Combined suppression of the intrarenal and circulating vasoconstrictor renin-ACE-ANG II axis and augmentation of the vasodilator ACE2-ANG 1-7-Mas axis attenuates the systemic hypertension in Ren-2 transgenic rats exposed to chronic hypoxia.

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.

Intrapulmonary activation of the angiotensin-converting enzyme type 2/angiotensin 1-7/G-protein-coupled Mas receptor axis attenuates pulmonary hypertension in Ren-2 transgenic rats exposed to chronic hypoxia.

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.

Protein remodeling of extracellular matrix in rat myocardium during four-day hypoxia: the effect of concurrent hypercapnia.

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.

Voltage-gated calcium channels mediate hypoxic vasoconstriction in the human placenta.

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.

Dehydroepiandrosterone sulphate reduces chronic hypoxic pulmonary hypertension in rats.

Pathogenesis of pulmonary hypertension includes vascular smooth muscle cell membrane depolarisation and consequent calcium influx. Usually, calcium-gated potassium channels are activated under such conditions and repolarise the membrane. However, in pulmonary hypertension they are downregulated. The authors hypothesised that pharmacological augmentation of these channels would reduce pulmonary hypertension. Dehydroepiandrosterone sulphate (DHEA-S, 0.1 mg x mL(-1)), a recently characterised activator of calcium-gated potassium channels, was given to rats in drinking water. Pulmonary arterial blood pressure, increased by 4 weeks of hypoxia (from 15 +/- 0.2 to 29.4 +/- 2.5 mmHg), was selectively attenuated in rats treated with DHEA-S for the whole duration of the hypoxic exposure (23.9 +/- 0.9 mmHg) and in rats given DHEA-S only after pulmonary hypertension had fully developed (last 2 weeks of hypoxia; 24.4 +/- 1.4 mmHg). Pulmonary vascular remodelling and right ventricular hypertrophy associated with pulmonary hypertension were also reduced by DHEA-S. Cardiac index and systemic arterial blood pressure did not differ among the groups. The authors conclude that treatment with an activator of calcium-gated potassium channels, dehydroepiandrosterone sulphate, known to be well tolerated by humans, reduces hypoxic pulmonary hypertension in rats.

Hyperoxia and recovery from hypoxia alter collagen in peripheral pulmonary arteries similarly.

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 microm) 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 alpha2 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). We conclude that chronic moderate hyperoxia and recovery from chronic hypoxia have a similar effect on collagenous proteins of the peripheral pulmonary arterial wall.

[Anorectics and pulmonary hypertension]. / Anorektika a plicní hypertenze.

Anorectics (appetite-suppressant drugs) are frequently requested by patients. Their usage, however, can have serious, life-threatening side effects, such as pulmonary hypertension and valve defects. The association of anorexigen use with pulmonary hypertension was first detected at the end of the sixties. Back than, the incidence of pulmonary hypertension, diagnosed as primary, increased soon after an anorexigen, aminorex was introduced. After aminorex was recalled several years latter, the incidence of the disease returned to the usual low levels. A recent epidemiological study proved that a newer anorexigen, fenfluramine (or its stereoisomer, dexfenfluramine) considerably increases the risk of pulmonary hypertension. Currently, it is unclear how the anorectics contribute to the development of pulmonary hypertension. One possibility may be the increase in plasma serotonin concentration. Serotonin is a pulmonary vasoconstrictor in many species. However, even if this mechanism plays any role in humans, it cannot completely explain the influence of anorectics on the pulmonary circulation. The anorectics cause membrane depolarization of the pulmonary vascular smooth muscle cells by inhibiting potassium channel activity. The depolarization activates voltage-operated calcium channels, thus increasing intracellular calcium ion concentration, which is the well-known stimulus for vasoconstriction. The increase in vascular tension can be especially significant when there is a deficiency in mechanisms acting against vasoconstriction, such as endothelial production of nitric oxide (NO). Such pre-existing defects may be the reason why only a fraction of patients using anorectics actually develop pulmonary hypertension.

Perinatal history of hypoxia leads to lower vascular pressures and hyporeactivity to angiotensin II in isolated lungs of adult rats.

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 (approximately 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 microM). 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 microg) 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.

[Mechanisms of remodeling of pulmonary blood vessels in chronic hypoxia]. / Mechanizmus rekonstrukce plicního cévního reciste pri chronické hypoxii.

Chronic lung hypoxia results in the hypoxic pulmonary hypertension, which is caused by the remodeling of peripheral pulmonary blood vessels. Vascular smooth muscle cells proliferate into the prealveolar arteries, the turnover and deposition of connective tissue proteins is increased. We observed an enhanced collagenolytic activity in the extracts from isolated peripheral lung arteries of hypoxic rats. SDS electrophoresis of collagenous proteins extracted from these vessels showed presence of the low molecular weight cleavages of collagen type I. We hypothesize that the activation of collagenolytic metalloproteinases is related to the release of reactive oxygen species, NO and products of their interaction (peroxynitrite). Collagen cleavages may stimulate mesenchymal proliferation in the vascular wall.