Aortic vasoconstriction related to smooth muscle cells ET-A and ET-B receptors is not involved in hypoxia-induced sustained systemic arterial hypertension in rats.

OBJECTIVES: We report in the present study the role of endothelin (ET-1) and ET-1 receptors in the sustained hypoxia-induced systemic hypertension. METHODS: Wistar rats were randomly assigned to live continuously in hypobaric hypoxia (CH rats) or normoxia (N rats). At the end of hypoxic stress exposure (5 weeks at 450 mm Hg), measurements of mean systemic arterial pressure were done. The effects of ET-1 in the presence or not of the endothelium and/or of specific ET-A inhibitors (BQ-123) or ET-B inhibitors (BQ-788), have been investigated in an isolated model of rat thoracic aorta. Finally, plasmatic ET-1 concentrations have been determined by assay procedure. RESULTS: Following five weeks of chronic hypoxic stress, CH rats presented a significant increase of mean systemic arterial pressure (N: 129.1+/-6.8 mm Hg vs CH: 152.5+/-3.4 mm Hg; P<0.05). Despite of this hypoxia-induced hypertension, ET-1 plasmatic concentration was not different between N and CH rats. Finally, CH rats presented a reduce response to ET-1 when compared to N rats. This phenomenon seems to be associated to the ET-A vascular smooth muscle cell receptors, since difference between N and CH rats was still present in endothelium denuded aortic rings in the presence or not of the specific ET-B inhibitors (BQ-788). In addition, in the presence of the specific ET-A inhibitor (BQ-123) response to ET-1 was abolished in N and CH rats to the same extent (N:-98%; CH:-99%). CONCLUSION: This work clearly suggests that, following long term exposure to hypoxia, ET-1 and ET-1 receptors are not involved in the persistence of systemic hypertension in a rat model, and that chronic exposure to severe hypoxic stress was associated with a downregulation of the ET-A receptors response to ET-1.

Chronic hypoxia exposure depresses aortic endothelium-dependent vasorelaxation in both sedentary and trained rats: involvement of L-arginine.

This study was designed to test the hypothesis that the previously demonstrated training-induced improvement of the endothelium vasodilator function would be blunted under conditions of chronic hypoxia exposure as a result of deleterious effects of hypoxia per se on the nitric oxide pathway. Sea-level-native rats were randomly assigned to N (living in normoxia), NT (living and training 5 days/wk for 5 wk in normoxia), CH (living in hypoxia, 2,800 m), and CHT (living and training 5 days/wk for 5 wk in hypoxia, 2,800 m) groups. Concentration-response curves to acetylcholine (ACh; 10(-9) to 10(-4) M) with or without L-arginine (10(-3) to 10(-5) M) and/or nitro-L-arginine methyl ester (10(-5) M) were assessed on aortic isolated rings. The main finding was that chronic hypoxia severely depressed maximal ACh-responses of aortic rings in both sedentary and trained groups. However, chronic hypoxia did not interfere with training-induced increases in maximal ACh responses, considering that maximal ACh vasorelaxation was improved in CHT rats to the same extent as in NT rats when both groups were directly compared with their sedentary counterparts. It should be pointed out that the vasodilator response to ACh was restored in CH and CHT rats to the level obtained in N and NT rats, respectively, by an in vitro L-arginine addition. A hypoxia-induced decrease in L-arginine bioavailability resulting from acclimatization at altitude may be involved in this limitation of the NO pathway in CH and CHT rats. These results are of importance for aerobic performance as the specific vascular adaptations to training at altitude could contribute to limit peripheral vasodilatation and subsequently blood flow during exercise.

Alteration of endothelium-mediated vasodilator response in the rat hindlimb vasculature consecutive to chronic hypoxic stress: NO and EDHF involvement.

The previously documented impairment of hindlimb blood flow consecutive to chronic hypoxia might be related to endothelial vasomotor dysfunction. The aim of this study was to assess in-vivo the effect of chronic hypoxic stress on endothelium-mediated vasodilator response of hindlimb vascular bed, especially as regards to endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide (NO) pathway contribution. Dark Agouti rats were randomly assigned to live at barometric pressure approximately 760 mmHg (N rats) or approximately 550 mmHg (CH rats). Under anesthesia, catheters were placed in the carotid artery for arterial pressure measurement, and in the saphenous vein and iliac artery for drug delivery. Hindlimb blood flow (HBF) was measured by transit-time ultrasound flowmetry, at baseline and during endothelium-dependent vasodilator response induced by intra-arterial injection of acetylcholine (0.75 ng and 7.5 ng) with and without specific blockers of NOS (L-NAME) and EDHF (Charybdotoxin+Apamin). HBF and hindlimb vascular conductance changes in response to ACh infusion were significantly lower in CH than in N rats. The mechanisms responsible for this blunted response involved impairment in both NO pathway and EDHF. The chronic hypoxia-induced alteration of NO pathway was mainly related to the bioavailability of its substrate l-Arginine, since the infusion of l-Arginine restored the endothelial response to ACh in CH rats to the level of N rats. These results demonstrate that the impairment in endothelium-mediated vasodilator response of the hindlimb vascular tree induced by chronic hypoxic stress involves both NO and EDHF.

Paradoxical effects of endurance training and chronic hypoxia on myofibrillar ATPase activity.

This study aimed to determine the changes in soleus myofibrillar ATPase (m-ATPase) activity and myosin heavy chain (MHC) isoform expression after endurance training and/or chronic hypoxic exposure. Dark Agouti rats were randomly divided into four groups: control, normoxic sedentary (N; n = 14), normoxic endurance trained (NT; n = 14), hypoxic sedentary (H; n = 10), and hypoxic endurance trained (HT; n = 14). Rats lived and trained in normoxia at 760 mmHg (N and NT) or hypobaric hypoxia at 550 mmHg (approximately 2,800 m) (H and HT). m-ATPase activity was measured by rapid flow quench technique; myosin subunits were analyzed with mono- and two-dimensional gel electrophoresis. Endurance training significantly increased m-ATPase (P < 0.01), although an increase in MHC-I content occurred (P < 0.01). In spite of slow-to-fast transitions in MHC isoform distribution in chronic hypoxia (P < 0.05) no increase in m-ATPase was observed. The rate constants of m-ATPase were 0.0350 +/- 0.0023 s(-1) and 0.047 +/- 0.0050 s(-1) for N and NT and 0.033 +/- 0.0021 s(-1) and 0.038 +/- 0.0032 s(-1) for H and HT. Thus, dissociation between variations in m-ATPase and changes in MHC isoform expression was observed. Changes in fraction of active myosin heads, in myosin light chain isoform (MLC) distribution or in MLC phosphorylation, could not explain the variations in m-ATPase. Myosin posttranslational modifications or changes in other myofibrillar proteins may therefore be responsible for the observed variations in m-ATPase activity.