Robert F. Grover

Oxygen transport in the llama (LAma glama)

Abstract Three male llamas 5–14 months old and born at sea level were studied first at 260 m altitude, and again after 5 and 10 weeks at 3420 m. Observations were made with the animals awake, standing and unsedated, at rest breathing air, acute hypoxia, acute hyperoxia and during treadmill exercise. O 2 tension, O 2 content, O 2 saturation and pH were measured on arterial and mixed venous blood. These data were adjusted to pH 7.40 and 37.0 °C to permit the construction of Hb-O 2 dissociation curves. Cardiac output () was measured by dye dilution. Llama Hb has a high affinity for O 2 : P 50 of 22.7 mm Hg at sea level, and 23.7 mm Hg at altitude, indicating no decrease in the affinity of Hb for O 2 at altitude. Exposure to 3420 m resulted in a decrease in Pao-from 87 to 51–53 mm Hg, but SaO 2 remained above 92%. With an increase in Hb concentration from 10.6 to 11.8 g per 100 ml, there was no decrease in CaO 2 . Furthermore, there was no change in , (CaO 2 -CVO 2 ), or systemic O 2 transport ( × CaO 2 ). Under all conditions, PVO 2 was lower than in most other mammals, but always exceeded 20 mm Hg, reflecting the efficient mechanisms of O 2 extraction in the llama.

Tolazoline hydrochloride (Priscoline) An effective pulmonary vasodilator

Abstract Eight infants and young children who had ventricular septal defects and high pulmonary vascular resistances were carefully selected to illustrate the pulmonary vasodilator effects of tolazoline. In each of these 8 patients, tolazoline produced a marked reduction in pulmonary hypertension (average decrease, 28 mm. Hg) and an impressive decrease in pulmonary vascular resistance (over 50 per cent) to normal levels. The effects of tolazoline on the cardiovascular dynamics of 11 normal subjects were also examined and found to be minimal. When tolazoline is delivered directly into the pulmonary artery in a dose of 1 mg. per kilogram over 45 seconds, it is highly effective in relieving pulmonary vasoconstriction.

High Altitude-Induced Pulmonary Hypertension in Normal Cattle

Six months residence at an altitude of 10,000 feet produced significant pulmonary hypertension and arterial oxygen desaturation (86 per cent) in 10 normal steers born at 3,600 feet. Six of these animals, during the course of the experiment, showed a rise in mean pulmonary arterial pressure from 27 to 45 mm. Hg. The remaining four animals developed more severe pulmonary hypertension, and two with mean pressures greater than 100 mm. Hg had right heart failure. All 10 showed right ventricular hypertrophy proportional to the degree of pulmonary hypertension. Ten steers of similar age and origin, maintained as controls at 5,000 feet, showed a mean pulmonary arterial pressure of 27 mm. Hg throughout the experiment. The pulmonary hypertension observed at high altitude is considered to be due to an increased pulmonary vascular resistance resulting from a reduction in the total cross-sectional area of the pulmonary vascular bed. Chronic hypoxia appeared to be the most important etilogical factor responsible for initiating the hypertension. The observed beneficial effects of 100 per cent oxygen inhalation and the prompt recovery of an affected animal when moved to lower altitude supported the concept of pulmonary hypertension induced by hypoxia.

Hemodynamics in normal cattle.

A satisfactory method has been described for conducting hemodynamic studies in cattle. With the animals in normal standing position, and without sedation or tranquilization, cardiac catheterization can be readily performed. With a muzzle mask, ventilatory studies are also feasible. Using this method, each of 10 normal steers was studied four times during a six-month period. This permitted the establishment of normal values for a number of circulatory measurements. In addition, an evaluation of chlorpromazine administration in normal cattle demonstrated some of the numerous complex effects of this drug on the cardiovascular and respiratory systems. These included hemodilution, hypoventilation, and a marked reduction of the arteriovenous oxygen difference.

Exercise-dependent ventilatory sensitivity to hypoxia in Andean natives.

In Andean natives (NAT), the ventilatory response to hypoxia is blunted at rest but potential interaction with exercise has been little studied. Therefore, during three levels of submaximal exercise, 13 NAT were compared with 6 sojourners (SOJ) acclimatized at 4,360 m for an average of 7 months. Exercise ventilation was measured first breathing oxygen (PI(O(2)) 410 Torr) and then ambient air (PI(O(2)) 86 Torr). In SOJ ventilation was increased by hypoxia at all three exercise levels including the mildest. In NAT, however, the threshold for hypoxic sensitivity was displaced, but during exercise above this threshold hypoxia increased ventilation at a rate similar to that seen in SOJ. At the heaviest workload, ventilation was increased by hypoxia 18% in NAT compared with 30% in SOJ. Thus, during exercise Andean NAT do exhibit a ventilatory sensitivity to hypoxia, the magnitude of which is dependent upon exercise intensity.

The paradox of hypoxic pulmonary hypertension (2013 Grover Conference series)

Just 6 decades ago, the introduction of right heart catheterization provided investigators their very first opportunity to explore the previously inaccessible pulmonary circulation. This marked the dawn of the new era of pulmonary vascular physiology. Just measuring the pulmonary arterial pressure for the first time was noteworthy. Virtually nothing was known about the regulation of the pulmonary blood vessels. Interestingly, one of the very first investigations was to measure the effect of acute hypoxia in man.1 A rise in pulmonary arterial pressure was noted, but this was erroneously ascribed to a passive response of increasing pulmonary blood flow. Shortly, a follow-up publication acknowledged the overestimation of cardiac output, and when this was corrected, the increase in pressure was attributed to pulmonary vasoconstriction. This was the physiological response to acute hypoxia, but obviously, the effects of long-term chronic hypoxia were completely unknown.

The herd shot “round the world”

My story begins on the third day of July in the year 1960. Early that morning, one could have seen Bill Wilson driving a heavily loaded, 18-wheel cattle truck as he began his ascent up the winding road that leads to the summit of the mountain. However, his destination was Summit Lake Flats (Fig. 1A), a broad stretch of tundra lying just below the peak but well above tree line at an elevation of 12,700 feet. He was carrying a load of 10 yearling Hereford steers, 12 Rambouillet/Suffolk spring lambs, and four tons of hay, straw, and pellet feed (Fig. 1B). Bill had been instructed to deliver his cargo to a portable corral that my colleague Jack Reeves and I had fabricated down in Denver. Estelle Grover, my wife, and Donald Will, a veterinarian and previous collaborator in 1958,[1] were coinvestigators on this project.

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.

John T. Reeves, MD

One of the highlights of each Hypoxia Symposium is the honoring of an outstanding individual for his or her career contributions to the field. For this 12th International Symposium, John T. (Jack) Reeves, MD, was selected to receive this honor. No one is more deserving, and I say this having had the privilege of Jack’s friendship for nearly half a century.