The aim of the present study was to test the hypothesis that chronic hypoxia would aggrav ate hypertension in Ren-2 transgenic rats (TGR), a well-defined monogenetic model of hypertension with increased ac tivity of endogenous renin- angiotensin system (RAS). Systolic blood pressure (SBP) in conscious rats and mean arterial pressure (MAP) in anesthetized TGR and normotensive Hannover Sprague-Dawley (HanSD) rats were determined under normoxia that was either continuous or interrupted by two weeks' hypoxi a. Expression, activities and concentrations of individual components of RAS were studied in plasma and kidney of TGR and HanSD rats under normoxic conditions and after exposure to chronic hypoxia. In HanSD rats two weeks' exposure to chroni c hypoxia did not alter SBP and MAP. Surprisingly, in TGR it de creased markedly SBP and MAP; this was associated with substantial reduction in plasma and kidney renin activities and also of angiotensin II (ANG II) levels, without altering angiotensin-converting enzyme (ACE) activities. Simultaneously, in TGR the exposu re to hypoxia increased kidney ACE type 2 (ACE2) activity and angiotensin 1-7 (ANG 1-7) concentrations as compared with TGR under continuous normoxia. Based on these results, we propose that suppression of the hypertensiogenic ACE-ANG II axis in the circulation and kidney tissue, combined with augmentation of the intrarenal vasodilator ACE2-ANG 1-7 axis, is the main mechanism responsible for the blood pressure-lowering effects of chronic hypoxia in TGR., L. Červenka, J. Bíbová, Z. Husková, Z. Vańourková, H. J. Kramer, J. Herget, Š. Jíchová, J. Sadowski, V. Hampl., and Obsahuje bibliografii
Chronic lung hypoxia results in hypoxic pulmonary hypertension. Concomitant chronic hypercapnia partly inhibits the effect of hypoxia on pulmonary vasculature. Adult male rats exposed to 3 weeks hypoxia (Fi02=0.1) combined with hypercapnia (FiC02=0.04-0.05) had lower pulmonary arterial blood pressure, increased weight of the right heart ventricle, and less pronounced structural remodeling of the peripheral pulmonary arteries compared with rats exposed only to chronic hypoxia (Fi02=0.1). According to our hypothesis, hypoxic pulmonary hypertension is triggered by hypoxic injury to the walls of the peripheral pulmonary arteries. Hypercapnia inhibits release of both oxygen radicals and nitric oxide at the beginning of exposure to the hypoxic environment. The plasma concentration of nitrotyrosine, the marker of peroxynitrite activity, is lower in hypoxic rats exposed to hypercapnia than in those exposed to hypoxia alone. Hypercapnia blunts hypoxia-induced collagenolysis in the walls of prealveolar pulmonary arteries. We conclude that hypercapnia inhibits the development of hypoxic pulmonary hypertension by the inhibition of radical injury to the walls of peripheral pulmonary arteries., M. Chovanec ... [et al.]., and Obsahuje seznam literatury
a1_Chronic hypoxia causes pulmonary hypertension, the mechanism of which includes altered collagen metabolism in the pulmonary vascular wall. This chronic hypoxic pulmonary hypertension is gradually reversible upon reoxygenation. The return to air after the adjustment to chronic hypoxia resembles in some aspects a hyperoxic stimulus and we hypothesize that the changes of extracellular matrix proteins in peripheral pulmonary arteries may be similar. Therefore, we studied the exposure to moderate chronic hyperoxia (FiO2 = 0.35, 3 weeks) in rats and compared its effects on the rat pulmonary vasculature to the effects of recovery (3 weeks) from chronic hypoxia (FiO2 = 0.1, 3 weeks). Chronically hypoxic rats had pulmonary hypertension (Pap = 26±3 mm Hg, controls 16±1 mm Hg) and right ventricular hypertrophy. Pulmonary arterial blood pressure and right ventricle weight normalized after 3 weeks of recovery in air (Pap = 19±1 mm Hg). The rats exposed to moderate chronic hyperoxia also did not have pulmonary hypertension (Pap = 18±1 mm Hg, controls 17±1 mm Hg). Collagenous proteins isolated from the peripheral pulmonary arteries (100-300 mm) were studied using polyacrylamide gel electrophoresis. A dominant low molecular weight peptide (approx. 76 kD) was found in hypoxic rats. The proportion of this peptide decreases significantly in the course of recovery in air. In addition, another larger peptide doublet was found in rats recovering from chronic hypoxia. It was localized in polyacrylamide gels close to the zone of a2 chain of collagen type I. It was bound to anticollagen type I antibodies. An identically localized peptide was found in rats exposed to moderate chronic hyperoxia. The apparent molecular weight of this collagen fraction suggests that it is a product of collagen type I cleavage by a rodent-type interstitial collagenase (MMP-13)., a2_We conclude that chronic moderate hyperoxia and recovery from chronic hypoxia have a similar effect on collagenous proteins of the peripheral pulmonary arterial wall., J. Novotná, J. Bíbová, V. Hampl, Z. Deyl, J. Herget., and Obsahuje bibliografii
The present study was performed to evaluate the role of intrapulmonary activity of the two axes of the renin-angiotensin system (RAS): vasoconstrictor angiotensin-converting enzyme (ACE)/angiotensin II (ANG II)/ANG II type 1 receptor (AT 1 ) axis, and vasodilator ACE type 2 (ACE2)/angiotensin 1-7 (ANG 1-7)/ Mas receptor axis, in the development of hypoxic pulmonary hypertension in Ren-2 transgenic rats (TGR). Transgene-negative Hannover Sprague-Dawley (HanSD) ra ts served as controls. Both TGR and HanSD rats responded to two weeks' exposure to hypoxia with a significant increase in mean pulmonary arterial pressure (MPAP), however, the increase was much less pronounced in the former. The attenuation of hypoxic pulmonary hypertension in TGR as compared to HanSD rats was associated with inhibition of ACE gene expression and activity, inhibition of AT 1 receptor gene expression and suppression of ANG II levels in lung tissue. Simultaneously, there was an increase in lung ACE2 gene expression and activity and, in particular, ANG 1-7 concentrations and Mas receptor gene expression. We propose that a combination of su ppression of ACE/ANG II/AT 1 receptor axis and activation of ACE2/ANG 1-7/Mas receptor axis of the RAS in the lung tissue is the main mechanism explaining attenuation of hypoxic pulmonary hypertension in TGR as compared with HanSD rats., V. Hampl, J. Herget, J. Bíbová, A. Baňasová, Z. Husková, Z. Vaňourková, Š. Jíchová, P. Kujal, Z. Vernerová, J. Sadowski, L. Červenka., and Obsahuje bibliografii
The most dramatic changes in pulmonary circulation occur at the time of birth. We hypothesized that some of the effects of perinatal hypoxia on pulmonary vessels are permanent. We studied the consequences of perinatal exposure to hypoxia (12 % O2 one week before and one week after birth) in isolated lungs of adult male rats (~12 weeks old) perfused with homologous blood. Perfusion pressure-flow relationship was tilted towards lower pressures in the perinatally hypoxic as compared to the control, perinatally normoxic rats. A non-linear, distensible vessel model analysis revealed that this was due to increased vascular distensibility in perinatally hypoxic rats (4.1±0.6 %/mm Hg vs. 2.3±0.4 %/mm Hg in controls, P = 0.03). Vascular occlusion techniques showed that lungs of the perinatally hypoxic rats had lower pressures at both the pre-capillary and post-capillary level. To assess its role, basal vascular tone was eliminated by a high dose of sodium nitroprusside (20 µM). This reduced perfusion pressures only in the lungs of rats born in hypoxia, indicating that perinatal hypoxia leads to a permanent increase in the basal tone of the pulmonary vessels. Pulmonary vasoconstrictor reactivity to angiotensin II (0.1-0.5 µg) was reduced in rats with the history of perinatal hypoxia. These data show that perinatal hypoxia has permanent effects on the pulmonary circulation that may be beneficial and perhaps serve to offset the previously described adverse consequences., V. Hampl, J. Bíbová, J. Herget., and Obsahuje bibliografii
The vessels on the fetal side of the placenta differ from most other vascular beds except the lungs in that they respond to acute hypoxia by vasoconstriction. An essential role of calcium influx in the mechanism of this hypoxic fetoplacental vasoconstriction (HFPV) has been shown previously. That finding does not, however, exclude the possible involvement of other mechanisms of vascular tone regulation. In this study we tested the hypothesis that Rho-kinase-mediated calcium sensitization is involved in HFPV. We used a model of isolated rat placenta dually perfused (from both the maternal and fetal side) with Krebs salt solution saturated with normoxic and hypoxic gas mixture respectively at constant flow rate. Rho-kinase pathway was inhibited by fasudil (10 μM). We found that fasudil reduced basal normoxic fetoplacental vascular resistance and completely prevented HFPV. This suggests that the activity of Rho-kinase signaling pathway is essential for HFPV., P. Kafka, ... [et al.]., and Obsahuje seznam literatury