictor mechanisms.
UNLABELLED: Our aim was to investigate the role played by endothelial nitric oxide (NO) during acute vascular response to hypoxia, as a modulator of both vascular tone (through guanylate cyclase (sGC) activation) and mitochondrial O2 consumption (through competitive inhibition of cytochrome-c-oxydase (CcO)). Organ bath experiments were performed and O2 consumption (Clark electrode) was determined in isolated aorta, mesenteric and pulmonary arteries of rats and eNOS-knockout mice. All pre-contracted vessels exhibited a triphasic hypoxic response consisting of an initial transient contraction (not observed in vessels from eNOS-knockout mice) followed by relaxation and subsequent sustained contraction. Removal of the endothelium, inhibition of eNOS (by L-NNA) and inhibition of sGC (by ODQ) abolished the initial contraction without altering the other two phases. The initial hypoxic contraction was observed in the presence of L-NNA+NO-donors. L-NNA and ODQ increases O2 consumption in hypoxic vessels and increases the arterial tone in normoxia but not in hypoxia. When L-NNA+mitochondrial inhibitors (cyanide, rotenone or myxothiazol) were added, the increase in tone was similar in normoxic and hypoxic vessels, which suggests that inhibition of the binding of NO to reduced CcO restored the action of NO on sGC. CONCLUSION: A complex equilibrium is established between NO, sGC and CcO in vessels in function of the concentration of O2: as O2 falls, NO inhibition of mitochondrial O2 consumption increases and activation of sGC decreases, thus promoting a rapid increase in tone in both pulmonary and systemic vessels, which is followed by the triggering of NO-independent vasodilator/vasoconstrictor mechanisms.
Authors: Allyson G Hindle; Kaitlin N Allen; Annabelle J Batten; Luis A Hückstädt; Jason Turner-Maier; S Anne Schulberg; Jeremy Johnson; Elinor Karlsson; Kerstin Lindblad-Toh; Daniel P Costa; Donald B Bloch; Warren M Zapol; Emmanuel S Buys Journal: Am J Physiol Regul Integr Comp Physiol Date: 2019-03-20 Impact factor: 3.619
Authors: L C Yang; R T Zhang; L J Guo; H Xiao; L Y Zu; Y Y Zhang; Q Cheng; Z L Zhao; Q G Ge; W Gao Journal: Beijing Da Xue Xue Bao Yi Xue Ban Date: 2020-12-28