Alan Tucker

Role of vascular smooth muscle in the development of high altitude pulmonary hypertension: an interspecies evaluation.

There is a marked variability in the degree of pulmonary hypertension induced by long-term exposure to altitudes above 3000 m among low altitude species, ranging from hyporesponders (sheep and dogs) to hyper-responders (cattle and pigs). The amount of inherent muscularization of small pulmonary arteries appears to be a determinant of this hypertensive response, as does the presence or absence of collateral ventilation. Hyper-responders also exhibit marked pulmonary vascular hypertrophy when exposed to long-term hypoxia. Humans exhibit similar inter- and intra-population variability. Animal species indigenous to high altitudes exhibit less variable, attenuated pulmonary hypertensive responses with little pulmonary vascular hypertrophy. This attenuated response is also apparent among human high altitude populations, particularly in Andean and Tibetan populations. Thus, successful adaptation to high altitudes is evident in species that do not sustain the acute cardiopulmonary compensations that occur upon initial exposure to high altitude.

Lung Volumes and Maximal Respiratory Pressures in Collegiate Swimmers and Runners

To determine whether respiratory muscle strength is related to pulmonary volume differences in athletes and nonathletes, 11 intercollegiate female swimmers, 11 female cross-country runners, and two nonathletic control groups, matched to the athletes in height and age, were evaluated for pulmonary parameters including maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax). Swimmers exhibited larger (p less than .05) vital capacities (VC), residual lung volumes (RV), inspiratory capacities (IC), and functional residual capacities (FRC) than both the runners or the controls but no difference (p greater than .05) in either PImax or inspiratory flow (FIV 25%-75%). Timed expiratory volumes (FEV 0.5 and FEV 1.0) were significantly (p less than .05) lower in the swimmers than in the controls. These data suggest that an adaptational growth may be responsible, in part, for the augmented static lung volumes demonstrated in swimmers.

Pulmonary microembolism: Attenuated pulmonary vasoconstriction with prostaglandin inhibitors and antihistamines

The mechanism(s) involved in the pulmonary vascular and airway responses to pulmonary microembolism have not been clearly defined. Therefore, we determined the effects of specific prostaglandin and histamine blockade on the hemodynamic and arterial blood gas tension responses to particulate microembolism (200 mu glass beads) in intact anesthetized dogs. The marked increases in pulmonary arterial pressure and pulmonary vascular resistance observed in the untreated dogs were attenuated, but not abolished, following both prostaglandin blockade (with either meclofenamate or polyphloretin phosphate) and histamine blockade (with chlorpheniramine and metiamide) at 5 minutes, and were still attenuated 30 minutes post embolization. Combined prostaglandin and histamine blockade further attenuated, but again did not abolish, the pulmonary vascular responses. Cardiac outputs and systemic arterial pressures were unchanged from control by embolism. The alveolar hypoventilation (decreased arterial oxygen tension and increased carbon dioxide tension) observed in the untreated embolized dogs was prevented only with the prostaglandin inhibitors. Pulmonary microembolism in intact dogs, therefore, appears to induce vasoconstriction mediated partially by prostaglandin and histamine action, and alveolar hypoventilation mediated by prostaglandin, but not histamine, action.

Cardiopulmonary response to acute altitude exposure: water loading and denitrogenation.

In order to determine if a positive water balance would impair cardiovascular and ventilatory adjustments during acute altitude exposure, six healthy male subjects were exposed to 4570 m for 2 h with and without water loading. No significant differences in any of the measured variables were observed between normal and overhydrated subjects. In order to determine if rapid ascent to altitude involves the formation of nitrogen bubbles which could impair gas exchange, 11 subjects were exposed to 4570 m with and without denitrogenation (by breathing 100% O2 prior to ascent) and 6 subjects were exposed to normobaric hypoxia (14% O2). Prior O2 breathing reduced the hyperventilatory and alkalotic responses to altitude, tachycardia did not develop, and systemic blood pressure fell, despite the fact that arterial desaturation was similar to that during the untreated altitude exposure. Reduced urine flow and increased urine osmolality were observed in two subjects at 4570 m, but these changes were not observed in the same subjects after O2 breathing. Breathing 14% O2 also produced the same degree of arterial desaturation but the hyperventilatory response was significantly greater than in the prior altitude exposures. Heart rate, blood pressure, and urine flow and osmolality were not altered and symptoms of altitude illness were minimal. Thus, neither of our hypotheses proved to be correct; however, we did observe a prolonged effect of O2 breathing on the hypoxic ventilatory response, and a potential effect of hypobaria on ventilation.

Pulmonary vascular changes in young and aging rats exposed to 5,486 m altitude.

Young (YNG) and middle-aged (MA) male rats were exposed to 5,486 m for durations ranging from 1 to 42 days to determine the effect of age on the progression of polycythemia, right ventricular hypertrophy (RVH), lung vascular muscularization, and pulmonary vascular responsiveness. Other rats were exposed for 42 days at 5,486 m and were then allowed to recover at 1,520 m for periods up to 42 days. The progression and subsequent regression of polycythemia and RVH with altitude exposure were similar for YNG and MA rats. However, YNG rats exhibited vascular muscularization during the altitude exposure, characterized by hypertrophy of smooth muscle cells, whereas MA rats exhibited little or no change in vascular morphology. Lungs from both altitude-exposed YNG and MA rats exhibited blunting of acute hypoxic pulmonary vasoconstriction upon exposure to 5,486 m, with more severe blunting apparent in MA rats. Pressor responses to angiotensin II (AII) were potentiated in lungs from high altitude rats, particularly in the YNG rats, and this increased responsiveness persisted during the recovery period. A positive correlation was found in YNG rats between the degree of vascular muscularization and the pressor response to AII, suggesting that increased muscle mass was partially responsible for the potentiated AII responses. However, MA rats did not exhibit the same correlation for AII, and neither YNG nor MA rats exhibited increased responsiveness to 5-hydroxytryptamine. The results indicate that age influences the morphologic responses to altitude exposure and vascular responsiveness to AII, but does not affect the polycythemic response or the degree of RVH.

Lung endothelial cell proliferation in normal and pulmonary hypertensive neonatal calves

Tremendous changes in pressure and flow occur in the pulmonary and systemic circulations after birth, and these hemodynamic changes should markedly affect endothelial cell replication. However, in vivo endothelial replication rates in the neonatal period have not been reported. To label replicating endothelial cells, we administered the thymidine analog bromodeoxyuridine to calves ∼1, 4, 7, 10, and 14 days old before they were killed. Because we expected the ratio of replicating to nonreplicating cells to vary with vascular segment, we examined the main pulmonary artery, a large elastic artery, three sizes of intrapulmonary arteries, the aorta, and the carotid artery. In normoxia for arteries < 1,500 μm, ∼27% of the endothelial cells were labeled on day 1 but only ∼2% on day 14. In the main pulmonary artery, only ∼4% of the endothelial cells were labeled on day 1 and ∼2% on day 14. In contrast, in the aorta, ∼12% of the endothelial cells were labeled on day 1 and ∼2% on day 14. In chronically hypoxic animals, only ∼14% of the endothelial cells were labeled on day 1 in small lung arteries and ∼8% were still labeled on day 14. We conclude that the postnatal circulatory adaptation to extrauterine life includes significant changes in endothelial cell proliferation that vary dramatically with time and vascular location and that these changes are altered in chronic hypoxia.Tremendous changes in pressure and flow occur in the pulmonary and systemic circulations after birth, and these hemodynamic changes should markedly affect endothelial cell replication. However, in vivo endothelial replication rates in the neonatal period have not been reported. To label replicating endothelial cells, we administered the thymidine analog bromodeoxyuridine to calves approximately 1, 4, 7, 10, and 14 days old before they were killed. Because we expected the ratio of replicating to nonreplicating cells to vary with vascular segment, we examined the main pulmonary artery, a large elastic artery, three sizes of intrapulmonary arteries, the aorta, and the carotid artery. In normoxia for arteries < 1,500 micron, approximately 27% of the endothelial cells were labeled on day 1 but only approximately 2% on day 14. In the main pulmonary artery, only approximately 4% of the endothelial cells were labeled on day 1 and approximately 2% on day 14. In contrast, in the aorta, approximately 12% of the endothelial cells were labeled on day 1 and approximately 2% on day 14. In chronically hypoxic animals, only approximately 14% of the endothelial cells were labeled on day 1 in small lung arteries and approximately 8% were still labeled on day 14. We conclude that the postnatal circulatory adaptation to extrauterine life includes significant changes in endothelial cell proliferation that vary dramatically with time and vascular location and that these changes are altered in chronic hypoxia.

Low-Dose Carbon Monoxide Does Not Reduce Vasoconstriction in Isolated Rat Lungs

Recent studies have demonstrated that nitric oxide (NO) acts as a pulmonary vasodilator when inhaled in low concentrations. Due to the physicochemical similarities between NO and carbon monoxide (CO), it was speculated that low concentrations of CO would have similar effects in the isolated rat lung. The purpose of this study was to determine the role of CO (200 and 1000 ppm) in modulating hypoxia- and angiotensin II (AII)-induced pulmonary vasoconstriction, using isolated salt-perfused lungs of normotensive (CON) or pulmonary hypertensive male rats. Pulmonary hypertensive rats (ALT), induced by simulated altitude exposure (4572 m; 430 mm Hg for 32-48 days), were studied to determine the actions of low-dose CO in a remodeled pulmonary vascular bed. Right ventricular hypertrophy and polycythemia were evident in the ALT rats, suggesting that simulated altitude exposure induced pulmonary hypertension and consequent pulmonary vascular remodeling. CO did not significantly affect pulmonary vascular responses to acute hypoxia (6% CO2, balance N2) in either CON or ALT rats. There were also no significant differences in pulmonary pressor responses to AII injections (0.2 or 0.4 micrograms) in CON or ALT lungs either immediately following or during an acute hypoxia + CO exposure. Therefore, acute low-dose CO exposure (< 1000 ppm) does not appear to attenuate pulmonary vasoconstriction in isolated rat lungs.

Density and ultrastructure of mast cells in lung vessels of aging rats exposed to and recovering from chronic hypoxia

SummaryA decrease in pulmonary vascular responsiveness in aging animals during exposure to chronic hypoxia has been previously reported; however, morphological documentation is lacking. Lungs from young (3–5 months) and aging (12–14 months) Sprague-Dawley rats, exposed to and recovering from chronic hypoxia, were morphometrically analyzed at the light-microscopic level for changes in perivascular mast cells, and at the electron-microscopic level for cellular alterations. While young rat lungs showed proliferation of mast cells around elastic and muscular pulmonary arteries and arterioles, perivascular mast cell density in lungs of aging rats was significantly greater than in young rat lungs. At the ultrastructural level, perivascular mast cells in aging hypoxic rats showed numerous profiles of cellular extensions that contained remnants of discharged secretory vesicles. The results suggest that increased proliferation of perivascular mast cells as well as increased secretory activity of vasoactive substances in aging animals might represent a humoral determinant of the hyporesponsiveness of pulmonary vessels that occurs with increasing age during chronic hypoxia.

Hypoxic Pressor Responses in Lungs from Rats Acutely Exposed to Simulated High Altitude

Male Sprague-Dawley rats were exposed to 6, 3 or 1 h of simulated high altitude (380 Torr). The isolated perfused lung of each animal was challenged with 4 sequential periods of hypoxia, angiotensin II (AII), and 5-hydroxytryptamine (5-HT) following altitude exposure. Isolated perfused lungs of low altitude control rats were similarly challenged. The acute hypoxic vasoconstrictor response was significantly reduced in animals exposed to 3 and 6 h of high altitude compared to low altitude control animals. The hypoxic pressor response was not significantly different from control in animals exposed to 1 h of simulated altitude. Pressor responses to AII and 5-HT following altitude exposure were not significantly different from controls.

Sympathetic and metabolic correlates of hypoxic moderation of spontaneous hypertension in the rat

Abstract Exposure to hypobaric hypoxia (H: simulated altitude = 3658 m) was initiated in 5-week-old, male spontaneously hypertensive (SHR) and Wistar-Kyoto (WKy) normotensive rats while normoxic controls (N) for both groups were maintained under laboratory conditions. Significant attenuation of systolic arterial blood pressure was evident in SHR-H relative to SHR-N (125 ± 6 vs 145 ± 5 mm Hg; P < 0.05) but not in WKy-H relative to WKy-N (WKy-H, 116 ± 2 vs WKy-N, 117 ± 5 mm Hg). Hypoxia significantly decreased metabolic efficiency in both normotensive and hypertensive rats, although being both more severe and accompanied by significantly impaired growth rate in SHR-H. Urinary excretion of norepinephrine in the SHR was elevated relative to WKy, irrespective of altitude treatment, while hypoxia elicited similar increases in urinary excretion of norepinephrine in both SHR and WKy. Myocardial and adrenal contents of norepinephrine were significantly reduced following 3 days of simulated altitude exposure in both strains of rats. Tissue contents of norepinephrine in hypoxic rats returned to normoxic levels by 21 days of simulated altitude. Both urine and tissue indices provided consistent indirect evidence that changes in sympathetic neuronal activity in response to hypoxia were similar in normotensive and hypertensive rats. These findings suggest that prior reports of reduced α-adrenergic responsiveness in vasculature from hypoxia-exposed SHR reflect a postsynaptic event that is regulated independently of norepinephrine release from sympathetic nerve terminals.