M. Kazim Husain

Vasopressin and Neurophysin: High Concentrations in Monkey Hypophyseal Portal Blood

Vasopressin and its binding protein, neurophysin, were measured by radioimmunoassay in the hypophyseal portal blood of monkeys after cannulation of individual long portal veins. Mean vasopressin concentrations (13,800 picograms per milliliter) in portal blood were more than 300 times as high as those in the systemic circulation (42 picograms per milliliter). Neurophysin concentration was approximately 25 times as high in portal as in systemic blood. By immunoperoxidase techniques, high concentrations of neurophysin were demonstrated around portal capillaries of the median eminence. These studies indicate direct secretion of vasopressin and neurophysin into the portal circulation; the quantities secreted during stress may be sufficient to exert significant effects on secretion of anterior pituitary hormone.

Vasopressin secretion induced by hypoxia in sheep: Developmental changes and relationship to β-endorphin release☆☆☆

To investigate the developmental changes in the secretion of vasopressin and the potential role of beta-endorphin as a stimulus to the release of vasopressin, the concentrations of these peptides were measured in fetal, newborn, and adult sheep after episodes of induced hypoxia. The studies confirm that hypoxia is a potent stimulus to the release of both vasopressin and beta-endorphin in the fetal animal. In both the newborn lamb and the ewe, more profound hypoxia is necessary for a similar release. In the fetus, the release of both vasopressin and beta-endorphin after hypoxia increased with gestational maturation. A comparison of control concentrations of both peptides, the discordance of release in the newborn lamb, and the absence of a change in concentrations of vasopressin with infusion of beta-endorphin implies that these hormones are released in parallel but independently during hypoxic stress.

Renal response of fetal lamb to complete occlusion of umbilical cord

The renal response of the fetal lamb to repeated complete occlusion of the umbilical cord was studied in nine chronically instrumented animals. Five episodes of occlusion of the umbilical cord, each lasting for two minutes, produced a twofold rise in fetal urine osmolality and sodium, chloride, and potassium concentrations. Output of urine and glomerular filtration rate remained essentially unchanged while free water clearance decreased from a control of +0.10 to -0.02 ml. per kilogram per minute at the end of the fifth episode. Electrolyte concentrations in urine remained elevated for at least two hours following the occlusions. In addition to changes in urine composition, there was a 50- to 200-fold increase in the fetal plasma concentration of vasopressin. These studies indicate that complete interruption of the umbilical circulation, even though of short duration, produces disturbances in fetal renal function that can lead to loss of electrolytes in the urine. They provide an explanation for the low sodium levels reported in asphyxiated newborn infants in renal failure.

Plasma Renin, Catecholamine, and Vasopressin during Nitroprusside-induced Hypotension in Ewes

The effect of acute nitroprusside-induced hypotension on plasma renin activity, catecholamine, and vasopressin concentrations was examined in eight chronically catheterized, conscious ewes. Nitroprusside was infused intravenously for one hour at rates adjusted to achieve a 20% decrease in mean blood pressure (dose range: 14–50 mg, or about 5.8–18.5 μg·kg-1·min-1). During hypotension, renin activity increased from 1.39 ± 0.49 to 3.92 ± 1.38 ng·ml-1.·h-1, catecholamine concentrations remained unchanged, and vasopressin increased from 1.7 ± 0.4 to 110 ± 52.7 pg/ml. A significant positive correlation was obtained between total nitroprusside dose and peak vasopressin level (r=0.749, P =0.015). No significant change in arterial-blood (PH, PO2, PCO2, plasma osmolality, or sodium concentration were observed throughout the experiment, thus eliminating the possibility of osmolar or hypoxic stimuli for the increased renin activity and vasopressin release. The magnitude of vasopressin release found in our studies implies that it plays a more important role than renin in defense against acute hypotension. In addition, the authors experiments suggest that variation in vasopressin release may be responsible for the variation of the dose of nitroprusside required to maintain hypotension.

Vasopressin concentration in amniotic fluid as an index of fetal hypoxia: mechanism of release in sheep.

Summary: Hypoxia is a potent stimulus to the release of vasopressin in fetal sheep and, in turn, plasma concentrations of the hormone correlate inversely with fetal oxygenation. Because the fetal kidney contributes to vasopressin clearance, we propose that measurement of increased amounts of vasopressin in amniotic fluid would be indicative of fetal hypoxia. We therefore measured concentrations of vasopressin in amniotic fluid under resting conditions, during and after fetal hypoxia, and with intravenous and intra-amniotic administration of vasopressin in 15 chronically instrumented fetal lambs 111–141 d gestation. In the resting state mean (±SE) vasopressin concentrations in amniotic fluid (1.6 ± 0.3 pg·ml-1) did not differ from those in maternal (1.4 ± 0.4 pg·ml-1) or fetal (1.8 ± 0.2 pg·ml-1) plasma. After exposure of the ewe to 10% O2 or partial occlusion of the umbilical cord, vasopressin concentrations in fetal plasma increased significantly (P < 0.001) to 200 ± 59 pg.ml-1 with a delayed increase in amniotic fluid concentrations (P < 0.03) to 15.8 ± 4.5 pg.ml-1. This rise in concentration of vasopressin in amniotic fluid was sustained for at least 24 h and levels at that time were highly correlated with peak plasma concentrations (r = 0.83, P < 0.001). Intravenous infusion of vasopressin into the fetus was accompanied by an equally significant (P < 0.02) and sustained increase of vasopressin in amniotic fluid. After intraamniotic injection of vasopressin, levels remained increased for at least 24 h.In the third trimester of ovine gestation amniotic fluid vasopressin concentration was a reliable indicator of prior fetal hypoxia. Parallel amounts of antidiuretic activity measured by bioassay and vasopressin by radioimmunoassay confirmed the presence of active hormone in amniotic fluid. Hypoxia alone was not a stimulus to passage of meconium and increased concentrations of vasopressin in fetal plasma were not associated with expulsion of meconium in utero. Despite elevated concentrations of vasopressin in amniotic fluid, no associated changes in intra-uterine pressure were discerned.

Excretion of vasopressin in the hypoxic lamb: comparison between fetus and newborn.

Summary: The factors associated with increased renal excretion of vasopressin (VP) were examined in the hypoxic fetus and newborn. Studies were conducted on six chronically instrumented fetal (117-136 days gestation) and seven newborn lambs (2-6-dayold). Hypoxia was produced by administration of 10% oxygen to the ewe or neonate for 30 min. This procedure caused a 50% reduction in PaO2, no significant change in pHa in either fetus or neonate and a slight fall in PaCO2. Hypoxia caused an increase in VP concentrations in plasma from 1.3 ± 0.53 to 46.4 ± 4.71 pg/ml in the fetus and from 5.9 ± 2.80 to 50.2 ± 26.68 pg/ml in the neonate. After hypoxia there was a fall in urine output from 0.27 ± 0.045 to 0.17 ± 0.046 ml/(min·kg) in the fetus and from 0.15 ± 0.033 to 0.09 ± 0.022 ml/(min·kg) in the newborn. The corresponding values for urine osmolality were the following: 168 ± 30.8 to 325 ± 30.6 mOsm/kg in the fetus and 388 ± 65.4 to 523 ±51.8 mOsm/kg in the newborn. VP concentration in urine increased from 13 ± 9.4 to a maximum of 176 ± 32.4 pg/ml after 30 min of recovery in the fetus and 39 ± 4.6 to 278 ± 132.5 pg/ml after 1 h of recovery in the newborn. These levels remained high for at least 1 h after the end of hypoxia. There was a good linear correlation between plasma VP levels and the corresponding urine levels and excretion rates in both the fetus and newborn. No correlation was found between VP urinary excretion and either osmolar excretion or GFR. These results, therefore, indicate that urinary VP levels and excretion rates can be used as a reflection of levels in plasma after hypoxia.

Plasma Vasopressin, Renin, and Catecholamines during Nitroprusside-Induced Maternal and Fetal Hypotension in Sheep

ABSTRACT: The release of vasopressin, renin, and catecholamines by the fetus during either maternal or fetal hypotension was examined in chronically catheterized fetal lambs. Nitroprusside was infused intravenously for 1 h into seven pregnant ewes (maternal hypotension) or nine fetal lambs (fetal hypotension); the rates were adjusted to achieve a 15 to 30% decrease in mean blood pressure. During maternal hypotension, mean ± SE vasopressin in maternal plasma increased from 1.2 ± 0.2 pg · ml-1 to 208 ±153 pg · ml-1 and plasma renin activity increased from 1.5 ± 0.3 ng · ml-1 · h-1 to 6.6 ± 1.6 ng · ml-1 · h-1. Fetal vasopressin and plasma renin activity also increased during the same interval from 1.1 ± 0.3 to 16.9 ± 7.5 pg · ml-1 and 3.7 ± 1.1 to 10.5 ± 2.85 ng · ml-1 · h-1, respectively; but no changes were observed in fetal blood pressure, heart rate, or acid base status. During fetal hypotension, mean vasopressin in fetal plasma increased from 4.3 ± 3.4 pg · ml-1 to 1054 ± 772 pg · ml-1, plasma renin activity increased from 5.7 ± 2.2 ng · ml-1 to 22.2 ± 7.1 ng · ml-1 · h-1, and total catecholamines from 174 ± 58 pg · ml-1 to 810 ± 416 pg · ml-1. There was no change in fetal heart rate, acid base status, osmolality, or sodium concentration. The fetus became and remained hypertensive for at least 1 h after the end of infusion. This prolonged hypertension was associated with elevated levels of vasopressin and plasma renin activity. Peak vasopressin levels were proportional to the total nitroprusside dose in both the ewe and fetus (maternal r = 0.796, fetus r = 0.870). These experiments indicate that as in the adult, vasopressin and the renin-angiotensin system in the fetus are stimulated by euvolemic hypotension and may play an important role in the maintenance of fetal blood pressure during an hypotensive challenge. We speculate that the prolonged rebound hypertension represents immaturity of the fetus to fine tune the regulation, release, or metabolism of vasoactive mediators. More likely, the hypertension and elevated hormone levels represent homeostatic mechanisms to combat the nitro-prusside-induced diminished cardiac output. Lastly, fetal release of vasopressin, renin-angiotensin, and norepinephrine during maternal hypotension suggests that they are sensitive indicators of early fetal compromise.

497 FETAL CIRCADIAN RHYTHMS: CYCLES OF VASOPRESSIN (VP) LEVELS IN CEREBROSPINAL FLUID (CSF) NOT BLOOD

Besides classical effects on water balance and blood pressure, vasopressin has important functions in brain including modulation of behavioral processes and memory consolidation. In adult animals immunoactive VP in CSF exhibits a circadian pattern of release suggesting that the CSF may be a conduit for the effects of VP on diverse brain areas. To characterize the release of VP by the fetus, CSF was withdrawn continuously (1.0 ml/hr × 3 days) from the prechaismatic fossa of 5 chronically instrumented fetal sheep at 108 to 146 d gestation in 7 studies and plasma sampled intermittently (1.5 ml q 4h ×1 day) in 3 studies. Using a specific VP RIA,daily rhythms of VP in CSF were found for each fetus. Temporal profiles showed low levels of VP (12–25 pg/ml) during daylight alternating with high levels at night (30–45 pg/ml). Cycle length by frequency domain analysis was 22 to 24 hrs<. No similar fluctuations in plasma VP levels (2.1±1.0 pg/ml) were found. The amplitude of the CSF rhythms was increased (125 pg/ml) with chronic hypoxia, acute hemorrhage and in the days immediately preceding term delivery.We conclude that circadian rhythms of VP concentration in CSF but not plasma are present in the fetus during the final 25% of gestation. Changes in the amplitude and/or period of these rhythms may be important in the timing of parturition and the fetal response to suboptimal intrauterine condition.

398 CLEARANCE OF VASOPRESSIN BY THE FETUS AND NEWBORN

These studies were initiated in order to compare the volume and rate of distribution, the rates of metabolism and excretion of VP by the fetus to those of the newborn. Vasopressin - 2ng/kg was injected intravenously to six fetal and four neonatal lambs and VP levels were measured in sequential plasma and urine samples. Vasopressin disappeared from plasma as an exponential function composed of two components. The first phase, representing distribution, was similar in both the fetus and newborn with T½ of 1.75 minutes. The second phase, representing excretion and metabolism, was slightly faster in the fetus than newborn, T½ being 17 and 25 minutes respectively. Plasma concentrations extrapolated to zero time gave a volume of distribution of 285 ml/kg in the fetus and 225 ml/kg in the newborn. Data on urine concentrations show that when given as a bolus, fetal renal excretion of non-metabolized VP was minimal while in the neonate it represented 7-10% of the dose.These results indicate that the rate of distribution of VP is essentially the same in both the fetus and newborn but the volume of distribution is slightly higher in the fetus. Despite the lack of contribution of the fetal kidney, the rate of clearance of VP is slightly faster in the fetus suggesting a role for the placenta in the metabolism of VP.

Plasma vasopressin, renin and catecholamines during nitroprusside-induced hypotension in the newborn lamb.

The circulating levels of vasopressin, catecholamines and renin activity before, during and following a 10-20% fall in mean arterial blood pressure induced by sodium nitroprusside were measured in six chronically catheterized lambs during the first week of life. No significant changes in pHa, PaO2, PaCO2, Plasma sodium or osmolality were observed during or following the infusion of sodium nitroprusside at an average of 12 g.kg-1.min-1 (table I). However, the fall in blood pressure at the end of 60 minutes infusion, was associated with significant increases in the plasma levels of vasopressin from a control value of 2.4 +/- 0.57 to a maximum of 35.1 +/- 16.3 pg/ml (p = .002), renin activity from 6.7 +/- 1.56 to 27.4 +/- 11.44 ng.ml-1.hr-1 (p = .003), and catecholamines from 189.3 +/- 42.15 to 543.3 +/- 100.52 pg.ml-1 (p = .0001). The increase in vasopressin is lower, while that of PRA was higher and catecholamines similar to those found in the ewe. Plasma renin activity (PRA) and catecholamine levels remained elevated for at least 30 minutes following the end of the infusion while the mean blood pressure rose significantly above control levels and remained elevated for twenty minutes. We speculate that the persistent elevated levels of vasoactive mediators are responsible for the prolonged rebound hypertension following the cessation of the nitroprusside infusion and is the result of an immaturity of either a feedback process or metabolism of the vasoactive mediators or a combination of both mechanisms. This rebound hypertension could have adverse effects particularly in the very immature neonate.