Douglas N Weismann

Ontogeny of Single Glomerular Perfusion Rate in Fetal and Newborn Lambs

Summary: The developmental pattern of regional glomerular density and glomerular perfusion rate (GPR) was studied in 20 chronically catheterized fetal lambs between 106 and 140 days of gestation (term, 145 days) and in six newborn lambs between 3 and 19 days of age. The present study demonstrates for the first time in lambs that the nephrogenic zone disappears around 130 days of gestation and that the total glomerular counts per kidney in fetuses over 130 days (468296 ± 41173 glomeruli per kidney) is not significantly different than in newborn lambs (433704 ± 21553). Glomerular density, determined in four cortical zones (zone I being the outermost portion of the cortex) did not show any significant changes during fetal life; however, significant decreases in glomerular density were observed in each cortical zone after birth. The relative distribution of glomeruli during fetal life decreased in the outer portion (zones I and II) and increased in the inner portion (zones III and IV) of the cortex as fetuses matured and approached term. After birth, this difference became even more prominent; the outer cortical fraction (zone I) decreased from 49.6 ± 2.9% in fetuses of less than 120 days to 37.8 ± 1.5% (P < 0.05) in newborn lambs, whereas the fraction found in zone III increased from 14.9 ± 1.3% to 20.8 ± 0.7% (P < 0.05). Small but significant increases in glomerular filtration rate (GFR) (P < 0.01) and total renal blood flow (P < 0.05) were observed during fetal life: GFR and total renal blood flow increased, respectively, from 1.84 ± 0.11 and 37 ± 2 ml/min in fetuses <120 days to 3.05 ± 0.2 and 46 ± 4 ml/min in fetuses >130 days gestation. During the same period, filtration fraction (FF) did not increase significantly whereas a significant (P < 0.01) 58% increase in FF was observed after birth: FF increased from 10.16 ± 0.74% in fetuses >130 days gestation to 16.12 ± 1.66% in newborn lambs. Renal vascular resistance decreased from 1.03 ± 0.08 mm Hgml-1 min-1 in fetuses >130 days to 0.51 ± 0.05 mm Hgml-1min-1 (P < 0.01) in newborn lambs. Glomerular perfusion rate (GPR), computed for each cortical zone did not change significantly during the last trimester of gestation. After birth, GPR increased almost three times in zones I and II (from 69.2 ± 8.9 and 53.6 ± 4.2 nl/min in fetuses >130 days to 206.9 ± 16.8 and 161.3 ± 20.7 nl/min in newborn lambs, respectively), doubled in zone III (from 55.6 ± 10 nl/min in fetuses >130 days to 119.5 ± 8.9 nl/min in newborn lambs) and remained unchanged in zone IV when compared to fetal GPR values. After birth, the increase in GFR correlated closely with the GPR increase in zone I (r = 0.87) and zone II (r = 0.87), suggesting that the developmental pattern of GFR after birth may depend on the increase in GPR in the outer zones of the renal cortex.Speculation: The addition of new nephron units may be an important determinant of glomerular filtration rate (GFR) in fetuses of less than 130 days of gestation. In fetuses over 130 days of gestation, the addition of new nephron units is no longer a factor to explain the increase in fetal GFR but other factors such as increases in surface area for filtration, effective filtration pressure and capillar filtration coefficient may then play an important role. After birth, one can speculate that a decrease in glomerular vascular resistance is a major determinant in the postnatal increase in glomerular perfusion rate and GFR.

Immune Thrombocytopenia and Elemental Mercury Poisoning

Three cases of severe mercury toxicity occurring within a family are reported. Two cases of thrombocytopenia occurred in this family and represent the second such report in the literature of an association between elemental mercury toxicity and thrombocytopenia. Three of the children presented with a combination of dermatologic and neurologic manifestations reminiscent of acrodynia or pink disease. Each of the four children in this family were treated with dimercaptosuccinic acid. The hazard of vacuuming spilled mercury and appropriate clean-up procedures are described.

Renal hemodynamic responses to hypoxemia during development: relationships to circulating vasoactive substances.

ABSTRACT: Chronically catheterized fetal lambs (n = 11, gestational age 111–139 days) and neonatal lambs (n = 20, postnatal age 4–30 days) were studied to explore during development the relationship of renal hemodynamic responses during hypoxemia to plasma epinephrine concentration (E), plasma norepinephrine concentration (NE), plasma arginine vasopressin concentration (AVP), and plasma renin activity (PRA). A low oxygen gas mixture (11.1 ± 0.1% O2) was administered for 30 min to the pregnant ewe or neonatal lamb to induce hypoxemia with maintenance of normal arterial pCO2 and pH. Arterial blood pressure was recorded continuously and renal blood flow (RBF) was determined by the radiolabeled micro-sphere technique. Moderate hypoxemia (pO2 16 ± 2 torr and 33 ± 6 torr in fetus and neonate, respectively) induced increases in E, NE (measured by radioenzymatic assay), and AVP (measured by radioimmunoassay) in both fetus and neonate. PRA (measured by radioimmunoassay) also increased in response to hypoxemia in neonatal lambs. The change in mean arterial pressure with hypoxemia (ΔMAP) was significant in fetuses (ΔMAP 8 ± 14%, p < 0.05) but not in lambs (ΔMAP 1 ± 10%, p > 0.5). Similarly, the change in renal blood flow with hypoxemia (ΔRBF) was significant (ΔRBF-51 ± 24%, p < 0.001) in fetuses but not in neonatal lambs (ΔRBF-9 ± 38%, p > 0.1). These results reflected a change in renal vascular resistance with hypoxemia (ΔRVR) that was significant in fetal lambs (ΔRVR 169 ± 168%, p < 0.01) but not in neonatal lambs (ΔRVR 51 ± 180%, p > 0.2). The relationships of these renal hemodynamic responses to the measured vasoactive substances, and the influence of their interactions to produce these responses, were assessed by response surface regression analysis. The response surface regression model of responses to hypoxemia of E (ΔE), NE (ΔNE), AVP (ΔAVP), and PRA (ΔPRA) to ΔMAP and ΔRVR over the entire development period fit the data well (adjusted R2 0.8427 and 0.8274, respectively). ΔE was the most predictive of the components for both ΔMAP and ΔRVR (F ratio 7.89 and 7.25, respectively). Contour plots of the interaction of AE with postconceptional age and ΔNE demonstrated considerable age dependence of the relationship of ΔE and ΔNE to ΔMAP and ΔRVR during development. The results are consistent with the hypothesis that asynchronous maturation of vascular β-adrenergic (vasodilatory) and α-adrenergic (vasoconstrictor) effector mechanisms occurs throughout the fetal/neonatal period.

Hypoxemia increases renin secretion rate in anesthetized newborn lambs

The response of renin secretion rate (RSR) to acute systemic hypoxemia (mean arterial p02 34±8 torr) was studied in mechanically ventilated, anesthetized newborn lambs 5–10 days of age (n=6). Ventilation of these lambs with room air (normoxemia) was followed by administration of low oxygen inhaled gas mixture (fi02 0.11) which was associated with no change in arterial pC02, pH, mean arterial pressure (MAP), renal blood flow (RBF, measured by electromagnetic flow probe), and calculated renal vascular resistance (RVR). Arterial plasma renin activity (PRAA 4.28±1.73 to 6.46±3.00 ng AI/ml · hr), renal vein plasma renin activity (PRARV, 6.26±3.79 to 11.44±7.11 ng AI/ml · hr) and renin secretion rate (RSR, 19.86±21.70 to 51.32±48.54 units/min · KgBW) increased significantly (p<0.05) in response to hypoxemia. Restoration of normoxemia (arterial p02 100±18 torr) was associated with significant decline in MAP (to 65±14 mmHg) and RBF (to 9.0±2.1 ml/min · KgBW) and further increases in PRAA (to 8.98±3.40 ng AI/ml · hr), PRARV (to 19.04±10.62 ng AI/ml · hr) and RSR (to 88.6±77.6 units/min · KgBW). PRAA correlated strongly with PRARV (r=0.84) and RSR (r=0.60) in these lambs. These results suggest that PRAA, PRARV and RSR increase in response to hypoxemia in anesthetized lambs by a mechanism other than renal arterial baroreceptor stimulation, although this mechanism may be active during recovery from hypoxemia. Furthermore, PRAA closely approximates RSR in newborn lambs under these conditions.

Organ Tissue Blood Flow Responses to Hypoxemia in Lambs: Effect of Angiotensin Converting Enzyme Inhibitor

Summary: Chronically-catheterized lambs (n = 21), 2–38 days of age, were studied to test the hypothesis that the products of angiotensin converting enzyme (ACE) activity are involved in control of baseline arterial pressure and organ tissue blood flow and the redistribution of organ tissue blood flow in response to normocapnic hypoxemia in the maturing lamb. ACE activity was inhibited by administration of captopril [2.5 μg/(kg ± min)], which significantly (P < 0.01) decreased arterial concentrations (mean ± S.D.) of angiotensin-II (from 105.0 ± 33.9 to 67.0 ± 25.9 pg/ml) and aldosterone (from 115.0 ± 105.0 to 53.8 ± 28.6 pg/ml) and inhibited by greater than 90% the vasopressor response to an intravenous bolus of angiotensin-I (1 μg/kg). Baseline mean arterial pressure was significantly (P < 0.01) decreased from 78 ± 8 to 66 ± 10 mmHg) and remained depressed during hypoxemia (67 ± 12 mmHg) and recovery (62 ± 9 mmHg) periods. Baseline heart rate was unchanged by ACE inhibition (from 181 ± 33 to 188 ± 35 beats/min) but increased (P < 0.01) significantly in response to hypoxemia (to 233 ± 52 beats/min). Baseline heart, adrenal, jejunum, ileum, and skeletal muscle tissue blood flow, measured by radiolabeled microspheres, were not significantly (P > 0.05) changed by ACE inhibitor. Baseline liver tissue blood flow increased slightly [from 0.10 ± 0.10 to 0.16 ± 0.12 ml/(min ± g)] but significantly (P < 0.05) during ACE inhibitor treatment, and spleen tissue blood flow decreased significantly [from 2.54 ± 1.03 to 1.31 ± 0.61 ml/(min ± g)]. Normocapnic hypoxemia (Po2 42 ± 6 torr; oxyhemoglobin saturation 50.7 ± 18.0%) for 30 min during ACE inhibition was associated with increased (P < 0.01) heart [from 2.72 ± 1.52 to 8.87 ± 5.78 ml/(min ± g)] and adrenal [from 2.75 ± 1.88 to 6.43 ± 2.82 ml/(min ± g)] tissue blood flow, decreased (P < 0.01) spleen [from 1.31 ± 0.60 to 0.48 ± 0.57 ml/(min·g)] tissue blood flow, and unchanged (P > 0.05) blood flow to jejunum [from 2.51 ± 0.67 to 2.63 ± 2.00 ml/(min ± g)], ileum [from 0.82 ± 0.28 to 0.84 ± 0.42 ml/(min ± g)], liver [from 0.19 ± 0.13 to 0.43 ± 0.41 ml/(min ± g)] and skeletal muscle [from 0.11 ± 0.09 to 0.48 ± 0.57 ml/(min ± g)] tissues. Responses to hypoxemia were similar in control lambs, except that comparisons of the change (Δ) in tissue blood flow in response to hypoxemia in control versus captopril-treated lambs for ileum [Δileum −0.32 ± 0.29 versus 0.03 ± 0.40 ml/(min ± g)] and jejunum [Δjejunum −1.60 ± 2.20 versus 0.60 ± 2.00 ml/(min ± g)] demonstrated a greater fall in blood flow to these tissues in response to hypoxemia in control lambs. Thus, the products of ACE may be important in maintenance of baseline arterial pressure in the maturing animal. Furthermore, these products may be important in splanchnic vasoconstrictive responses to stress such as hypoxemia in the maturing animal.

Indomethacin supresses renal vasodilation in response to local renal hypoxemia

Abstract Acute local renal hypoxemia (renal arterial pO 2 36±10 torr) was produced in anesthetized dogs during fixed volume perfusion of the kidney in situ with blood passed through an extracorporeal oxygen desaturating circuit. Local renal hypoxemia for 20 minutes was associated with a fall in renal perfusion pressure secondary to a decrease in renal vascular resistance. Treatment of these animals with indomethacin, 5 mg per kg intravenously, reversed the fall in renal perfusion pressure and renal vascular resistance in response to local renal hypoxemia. Systemic arterial blood pressure and arterial blood gases remained unchanged throughout these experiments. This study demonstrates that local renal hypoxemia reduces renal vascular resistance. Indomethacin treatment blocks this local renal vascular response to hypoxemia, suggesting that the response may be modulated by prostaglandins.

Tissue Oxygen Delivery in Lambs: Effect of Postnatal Age and Acute Hypoxemia

Organ tissue arterial oxygen delivery in relation to postnatal age and acute hypoxemia (arterial pO2 34 +/- 5 Torr for 30 min) was studied in chronically catheterized, non anesthetized lambs 2-38 days of age. Baseline tissue oxygen delivery to heart and skeletal muscle correlated significantly with postnatal age. Acute hypoxemia induced significantly decreased oxygen delivery to kidney, spleen, ileum, jejunum and skeletal muscle without significant relation to postnatal age. Hypoxemia also induced increased arterial oxygen capacity and hemoglobin concentration which correlated significantly with postnatal age. These results suggest that baseline organ tissue oxygen delivery and response to hypoxemia remain constant during early postnatal maturation. Furthermore, hypoxemia may induce an apparent shift of fluid from the intravascular compartment which is greater in older lambs.

1655 IRON BALANCE IN A DEFEROXAMINE (D) TREATED HEMODIALYSIS PATIENT

To study the route of iron removal by D in an anephric, hemodialyzed, iron-overloaded adolescent we performed iron-balance studies before and after D infusion on 2 separate occasions. Study #1 lasted 5 days and included 2 dialyses after D infusion. Study #2 lasted 4 days and included 1 dialysis after D infusion. Following baseline dialysis, carmen red was given as a stool marker and D was infused (2g IV, over 4 hrs). Carmen red was given again at the end of each study and all stool was collected between the markers. D was infused only once in each study. Dietary iron averaged 7.2 mg per day.Average post p fecal iron in both studies was 22.0 mg/day, but study #2 showed that the majority was excreted during the 2 days following D infusion. Iron removal by dialysis was minimal compared with the fecal route. Our data demonstrate that D effectively removes iron when infused after dialysis and that stool is the principal route of iron removal.

333 EFFECT OF CAPTOPRIL ON POTASSIUM INDUCED ALDOSTERONE SECRETION IN NEWBORN LAMBS

The role of endogenous angiotensin-II (A-II) production in modulation of potassium (K+) induced increase in serum aldosterone concentration (Aldo) was studied in chronically-catheterized newborn lambs 10-14 days of age. Captopril (5 ug/kg/min) was given to one group of lambs (Exp) to block the conversion of angiotensin-I (A-I) to A-II, whereas the control group (C) received only 5% dextrose in water (0.1 ml/min). All lambs received dexamethasone phosphate (0.1 mg/kg/dose) 12 hours and 2 hours prior to potassium infusion (KCl) to suppress adrenocorticotropin (ACTH) secretion. Data are expressed as mean ± SD. Blockade of A-II formation by captopril was documented by 1) at least 90% inhibition of vasopressor response (from 25±8 mmHg pre- to 2±2 mmHg post-captopril) to a bolus of A-I (1 ug/kg) without altering vasopressor response (26±8 mmHg) to A-II (0.5 ug/kg); 2) decrease in baseline serum A-II (from 68.1±41.2 to 46.2±18.5 pg/ml); and 3) increase in baseline plasma renin activity (from 13.7±4.4 to 157±138 ng/ml/hr). KCl (1.80±0.09 mEq/kg) in C increased serum K+ (from 3.8±0.1 to 5.5±0.4 mEq/L, p<0.001) and Aldo (from 22.6±11.8 to 97.3±46.6 pg/ml, p<0.001). KCl (1.77±0.03 mEq/kg) in Exp increased serum K+ (from 3.9±0.4 to 5.7±0.6 mEq/L, p<0.001) in a similar fashion to C, but the increment in Aldo (from 22.7±19.3 to 55.2±61.6 pg/ml, p<0.05) was suppressed relative to C. These data suggest that endogenous A-II is a modulater of K+-induced aldosterone secretion in ACTH suppressed newborn lambs.

THE EFFECT OF ARGININE VASOPRESSIN |[lpar]|AVP|[rpar]| IN MODULATING CARDIOVASCULAR RESPONSE IN HYPOXEMIC |[lpar]|HPX|[rpar]| NEWBORN LAMBS

To evaluate the role of AVP in modulating the hemodynamic response to HPX, chronically catheterized newborn lambs (5-19 days) were studied using a selective antagonist, d(CH2)5Tyr(Me)AVP, to the vasopressor response of AVP. Experimental lambs received a 100 ug bolus infusion of AVP-inhibitor prior to the onset of HPX; control lambs received the vehicle only. Using microspheres, cardiac output (C.O.) and organ flow were measured in both groups.x ± SEM, * for p<0.05. HPX resulted in a similar increase in C.O. and organ flow to critical organs (heart, brain and adrenal) in both groups of animals. In addition, vasoactive substances (epinephrine, norepinephrine, and angiotensin II) were measured and increased similarly in both groups. Thus, AVP does not appear to play a critical role in the cardiovascular response to HPX in newborn lambs.