John H.G. Rankin

Effects of acute through life-long hypoxic exposure on exercise pulmonary gas exchange.

Abstract The adequacy, efficiency and control of pulmonary gas exchange during exercise was compared among groups who were exposed for various durations of time to moderate hypoxia (3100 m altitude, P i O2 100 mm Hg. These groups included native lowlanders during acute, shortterm (4 to 45 days) and long-term (1–16 yr) exposure and native highlanders of 1 to 3 generations exposure. The working sojourner depended almost entirely on his ventilatory adaptation for maintaining adequate pulmonary and systemic O2 transport at 3100 m. Exercise D lco , VC, (A-a) DO2 and Hb concentration were unchanged from acute through 21 days exposure, although (A-a) DO2 widened after 45 days at 3100 m. In contrast to the sojourner, the resident of 3100 m hypoventilated during exercise and maintained PaCO2 at or above resting levels. He depended on a high O2 carrying capacity and most importantly on an increased D lco and Vc and narrowed (A-a) D o2 for his enhanced systemic O2 delivery during work. No differences in the pulmonary response to work were found among long-term and native residents of 3100 m. Hence, the highlander avoided the high levels of ventilatory work and exertional dyspnea experienced by the sojourner without compromising systemic O2 delivery.

Subepicardial vasodilator reserve in the presence of critical coronary stenosis in dogs

Abstract Critical coronary stenosis is the term used to describe obstruction that eliminates reactive hyperemia presumably because downstream arterioles have dilated maximally to compensate for a proximal stenosis. However, evidence of distal vasomotor capacity exists despite the presence of severe constriction. Coronary blood flow in the left circumflex artery and blood pressure in the aorta and distal circumflex artery were studied in six open chest, anesthetized dogs. The circumflex artery was obstructed sufficiently to eliminate 95 to 98 percent of reactive hyperemia, but resting coronary blood flow was not reduced. The regional distribution of myocardial blood flow was studied with tracer microspheres (diameter 15 μm) before and after intracoronary injection of adenosine (5 μmoles) and after the release of a 15 to 20 second occlusion. The subendocardial to subepicardial ratio of flow in the obstructed bed was not changed by the stenosis (ratio 1.23 ± 0.10 [mean ± standard error of the mean] versus 1.28 ± 0.07, difference not significant). Administration of adenosine decreased subendocardial flow from 0.95 ± 0.07 to 0.73 ± 0.08 ml/min per g (p

Control of exercise hyperpnea under varying durations of exposure to moderate hypoxia

Abstract Ventilation and arterial acid-base status at rest and during steady-state work at P i O 2 100, 145 and 250 mm Hg, were studied in: (1) lowlanders at sea level and after 4, 21 and 45 days sojourn at 3100 m altitude; (2) lowlanders residing for 2–15 years at 3100 m; and (3) native altitude residents. The total ventilatory changes at rest and work in the sojourner between ambient conditions at 250 and 3100 m altitudes were attributed: (a) to (acute) hypoxia alone, particularly during moderate to severe exercise; and (b) to the secondary effects of altitude sojourn which accounted for most of the final levels of hyperventilation achieved under all conditions of rest and work, and were complete after 4 days sojourn. Because of: (a) the absence of a significant respiratory alkalosis in response to acute hypoxia at rest, and (b) the normal ventilatory acclimatization to altitude in a lowlander subject who was non-responsive to hypercapnic-hypoxic stimuli combinations, it was reasoned that current theories based on a restoration of CSF [H + ] were not sufficient to explain the hyperventilation obtained upon sojourn to 3100 m. In residents of 3100 m: (a) Exercise e was significantly lower, Pa CO 2 higher (PIo2100), and the Δe with removal of hypoxemia less than in the sojourner at 3100 m, but similar to the sojourners results obtained during acute hypoxic exposure at sea-level; and (b) native residents and resident low-landers were similar in all respects. Sojourner-resident differences in hypoxic exercise hyperpnea at 3100 m were attributed primarily to the acquired hyper-responsiveness in the sojourner and to a lesser extent to some degree of subnormal ventilatory chemosensitivity in the resident.

A role for prostaglandins in the regulation of the placental blood flows.

Abstract A model is proposed for the regulation of the placental blood flows to the near-term pregnancy. The model has three features. 1) The maternal uterine and fetal placental tissues can synthesize constrictor and dilator prostaglandins. 2) Prostaglandins can cross the placenta. 3) There must exist a prostaglandin which has a vasodilating action in one of the placental circulations and a vasoconstricting action in the other circulation. Evidence is provided to indicate that in the sheep, prostaglandin E 2 (PGE 2 ) can cross the placenta and has a vasodilating action in the uterine placental circulation and a vasoconstricting action in the umbilical placental circulation. The placenta and the lung are compared and PGE 2 is shown to have similar actions in each of these organs.

The pathophysiology of the anophthalmic socket. Part II. Analysis of orbital fat.

The pathophysiologic mechanisms responsible for the clinical features of the anophthalmic socket are poorly understood. Atrophy of orbital fat has been thought to be a major contributing cause of enophthalmos and the superior sulcus deformities that develop after enucle-ation, but it has never been demonstrated histopathologically or confirmed by scientific analysis. This study was undertaken to investigate the changes that occur in the orbital fat compartment of the anophthalmic socket in an animal model by measuring orbital soft tissue mass and evaluating adipocyte cell size. Instead of reduction in the tissue mass, a statistically significant greater weight of the fat and connective tissue compartment was found in the anophthalmic orbit by nearly 13% compared to the control orbit in the animals in the long-term group. No significant change in the mean maximal diameter of adipocytes developed 7 months after enucleation. These analyses do not support the concept that orbital fat atrophy or a reduction of metabolic activity occurs in the anophthalmic socket in this animal model. From these results and our previous findings that the circulation dynamics and blood flow to orbital tissues do not change after enucleation, we propose that the pathophysiologic basis of the problems associated with anophthalmos is a disturbance in the spatial architecture and interrelationships of the multiple tissue components of the orbit, not a change in the orbital blood flow or development of fat atrophy.

Fetal heart rate variability and behavioral state: Analysis by power spectrum

OBJECTIVE We attempted to determine the relationship between the fetal heart rate power spectrum and fetal state. STUDY DESIGN Interbeat intervals, electrocortical activity, and fetal breathing movements were recorded from five near-term fetal lambs. Interbeat intervals were taken from epochs of low-voltage electrocortical activity with breathing, low-voltage electrocortical activity without breathing, and high-voltage electrocortical activity without breathing. Power spectral techniques were applied to determine the underlying frequencies contributing to fetal heart rate variability. Spectral analysis was also performed on fetal breathing data from three animals. RESULTS Significant differences were found between low-voltage electrocortical activity with breathing and high-voltage electrocortical activity without breathing at 0.62 Hz and from 1.09 to 1.56 Hz. There was no clear relationship between the breathing and heart rate spectra. CONCLUSIONS Fetal heart rate is mediated by both state and respiratory variables. The respiratory component is not strictly related to respiratory rate.

Antigens in moldy hay as the cause of farmer's lung.

Summary Sera from farmers lung patients and non-farmers lung control individuals were reacted with trichloroacetic acid extracts of moldy hays. All the sera from patients with acute symptoms and two-thirds of the total which included recovered farmers lung patients formed specific precipitin lines with the moldy hay extracts. No precipitin lines were obtained with sera from healthy farmers who had no history of farmers lung or with extracts of good hay. Evidence is presented to show that farmers lung is associated with the presence of specific antibodies in the patients“sera against antigens found in moldy hays and that these antigens are the cause of farmers lung.

The effect of pregnancy on the angiotensin II pressor response in the rabbit

The pressor response to angiotensin II was measured in unanesthetized, chronically catheterized pregnant and nonpregnant rabbits. Angiotensin II was infused intravenously for 10 minutes at a dose of 50 and 124 ng/kg/min. No difference in control mean arterial blood pressure was observed between pregnant and nonpregnant rabbits. The pressure change in response to angiotensin II was significantly greater in nonpregnant rabbits than in pregnant rabbits (P less than 0.002). Plasma samples were analyzed for angiotensin II concentration by radioimmunoassay. The results showed that there was no difference in plasma angiotensin II concentration between pregnant and nonpregnant rabbits following angiotensin II infusions. In a separate series we observed the effect of 5 mg of phenoxybenzamine on the pressor response to angiotensin II. After phenoxybenzamine treatment the control mean arterial blood pressure was significantly greater in nonpregnant rabbits than in pregnant rabbits, but the change in pressure in response to angiotensin II in nonpregnant rabbits was not significantly different from that of pregnant rabbits. These results show (1) that pregnant rabbits have a decreased sensitivity to angiotensin II, (2) that this decreased sensitivity is not due to differences in plasma concentration of angiotensin II, and (3) that this differential sensitivity to angiotensin II can be prevented by alpha-receptor blockade.

The effect of prostacyclin on angiotensin II-induced placental vasoconstriction

Significant alterations in vascular responsiveness to angiotensin II have been documented during pregnancy. We have observed that prostacyclin, a potent vasodilating prostaglandin, does not dilate the ovine placental vasculature. However, we thought it might modulate the placental vasoconstriction produced by angiotensin II. Regional blood flows and resistances were measured by the radioactive microsphere technique in six near-term sheep. Blood flows were measured in the control condition and 15 minutes after beginning an infusion of angiotensin II at 5 micrograms/min (T1). Additional measurements were made 15 minutes after the addition of 50 micrograms/min of prostacyclin to the angiotensin II infusate (T2) and 15 minutes after withdrawing prostacyclin from the angiotensin II infusion (T3). Mean arterial pressure rose in response to angiotensin II and decreased significantly with prostacyclin administration. The renal and uterine nonplacental vascular beds showed the expected vasoconstriction in response to angiotensin II, which was then reversed to control levels by prostacyclin infusion. Unexpectedly, prostacyclin did not reverse the angiotensin II vasoconstriction in the placenta but further increased resistance (p less than 0.03). Placental resistance changed from 0.33 +/- 0.04 peripheral resistance units in the control condition to 0.42 +/- 0.06 peripheral resistance units for T1 (p less than 0.03), and prostacyclin infusion further increased placental resistance to 0.63 +/- 0.10 peripheral resistance units for T2 (p less than 0.03). We conclude that the placental vascular response to prostacyclin is different from that of other organs and that prostacyclin does not dilate, but further constricts the placenta in the near-term sheep with angiotensin II-induced systemic vasoconstriction.

Anomalous responses of tumor vasculature to norepinephrine and prostaglandin E2 in the rabbit.

SUMMARY We used 25-/im microspheres to compare blood flow to the V-2 carcinoma in the awake, unanesthetized rabbit with blood flow to other organs. Injection of norepinephrine (50 jig) into the left ventricle caused a 41fold [95% confidence interval = (25-69)] increase in tumor vascular resistance (P < 0.01). This was more than one order of magnitude greater than the increase in resistance in any other organ. Prostaglandin E2 (50 fig) injected into the left ventricle caused a 7-fold (4-13) increase in tumor vascular resistance (P < 0.01) and no significant increase of the vascular resistance of other organs. The change in tumor vascular resistance was not completely due to an increased level of circulating catecholamines because a 2-fold (1.6-3.4) increase in the resistance (P < 0.01) was seen when prostaglandin E, was injected into the left ventricle of animals pretreated with phenoxybenzamine. The prostaglandin E2-induced tumor vasoconstriction was not due to an increased level of circulating angiotensin II because in animals in which a and angiotensin receptors were blocked, prostaglandin E2 increased the tumor vascular resistance by a factor of 3 (2.3-5.5) (P < 0.01). The tumor vasculature appears to be hypersensitive to a-receptor activation and responds to prostaglandin E2 with vasoconstriction which cannot be accounted for by an increased level of circulating catecholamines or angiotensin II. In these experiments, the vasculature of the tumor responded to pharmacological agents in a manner that was not displayed by the vasculature of other organs. It may be possible to selectively control tumor blood flow without adversely affecting the blood flow to other organs of the host.