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Twenty-five mid-gestation guinea pigs were studied to determine the nature of spontaneous uterine contractures and elucidate the temporal relationship between blood flow and contractile activity. In the first protocol, 15 mid-gestation guinea pigs with indwelling vascular catheters were studied. Blood flows were measured by radioactive microsphere technique during rest, uterine contracture, and, in six animals, 1 minute after contracture activity. During contracture, maternal blood flow to the placenta closest to the electrode fell to 81.3 ± 5.3% of control (n = 15, P ±. 01) and then rose to 130.4 ± 10.2% of control (P ≤. 01) 1 minute after a contracture. The corresponding relationships were also significant for placental vascular resistance and constitute a reactive hyperemic response of the placenta to uterine contracture. No such phenomenon was observed in the more remote placentas on either the ipsilateral or contralateral side.To investigate the nature of contractile activity, electrodes were placed ...

In order to determine the effect of the narcotic analgesic oxymorphone hydrochloride (Numorphan, DuPont) on fetal heart rate (FHR) variability, mathematical indices of short-term and long-term FHR variability were determined continuously from R–R intervals of the electrocardiogram in eight chronically instrumented ovine fetuses for 60 min before and after a maternal intravenous bolus of 0.04 mg/kg oxymorphone. The index of short-term variability decreased from 12.7 ± 2.0 during control to 9.7 ± 1.7 during the period from 10 to 30 min after oxymorphone administration during periods of low-voltage, high-frequency electrocortical activity (LVHF ECoG) (P < 0.05). Mean FHR was decreased from 169 ± 8 beats per minute (bpm) during control to 155 ± 7 bpm 30 to 50 min after oxymorphone (P < 0.05). Fetal electrocortical activity was also determined and the decrease in FHR short-term variability occurred despite an increase in the percent time spent in LVHF electrocortical activity from 53 ± 4% during the control pe...

Our purpose was to test the effects of terbutaline on uterine electric and contractile responses to prostaglandin E2.In five late-gestation ewes, prostaglandin E2 (22.9 +/- 2.3 micrograms/min for 3 minutes) was given twice at 30-minute intervals during control. Terbutaline sulfate (2 micrograms/min) was then infused for 30 minutes. Prostaglandin E2 challenge was repeated 10 minutes after the onset of terbutaline infusion and thereafter at 30-minute intervals. Two-way analysis of variance for repeated measures revealed a significant main effect for time (p less than or equal to 0.0001) and between time and response (p less than or equal to 0.05).Both electric (p less than or equal to 0.0001) and intrauterine pressure (p less than or equal to 0.0001) responses were suppressed during terbutaline. The influence on intrauterine pressure persisted 10 minutes after terbutaline (p less than or equal to 0.01) while the electric response was not different from control.Terbutaline initially diminishes both uterine contractile and electric activity, but electric recovery precedes contractile recovery.

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 enucleation, 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.

A wide variety of complications of the anophthalmic socket develop in patients after enucleation, including enophthalmos, superior sulcus deformities, eyelid malpositions, implant migration and extrusion, poor prosthetic motility, and socket contraction. Changes in the orbital blood flow and metabolic activity of the socket tissues and atrophy of the orbital fat occurring after enucleation have been suggested as two theoretical mechanisms that result in the development of these clinical conditions. Lack of scientific evidence and a limited understanding of the pathophysiologic basis of the features of anophthalmos led us to evaluate the validity of these proposed mechanisms in an animal model. Selected parameters of the normal orbits were compared with the contralateral anophthalmic orbits at different time intervals after surgery. Orbital blood flow was studied with selective ophthalmic artery angiography and radioactive microsphere techniques. Ophthalmic arteriography demonstrated symmetric caliber and filling characteristics of the major orbital vessels of the control and experimental orbits, although their topographic course was slightly more tortuous in the anophthalmic socket. Results of radioactive microsphere analysis of capillary blood flow per weight of the different orbital tissue compartments of the animals in the long-term group showed no significant difference between the normal and anophthalmic sockets. These findings provide evidence that the circulation dynamics and blood flow to orbital tissues do not change after enucleation surgery.

OBJECTIVE: The differential vasoactive effects of hydralazine on the uteroplacental vascular bed were studied. STUDY DESIGN: After control measurements were taken, near-term chronically prepared pregnant sheep were continuously infused with angiotensin II. Maternal arterial pressure was increased by 32 mm Hg. Hydralazine was then administered; the effects on regional resistance and blood flow were evaluated with a radionuclide-labeled microsphere technique. Analysis of variance for repeated measures was used to compare observations. RESULTS: When compared with the hypertensive state, hydralazine caused the following changes by 40 minutes (mean ± SEM): Although maternal blood pressure fell 31% ± 5% ( p = 0.0005), placental blood flow was unchanged, total uteroplacental blood flow increased 24% ± 8% ( p = 0.03), total uteroplacental resistance decreased 43% ± 4% ( p = 0.0002), placental resistance decreased 19% ± 9% ( p = 0.01 ), myoendometrial blood flow increased 390% ± 82% ( p = 0.0005), and myoendometrial resistance decreased 82% ± 4% ( p = 0.0005). CONCLUSIONS: In angiotensin II-induced hypertensive ewes, hydralazine is an effective dilator of the uteroplacental vascular bed and can maintain placental blood flow while reducing blood pressure. (AM J OBSTET GYNECOL 1992;167:1672-8.)

Tracheal blood flow before and after division of the segmental tracheal blood supply with and without application of a polypropylene spiral prosthesis was measured in dogs by radiolabeled microsphere injection. Ischemia of the central part of the trachea, from the mid-cervical to mid-thoracic regions, was observed immediately after division of the segmental tracheal blood supply with and without polypropylene spiral prosthesis application. On day 3, tracheal blood flow was significantly decreased in the central part of the trachea with and without polypropylene spiral prosthesis application. On day 7, tracheal blood flow was significantly increased throughout the trachea, with no significant differences between animals with and without prosthesis application. There was no evidence of a collateral source of blood supply to the trachea. Surgical division of the segmental tracheal blood supply of the trachea. Surgical division of the segmental tracheal blood supply of the entire trachea is not recommended.

The distribution of the uterine and umbilical blood flows over the surface of the placenta was measured in 9 near-term sheep in an effort to assess the effects of surgical stress. The blood flows were observed to be relatively evenly distributed over the surface of the placenta. It was determined that the heterogeneity of distributions observed in the study could have caused the transplacental clearance of a very diffusible molecule to decrease by no more than 2%. It is concluded that at the macroscopic level, in both the acute and chronic conditions, the uterine and umbilical blood flows of the near-term sheep are relatively evenly distributed over the surface of the placenta and that this distribution per se does not significantly contribute to transplacental concentration gradients.

SummaryThe administration of norepinephrine (50 μg/kg) to the fetuses of nine sheep caused an increase in fetal arterial pressure (Control = 30 mm Hg; Test = 56 mm Hg; P > 0.001) and vasoconstriction in the fetal kidney (Control = 3.79 mm Hg × min/ml × kg; Test = 16.24 mm Hg × min/ ml × kg; P > 0.001), placental membranes (Control = 2.74 mm Hg × min/ml × kg; Test = 17.79 mm Hg × min/ml × kg; P > 0.004), and fetal cotyledons (Control = 0.178 mm Hg × min/ml × kg; Test = 0.706 mm Hg × min/ml × kg; P > 0.003). These results indicate the presence of alpha receptors in these organs. The uterine blood flow fell subsequent to the injection of norepinephrine to the fetus and this response was abolished by phenoxybenzamine blockade of the circulation of four fetuses even though we could demonstrate no phenoxybenzamine blockade in the uterine circulation of these animals.Supported by Grant No. HD 06736.

Forskolin is a direct stimulant of adenylate cyclase and increases cAMP production. It also acts as a vasodilator. To study the effect of forskolin infusion on rabbit maternal vascular resistance, we instrumented 11 pregnant rabbits with catheters in the left ventricle, jugular vein, and left and right femoral arteries. After a 2-day recovery period, one of two protocols was performed. In the control period of the first protocol (N = 6), 50% ethanol in saline was infused at 0.103 ml.min-1 for 5-min. Forskolin (10(-3) M) in 50% ethanol was then infused for 5 min at 0.103 ml.min-1. After each infusion period, regional blood flows were measured by microsphere injection. Data are expressed as means +/- SEM. Blood pressure decreased from 81 +/- 3 to 79 +/- 3 mm Hg, (P less than 0.05, N = 10) during forskolin infusion. Total placental resistance fell from 180.3 +/- 10.7 to 133.8 +/- 12.0 mm Hg.min.ml-1 per gram, P less than 0.05. Cerebral, coronary, and renal vascular resistance fell significantly. During the second protocol (N = 5), angiotensin II (0.05 microgram.min-1) was infused for 5 min followed by the addition of forskolin (10(-3) M at 0.103 ml.min-1) to the infusate. Regional blood flows, vascular resistances and blood pressures were determined. Blood pressure fell from 99 +/- 6 to 92 +/- 7 mm Hg (P less than 0.05) when forskolin was added to the infusate. Placental resistance fell from 202.5 +/- 21.6 to 158.0 +/- 29.0 mm Hg.min.ml-1 per gram (P less than 0.05). While cerebral vascular resistance did not change, renal and coronary resistances fell in response to forskolin. This study demonstrates that forskolin is able to dilate rabbit placental vessels alone and in the presence of the vasoconstrictive agent angiotensin II.

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.

To examine the effects of right ventricular (RV) hypertrophy on regional myocardial blood flow and coronary vascular reserve, hemodynamics and myocardial blood flow (15-micrometers radio-nuclide-labeled microspheres) were studied in 12 unanesthetized adult ponies before and during intravenous isoproterenol HCl infusion (1 microgram.kg-1.min-1). Six ponies served as controls, whereas in each of the others the main pulmonary artery (PA) had been banded 35-90 days prior to the study. Marked RV hypertrophy was present in PA-banded animals. In these ponies, there was a significant increase in RV systolic pressure (147%), heart rate (88%), RV tension-time index (279%), and RV myocardial blood flow (137%), while their RV coronary vascular resistance was only 40% of that for control ponies. Blood flow in right side of the interventricular septum was also significantly higher in the PA-banded ponies. Endo/epi perfusion ratio exceeded 1.00 for both ventricular freewalls in all animals. With isoproterenol infusion, there was a marked increase in myocardial blood flow in both groups. However, in PA-banded ponies the endo/epi flow ratio decreased precipitously below 1.00 in both ventricular freewalls. In control ponies this did not happen in the RV freewall, and RV coronary vascular resistance decreased to 19% of its control value. In PA-banded ponies, the magnitude of decline in RV coronary vascular resistance was much smaller, only 32% of that for control ponies. It is concluded that, unlike in LV hypertrophy, transmural myocardial blood flow per unit mass is much higher in the hypertrophied RV myocardium of adult resting ponies, and this higher RV perfusion occurs at the expense of curtailed RV coronary vascular reserve.

Estrogen results in delayed uterine hyperemia. We postulate that the leukotrienes may be the mediators of the uterine vascular responses to estrogen. To test this hypothesis, we gave FPL 55712, a selective leukotriene antagonist, to estrogen-primed, nonpregnant rabbits and measured regional blood flows by the radioactive microsphere technique. In 10 chronically catheterized animals, blood flows were measured in the control condition (C), and again 2 hours after systemic administration of estradiol (EST). Thirty minutes before administration of estradiol, five animals received systemic FPL 55712, whereas five animals received vehicle only. The vehicle group showed the expected increase in uterine blood flow from 0.62 +/- 0.1 to 2.72 +/- 0.4 ml X min-1 X gm-1, and decrease in uterine resistance from 144 +/- 31 to 34 +/- 8 peripheral resistance units (PRU) X gm, with a resistance ratio (estradiol/C) of 0.23 +/- 0.01. Unexpectedly, the FPL 55712 group showed a further increase in uterine blood flow from 0.66 +/- 0.1 to 4.60 +/- 0.3 ml X min-1 X gm-1, and a decrease in resistance from 133 +/- 25 to 17 +/- 1 PRU X gm, with a resistance ratio of 0.13 +/- 0.02. The leukotriene antagonist FPL 55712 potentiates estrogen-induced uterine hyperemia by 77% (P less than 0.001). These data suggest that leukotrienes do not mediate, but rather inhibit, the uterine vascular responses to estrogen.

We have examined the effects of PGI2, 50 microgram/kg, on norepinephrine induced placental vasoconstriction in 6 chronically catheterized near-term sheep. Regional blood flows were measured with radioactive microspheres. Control flows were measured. Norepinephrine was than infused at 50 microgram/min throughout the experiment. After 15 min the blood flows were again measured and PGI2 was then added to the infusate at 50 microgram/min. In 15 min regional blood flows were again measured and the PGI2 infusion was stopped. Regional blood flows were measured for the last time 15 min later. The renal and nonplacental uterine vasculatures behaved in a predictable manner. There was constriction with norepinephrine but PGI2 opposed the effects of norepinephrine and decreased the resistance towards the normal levels. The placenta did not behave as did the other organs. Norepinephrine increased placental resistance but PGI2 did not decrease the resistance and severely depress the placental blood flows. PGI2 does not appear to oppose norepinephrine induced placental vasoconstriction.

Hemodynamics, myocardial function, and regional myocardial blood flow (MBF) were measured in 6 closed-chest ponies anesthetized with ketamine hydrochloride before (control) and after creation of acute right ventricular systolic hypertension (RVSH) during normoxia and isocapnic hypoxia. The right ventricular (RV) systolic pressure during each RVSH approached 90 mmHg. There were significant alterations in the pattern of total ventricular MBG distribution in favor of the RV. Because RV myocardium received proportionate increments to its endocardium as well as epicardium, it is concluded that autoregulation in the RV coronary vascular bed had not been abolished even during hypoxia + RVSH. Marked increase in MBF to the right side of the septum during each RVSH with little change in perfusion to other regions suggests that RV contraction is supported by the right side of the septum. Because these increments occurred with decreased RV coronary driving pressure they were the consequence of compensatory coronary vasodilatation. The slow heart rate of the pony in the presence of a large coronary vasodilatory reserve may have been the major factor in allowing large increments in MBF to the stressed regions despite decreased coronary driving pressure.

SummaryThe placentas of eight near-term goats were perfused with blood containing C2H2. The adult goats breathed gas containing N2O. Catheters were placed in a maternal femoral artery and uterine vein. Knowledge of the perfusion rate and N2O and C2H2 concentrations in the maternal artery, uterine vein, umbilical arteries, and umbilical veins, permitted the calculation of the uterine blood flow.The uterine flow was calculated before and after a change in the rate of the umbilical perfusion. Fourteen such observations were made. In 13 cases the uterine flow changed in the same direction as did the umbilical flow (P < 0.005). The magnitude of the change in uterine flow indicated that the mechanism whereby the change was mediated had a gain of greater than 1.This work was supported by Grants PHS HE05499, HE06336, and HD2313 and by the Oregon Heart Association.The authors wish to acknowledge the assistance of Mr. J. E. Welch and Mr. R. Ackley in the conduction of the experimental protocols.

We have previously shown that FPL 55712, a specific leukotriene receptor antagonist, potentiates estrogen induced uterine hyperemia in nonpregnant rabbits. We therefore chose to investigate the vascular responses of pregnant rabbits to leukotriene blockade. Nine unanesthetized animals carrying 46 viable fetuses were used in this study. Regional blood flows were measured by the radioactive microsphere technique. In 5 rabbits control blood flows were measured after vehicle administration and FPL 55712, 1 mg/kg bolus, followed by infusion of 100 micrograms/kg/min was given via the jugular vein. Regional blood flows were measured again after 10 minutes of infusion. The procedural order was reversed in the remaining 4 animals. Resistance was calculated as mean arterial pressure divided by total flow to an organ. FPL 55712 decreased the blood pressure from 83 +/- 2 to 76 +/- 3 mmHg (P less than .001). Uterine resistance was not significantly changed (387 +/- 44 to 362 +/- 42 mmHg X ml-1 X min X gm), but renal resistance fell from 18.5 +/- 1.1 to 15.1 +/- 1.2 mmHg X ml-1 X min X gm (P less than .01). FPL 55712 induced maternal placental vasodilatation with resistance decreasing from 291 +/- 33 to 261 +/- 31 mmHg X ml-1 X min X gm (P less than .04). Vehicle administration did not cause dilation in any vascular bed. FPL 55712 appears to be a placental vasodilator whose action is most likely due to receptor blockade of the vasoconstrictive endogenous leukotrienes.

There are extensive data on the circulatory responses to prostaglandins during pregnancy, but little is known about the precursor endoperoxides. The endoperoxide analog (15S)-hydroxy-9α, 11α-(epoxymethano)prosta-5Z, 13E-dienoic acid (EPA1) was used to evaluate the circulatory effects of endoperoxides in pregnant sheep. Ten near-term ewes and their fetuses were chronically catheterized to permit the measurement of regional blood flows by the radioactive microsphere method. In five sheep a fetal IV bolus injection of 12.5 μg/kg EPA1 produced a significant increase in fetal blood pressure from 43 to 51 mm Hg, vascular resistance of the cotyledons from 0.06 to 0.09 PRU·kg−1, membranes from 0.84 to 3.15 PRU·kg−1, and kidneys from 1.18 to 1.94 PRU·kg−1. In five sheep a 10-min maternal infusion of 0.5 μg/kg/min EPA1 produced a significant increase in blood pressure from 89.0 to 115.0 mm Hg, resistance of the uterus from 0.49 to 1.10 PRU, and kidneys from 0.13 to 0.20 PRU. There was no significant change ...

The placental transfer of acetylsalicylic acid was studied in five near-term ewes and fetuses. The total clearance (C tot ) of acetylsalicylic acid from the fetal compartment was determined by bolus injection of 14 C-acetylsalicylic acid into the fetal compartment. C tot = C p + C f where C p is the placental clearance and C f is the fetal tissue clearance. 14 C-acetylsalicylic acid was then infused into the ewe. Fetal (F) and maternal (M) steady-state concentrations of acetylsalicylic acid were measured. During steady-state conditions, the influx of acetylsalicylic acid into the fetal compartment will equal the efflux, or C p × (M-F) = C f × F. Combining these two equations yields the following description of placental clearance: C p = C tot × F/M. Using this equation, we calculated C p = 0.57 ± 0.12 ml/min · kg and C f = 1.93 ± 0.22 ml/min · kg. Maternal and fetal placental flows were also measured using radioactively labeled microspheres. From these flows, a 99% degree of diffusion limitation was determined for the placental transfer of acetylsalicylic acid.

The administration of 10 mg/kg indomethacin to chronically catheterized near-term sheep resulted in a change in cotyledonary vascular resistance from 0.133 +/- 0.016 to 0.180 +/- 0.022 (mmHg . min)/ml (P less than 0.001). The noncotyledonary uterine vascular resistance increased to 191% of the original value (P less than 0.001) and the renal vascular resistance increased to 147% of the control value (P less than 0.001). The maternal blood pressure increased from 96 +/- 3.4 to 108 +/- 3.4 mmHg (P less than 0.001). Indomethacin (12 mg/kg) was given to nine fetuses, and observations were made in the control condition and at 15, 120, and 240 min. Cotyledonary vascular resistances were 144%, 152%, and 213% of the control values at those times. All changes were significant (P less than 0.03). The umbilical vascular resistance rose slowly throughout the study even though the concentration of indomethacin was falling during that time. These data suggest that this response may be an indirect effect. In the maternal circulation the rapid increase in the cotyledonary vascular resistance seen after indomethacin was probably due to a decreased level of endogenous prostaglandin synthesis.

To identify constituents of grain dust responsible for grain handlers' respiratory symptoms, 11 volunteer grain elevator workers underwent inhalation provocation tests with extracts of durum wheat, durum wheat airborne dust, and grain insects and mites. Factors that might influence the host response to the challenge were assessed. Five of the 11 subjects showed a greater than 20 percent decrement in FEV1 after inhalation of durum wheat extracts (airways reaction). The bronchial reactions were immediate in 1/5 and late in 4/5. These airway reactions were blocked by sodium cromoglycate. Only one subject showed airway reaction to durum wheat dust extract, and none reacted to mites or insect extracts. There was no change in DLCO, temperature, or in total C3 complement blood levels, nor was there evidence of activation of complement by the alternate or classic pathway. The airway response was not always related to the atopic status of the individual. The reaction is more likely to occur in subjects with preexisting airway obstruction and nonspecific bronchial hyperreactivity. Durum wheat has been identified as an inducer of occupational asthma in grain handlers. This reaction is probably due to specific or nonspecific mediator release. There was no apparent parenchymal or systemic reaction or complement activation detectable in the subjects' sera after inhalation of durum wheat extracts.

Local infusion of prostaglandin I2 (PGI2) has been reported to dilate the uteroplacental vasculature in a dose-dependent manner. In this experiment we attempted to distinguish the placental and nonplacental (uterine) components of this response over four concentrations of PGI2. Eleven near-term sheep were chronically instrumented for determination of regional blood flows by the use of radioactive microspheres. PGI2 was administered in a retrograde manner via a branch of the middle uterine artery at 1, 3, 10, and 20 micrograms/min. Flows were measured before (control) and after 5-minute infusions at each of the four concentrations (test). The uterine vasculature vasodilated in response to local PGI2 infusion. The 10 micrograms/min dose, for example, produced a mean (+/- SEM) flow of 0.70 +/- 0.07 ml/min/gm; the control value was 0.41 +/- 0.03 ml/min/gm (p less than 0.001). At 20 micrograms/min the test and control flows were 0.75 +/- 0.16 and 0.36 +/- 0.06 ml/min/gm (p less than 0.05), respectively. Uterine vascular resistance fell in a dose-dependent manner as well. There was no evidence of placental vasodilation at any of the doses tested. Renal vasodilation and decreased systemic arterial pressure at higher PGI2 doses suggest a recirculation effect. We conclude that PGI2 does not dilate the placental vasculature over the dose range of 1 to 20 micrograms/min and that the reported vasodilation of the uteroplacental vasculature is a result of decreased resistance in the uterine vasculature alone.

6-Keto-prostaglandin E1 (6-keto-PGE1) is a biologically active, stable metabolite of prostaglandin I2 (PGI2). It has vasoactive properties similar to those of PGI2 and it has been shown to decrease the resistance of the renal, mesenteric, and pulmonary vascular beds. PGI2 is synthesized by the pregnant uterus and is vasoactive in the ovine placenta. The effects of 6-keto-PGE1 on uterine and placental blood flow in pregnant ewes were determined for comparison with those of PGI2. Near-term ewes and their fetuses were chronically catheterized to permit the measurement of regional blood flow by the radioactive microsphere method. In six sheep a 5-minute maternal jugular infusion of 3.25 micrograms/kg/min of 6-keto-PGE1 decreased mean arterial blood pressure from 89 +/- 4.8 to 63 +/- 7.1 mm Hg. Uterine vascular resistance decreased from 0.55 +/- 0.11 to 0.35 +/- 0.05 peripheral resistance units (PRU), but maternal cotyledonary resistance increased from 0.19 +/- 0.04 to 0.27 +/- 0.03 PRU. In five sheep a fetal intravenous infusion of 18 micrograms/min of 6-keto-PGE1 decreased mean fetal blood pressure from 43 +/- 2 to 29 +/- 2 mm Hg. Cotyledonary vascular resistance increased from 0.30 +/- 0.02 to 0.55 +/- 0.09 PRU . kg-1. In these sheep there were no significant changes in maternal uterine, renal, or cotyledonary blood flows. These results indicate that 6-keto-PGE1 is similar to PGI2 in that it produces maternal cotyledonary vasoconstriction, hypotension, and vasodilation in other organs.

Many studies have shown that estrogen increases the blood flow to the pregnant and non-pregnant uterus (1-3), but the mechanism by which this vasodilation occurs has not been determined.It has been postulated that prostaglandins may mediate this vasodilation. Prostaglandins have been shown to play a role in the regulation of blood flow in the pregnant sheep uterus (4) and some studies have indicated that prostaglandins affect blood flows in non-pregnant uteri (5). Some investigators have also reported finding increased prostaglandin synthesis in uterine tissue following estrogen treatment (6, 7).The following experiment was designed to study the response of the uterine vasculature to estrogen treatment in the rabbit and to determine if prostaglandins are involved in this response through the use of the known prostaglandin synthetase inhibitors, indomethacin and meclofenamate.Materials and methods.Non-pregnant female New Zealand white rabbits weighing 1.7-3.5 kg were used in this study. Surgery was perform...

Blood flow to mammary tumor MT-W9B in minimally disturbed, unanesthetized inbred WF rats was measured with radioactively labeled 25-mu (diameter) microspheres. The distribution of the blood flow estimates was not described by a normal probability density function but could be normalized with a natural log transformation of the data. The relative blood flow to the tumor tissue was always greater than that to the surrounding normal tissue and was dependent on the tumor size, transplantation site (axillary vs. inguinal), and physiologic state of the animal. The growth of this tumor did not alter the blood flow to the adjacent normal tissues. However, the cardiac output and coronary blood flow increased with increasing tumor size. Two blood flow estimates could be performed on the same animal within a time-span of 15 minutes.

SummaryObservations were made of the responses of the uterine blood flow in the near-term pregnancy to occlusion of the umbilical circulation to a few cotyledons of the near-term sheep placenta and in one placenta of the multiparous rabbit pregnancy. It was found that the uterine blood flow declined to 67% of its predicted value 1 day after umbilical ligation in the sheep placenta and to 61% of its predicted value 1 day after the death of one of the fetuses of the rabbit pregnancy. The change in the uterine blood flow in response to the occlusion of the umbilical blood supply to the adjacent area is a local response and is similar in its time course and magnitude to the response of the whole placenta which has been previously observed by Raye et al. (9). This local response of the uterine blood flow is considered to be evidence that the uterine blood flow is in part determined and controlled by the structural or chemical nature of the adjacent fetal compartment.Supported by grant number HD-06736.

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.

The purpose of the study was to determine if a near-maximum exposure to air at increased atmospheric pressure causes gross fetal malformations, decreased birth weight, or death when administered to pregnant sheep during peak development of the embryo. Twenty-eight timed-pregnant sheep were alternately assigned to a series of 25- or 30-minute exposures at either 4.6 atmospheres absolute or surface pressure between days 12 and 40 of gestation. About day 130 of pregnancy, 11 experimental and eight control fetuses were recovered, weighed, measured, fixed, and examined for defects. No major structural malformations were present. One minor variation, an undescended testis, occurred in a treated fetus. The results indicate that a series of short, marginally tolerated “dives” by pregnant sheep during peak development does not affect fetal health or survival.

Rankin et al. have shown that prostacyclin does not dilate the ovine placenta, yet Clark et al. have shown that retrograde infusion of prostacyclin dilates the uterine vasculature. To determine the effects of prostacyclin on the sheep placenta, the two groups have collaborated. In five chronically catheterized near-term sheep, blood flows were measured by the radioactive microsphere technique. Control blood flows were measured and prostacyclin infused into the retrograde uterine artery catheter at 10 micrograms/min. The blood flows were again measured, and the area served by the catheter was then delineated by the injection of a green dye at the time of maternal euthanasia. The placenta and cotyledons were separated and the kidneys were obtained for assay. The systemic effects of prostacyclin were minimal and have been observed previously. The resistance of the myometrium fell from 566 +/- 99.9 to 322 +/- 63.9 mm Hg X ml-1 X min X gm (p less than 0.002). The placental tissue showed no change in resistance. When the tissues were combined, we observed a decrease in resistance from 0.38 +/- 0.18 to 0.32 +/- 0.14 mm Hg X ml-1 X min (p less than 0.004), thereby confirming the observation that there was indeed vasodilation downstream. However, the vasodilation was not in the placenta but in the myometrium, and we reconfirm our previous conclusion that prostacyclin does not dilate the sheep placenta.

SummaryThe vascular response to norepinephrine is expressed in terms of a resistance ratio which is defined as the ratio of the vascular resistance seen 1.5 min after norepinephrine administration to that seen before norepinephrine administration. The injection of 1 μg/kg of norepinephrine to near-term sheep significantly increased the vascular resistance of the placenta to a ratio of 2.27 ± 0.52 (mean ± SEM; N = 7). Pretreatment with 20 jug of prostaglandin E2 per minute significantly decreased the placental response to norepinephrine to a resistance ratio of 1.47 ± 0.21 which was 65% of the untreated response (N = 7). Pretreatment with 10 mg/kg indomethacin significantly increased the placental response to norepinephrine from a resistance ratio of 2.25 ± 0.70 to 2.71 ± 0.84, which is 120% of the untreated value (N = 6). Prostaglandin E2 attenuated the placental vascular response to norepinephrine and indomethacin potentiated this response.

We have examined the effect of adenosine given via retrograde uterine artery catheter at 25 mg/min to nine chronically catheterized near-term sheep pretreated with angiotensin II, 5 micrograms/min, via the jugular vein. Blood flows were measured by the microsphere technique. Flows were measured at rest, after 10 minutes of angiotensin II infusion, and after 1.5 minute of adenosine infusion. Blood pressure increased with angiotensin II infusion from 101 +/- 2.63 to 130 +/- 4.33 mm Hg (p less than 0.05) and then remained unchanged with local adenosine infusion at 129 +/- 4.33 mm Hg (NS). Organ resistances were: Tissue Control Angiotensin II Adenosine Uterine resistance/gm 299 +/- 0.04 767 +/- 83 (p less than 0.05) 355 +/- 37.7 (p less than 0.05) Cotyledonary resistance/gm 37.9 +/- 4.83 48.1 +/- 4.93 (p less than 0.05) 50.10 +/- 5.27 (p less than 0.05) The experimental uterine tissue resistance increased with angiotensin II and showed vasodilation in response to adenosine. The cotyledonary resistance increased with angiotensin II infusion but showed no change in response to adenosine. The maternal-placental response was anomalous. Angiotensin II-induced maternal-placental vasoconstriction cannot be opposed by the exogenous administration of adenosine.

SummaryThe injection of 10 μg angiotensin II to 5 near-term sheep caused significant increases in the renal, uterine and placental vascular resistances. After pretreatment with 10 mg/kg indomethacin the injection of 10 μg angiotensin II caused a significantly greater change in the vascular resistance of the kidneys and uterus. The response of the placental vasculature to angiotensin II was not affected by the pretreatment. Endogenous prostaglandins may play a role in modulating the response of the renal and uterine vascular beds to angiotensin II but this study provides no evidence to support the hypothesis that prostaglandins modulate the placental response to angiotensin II.

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

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.

We infused forskolin in 30% ethanol or 30% ethanol systemically in seven chronically catheterized near-term sheep to determine the response of ovine uterine musculature to cyclic adenosine monophosphate stimulation. Maternal and fetal arterial pressures, fetal venous pressure, intrauterine pressure, and uterine electromyogram activity were monitored continuously. Prostaglandin E 2 was infused at a delivery rate that caused a minimal 5 mm Hg increase in intrauterine pressure with definite contraction-like pressure spikes and associated uterine electromyogram activity. Forskolin (10 mg in 30% ethanol) or ethanol (vehicle) was then infused for 20 minutes. The prostaglandin E 2 challenge was repeated 3 minutes later and again every 30 minutes over a 2½-hour period. Data were analyzed by repeated measures analysis of variance. Infusion of ethanol ( n = 2) had no apparent effect on either the intrauterine pressure or the uterine electromyogram response to prostaglandin E2 challenge. Forskolin infusion ( n = 5) caused an attenuation of the intrauterine pressure response to prostaglandin E 2 for 93 minutes. This effect was greatest 33 minutes after the infusion ended when the integrated pressure signal was 37% of the initial prostaglandin E 2 response. The forskolin infusion had no effect on uterine electromyogram response to prostaglandin E 2 . We conclude that forskolin causes an uncoupling of excitation from contraction in the intact near-term ovine uterus.

Physical models have been constructed of placentas which have exchanging flows in several orientations. The effectiveness of heat transfer was measured in these models and was found to generally conform to that which was predicted from theoretical considerations. The results support the conclusion that the effectiveness of exchange in the primate placenta should be greater than that of a placenta which resembles a concurrent exchanger and less effective than a countercurrent configuration. Using the concurrent model we have demonstrated that the effectiveness of oxygen and carbon dioxide exchange were similar when the permeability of the placenta was high. When the permeability of the placenta was decreased we were able to demonstrate that the transfer of carbon dioxide was decreased, whereas that for oxygen was not changed. This is the same type of result which has been obtained by other investigators in living animals, where the analogous comparison was between inert gas and oxygen transfer and the different behavior of the gases was induced by the use of drugs which bind to cytochrome P450. The earlier results were held as evidence for the existence of a carrier mediated oxygen transport mechanism. The experiments reported here demonstrate that this result can be explained by non-specific decreases in placental permeability. Physical models of the placenta appear to be a useful bridge between theoretical and experimental physiology.

SummaryThe effects of various vasoactive agents on ovarian blood flows were measured using radioactive microspheres. Norepinephrine and angiotensin II decreased blood flow and increased vascular resistance significantly in the CL ovary with no significant changes in the ovary without CL. Pretreatment of the animal with prostaglandin E2 caused a twofold decrease in the response of the CL ovary to norepinephrine with no change in the response of the ovary without CL. Pretreatment with indomethacin did not affect the ovarian responses to norepinephrine. The only significant response of the ovary without CL was an increase in vascular resistance after indomethacin. The data suggest that prostaglandins are not responsible for maintaining vascular homeostasis in the corpus luteum of the near-term ovine ovary.

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.

SummarySera from farmer's lung patients and non-farmer's 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 farmer's 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 farmer's lung or with extracts of good hay. Evidence is presented to show that farmer's 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 farmer's lung.

SummarySix patients with Farmers Lung and 10 controls were challenged with an antigen extracted from moldy hay by aerosol inhalation. Precipitin reactions in agar gel im-munodiffusion were strongly positive in 4 patients, weakly reactive in one, and not present in one. Clinical, hematologic and physiologic data are presented on the 6 patients challenged in an identical manner and on the 10 control subjects. Responses to this challenge in the patient group were qualitatively identical to the reaction each patient experienced when exposed to moldy hay in the barn or silo. These moldy hay antigens are, thus, concluded to be the etiologic agents responsible for the disease, Farmers Lung.

Farmer's lung is a potentially serious and crippling disease that results from handling a variety of dusty, moldy organic materials. The symptoms are shortness of breath, cough, fever, chills, weight loss, and hemoptysis. This condition differs from silo filler's disease in both causation and symptoms. The roentgenographic findings are those of interstitial pneumonitis. Biopsy of the lung reveals a granulomatous interstitial pneumonitis with epithelioid and giant cells. This report is based on 39 cases. Lung biopsies were done in eight, and two cases are described in detail. Repeated exposure was followed by recurrence. No causative organism was found. A given exposure induced the disease in some persons while leaving others unaffected. Individual hypersensitivity to molds or to their products seemed to be a decisive factor. Antibiotic therapy is not primarily indicated. The essential treatment is for the patient to avoid repetition of the exposure.

Described here are the progressive changes in blood-flow distribution that accompany four-hour heart-lung bypass in dogs and the effects of perfusion rate on flow distribution and oxygen consumption. The corresponding changes produced by anesthesia alone and by the thoracotomy needed for a bypass procedure are also shown for comparison purposes. These data indicate that the bypass procedure itself puts a very significant stress on the test animals and that perfusion rates in excess of resting cardiac output are required to prevent hypoxia induced irreversible tissue damage.