Hypoxic vasoconstriction (HPV) has been shown to consist of a biphasic contraction change. The first phase of the hypoxic response peaks at approximately five minutes. The second phase is at about 30 minutes. The force of contraction of both phases of HPV were found to be significantly greater in pulmonary resistance vessels (PRV) than in pulmonary artery (PA) (P<0.01). The endothelium modulates the hypoxic response, especially of the second phase of HPV (68 % reduction in PRV) (P<0.05). In Ca2+-free solution, the first peak and the second peak of HPV were reduced to 11 and 32 % contraction in PRV and to 26 and 21 % contraction in PA. A calcium channel antagonist (amlodipine) caused significant dose-dependent inhibition of the first phase of HPV (P=0.001), with a significantly greater effect on PRV compared to PA (P<0.01). Levcromakalim caused a dose- dependent inhibition of HPV in PRV (58 % at 10 /utA). In contrast, HPV in PA was not significantly inhibited by levcromakalim. In conclusion, this study has confirmed that hypoxia induces a biphasic contractile response in isolated pulmonary arteries requiring extracellular calcium. Both amlodipine and levcromakalim inhibit hypoxic pulmonary vasoconstriction and these agents may be of value in the treatment of pulmonary hypertension.
Pneumonia was induced in rats by instillation of carrageenin (0.5 ml of 0.7 % solution) into the trachea. Three or four days after instillation, the lungs were isolated, perfused with blood of healthy rat blood donors, and ventilated with air + 5 % C02 or with various hypoxic gas mixtures. Pulmonary vascular reactivity to acute hypoxic challenges was significantly lower in lungs of rats with pneumonia than in lungs of controls. The relationship between 02 concentration in the inspired gas and Po2 in the blood effluent from the preparation was shifted significantly to lower Po2 in lungs with pneumonia compared to control ones. These changes were not present in rats allowed to recover for 2- 3 weeks after carrageenin instillation. We suppose that blunted hypoxic pulmonary vasoconstriction may contribute to hypoxaemia during acute pulmonary inflammation. Decreased Po2 in the blood effluent from the isolated lungs with pneumonia implies significant increase of oxygen consumption by the cells involved in the inflammatory process.
We investigated the influence of oxygenation of in vitro lung preparation on the pulmonary vascular reactivity. Small pulmonary vessels isolated from adult male Wistar rats exposed for 4 days to hypoxia (FiO2 = 0.1, group CH) were compared with those of normoxic controls (group N). The bath in the chamber of small vessel myograph was saturated with gas mixture containing either 21 % or 95 % of O2 with 5 % CO2 and we measured the reactions of vessels to acute hypoxic challenge with 0 % O2 or to PGF2α. We did not observe any difference of the contractile responses between both groups when the normoxic conditions were set in the bath. When the bath oxygenation was increased to 95 % O2, the contractions induced by hypoxic challenge and PGF2α decreased in chronically hypoxic rats and did not change in normoxic controls. We hypothesize that reduced reactivity of vessels from hypoxic rats in hyperoxia results from the effect of chronic hypoxia on Ca2+ signaling in the vascular smooth muscle, which is modulated by increased free radical production during the exposure to chronic hypoxia and further hyperoxia., M. Žaloudíková, M. Vízek, J. Herget., and Obsahuje seznam literatury
Adult rats born in hypoxia but raised in air are more reactive to acute hypoxic challenges. The relation between perfusion pressure and perfusion flow (P/Q plot) was analyzed in the preparation of ventilated perfused lungs isolated from 3 groups of adult rats. Control animals of the first group were born and lived in air, the second group was born in hypoxic chamber and then the rats were raised in air. Rats of the third group were bom in air and exposed to hypoxia in adulthood. The P/Q plot in rats born in hypoxia had lower slope than that in controls. Acute hypoxia in control group resulted in parallel shift of P/Q line to higher pressures. In rats born in hypoxia, however, both intercept with pressure axis and slope were increased. This may be explained by the participation of both collapsible and non-collapsible parts of pulmonary vascular bed in hypoxic pulmonary vasoconstriction. Analysis of distribution of pulmonary vascular resistances by the double occlusion technique confirmed this possibility. In rats born in hypoxia both arterial and middle vascular segment resistances increased during acute hypoxic challenge. In control rats, however, the increase in resistance was restricted to the middle segment only.
Interest surrounds the role of an NADPH oxidase-like enzyme in hypoxic pulmonary vasoconstriction (HPV). We have studied the effects of the NADPH oxidase inhibitors iodonium diphenyl (ID) and cadmium sulphate (CdSO4) upon HPV of isolated rat pulmonary arteries (n = 73, internal diameter 545± 23 mm). Vessels were preconstricted with prostaglandin F2a (PGF2a, 0.5 or 5 mM) prior to a hypoxic challenge. ID (10 or 50 mM), CdSO4 (100 mM) or vehicle (50 ml) was added for 30 min before re-exposure to PGF2a and hypoxia. ID and CdSO4 significantly inhibited HPV. In vessels preconstricted with 5 mM PGF2a, ID (10 and 50 mM) reduced HPV from 37.4± 5.6 % to 9.67± 4.4 % of the contractile response elicited by 80 mM KCl (P<0.05) and from 30.1± 5.0 % to 0.63± 0.6% 80 mM KCl response (P<0.01), respectively. CdSO4 (100 mM) reduced HPV from 29.4±4.0 % to 17.1±2.2% 80 mM KCl response (P<0.05). In vessels preconstricted with 0.5 mM PGF2a, ID (10 and 50 mM) reduced HPV from 16.0± 3.15% to 3.36± 1.44 % 80 mM KCl response (P<0.01) and from 15.0± 1.67 % to 2.82± 1.40 % 80 mM KCl response (P<0.001), respectively. Constriction to PGF2a was potentiated by ID. ID and CdSO4, at concentrations previously shown to inhibit neutrophil NADPH oxidase, attenuate HPV in isolated rat pulmonary arteries. This suggests that an NADPH oxidase-like enzyme is involved in HPV and could act as the pulmonary oxygen sensor., R. D. Jones, J. S. Thompson, A. H. Morice., and Obsahuje bibliografii
The potassium channel opening drug, pinacidil, has been examined in isolated perfused lungs taken from rats with hypoxic pulmonary hypertension (housed in 10 % oxygen for 7 days) and control rats. Inhibition by pinacidil (1 to 30 //M) of noradrenaline (NA)-induced vasoconstriction (NA infusions; /^-adrenoceptors blocked) and of hypoxic pulmonary vasoconstriction (HPV; ventilation for 3.5 -4.5 min with 0-1 % oxygen) were compared. The vasoconstrictor responses in preparations from control and hypoxic rats, respectively, were (mm Hg) NA 6.6±0.68 (6); 8.2±1.45 (9); HPV 7.8±1.03 (12); 8.8±0.93 (13). These responses were reversibly inhibited by pinacidil. In lungs from control rats pinacidil was 10-fold less potent against NA than against HPV, but in lungs from hypoxic rats it was equipotent against NA and HPV. When tested against NA, but not HPV, pinacidil was significantly more potent in lungs from hypoxic rats than control rats. It is postulated that NA-induced vasoconstriction in lungs from hypoxic rats, and HPV in both groups of rats, involve calcium influx through voltage-operated calcium channels. Consequently, these responses are readily inhibited by drugs such as pinacidil which open potassium channels and hyperpolarise the cell membrane. In contrast in lungs from control rats, NA-induced constriction may involve mainly intracellular calcium release and thus be less readily inhibited by the hyperpolarising effect of pinacidil.