Hypoxia-induced Vasoconstriction Research Articles

Rapid onset of hypoxic vasoconstriction in isolated lungs.

A fast-response O2 analyzer that samples air at low flow rates allows the quasi-instantaneous measurement of O2 concentration change in the airways of isolated blood-perfused rat lungs. This instrument and an oximeter were used to measure the stimulus-response delay time of hypoxic pulmonary vasoconstriction when the lungs were challenged with 10, 5, or 3% O2. The estimate for the shortest delay time between accomplished fall in airway O2 concentration and the onset of hypoxia-induced vasoconstriction was approximately 7 s. We found that the slope of pressure rise, but not the stimulus-response delay time, correlated with the magnitude of hypoxic vasoconstriction. Oscillations in pulmonary arterial pressure were observed when the lungs were challenged with 10% O2 but not when the challenge was 12, 5, or 3%, indicating perhaps that these oscillations were a threshold phenomenon. Established hypoxic vasoconstriction was sensitive to brief changes in airway O2 concentration. Vasodilation occurred when the gas mixture was switched from 3 to 21% O2 for two to five breaths, and vasoconstriction occurred when the gas was changed during a single breath from 5 to 3% O2.

Systemic Hypoxia Activates a Coronary Vasoconstrictor Reflex Response That Is Blocked by Prazosin

We assessed the presence of an alpha 1-adrenoceptor-mediated coronary vasoconstrictor reflex response during acute systemic hypoxia in eight chloralose-anesthetized dogs. We avoided local vasodilator responses to myocardial and coronary hypoxia and to circulating factors by perfusing the left common coronary artery at constant pressure with normoxic blood while the dogs were ventilated with 5% O2-95% N2. Left ventricular afterload was held constant by withdrawing arterial blood during hypoxia-induced peripheral vasoconstriction. Left ventricular (LV) preload, as indicated by left atrial pressure, was unchanged. beta-adrenoceptor-mediated coronary dilation and positive chronotropic and inotropic responses to hypoxia were blocked by propranolol. Para-sympathetic-mediated coronary dilation and bradycardia were blocked by atropine. Under these conditions, systemic hypoxia caused a 19.7 +/- 2.1% decrease in left common coronary blood flow. Blockade of left coronary alpha 1-adrenoceptors with prazosin prevented coronary vasoconstriction during repeated systemic hypoxia. In four other similarly prepared dogs, repeated systemic hypoxia without alpha 1-adrenoceptor blockade reproducibly reduced left coronary blood flow 16.3 +/- 3.5 and 15.7 +/- 3.1%, respectively. The results of this investigation provide the first evidence of a coronary vasoconstrictor reflex response to systemic hypoxia. This response is mediated by alpha 1-adrenoceptors.

Pharmacological evidence for the role of mediators in hypoxia-induced vasoconstriction in sheep isolated intrapulmonary artery rings

The aim of this study was to determine the likely mediator(s) involved in the hypoxic-induced contraction in sheep pulmonary artery rings in vitro by studying the effects of selective receptor antagonists and enzyme inhibitors. Hypoxia caused a contraction in arteries under resting force and when precontracted with 5-hydroxytryptamine (5-HT). Flurbiprofen, a cyclooxygenase inhibitor, reduced the hypoxic contraction in 5-HT-precontracted rings but augmented the first part of the hypoxic contraction under baseline force. Inhibition of nitric oxide by haemolysate increased the hypoxic contraction under resting force. Superoxide dismutase and N-t-butyl-α-phenylnitrone (PBN), free radical scavenging agents, and trypsin, a proteolytic enzyme, did not produce any significant effect on hypoxia-induced constriction. Propranolol plus phentolamine, β- and α-adrenoceptor antagonists respectively, did not produce any effect on hypoxic contraction under resting force, whereas these antagonists augmented hypoxic contraction in the presence of 5-HT. This combination of antagonists also caused a reduction of 5-HT contraction which was the result of α 2-adrenoceptor blockade. Verapamil, a calcium channel blocking drug, significantly reduced the 5-HT contraction, but did not reduce that caused by hypoxia either under resting force or in precontracted rings. These results suggest that hypoxic constriction in sheep isolated intrapulmonary artery is in part caused by reduced release of vasodilator prostanoids. This contraction does not involve voltage-operated calcium channels and is limited by release of endothelium-derived nitric oxide.

Effects of treatment with nasal continuous positive airway pressure on atrial natriuretic peptide and arginine vasopressin release during sleep in patients with obstructive sleep apnoea

1. Patients with obstructive sleep apnoea have increased diuresis during sleep, which decreases with nasal continuous positive airway pressure treatment. These changes have been attributed to an increased release of atrial natriuretic peptide in obstructive sleep apnoea, and its decrease with continuous positive airway pressure treatment. 2. In order to clarify the change in plasma atrial natriuretic peptide level and to investigate the underlying mechanisms, blood samples were taken at 10 min intervals from nine patients with obstructive sleep apnoea during two nights when the patients were either untreated or treated with continuous positive airway pressure. Polysomnographic monitoring, including transcutaneous oximetry, and measurement of oesophageal pressure were performed simultaneously. Plasma arginine vasopressin was also measured. 3. The plasma level of arginine vasopressin did not change. The level of atrial natriuretic peptide was high and exhibited secretion bursts in six out of the nine patients; it drastically decreased with continuous positive airway pressure treatment. 4. Across the patients, the mean plasma levels of atrial natriuretic peptide was correlated with the degree of hypoxaemia and the degree of oesophageal pressure swings during the sleep apnoeas. 5. Within the patients, cross-correlation studies suggested that the atrial natriuretic peptide secretory bursts were related either to the oesophageal pressure swings or to the apnoea-related hypoxaemia. 6. We conclude that release of atrial natriuretic peptide decreases with continuous positive airway pressure treatment in those patients with obstructive sleep apnoea who have increased release of atrial natriuretic peptide before treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cyclic guanosine monophosphate on hypoxic and angiotensin-II-induced pulmonary vasoconstriction

We examined, in isolated blood perfused rat lungs, the effect of the cell permeable 8-bromo derivative of cGMP on pulmonary vasoconstriction induced by either alveolar hypoxia or angiotensin II. 8-Bromo cGMP dose-dependently reduced both hypoxia-(IC50 = 2.2 X 10(-5) M) and angiotensin-II-induced pulmonary vasoconstriction (IC50 = 5.0 X 10(-5) M). This effect of 8-bromo cGMP on pulmonary vasoconstriction was not affected by cyclooxygenase blockade. M & B 22948 (0.1 mM), an inhibitor of cGMP-phosphodiesterase, reduced synergistically with 8-bromo cGMP the hypoxia or angiotensin-II-induced vasoconstriction. The cGMP-phosphodiesterase inhibitor M & B 22948, by itself, selectively reduced hypoxia-induced vasoconstriction, suggesting a modulating effect of endogenous cGMP during hypoxic vasoconstriction.

Dibutyryl cyclic adenosine monophosphate inhibits pulmonary vasoconstriction.

The effects of the cell-permeable dibutyryl derivative of cyclic AMP on the vascular reactivity of isolated perfused rat lungs were examined. In lungs perfused with homologous blood, pulmonary arterial infusion of db-cAMP (30 micrograms/min) inhibited hypoxia-induced vasoconstriction (IC50 = 6.3 X 10(-5) M) and vasoconstriction due to bolus injection of angiotensin II (IC50 = 8.2 X 10(-5) M). Cyclic AMP phosphodiesterase inhibition by aminophylline acted synergistically with db-cAMP in the reduction of hypoxia-induced vasoconstriction. Somatostatin, an inhibitor of adenylate cyclase, prevented the decay of hypoxic vasoconstriction typically observed in isolated lungs, suggesting that a rise in intracellular cAMP may occur during hypoxic vasoconstriction as a consequence of activation of the adenylate cyclase. In lungs perfused with cell and protein-free salt solution, db-cAMP inhibited both initial and prolonged vasoconstriction following bolus injection of 2 microgram leukotriene C4. Thus, db-cAMP inhibited pulmonary vascular reactivity nonspecifically.

Effects of respiratory alkalosis on thromboxane-induced pulmonary hypertension in piglets.

Acute hypoxic pulmonary vasoconstriction is attenuated by respiratory alkalosis. It is unknown if alkalosis similarly reduces pulmonary vasoconstriction produced by thromboxane A2. Respiratory alkalosis does not always attenuate persistent pulmonary hypertension in newborns, some of whom have elevated serum thromboxane B2 levels. We hypothesized that alkalosis attenuates thromboxane-induced pulmonary vasoconstriction less than it does hypoxic pulmonary vasoconstriction in infants. Hemodynamic responses to respiratory alkalosis during pulmonary vasoconstriction produced in random order by breathing 12% inspired oxygen and by infusing 0.1 micrograms/kg/min of the thromboxane-mimetic U46,619 were compared in eight 2-wk-old piglets. Hypoxia increased mean pulmonary artery pressure from 12 +/- 3 to 29 +/- 2 mm Hg and pulmonary vascular resistance (PVR) from 11 +/- 4 to 25 +/- 8 mmHg/L/min; U46,619 increased pulmonary artery pressure from 16 +/- 5 to 37 +/- 6 mm Hg and PVR from 14 +/- 5 to 51 +/- 17 mm Hg/liter/min. U46,619 also decreased cardiac output accounting in part for the greater increase in PVR compared to hypoxia-induced vasoconstriction. Respiratory alkalosis decreased PVR to 14 +/- 6 mm Hg/liter/min during exposure to hypoxia and to 28 +/- 9 mm Hg/liter/min during infusion of U46,619. In six additional piglets with U46,619-induced pulmonary vasoconstriction, the effects of lung stretch and hypocapnic alkalosis were separated by doubling tidal volume and then adding inspired CO2 to return PaCO2 to prehyperventilation levels. Respiratory alkalosis decreased PVR from 52 +/- 36 to 35 +/- 21 mm Hg/liter/min. Despite the increased tidal volume, PVR increased to 53 +/- 35 Hg/liter/min when PaCO2 returned to 44 +/- 5 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxia-induced fetoplacental vasoconstriction in perfused human placental cotyledons

Effects of maternal hypoxia on fetoplacental vascular resistance in the human placenta were investigated in an in vitro model in which single anatomic subunits (cotyledons) from term placentas were perfused at constant flow through both fetal and maternal circuits by means of a physiologic salt solution containing dextran. Acute reduction of oxygen tension in the maternal perfusate induced prompt fetoplacental vasoconstriction that recovered rapidly on restoration of oxygen to the perfusate. The response, hypoxic fetoplacental vasoconstriction, could be repeatedly demonstrated in the same cotyledon. The time course of hypoxic fetoplacental vasoconstriction was inversely related to oxygen tension of maternal arterial and maternal and fetal venous perfusates. Maternal and fetal venous perfusate pH and PCO2 did not change during the response. It is concluded that hypoxic fetoplacental vasoconstriction is triggered by decreased oxygen availability. It is suggested that hypoxic fetoplacental vasoconstriction may play a role in local regulation of human fetoplacental blood flow in vivo and may contribute to poor fetal prognosis in preeclampsia.

Involvement of calcium in coronary vasoconstriction due to prolonged hypoxia

In this study we employed a hypoxic rat heart model for investigating the mechanisms of coronary spasm. Perfusion of the isolated heart with hypoxic medium resulted in initial coronary dilatation followed by sustained constriction. Pretreatment of rats with 5 mg/kg reserpine did not alter the rate or the magnitude of constriction during 60 minutes of hypoxic perfusion. The hypoxia-induced vasoconstriction was not affected by the inclusion of either 1 or 10 μg/ml phentolamine in the perfusion buffer, but phenoxybenzamine (0.1 and 1 μg/ml) significantly attenuated the degree of constriction. Since phenoxybenzamine and phentolamine were equally effective in preventing the phenylephrine-induced coronary constriction, it is unlikely that the effect of phenoxybenzamine was due to an α-receptor blocking property but instead may be accounted for by its calcium channel blocking action. Two calcium channel blockers, verapamil and D-600 (0.1 and 1 μg/ml), were also effective. The rate of rise in coronary pressure was substantially reduced by decreasing the concentration of calcium and was increased by elevating the concentration of calcium in the perfusion medium, but the magnitude of hypoxia-induced constriction was not affected. These results are consistent with the suggestion that the coronary constriction seen during hypoxia does not involve adrenergic mechanisms but is dependent upon the availability of calcium.

Hemodynamic effects of alpha-adrenergic blockade during hypoxia in fetal sheep

During hypoxemia there is a redistribution of cardiac output in the sheep fetus associated with increased vascular resistance in some fetal organs. The role of the alpha-adrenergic blocking drug to eight chronically instrumented hypoxemic sheep fetuses. We measured arterial blood pressure and heart rate, determined cardiac output and organ blood flows by means of radionuclide-labeled microspheres, and calculated vascular resistances in fetuses before and during hypoxia, and after injection of phenoxybenzamine 15 mg into the inferior vena cava of the hypoxemic fetus. Hypoxemia resulted in an increased vascular resistance in certain vascular beds. Alpha-adrenergic blockade during hypoxia abolished the increase in vascular resistance of the fetal body and caused an increase in the blood flow to some tissues which had a hypoxia-induced vasoconstriction. After alpha-adrenergic blockade during hypoxia, mean arterial blood pressure decreased from 48 +/- 6 to 42 +/- 6 mm Hg (p less than 0.05) and heart rate increased from 128 +/- 19 to 235 +/- 51 beats per minute (p less than 0.001). Cardiac output increased 23% and blood flow to the brain was maintained. We conclude that the alpha-adrenergic system is important in maintaining the redistribution of cardiac output that occurs in hypoxic fetal sheep.

Vascular resistance in atelectatic lungs: effects of inhalation anesthetics.

We have investigated the relative contribution of mechanical obstruction and hypoxia-induced vasoconstriction to the increased pulmonary vascular resistance (PVR) in atelectatic lungs. For this purpose we have utilized the previous observation that inhalation anesthetics inhibit the vasoconstrictor response to pulmonary hypoxia. The effects of halothane, enflurane and ether on PVR in atelectatic lungs have been explored. Two pairs of isolated rat lungs were perfused in series at constant flow. One of the preparations was made atelectatic by airway occlusion subsequent to ventilation with a high PO2 gas (95% O2). Ventilation of the other preparation continued with hypoxic gas (2% O2), resulting in a gradual increase in PVR in both preparations. When maximum PVR was reached, one of the above inhalation anesthetics was administered to the atelectatic lungs via the ventilated lung preparation. This caused a dose-dependent, reversible reduction of PVR. The same effect was observed when pulmonary arterial PO2 was increased (greater than 66.5 kPa). Histological examination revealed that two out of four preparations were completely atelectatic 1 h after airway occlusion, whereas atelectasis was nearly complete in the other two. In two groups, airways were occluded for 1 h. In the first group PVR increased to 163% (median) above baseline level, as found during ventilation with high PO2. High arterial PO2 reduced PVR in the atelectatic lungs to 50% (median) above baseline, whereas papaverine induced a further PVR reduction, to 7% (median) above baseline. In the other group, papaverine was given before airway occlusion, and PVR increased to 10% (median) above baseline. Comparison of the two groups shows that mechanical obstruction accounts for about 6% (10/163) of the overall rise in PVR during atelectasis.

Effects of hypoxia on pulmonary vascular reactions and on lung cGMP and cAMP in pigs

Hypoxia leads to an elevation of the pulmonary vascular resistance (pvR) in pigs. This was accompanied by an increase of intraparenchymatous concentrations of cyclic GMP (cGMP), while cyclic AMP (cAMP) levels were not different from values measured during normoxia. The inhibition of the hypoxia-induced vasoconstriction by a β 2-receptor stimulating agent was associated with a remarkable increase in intraparenchymatous cAMP-concentrations and a decrease in cGMP levels. The correlation analysis between pvR versus the ratio cGMP/cAMP revealed a significant linearity. These data may suggest that cAMP and cGMP are involved in hypoxia induced pulmonary vasoconstriction and its pharmacological inhibition.

The effects of dopamine and isoproterenol on the pulmonary circulation

Dopamine and isoproterenol, although used primarily for their inotropic effects, are also potent vasoactive substances. To determine their effects on the pulmonary circulation, we cannulated the left lower lobe bronchus in 20 dogs to permit ventilation with either air or a mixture of 95% nitrogen and 5% carbon dioxide; systemic oxygenation was maintained by venitlating the right lung with 95% oxygen. The lobe was perfused at a controlled flow rate and left atrial pressure was held constant. Hypoxic ventilation increased the lobar vascular resistance by 52% (p less than 0.001). Dopamine infusion (20 mcg. per kilogram per minute) during air ventilation also increased lobar vascular resistance by 50% (p less than 0.001). During hypoxic ventilation, dopamine increased the resistance by an additional 19% (p less than 0.001). In contrast, isoproterenol (0.2 mcg. per kilogram per minute) abolished the hypoxic pressor response (p less than 0.001). Combined alpha- and beta-adrenergic blockade did not alter hypoxia-induced vasoconstriction, whereas phentolamine blocked the dopamine response and propranolol abolished the isoproterenol-induced vasodilation. These results indicate the following: (1) The hypoxic pressor response is independent of sympathetic innervation; (2) dopamine in dogs is a pulmonary vasoconstrictor; and (3) isoproterenol is a pulmonary vasodilator. If these findings can be extrapolated to man, isoproterenol may be the preferred inotropic agent in patients with an elevated pulmonary vascular resistance.

The pulmonary vasoconstrictor response to hypoxia: effects of inhibitors of prostaglandin biosynthesis.

The main purpose of the present work was to determine whether prostaglandins (PGs) synthetised in the lungs mediate the vasoconstrictor response to acute alveolar hypoxia. Isolated and ventilated lungs of rats were perfused at 37 degrees C with homologous blood at constant-volume, pulsatile inflow, and pressor responses to 3 min periods of standardized ventilation hypoxia recorded. Indomethacin, sodium meclofenamate and acetylsalicylic acid (all 100 mug/ml), which are potent inhibitors of PG biosynthesis, did not reduce the hypoxic vasoconstrictor response. Sometimes they even enhanced this response. We conclude that PGs do not mediate the hypoxia-induced vasoconstriction. We suggest that vasodilatory PGs might act to reduce and modify pulmonary arterial hypertension due to hypoxia.