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C W Leffler

Publications and source records attributed to C W Leffler.

At least 163 records · Page 9Linked to original sources
PubMed1987

Prostanoids and pial arteriolar diameter in hypotensive newborn pigs.

Effects of hypotensive hemorrhage on pial arteriolar diameter and cortical subarachnoid fluid prostanoid concentrations were investigated in newborn pigs. Chloralose-anesthetized piglets were equipped with closed cranial windows over the parietal cortex for observation of pial arterioles and collection of cerebrospinal fluid (CSF) passing over the cerebral surface (cortical subarachnoid CSF). Prostanoids in the CSF were determined by radioimmunoassay. Measurements of pial arterioles were made during normotension (63 +/- 4 mmHg) and hypotension (28 +/- 3 mmHg). Hypotension caused pial arteriolar diameters to increase from 162 +/- 22 to 193 +/- 22 microns. During normotension, the cortical subarachnoid prostanoid concentrations were (in ng/ml) prostaglandin E2 (PGE2) 2.6 +/- 0.7, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) 1.7 +/- 0.4, thromboxane B2 (TXB2) 0.25 +/- 0.02. Hypotension caused 6-keto-PGF1 alpha to increase 245 +/- 104% and PGE2 to increase 132 +/- 38%. TXB2 increased slightly (37 +/- 21%). Topical application of PGE2 and prostacyclin caused marked dilation of pial arterioles. Treatment of hypotensive newborn pigs with indomethacin caused constriction of pial arterioles to diameters not significantly different from the normotensive diameters. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow during hypotension in piglets.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Hypothermia reduces cerebral metabolic rate and cerebral blood flow in newborn pigs.

We examined effects of hypothermia on cerebral metabolic rate and cerebral blood flow in anesthetized, newborn pigs (1-4 days old). Cerebral blood flow (CBF) was determined with 15-micronS radioactive microspheres. Regional CBF ranged from 44 to 66 ml . min-1.100 g-1, and cerebral metabolic rate was 1.94 +/- 0.23 ml O2.100 g-1 . min-1 during normothermia (39 degrees C). Reduction of rectal temperature to 34-35 degrees C decreased CBF and cerebral metabolic rate 40-50%. In another group of piglets, we examined responsiveness of the cerebral circulation to arterial hypercapnia during hypothermia. Although absolute values for normocapnic and hypercapnic CBF were reduced by hypothermia and absolute values for normocapnic and hypercapnic cerebrovascular resistance were increased, the percentage changes from control in these variables during hypercapnia were similar during normothermia and hypothermia. In another group of animals that were maintained normothermic and exposed to two episodes of hypercapnia, there was no attenuation of cerebrovascular dilatation during the second episode. We conclude that hypothermia reduces CBF secondarily to a decrease in cerebral metabolic rate and that percent dilator responsiveness to arterial hypercapnia is unaltered when body temperature is reduced.

Animals↗
PubMed1987

Vasopressin responses to asphyxia and hemorrhage in newborn pigs.

Vasopressin may be important in maintenance of arterial pressure and redistribution of cardiac output in hypotensive and asphyxiated newborns. We used chronically instrumented, unanesthetized, 4-day-old pigs to investigate the effects of hypotensive hemorrhage and asphyxia on plasma vasopressin concentration and to determine the effects of cyclooxygenase inhibition on these responses. Asphyxia [arterial O2 partial pressure (PaO2) = 40-50 Torr, arterial CO2 partial pressure (PaCO2) = 60-80 Torr) increases plasma lysine vasopressin (LVP) from 2.2 +/- 0.8 to 52.4 +/- 15.0 microU/ml. Neither the baseline nor stimulated plasma LVP was affected by indomethacin (5 mg/kg) or meclofenamate (5 mg/kg). Hemorrhage (30 ml/kg) increased plasma LVP from 2.8 +/- 0.8 to 163.4 +/- 28.1 (20 min) and 135.1 +/- 18.5 microU/ml (60 min). The effects of vehicle and indomethacin (5 mg/kg) 20 min after hemorrhage on plasma LVP 60 min after hemorrhage were not different. Changes in plasma vasopressin caused by asphyxia and hemorrhage in the unanesthetized newborn pig are similar to the responses observed in adults of other species. This study does not suggest that prostanoids are involved in these responses in newborn pigs.

Animals↗
PubMed1987

Adrenergic mediation of vasopressin secretion in newborn pigs.

Effects of inhibition of alpha 1-(prazosin) and alpha 2-(yohimbine) adrenoreceptors on plasma lysine vasopressin concentration during normotension and hemorrhagic hypotension were studied in unanesthetized newborn pigs. During the normotensive period, treatment with prazosin and yohimbine both increased plasma lysine vasopressin concentration (vehicle = 3.4 +/- 1.21 microU/ml; prazosin = 35.8 +/- 10.8 microU/ml; and yohimbine = 20.1 +/- 9.5 microU/ml). Prazosin caused a decline in arterial pressure (vehicle = 60 +/- 6 mmHg; prazosin = 49 +/- 5 mmHg), which may account for the increase in plasma lysine vasopressin concentration, whereas yohimbine increased arterial pressure (73 +/- 3 mmHg). On hemorrhage to equivalent arterial pressure, plasma lysine vasopressin concentration increased to similar levels in vehicle- (110.3 +/- 28.7 microU/ml) and prazosin-treated (92.6 +/- 14.2 microU/ml) piglets. In contrast, on hemorrhage of yohimbine-treated piglets, the increase in plasma lysine vasopressin concentration was augmented remarkably (527.0 +/- 103.2 microU/ml) in comparison to the other groups. We conclude that, in unanesthetized newborn pigs, treatment with the alpha 2-adrenoreceptor antagonist yohimbine increased plasma lysine vasopressin concentration and markedly accentuated the vasopressin response to hemorrhage. An alpha 2-adrenergic receptor-mediated mechanism appears to be an important inhibitory component in the vasopressin secretory system of the newborn pig.

Animals↗
PubMed1987

Postjunctional alpha 2-adrenoceptors in pial arteries of anesthetized newborn pigs.

The purpose of this study was to characterize the nature of the postjunctional alpha-adrenoceptors (alpha 1 versus alpha 2) in the cerebral circulation of anesthetized newborn pigs. Diameters of pial arteries in anesthetized piglets, 1-6 days old, were examined using a 'closed' cranial window. We examined sympathetically mediated constriction of pial arteries in the presence and absence of alpha 1- (prazosin) or alpha 2- (yohimbine) adrenoceptor antagonists (1 mg/kg i.v.). Initial experiments demonstrated that prazosin and yohimbine attenuated constriction of pial arteries during topical administration to the pial surface of phenylephrine and clonidine, respectively. In one group, electrical stimulation of the ipsilateral superior cervical ganglion reduced pial arterial diameter from 176 +/- 26 (mean +/- SEM) to 153 +/- 24 microns, and this response was unaffected by prior administration of prazosin. In a second group, sympathetic nerve stimulation reduced pial arterial diameter from 175 +/- 23 to 148 +/- 19 microns, and this response was abolished by prior administration of yohimbine. After administration of yohimbine, pial arteries still constricted in response to topical phenylephrine and arterial hypertension. We conclude that sympathetic nerve stimulation in anesthetized newborn pigs constricts pial arteries via alpha 2-adrenoceptors.

Animals↗
PubMed1987

Effect of therapeutic dose of indomethacin on the cerebral circulation of newborn pigs.

The effects of treatment with 0.2 mg/kg of indomethacin on the cerebral blood flow and cerebral oxygen consumption of hypotensive, unanesthetized, newborn pigs were investigated. Hypotension was induced by hemorrhage (30 ml/kg) which reduced mean arterial pressure from 60 to 34 mm Hg. The decline in cerebral vascular resistance that occurred with hemorrhage allowed blood flow to all brain regions and cerebral oxygen consumption to continue unchanged. Treatment with 0.2 mg of indomethacin decreased plasma 6-keto-prostaglandin F1 alpha markedly and caused a modest increase in cerebral vascular resistance from 0.75 +/- 0.07 to 0.85 +/- 0.02 mm Hg X 100 g X min/ml at 40 min posttreatment. As a result, blood flow throughout the brain fell about 20%. Similarly, cerebral oxygen consumption declined from 2.88 +/- 0.13 to 2.03 +/- 0.21 ml O2/100 g X min following treatment of hypotensive piglets with 0.2 mg/kg of indomethacin. However, all piglets were conscious 40 min after treatment. We conclude that, although 0.2 mg/kg of indomethacin affects cerebral hemodynamics of hypotensive piglets, the effects are very modest in comparison to large increases in cerebral vascular resistance, decreases in cerebral blood flow and oxygen consumption, and coma that follow treatment of hypotensive piglets with 5 mg/kg of indomethacin.

Animals↗
PubMed1987

Indomethacin does not alter the circulating catecholamine response to asphyxia in the neonatal piglet.

The response of circulating catecholamines to asphyxia in unanesthetized, spontaneously breathing neonatal piglets was measured before and after treatment with indomethacin. Prior to treatment with indomethacin, baseline levels [geometric mean, pg/ml (95% confidence limits)] of D, E, and N were 162 (99-266), 174 (52-579), and 380 (286-506), respectively. Inhalation of 10% O2/9% CO2 for 20 min caused significant increases in arterial levels of all three catecholamines to 389 (230-659, 1514 (993-2306), and 3802 (2731-5293), respectively. Treatment with indomethacin (5 mg/kg, intravenous) did not significantly alter either baseline levels of the catecholamines or the levels after 20 min of the asphyxiating gas. In time control piglets, baseline levels and the response to asphyxia were similar before and after placebo. These results suggest that the circulating catecholamine response to asphyxia of the neonatal piglet is independent of the prostaglandin system.

Animals↗
PubMed1986

Effects of indomethacin on cardiac output distribution in normal and asphyxiated piglets.

We determined the effect of breathing 9% CO2/10% O2/81% N2 (asphyxia) on cardiac output distribution (microspheres) in 4-5 day old unanesthetized, chronically instrumented piglets prior to and following intravenous indomethacin administration. Thirty minutes of asphyxia caused PaCO2 to increase from 35 +/- 2 mmHg to 66 +/- 2 mmHg, PaO2 to decrease from 73 +/- 4 mmHg to 41 +/- 1 mmHg, and pH to decrease from 7.52 +/- 0.05 to 7.21 +/- 0.07. Arterial pressure was increased slightly but cardiac output was not changed significantly. Asphyxia caused blood flow to the brain, diaphragm, liver, heart, and adrenal glands to increase while causing decreases in blood flow to the skin, small intestine, and colon. Blood flows to the stomach and kidneys tended to decrease, but the changes were not significant. Treatment with indomethacin during asphyxia did not alter arterial pressure or cardiac output but decreased cerebral blood flow to the preasphyxiated level and decreased adrenal blood flow about 20%. Indomethacin did not alter blood flow to any other systemic organ. At this time the piglet was allowed to breathe air for 2.5 hr undisturbed. Two and a half hours after indomethacin administration, blood flows to all organs returned to the preasphyxia control levels with the exception of cerebral blood flow which was reduced (93 +/- 13 to 65 +/- 7 ml/100 g X min). Three hours after indomethacin administration, the cerebral hyperemia caused by asphyxia was less (134 +/- 17 ml/100 g X min) than prior to indomethacin (221 +/- 15 ml/100 g X min). Indomethacin did not alter the asphyxia-induced changes to any other systemic organ.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Leukotrienes increase levels of prostanoids in cerebrospinal fluid in piglets.

We investigated effects of exogenous leukotrienes (C4, D4, or E4) on levels of prostanoids in cerebrospinal fluid in newborn pigs (1-5 days). A "closed" cranial window was placed over the parietal cortex. Pial arterial diameter was measured with a microscope and electronic micrometer system. Levels in cerebrospinal fluid (CSF) of 6-keto-Prostaglandin F1 alpha (6-keto-PGF1 alpha), Thromboxane B2 (TXB2), and Prostaglandin E2 (PGE2) were measured by radioimmunoassay. Topical application of leukotrienes C4, D4, or E4 (5,000 ng/ml) similarly constricted pial arteries by 15 +/- 2% (n = 14) (mean +/- SEM). In addition, leukotrienes increased levels of 6-keto-PGF1 alpha from 806 +/- 136 to 1,612 +/- 304 pg/ml (n = 13), TXB2 from 161 +/- 31 to 392 +/- 81 pg/ml (n = 10), and PGE2 from 2,271 +/- 342 to 4,636 +/- 740 pg/ml (n = 13). Each type of leukotriene had similar effects on prostanoid synthesis. In other experiments (n = 5), we found that 2.0 ng/ml PGE2 in CSF dilated pial arteries by 24 +/- 8% and that 1.0 ng/ml PGI2 dilated pial arteries by 15 +/- 6%. These results indicate that leukotrienes are able to increase levels of prostanoids in cerebral cortex.

Animals↗
PubMed1986

Effects of sodium chloride on pregnant sheep with reduced uteroplacental perfusion pressure.

This study investigated the effects of NaCl supplementation (5 mEq/kg/day) on the arterial pressure of pregnant and nonpregnant sheep with and without reduction of uteroplacental perfusion pressure. In pregnant sheep receiving NaCl supplementation during the third trimester, reduction of aortic pressure caudal to the kidneys to 65% of the upstream pressure (occlusion) caused a progressive increase in mean arterial pressure from 89 +/- 3 to 110 +/- 3 mm Hg over 2 weeks. Occlusion was accompanied by a decrease in urine flow. Six of seven sheep died or were killed because of severe respiratory distress. No abnormalities were detected in nonpregnant sheep or pregnant sheep receiving NaCl supplementation only. Pregnant sheep that were occluded but received no supplementary NaCl did not become hypertensive but aborted about 2 weeks after occlusion. These results indicate that reduction of uteroplacental perfusion pressure causes hypertension in NaCl-supplemented pregnant sheep but not in sheep receiving a normal, low sodium diet.

Animals↗
PubMed1986

Maintenance of cerebral circulation during hemorrhagic hypotension in newborn pigs: role of prostanoids.

The possibility that the prostanoid system contributes to the capability of the newborn piglet to maintain cerebral blood flow and cerebral metabolic rate during hypotension was investigated. The effect of hemorrhage on net (arterial-to-venous) cerebral prostacyclin production and the effects of indomethacin on cerebral hemodynamic response to hemorrhage and on the cerebral oxygen utilization following hemorrhage were determined in chronically instrumented, unanesthetized newborn pigs. Hemorrhage decreased arterial pressure about 35% but did not affect cerebral blood flow or cerebral O2 consumption. Hemorrhage was accompanied by an increase in net cerebral 6-keto-PGF1 alpha production from 4.0 +/- 1.1 to 15.3 +/- 4.9 ng/100g X min (mean +/- SEM). Indomethacin treatment of piglets following hemorrhage inhibited the net cerebral production of 6-keto-PGF1 alpha and caused a decrease in blood flow (approximately equal to 40%) to all brain regions within 20 minutes. The decrease in cerebral blood flow was the result of an increase in cerebral vascular resistance of 57 and 180%, 20 and 40 minutes post treatment, respectively. Cerebral O2 consumption was reduced from 2.5 +/- 0.3 ml/100 g X min to 1.5 +/- 0.3 ml/100 g X min 20 minutes following treatment of hemorrhaged piglets with indomethacin and to 1.1 +/- 0.3 ml/100 g X min 40 minutes after treatment. Six of 8 piglets for whom the data were recorded that were administered indomethacin following hemorrhage became comatose with cerebral O2 consumption of 0.4 +/- 0.1 ml O2/100 g X min by 40 minutes after treatment. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow and cerebral metabolic rate during hypotension in the newborn.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Effects of leukotrienes C4, D4, and E4 on cerebral arteries of newborn pigs.

We examined effects of topical application of leukotrienes (LT) C4, D4, and E4 on cerebral arteries of newborn pigs in vivo. Diameters of pial arteries were measured using a cranial window method during application of artificial cerebrospinal fluid without drug, and cerebrospinal fluid containing LT C4, D4, and E4 (1, 10, 100, 1000, and 5000 ng/ml). Control diameters ranged from 51-345 micron. All three LT constricted pial arteries in a dose-dependent manner, with a threshold for detectable response at 10 ng/ml (7 +/- 3% for LTD4). The magnitude of constrictor response at the highest dose was 23 +/- 3% for LTC4, 17 +/- 2% for LTD4, and 17 +/- 3% for LTE4. The specific receptor antagonist FPL 55712 blocked the constrictor response to LT. We conclude that LT are potent constrictors of cerebral arteries in newborn pigs.

Animals↗
PubMed1985

Gastroduodenal ulceration in rabbits producing antibodies to prostaglandins.

The consistent occurrence of gastric and duodenal ulcers was observed in laboratory rabbits used for production of high-titer plasma antibody to 6-keto PGF1 alpha and PGE2. Perforations developed in 7 of 10 animals, usually just distal to the pyloroduodenal junction. The remaining rabbits showed gross and/or microscopic evidence of imperforate ulcers and erosions. These lesions appeared to be direct pathologic complications of an immune response directed against prostaglandins since animals immunized against met-enkephalin with similar methods had no ulcers.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Effects of high frequency oscillatory ventilation compared to conventional ventilation upon pulmonary vascular prostanoid production in neonatal piglets.

In order to investigate the possibility that high-frequency oscillatory ventilation (HFO) might preferentially stimulate intrapulmonary prostacyclin (PGI2) synthesis thereby decreasing pulmonary vascular smooth muscle tone, we determined pulmonary prostacyclin and thromboxane production in neonatal piglets ventilated by conventional means and by HFO (8 Hz). There was no detectable release of prostacyclin or thromboxane into blood passing through the lungs (i.e., pulmonary arterial concentrations were greater than aortic concentrations) during ventilation by conventional means or during HFO. Furthermore, there were no differences between the two modes of ventilation in cardiac output, systemic or pulmonary vascular resistance, or pulmonary vascular response to hypoxia/hypercapnia. We conclude that HFO does not stimulate pulmonary prostacyclin production and does not affect pulmonary vascular resistance or the pulmonary vasoconstriction associated with alveolar hypoxia/hypercapnia when compared to conventional ventilation in anesthetized newborn piglets.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Changes in plasma arginine vasopressin during transition from fetus to newborn following minimal trauma delivery of lambs and goats.

Vasopressin in umbilical arterial and venous blood is high at delivery and may be important in the maintenance of arterial pressure and absorption of lung liquid. We used chronically instrumented near-term fetal lambs and goats to investigate the changes in plasma vasopressin that occur during perinatal cardiovascular transition following cesarean section without labor. Plasma arginine vasopressin was more than 5 times greater 15 min following birth than immediately prior to clamping the umbilicus, and it fell progressively over the ensuing 2-5 h to levels not significantly different from before birth. Fifteen min after delivery, neither arterial pressure, blood gases, nor pH appeared to account for the increase.

Animals↗
PubMed1985

Prostanoids in cortical subarachnoid cerebrospinal fluid and pial arterial diameter in newborn pigs.

These studies were designed to investigate the relationship between cerebral prostanoid synthesis and pial arterial caliber in chloralose-anesthetized newborn pigs with normal blood gases and pH and during combined arterial hypoxia and hypercapnia. Piglets less than 5 days old were equipped with closed cranial windows to allow direct observation of pial vessels, application of prostaglandin E2, and sampling of cortical subarachnoid cerebrospinal fluid. We found that prostanoids accumulate in cerebrospinal fluid on the cortical surface. The only prostanoid detected in arterial blood was 6-keto-prostaglandin F1 alpha [442 +/- 74 pg/ml (radioimmunoassay)]. Only small quantities of 6-keto-prostaglandin F1 alpha (214 +/- 53 pg/ml) and thromboxane B2 (122 +/- 18 pg/ml) were found in cerebrospinal fluid from the cisterna magna. Higher concentrations of 6-keto-prostaglandin F1 alpha (1056 +/- 159 pg/ml), thromboxane B2 (229 +/- 64 pg/ml), and prostaglandin E2 (4235 +/- 269 pg/ml) were found in cortical subarachnoid fluid. In contrast to arterial and cisternal concentrations, the concentrations of 6-keto-prostaglandin F1 alpha, thromboxane B2, and prostaglandin E2 in cortical subarachnoid fluid were increased reversibly by ventilation with 9% carbon dioxide, 10% oxygen, (6-keto-prostaglandin F1 alpha, 5436 +/- 1576 pg/ml; thromboxane B2, 694 +/- 122 pg/ml; and, prostaglandin E2, 12,455 +/- 3688 pg/ml). Further, pial arteries dilated in response to topical application of prostaglandin E2 at the concentration that was found in cortical subarachnoid fluid during combined hypoxia and hypercapnia. Systemic administration of indomethacin trihydrate (5 mg/kg) markedly reduced cortical subarachnoid fluid prostanoid concentrations and attenuated the pial artery vasodilation induced by combined hypoxia and hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗