Andrew F. Phippard

Circulatory adaptation to pregnancy--serial studies of haemodynamics, blood volume, renin and aldosterone in the baboon (Papio hamadryas).

To test the hypothesis that haemodynamic changes in pregnancy precede any significant increase in circulating blood volume, serial haemodynamic studies were performed in eight baboon pregnancies using Swan-Ganz catheterization and arterial cannulation. Simultaneous measurements were made of red cell and plasma volumes, and of plasma renin activity and aldosterone concentration. Haemodynamic changes identified by 4 weeks gestation included significant (P less than 0.01) reductions in right atrial pressure, systemic and pulmonary arterial pressures, and systemic and pulmonary vascular resistance. Stroke volume increased in early pregnancy (P less than 0.01), with a consequent increase in cardiac output. Plasma renin activity and aldosterone concentration were elevated by 4 weeks (P less than 0.01), but plasma volume did not expand until 12 weeks. At no stage in middle or late pregnancy was cardiac filling pressure increased. These results provide the first haemodynamic evidence that pregnancy is a state of reduced effective blood volume associated with vasodilatation from the early weeks.

Fetotoxicity of angiotensin-converting enzyme inhibition in primate pregnancy: A prospective, placebo-controlled study in baboons (Papio hamadryas)

OBJECTIVES Serious concerns have been raised about angiotensin-converting enzyme inhibition in pregnancy. The central question remains: does toxicity of angiotensin-converting enzyme inhibition pertain to pregnant humans? STUDY DESIGN A prospective, placebo-controlled study was performed to investigate the effect of angiotensin-converting enzyme inhibition on pregnancy outcome in the baboon. Subjects (N = 12) received active and placebo treatments sequentially in a crossover protocol. Data were analyzed with two-sample t tests, analysis of variance, Fishers exact test, or Kaplan-Meier survival analysis, where appropriate. RESULTS Chronic administration of enalapril (7.5 mg per day) from before conception achieved moderate but sustained angiotensin-converting enzyme inhibition as determined by repeated measures of renin-angiotensin system parameters (serum angiotensin-converting enzyme activity, plasma renin activity and plasma angiotensin I, angiotensin II, and aldosterone concentrations). Serum angiotensin-converting enzyme activity was significantly reduced throughout (< 10 nmol.ml-1.min-1, p < 0.01), with significant increases in plasma renin activity and angiotensin I (p < 0.01). Angiotensin II and aldosterone were maintained unchanged compared with placebo. There was a significant incidence of fetal death or intrauterine growth retardation in fetuses exposed to enalapril (eight of 13, zero on placebo, p < 0.01). When the definition of adverse pregnancy outcome was restricted to fetal death alone (four of 13) the difference remained significant (p < 0.05). Maternal arterial pressure was unchanged before conception, but a small and significant fall (10 to 15 mm Hg, p < 0.01) was detected throughout pregnancy. There was no fetal malformations. CONCLUSION The study provides definitive evidence for serious consequences of angiotensin-converting enzyme inhibition in pregnancy of high-order primates.

Effect of angiotensin II on baroreceptor reflex control of heart rate in conscious baboons.

Studies of the baroreceptor-heart rate reflex were performed in four conscious, unrestrained male baboons to determine whether changes in circulating angiotensin II within the physiological range are associated with alterations in baroreceptor reflex sensitivity. With the animals on a high sodium intake, studies were performed before and during graded angiotensin II infusion (10 and 20 ng/kg/min). To separate effects on baroreceptor reflex function mediated by angiotensin II-induced increases in arterial pressure, these studies were repeated on a different day with simultaneous glyceryl trinitrate infusion to prevent increases in pressure during angiotensin II infusion. With the animals on a low sodium intake, studies were performed before and after angiotensin converting enzyme inhibition with captopril (1 and 5 mg/kg). These studies were also repeated on a separate day during simultaneous phenylephrine infusion to prevent a decrease in pressure with captopril. Reduction in sodium intake had no significant effect on arterial pressure, heart rate, or plasma volume, although arterial plasma angiotensin II concentration and renin activity were significantly increased (p less than 0.01). Infusion of angiotensin II produced a significant reduction in baroreceptor reflex sensitivity (p less than 0.01), and converting enzyme inhibition produced a significant increase (p less than 0.05). These effects accompanied significant increases and decreases in arterial angiotensin II concentration, respectively (p less than 0.01), but were independent of angiotensin II-related changes in arterial pressure. The data indicate that physiological variations in circulating angiotensin II have a direct effect on sensitivity of the baroreceptor-heart rate reflex.

A baboon (Papio hamadryas) model of insulin‐dependent diabetes

Over a period of four years, streptozocin has been used to induce diabetes in 10 baboons, all of whom are insulin dependent. We describe our experience with their husbandry, induction of diabetes, insulin therapy, metabolic control and growth rate. Streptozocin dosage of 60 mg/kg readily induces hyperglycemia with minimal hepatic or renal toxicity. Using a once daily injection of mixed short and intermediate acting insulins at a dosage of 2–4 U/kg, it is possible to maintain a degree of metabolic control similar to that attained in patients.

Gastric haemorrhage and perforation caused by a trichobezoar in a baboon (Papio hamadryas)

A captive-bred male baboon presented with severe evidence of blood loss and melaena. An upper gastrointestinal radiological study with Gastrografin showed a large trichobezoar. Laparotomy confirmed its presence and revealed gastric ulceration with perforation and generalized peritonitis. The condition was successfully treated by surgery.

Fetal ultrasonography: Normal biometric ranges in the baboon (Papio hamadryas)

Normal biometric ranges for fetal growth in a captive breeding baboon (Papio hamadryas) colony are described. Measurements include crown‐rump length, biparietal diameter, binocular distance, head circumference, abdominal circumference, femur length and amniotic fluid index. The pattern of fetal growth is compared with other baboon subspecies and man. The uses and limitations of such data for breeding colony management and optimum utilisation of experimentally derived data are discussed.

EFFECT OF ANTIHYPERTENSIVE DRUGS ON NEONATAL BLOOD PRESSURE

1. This study evaluates the perinatal outcome of infants born to ninety‐five mothers with hypertension in pregnancy whose blood pressure was treated in a double blind trial comparing clonidine hydrochloride (C) and α‐methyldopa (A).

Helminthic infestation complicated by intussusception in baboons (Papio hamadryas).

Two juvenile baboons presented with diarrhoea, which did not resolve completely following antibiotic therapy. Ileal intussusception was identified at autopsy in both cases. Trichuris was the only gastrointestinal pathogen for which evidence could be found. This helminth is well-recognized as a cause of intussusception in human infants, but the complication has not been reported previously in non-human primates. It is likely to be fatal if undiagnosed.

Brainstem auditory evoked response development in preterm and term baboons (Papio hamadryas)

Brainstem auditory evoked responses were recorded longitudinally from 11 neonatal baboons (Papio hamadryas), 6 of which were preterm. Recordings were made in unsedated animals from day 161 to day 362 after conception (term = 182 days). The pattern of development of both waveform morphology and of wave latency was consistent with that seen in the human neonate, with a rapid maturation of the response during the perinatal period, and then a slower development to adult values. Brainstem conduction time was measured from the wave I to wave IV interval, and this demonstrated a similar pattern, with a rapid decrease in latency up to term, and then decreasing more slowly to reach adult values by 4 months of age in the baboon.

Angiotensin II Vascular Reactivity and Angiotensin II Metabolism in Pregnant and Non-Pregnant Baboons (Papio Hamadryas)

A serial study with cardiac catheterization of pregnant baboons was carried out to determine the effect of gestation on vascular responsiveness to exogenous angiotensin II (AII) over a ten-fold dose range, using the same animals as non-pregnant controls. The effect of pregnancy on arterial AII concentration, before and during AII administration, was also examined. There was a significant increase in endogenous AII from 4 weeks gestation, with progressive reductions in both total peripheral resistance and vascular reactivity to exogenous AII through early pregnancy. There were no significant reductions in the arterial plasma concentrations of AII achieved by AII infusion during pregnancy to account for its diminished effect on vascular resistance