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 (AT₁) 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) rats 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 AT₁receptor 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 suppression of ACE/ANG II/AT₁receptor 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.

• MeSH
• angiotensin I metabolismus   MeSH
• angiotensin II metabolismus   MeSH
• angiotensin konvertující enzym metabolismus   MeSH
• arteriální tlak MeSH
• hypoxie komplikace   enzymologie   patofyziologie   MeSH
• modely nemocí na zvířatech MeSH
• peptidové fragmenty metabolismus   MeSH
• plíce enzymologie   MeSH
• plicní hypertenze enzymologie   genetika   patofyziologie   prevence a kontrola   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• protoonkogenní proteiny metabolismus   MeSH
• receptor angiotensinu typ 1 metabolismus   MeSH
• receptory spřažené s G-proteiny metabolismus   MeSH
• renin-angiotensin systém * MeSH
• renin genetika   metabolismus   MeSH
• signální transdukce MeSH
• vazodilatace MeSH
• vazokonstrikce MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The aim of the present study was to test the hypothesis that chronic hypoxia would aggravate hypertension in Ren-2 transgenic rats (TGR), a well-defined monogenetic model of hypertension with increased activity 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 ́ hypoxia. 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 chronic hypoxia did not alter SBP and MAP. Surprisingly, in TGR it decreased 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 exposure 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.

• MeSH
• angiotensin I krev   MeSH
• angiotensin II krev   MeSH
• angiotensin konvertující enzym krev   MeSH
• hypertenze krev   genetika   patofyziologie   prevence a kontrola   MeSH
• hypoxie komplikace   enzymologie   patofyziologie   MeSH
• krevní tlak MeSH
• ledviny enzymologie   MeSH
• modely nemocí na zvířatech MeSH
• peptidové fragmenty krev   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• protoonkogenní proteiny krev   MeSH
• receptory spřažené s G-proteiny krev   MeSH
• renin-angiotensin systém * MeSH
• renin krev   genetika   MeSH
• signální transdukce MeSH
• vazodilatace * MeSH
• vazokonstrikce * MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

An increase in fetoplacental vascular resistance caused by hypoxia is considered one of the key factors of placental hypoperfusion and fetal undernutrition leading to intrauterine growth restriction (IUGR), one of the serious problems in current neonatology. However, although acute hypoxia has been shown to cause fetoplacental vasoconstriction, the effects of more sustained hypoxic exposure are unknown. This study was designed to test the hypothesis that chronic hypoxia elicits elevations in fetoplacental resistance, that this effect is not completely reversible by acute reoxygenation, and that it is accompanied by increased acute vasoconstrictor reactivity of the fetoplacental vasculature. We measured fetoplacental vascular resistance as well as acute vasoconstrictor reactivity in isolated perfused placentae from rats exposed to hypoxia (10% O(2)) during the last week of a 3-wk pregnancy. We found that chronic hypoxia shifted the relationship between perfusion pressure and flow rate toward higher pressure values (by approximately 20%). This increased vascular resistance was refractory to a high dose of sodium nitroprusside, implying the involvement of other factors than increased vascular tone. Chronic hypoxia also increased vasoconstrictor responses to angiotensin II (by approximately 75%) and to acute hypoxic challenges (by >150%). We conclude that chronic prenatal hypoxia causes a sustained elevation of fetoplacental vascular resistance and vasoconstrictor reactivity that are likely to produce placental hypoperfusion and fetal undernutrition in vivo.

• MeSH
• angiotensin II farmakologie   MeSH
• cévní rezistence účinky léků   MeSH
• chronická nemoc MeSH
• financování organizované MeSH
• gestační stáří MeSH
• hypoxie komplikace   patofyziologie   MeSH
• krevní tlak MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• nitroprusid farmakologie   MeSH
• placentární oběh účinky léků   MeSH
• potkani Wistar MeSH
• regionální krevní průtok MeSH
• růstová retardace plodu etiologie   patofyziologie   MeSH
• rychlost toku krve MeSH
• těhotenství MeSH
• vazodilatancia farmakologie   MeSH
• vazokonstrikce účinky léků   MeSH
• vazokonstriktory farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH

The combination of long-term hypercapnia and hypoxia decreases pulmonary vascular remodeling and attenuation of right ventricular (RV) hypertrophy. However, there is limited information in the literature regarding the first stages of acclimatization to hypercapnia/hypoxia. The purpose of this study was to investigate the effect of four-day hypoxia (10% O2) and hypoxia/hypercapnia (10% O2 + 4.4% CO2) on the protein composition of rat myocardium. Expression of the cardiac collagen types and activities of matrix metalloproteinases (MMPs) and of their tissue inhibitor TIMP-1 were followed. The four-day hypoxia changed protein composition of the right ventricle only in the hypercapnic condition; remodeling was observed in the extracellular matrix (ECM) compartments. While the concentrations of pepsin-soluble collagenous proteins in the RV were elevated, the concentrations of pepsin-insoluble proteins were decreased. Furthermore, the four-day hypoxia/hypercapnia increased the synthesis of cardiac collagen due to newly synthesized forms; the amount of cross-linked particles was not affected. This type of hypoxia increased cardiac collagen type III mRNA, while cardiac collagen type I mRNA was decreased. MMP-2 activity was detected on the zymographic gel through appearance of two bands; no differences were observed in either group. mRNA levels for MMP-2 in the RV were significantly lower in both the hypoxic and hypoxic/hypercapnic animals. mRNA levels for TIMP-1 were reduced in the RV of both the hypoxic and hypoxic/hypercapnic animals. Hypoxia with hypercapnia increased the level of mRNA (6.5 times) for the atrial natriuretic peptide (ANP) predominantly in the RV. The role of this peptide in remodeling of cardiac ECM is discussed.

• MeSH
• atriální natriuretický faktor biosyntéza   MeSH
• časové faktory MeSH
• extracelulární matrix - proteiny genetika   metabolismus   MeSH
• financování organizované MeSH
• hyperkapnie metabolismus   MeSH
• hypoxie metabolismus   MeSH
• kolagen typ III biosyntéza   MeSH
• kolagen typu I biosyntéza   MeSH
• krysa rodu rattus MeSH
• matrixové metaloproteinasy biosyntéza   MeSH
• myokard enzymologie   ultrastruktura   MeSH
• peptidové mapování MeSH
• potkani Wistar metabolismus   MeSH
• remodelace komor genetika   MeSH
• stanovení celkové genové exprese MeSH
• tkáňový inhibitor metaloproteinasy 1 biosyntéza   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

Unlike all vascular beds with the exception of the pulmonary circulation, fetoplacental vessels respond to acute hypoxia with vasoconstriction. While this hypoxic fetoplacental vasoconstriction (HFPV) is considered essential in the pathogenesis of intrauterine growth retardation, its mechanism is largely unknown. Hypoxia inhibits potassium channels and thus causes depolarization in fetoplacental vascular smooth muscle. We propose that this hypoxia-induced depolarization leads to vasoconstriction by activating voltage-dependent calcium (Ca) channels and Ca influx. We compared HFPV between isolated perfused human cotyledons treated with an inhibitor of L-type channels, nifedipine, and preparations receiving only vehicle. While the solvent (diluted DMSO) had no inhibitory effect on HFPV, the hypoxic responses were completely abolished even by a relatively low dose of nifedipine (1 nM). We conclude that activation of L-type Ca channels is an essential part of HFPV.

• MeSH
• financování organizované MeSH
• hypoxie patofyziologie   MeSH
• lidé MeSH
• placenta krevní zásobení   patofyziologie   MeSH
• placentární oběh fyziologie   MeSH
• těhotenství MeSH
• vápníkové kanály - typ L fyziologie   MeSH
• vazokonstrikce fyziologie   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH

Pathogenesis of hypoxic pulmonary hypertension is initiated by oxidative injury to the pulmonary vascular wall. Because nitric oxide (NO) can contribute to oxidative stress and because the inducible isoform of NO synthase (iNOS) is often upregulated in association with tissue injury, we hypothesized that iNOS-derived NO participates in the pulmonary vascular wall injury at the onset of hypoxic pulmonary hypertension. An effective and selective dose of an iNOS inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL), for chronic peroral treatment was first determined (8 mg/l in drinking water) by measuring exhaled NO concentration and systemic arterial pressure after LPS injection under ketamine+xylazine anesthesia. A separate batch of rats was then exposed to hypoxia (10% O2) and given L-NIL or a nonselective inhibitor of all NO synthases, N(G)-nitro-L-arginine methyl ester (L-NAME, 500 mg/l), in drinking water. Both inhibitors, applied just before and during 1-wk hypoxia, equally reduced pulmonary arterial pressure (PAP) measured under ketamine+xylazine anesthesia. If hypoxia continued for 2 more wk after L-NIL treatment was discontinued, PAP was still lower than in untreated hypoxic controls. Immunostaining of lung vessels showed negligible iNOS presence in control rats, striking iNOS expression after 4 days of hypoxia, and return of iNOS immunostaining toward normally low levels after 20 days of hypoxia. Lung NO production, measured as NO concentration in exhaled air, was markedly elevated as early as on the first day of hypoxia. We conclude that transient iNOS induction in the pulmonary vascular wall at the beginning of chronic hypoxia participates in the pathogenesis of pulmonary hypertension.

• MeSH
• aplikace orální MeSH
• arteria pulmonalis enzymologie   MeSH
• časové faktory MeSH
• chronická nemoc MeSH
• financování organizované MeSH
• hypoxie MeSH
• inhibitory enzymů aplikace a dávkování   farmakologie   MeSH
• krysa rodu rattus MeSH
• lysin aplikace a dávkování   farmakologie   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• oxid dusnatý MeSH
• plíce metabolismus   MeSH
• plicní hypertenze etiologie   patofyziologie   MeSH
• potkani Wistar MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   biosyntéza   MeSH
• vydechnutí MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• O autorovi
• Herget, Jan, 1945-2019 Autorita

• Publikační typ
• abstrakt z konference MeSH