Biomedical subjects

R F Grover

Publications and source records attributed to R F Grover.

At least 73 records · Page 4Linked to original sources

PubMed1976

Prostaglandin synthesis does not mediate the pulmonary vasodilatory effect of acetylcholine.

We wondered if inhibition of hypoxic pulmonary vasoconstriction by acetylcholine was mediated by prostaglandin synthesis. In 5 calves at a simulated altitude of 4,570 m, acetylcholine (10 mug/kg/min) decreased mean pulmonary arterial pressure and total pulmonary resistance by 24 +/- 2 and 35 +/- 3% before and by 21 +/- 2 and 27 +/- 4% after the administration of meclofenamate (2 mg/kg). Since there was no difference in the effect of acetylcholine before and after meclofenamate, it was concluded that pulmonary vasodilation by activation of muscarinic receptors was not dependent on prostaglandin synthesis.

Acetylcholine↗

PubMed1976

Measurement of cardiac output by electrical impedance at rest and during exercise.

A comparison was made between cardiac output values determined by the dye dilution and electrical impedance methods in ten subjects at rest and during graded exercise on a bicycle ergometer. The cardiac output values determined by the two methods were linearly related and significantly (P less than 0.001) correlated (r = 0.90). Movement artifact associated with exercise at maximum or near-maximum work loads caused severe distortion of the dZ/dt wave form and prevented calculation of impedance cardiac output at these levels of work. Use of the lowest value of L (distance between mean value of L in the impedance stroke volume equation (SV = p(L2/ZO2) (dZ/dt)mt), resulted in nearly identical values for the least-squares line and equalvalue line of impedance and dye cardiac outputs. Although absolute values of cardiac output determined by the two methods were not identical in all subjects the changes in cardiac output were nearly identical during the different levels of exercise. The data support the validity of the impedance method as a noninvasive, atraumatic measure of cardiac output at rest and during graded exercise.

Adult↗

PubMed1976

Sustained venoconstriction in man supplemented with CO2 at high altitude.

Venoconstriction occurs at high altitude. This study sought to determine whether hypoxia or hypocapnia is the cause of the venoconstriction. Five male subjects were exposed to 4,000-4,400 m (PB 440-465 mmHg) with supplemental 3.77 +/- 0.02% CO2 in a hypobaric chamber for 4 days. Similar alveolar O2 tensions were obtained in four control subjects exposed to 3,500-4,100 m (PB 455-492 mmHg) without CO2. A water-filled plethysmograph was used to determine forearm flow and venous compliance. Systemic blood pressure was measured with the cuff procedure. Catecholamines were measured in 24-h urine collections. Venous compliance fell at high altitude in both groups and was less (P less than 0.01) than control values. Forearm flow and resistance were unaltered at altitude in the group with CO2 supplementation while forearm flow decreased and resistance increased in the hypocapnic group at 72 h of exposure. Urinary catecholamines increased in the group with CO2 and remained unaltered in the hypocapnic group. It is concluded that hypoxia is responsible for decreasing venous compliance, and hypocapnia for increasing resistance and decreasing flow. Group differences observed in urinary catecholamines may be explained by differences in arterial pH.

Adolescent↗

PubMed1976

Failure of histamine antagonists to prevent hypoxic pulmonary vasoconstriction in dogs.

The role of histamine as a mediator of hypoxic pulmonary vasoconstriction was examined in intact anesthetized dogs. Antagonism of histamine vasoconstrictor (H1) receptors with a classic antihistaminic drug (chlorpheniramine) failed to prevent or modify the pulmonary vascular responses to hypoxia (10% O2). Blockade of histamine vasodilator (H2) receptors with a newly synthesized blocking agent (metiamide) potentiated the vasoconstriction induced by hypoxia and prevented the normal increase in heart rate. Combined H1- and H2-receptor blockade also did not prevent or reduce the hypoxic pulmonary pressor response, although it did effectively abolish the cardiovascular actions of infused histamine. In other dogs, histamine infused (3.6 mug/kg per min) during hypoxia attenuated the pulmonary vasoconstriction induced by hypoxia. The results imply that, in the dog, histamine does not mediate hypoxic pulmonary vasoconstriction. However, histamine does appear to be released during hypoxia, and it may play a role in modulating the pulmonary vascular responses to hypoxia by opposing the hypoxia induced vasoconstriction. The results also imply that histamine may be responsible for the increase in heart rate during hypoxia.

Animals↗

PubMed1976

Platelet antiserum inhibits hypoxic pulmonary vasoconstriction in the dog.

The literature suggests that platelets might help mediate the pulmonary vascular pressor response to hypoxia. This study evaluated the hypoxic response in dogs rendered acutely thrombocytopenic by the administration of platelet antiserum. Between 30 and 90 min after the antiserum the pulmonary vasoconstrictor response to hypoxia was virtually abolished, but subsequently returned at a time when the number of circulating platelets remained very low. The prior administration of meclofenamate completely preserved the hypoxic response, though the platelet count still fell precipitously. We conclude that circulating platelets are not necessary for hypoxic vasoconstriction. It is possible that the reaction between platelets and antiserum evokes the synthesis of a dilator prostaglandin which might be responsible for the temporary inhibition of the pressor response to hypoxia but this remains to be proven.

Animals↗

PubMed1976

Depressed myocardial function in the goat at high altitude.

To determine if depressed myocardial function contributes to the reported decrease in cardiac performance at high altitude, six chronically instrumented, unsedated goats were studied before, during, and after 2-wk exposure to hypobaric hypoxia (PaO2 44 mmHg). Undistorted ventricular pressure wave form was obtained from a miniature transducer implanted in the left ventricular cavity. The relationship between (dP/dt)/28P and P was extrapolated to obtain Vmax as an index of myocardial function. With beta sympathetic blockade (practolol) and pacing to reproduce heart rates, Vmax was uniformly and significantly depressed (P less than 0.01) during chronic hypoxia, and returned to control values following descent to low altitude. Likewise, stroke volume following saline infusion was decreased at high altitude and returned to control values following descent. Acute relief of hypoxia at high altitude by administration of 100% oxygen by mask did not reverse the depressed Vmax. These findings indicate that chronic hypobaric hypoxia produces a depression of myocardial function which is reversible by chronic but not acute relief of hypoxia.

Adaptation, Physiological↗

PubMed1976

Prostaglandin synthetase inhibitors do not decrease hypoxic pulmonary vasoconstriction.

Prostaglandins are naturally occurring substances with powerful vasoactive effects that are released from tissues during hypoxia or ischemia. Several workers have suggested that a prostaglandin may help to mediate the pulmonary vascular pressor response to alveolar hypoxia. To investigate this possibility, we have measured the pressor responses to hypoxia before and after prostaglandin synthesis antagonism with meclofenamate in eight anesthetized dogs, two groups of awake calves (n=10 and =5), and nine isolated, perfused rat lungs. In addition, synthesis was inhibited by the use of indomethacin in nine additional dogs. The stability of the pulmonary vascular response to repeated hypoxic challenges was demonstrated in nine other dogs. In each species and with both prostaglandin antagonists, the pulmonary pressor responses to hypoxia were significantly increased rather than reduced. We conclude that prostaglandins do not mediate the pulmonary vasoconstriction caused by hypoxia. The consistent increase observed suggests that hypoxic vasoconstriction stimulates prostaglandin synthesis, the net effect of which is pulmonary vasodilatation which opposes the constriction.

Animals↗

PubMed1976

Alterations in the coronary circulation of man following ascent to 3,100 m altitude.

Alterations in coronary blood flow associated with adaptation to high altitude were examined. Three normal men native to low altitude were studied, first at sea level, and again after 10 days' sojourn at 3,100 m altitude. During rest at high altitude, a 32% decrease in coronary blood flow was largely offset by a 28% increase in coronary arterial O2 extraction to maintain myocardial O2 delivery. The increase in O2 extraction resulted mainly from a decrease in coronary sinus blood O2 content and saturation. However, coronary sinus O2 tension remained constant, implying a decrease in the affinity of hemoglobin for O2. These observations are consistent with the hypothesis that coronary blood flow is regulated to maintain constant myocardial tissue O2 tension (as reflected here by coronary sinus blood O2 tension). The absence of a decrease in coronary sinus O2 tension or a decrease in myocardial lactate extraction imply that myocardial hypoxia did not develop. Therefore, myocardial hypoxia is not the basis for the decrease in cardiac stroke volume at high altitude reported previously and also observed in the present study.

Adaptation, Physiological↗

PubMed1976

Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs.

The role of a transmembrane calcium influx in hypoxic pulmonary vasoconstriction was studied in isolated, blood-perfused, rat lungs. We reasoned that, if the influx of extracellular calcium mediated the hypoxic mechanism, pressor responses to alveolar hypoxia (2.5% O2) would be susceptible to inhibition by the calcium antagonists verapamil (2 X 10(-5) to 2 X 10(-1) mM) and SKF 525A (2.6 to 260 mM). Susceptibility of hypoxic pressor responses to inhibition by these calcium antagonists was contrasted to that of pressor responses elicited by the humoral vasoconstrictors angiotensin II(1 or 0.5 mug) and prostaglandin F2alpha (10 myg). Since neither saralasin (0.5 muM), a competitive antagonist of angiotensin II, nor meclofenamate (6.8 muM), an inhibitor of prostaglandin synthesis, depressed hypoxic pressor responses, it was concluded that these humoral transmitters were not directly involved in the hypoxic mechanism, and therefore served as independent reference agonists. The order of susceptibility of pulmonary pressor responses to inhibition by verapamil was hypoxia greater than angiotensin II greater than prostaglandin F2alpha. SKF 525A also reduced pressor responses to hypoxia more readily than those to angiotensin II. The greater inhibition of hypoxic pulmonary vasoconstriction by both calcium antagonists suggested that the hypoxic mechanism was critically dependent on the transmembrane influx of extracellular calcium. Mediation of the hypoxic response by this type of excitation-contraction coupling is consistent with the idea that hypoxia has a direct depolarizing effect on the vascular smooth muscle. It also provides a unifying explanation for inhibition of the hypoxic mechanism by various agents that have depressant or stabilizing actions on membranes in addition to other pharmacological effects.

Angiotensin II↗

PubMed1976

Maintained stroke volume but impaired arterial oxygenation in man at high altitude with supplemental CO2.

Hypobaric hypoxia causes hypocapina and alkalosis, hemoconcentration and increased hematocrit, and a decreased cardiac stroke volume. To assess the role of the hypocapnic alkalosis in causing these other changes, five men were exposed to hypobaric hypoxia at a barometric pressure (PB) of 440 torr with an alveolar O2 tension of 55 torr for 5 days with 3.77% CO2 added to the atmosphere to prevent alkalosis. They did not lose weight, and arterial CO2 tension, pH, and cardiac stroke volume were unchanged. An unchanged hematocrit implied an unchanged plasma volume. During exercise to maximum, stroke volumes equaled sea level values but arterial hypoxemia was profound, the arterial O2 tension being 39 torr. By contrast, three men at high altitude without CO2 supplementation (PB=455 torr; alveolar PO2=56 torr) had weight loss, hypocapnia, alkalosis, and decreased stroke volume. Increased hematocrits suggested decreased plasma volumes. During exercise, arterial PO2 (48 torr) was higher than in the group receiving CO2. Maximum oxygen uptakes were decreased to a similar degree in the two groups. Catecholamine excretion doubled in the group with CO2 but in the group without CO2 catechoamine excretion was unchanged. A normal pH at high altitude apparently maintained plasma volume, which, with the increased catecholamine excretion, may have prevented a decrease in stroke volume. However, the subjects with CO2 added did not have enhanced oxygen transport, because their arterial oxygenation was impaired.

Adult↗

PubMed1976

Attenuation of hypoxic pulmonary vasoconstriction by verapamil in intact dogs.

The hypothesis that hypoxic pulmonary vasoconstriction is mediated directly by depolarization of the vascular smooth muscle was tested in anesthetized dogs. Pulmonary vascular responses to hypoxia were first determined in eight dogs during 20-min exposures to 10% O2. Each animal was then treated with verapamil (0.5 mg/kg, iv), to block transmembrane Ca2+ influx in an attempt to abolish the vasoconstrictor responses to hypoxia. The hypoxic exposures were then repeated, and the pulmonary vascular responses were compared to the control responses. Verapamil administration attenuated hypoxic pulmonary vasoconstriction, but did not abolish the responses to hypoxia. Pulmonary vascular resistance increased 87% during the control hypoxic exposure, but increased only 38% during hypoxia after verapamil. The response to another vasoconstrictor, prostaglandin F2alpha, was not reduced by verapamil indicating a different mechanism of mediation. These results suggest that the pulmonary vasoconstrictor response to alveolar hypoxia, in the intact dog, involves transmembrane Ca2+ influx, and are consistent with the idea that hypoxia acts primarily by directly depolarizing vascular smooth muscle, rather than acting indirectly through a chemical mediator.

Animals↗

PubMed1976

Endotoxin and prevention of hypoxic pulmonary vasoconstriction.

Endotoxin is known both to stimulate prostaglandin production and to abolish the pulmonary vascular pressor response to hypoxia. The present study demonstrated that two inhibitors of prostaglandin synthesis, meclofenamate and indomethacin, prevent loss of pulmonary vasoconstriction due to hypoxia when sublethal doses of endotoxin are administered. This suggests that endotoxin may stimulate the production of a dilator prostaglandin which would oppose the hypoxic vasoconstriction, but other ways in which these inhibitor drugs might act are considered. Endotoxin damages platelets and leukocytes, both of which can form prostaglandins and could be the source of a dilator prostaglandin. However, in these experiments endotoxin abolished the hypoxic pressor response in dogs rendered severely thrombocytopenic by platelet antiserum. This suggests that platelets are not involved. In further experiments blood from anesthetized dogs was circulated through glass bead columns. Changes in the leukocyte count following perfusion were correlated with changes in the subsequent pressor response to hypoxia. The possibility that leukocytes may be involved in the effect of endotoxin on the hypoxic pressor response is considered.

Animals↗

PubMed1976

Increased 2,3-diphosphoglycerate during normocapnic hypobaric hypoxia.

The effect of 96 h of exposure to hypobaric hypoxia with and without 3.8% CO2 supplementation was studied in two groups of subjects. Five subjects (CO2) were exposed to 440-465 mm Hg barometric pressure (4000-4400 m), and 4 subjects (no-CO2) were exposed to 455-492 mm Hg (3500-1400 m) in order to produce similar levels of resting end-tidal PO2. After 24 h, 2,3-DPG levels of both groups significantly increased and remained elevated. The CO2 group had higher levels than the non-CO2 group after 48 and 72 h. Concurrent measurements of P50 showed similar changes over the same time course. Mean corpuscular hemoglobin concentrations remained normal for 48 h and then decreased in both groups, the CO2 group showing the larger decrease. We conclude that altitude exposure may produce an increase in 2,3-DPG without the presence of respiratory alkalosis previously thought necessary.

Adolescent↗

PubMed1976

Minoxidil reduces pulmonary vascular resistance in dogs and cattle.

Minoxidil has a direct dilator effect on the systemic arterial smooth muscle. It is potentially an important drug in the treatment of systemic hypertension, especially when combined with beta blockade, which is used to control the associated tachycardia and increase in cardiac output. However, recent observations have suggested that minoxidil might cause pulmonary hypertension. Consequently, we examined the acute effect of monoxidil and propranolol, separately and in combination, on the pulmonary vasculature of the anesthetized dog and the awake calf during normoxia and hypoxia. In both species minoxidil reduced pulmonary vascular resistance. In the dogs this appeared to be the result of a direct action on the pulmonary vascular smooth muscle and in the cattle it was secondary to beta-receptor stimulation. Propranolol alone in the cattle increased the pulmonary pressor response to hypoxia. While we have not examined the possibility that chronic administration of minoxidil might cause pulmonary hypertension by some other mechanism, our acute studies suggest that it reduces, rather than increases, pulmonary vascular resistance. Furthermore, there seems to be a species difference in the mode of its action in dogs and cattle.

Animals↗

PubMed1975

Hemodynamic and ventilatory effects of skin-cooling in cattle.

Cooling the skin of cattle at an ambient temperature of 25 degrees C decreased cardiac output and increased systemic and pulmonary vascular resistances. Minute ventilation was reduced by about 50%. There was no change in alveolar ventilation as measured by arterial blood gases. These results indicate that thermoregulatory ventilation has significant cardiopulmonary effects in cattle at normal laboratory temperatures.

Animals↗

PubMed1975

Measurement of right ventricular volumes using 131I-MAA.

A method has been presented for determining the right ventricular residual ratio, that is, the ratio of the end-systolic volume to the end-diastolic volume during each cardiac cycle. 131I-MAA was injected as a bolus into the right ventricle, and the ratio of isotope remaining in the chamber during the succeeding cardiac cycles was determined with a collimated scintillation counter placed over the right ventricle. Since the counter detected the radioactivity from the entire right ventricular cavity, potential errors from incomplete mixing were minimized. The washout curve from the ventricle was distorted somewhat by the accumulation of isotope in intervening lung tissue. This distortion was eliminated by subtracting the build-up curve of radioactivity in the lung recorded simultaneously with a second scintillation counter positioned over the lateral chest wall. In 14 dogs anesthetized with chloralose, the right ventricular residual ratio was relatively constant at 40.4 plus or minus 3.1 per cent. Duplicate measurements differed by less than 3 per cent indicating the good reproducibility of the method. Right ventricular stroke volume was determined from cardiac output (dye dilution) and heart rate. With this and the simultaneously determined residual ratio (131I-MAA), end-diastolic volume could be calculated. Stroke volume and stroke work were highly correlated with end-diastolic volume, in keeping with the Frank-Starling mechanism.

Animals↗

PubMed1975

15-Methylation augments the cardiovascular effects of prostaglandin F-2alpha.

Intramuscular injection of the 15-methyl analogue of prostaglandin F-2alpha (15-ME-PGF-2alpha) is being used to initiate second trimester abortion. The natural prostaglandin F-2alpha (PGF-2alpha) is a known pulmonary pressor agent but there is little information about the cardiovascular effects of the analogue. Consequently, we compared the hemodynamic responses to the two forms in twenty-three anesthetized dogs. Given I.M. or I.V. 15-me-PGF-2alpha produced a greater and more sustained rise in pulmonary arterial pressure than PGF-2alpha. Intramuscular 15-me-PGF-2alpha also elicited a more prolonged increase in pulmonary vascular resistance than prostaglandin F-2alpha given I.M. or I.V. The methyl analogue (I.M. or I.V.) causes a greater initial fall in systemic arterial oxygen tension and cardiac output, and a greater increase in systemic resistance than I.M. PGF-2alpha. Breathlessness seen during abortion induced by prostaglandin F-2alpha or its methyl analogue may be caused by acute pulmonary hypertension in addition to bronchoconstriction.

Animals↗

PubMed1975

Prostaglandin E1 inhibits the pulmonary vascular pressor response to hypoxia and prostaglandin F2alpha.

In the anesthetised dog an infusion of exogenous prostaglandin E1 (100muG/min) inhibits the pulmonary vascular pressor response to hypoxia. Both 25 and 100muG/min PGE1 can reduce the transient pulmonary hypertension caused by a bolus of prostaglandin F2alpha. This suggests that hypoxia and PGF2alpha may share a final common pathway in producing pulmonary vasoconstriction. These results may help to explain the mechanism by which endotoxin inhibits the pulmonary vascular response to hypoxia. This effect is probably achieved by stimulating the production of an endogenous dilator prostaglandin. Exogenous PGE1 can mimic this effect.

Animals↗