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Biomedical subjects

C A Nankervis

Publications and source records attributed to C A Nankervis.

11 recordsLinked to original sources
PubMed2006

The effects of indomethacin tocolysis on the postnatal response of the ductus arteriosus to indomethacin in extremely low birth weight infants.

BACKGROUND: Antenal indomethacin reportedly decreases the responses of a symptomatic patent ductus arteriosus (sPDA) to postnatal indomethacin treatment. Whether a similar exposure affects the responses to indomethacin prophylaxis is unknown. OBJECTIVE: To evaluate the clinical responsiveness of ductus arteriosus to indomethacin prophylaxis and to the treatment of sPDA in extremely low birth weight (ELBW) infants following indomethacin tocolysis. METHODS: Retrospective cohort study of 58 ELBW infants whose mothers received indomethacin tocolysis (study) and 58 ELBW infants whose mothers did not (controls), matched by gender, gestational age (GA), birth weight and postnatal sPDA management (prophylaxis or early treatment). RESULTS: Indomethacin was used as a tocolytic at a median dose of 250 mg, for a duration of 2 days, and ending 1 day before delivery. Study and control mothers were comparable in demographics, antenatal steroid use, cesarean delivery, but were different in the incidence of preeclampsia and preterm labor. Study and control infants were similar in birth weight, GA, indomethacin prophylaxis, early sPDA treatment, mortality, necrotizing enterocolitis, severe intraventricular hemorrhage and stage 3-5 retinopathy of prematurity. Seventeen of 43 study and 16 of 43 control infants who received indomethacin prophylaxis developed sPDA and were combined with early treatment sPDA infants (15 to each group). Two of 32 study and two of 31 control infants underwent surgical ligation whereas the remaining were treated with indomethacin. Sixteen of 30 (53%) and 13 of 29 (45%) were successfully treated and did not require ligation. Study infants were divided according to their mothers' indomethacin total dose (28 infants received 225 mg). Both subgroups were demographically and clinically comparable and their response to indomethacin prophylaxis and treatment were similar. CONCLUSION: In ELBW infants, exposure to indomethacin tocolysis does not affect the clinical responsiveness of the ductus arteriosus to prophylaxis or that of the sPDA to indomethacin treatment.

Ductus Arteriosus↗
PubMed2001

Age-dependent changes in the postnatal intestinal microcirculation.

Significant changes occur in intestinal hemodynamics during the transition from fetal to newborn life and then again during the first postnatal month. Most importantly, basal vascular resistance substantially decreases following birth. It then decreases further between postnatal days 1 and 3, plateaus, and then begins a slow, progressive increase between postnatal days 12 and 30. The basal rate of intestinal blood flow mirrors the changes in vascular resistance in an inverse manner. The postnatal changes in vascular resistance appear to be mediated, in large part, by an increase in the constitutive and stimulated production of nitric oxide. Most importantly, the diameter of terminal mesenteric arteries (150-300 microm diameter) in newborn (i.e., 1 day old) swine is determined by three intrinsic vascular control systems: endothelial production of nitric oxide and endothelin, and the inherent myogenic response of vascular smooth muscle. In contrast, these vessels in older subjects (i.e., 35 days old) are primarily passive in nature and fail to demonstrate significant diameter change in response to blockade of endogenous nitric oxide production or endothelin receptors, or applied perturbations of pressure or flow rate. The circulatory physiology of the perinatal and newborn intestine is exceptional when compared to the adult condition inasmuch as several hemodynamic variables change quite dramatically between fetal and neonatal life and during the first postnatal month. The unique hemodynamic conditions that characterize the perinatal and newborn intestine appear to be part of the overall physiological transition that occurs as the fetus, once born, replaces the placenta with his gastrointestinal tract to obtain nutrition. The goal of this review is to describe the circulatory physiology of the perinatal and newborn intestine, with a particular emphasis on those portions of the intestinal microcirculation that have thus far been studied. First, however, it is important to discuss the age-dependent changes that occur within the intestinal circulation during perinatal and early newborn life.

Age Factors↗
PubMed2001

Endothelin ET(A) and ET(B) receptors in postnatal intestine.

We aimed to characterize endothelin (ET) receptors in the swine intestinal vasculature and to determine ischemia-reperfusion (I/R) effects on these receptors. Saturation and competitive binding assays were performed on mesenteric artery protein membranes from 1- and 40-day-old animals, both control and those subjected to 1 h of partial ischemia followed by 6 h of reperfusion in vivo. Scatchard analysis of saturation binding with (125)I-labeled ET-1 in membranes from endothelium-denuded (E(-)) vessels revealed that the maximum number of binding sites was greater in younger animals. Competitive (125)I-ET-1 binding was significant for a one-site model with ET-1, ET-3, and sarafotoxin S6c (S6c) in membranes from endothelium-intact (E(+)) and E(-) vessels in both age groups. The maximum number of ET-1 binding sites was significantly greater in younger animals. In the presence of the ET(A) receptor antagonist BQ-123, competitive (125)I-ET-1 binding was significant for a one-site model with ET-1 and S6c in membranes from E(+) vessels in both age groups. The maximum number of ET-1 binding sites was significantly greater in younger animals. After I/R, the maximum number of ET-1 binding sites was unchanged. In the presence of BQ-123, specific binding by ET-1 and S6c was eliminated in both age groups after I/R. These results suggest that both ET receptor populations are expressed to a greater degree in younger animals and I/R significantly affects the ET(B) receptor.

Animals↗
PubMed2001

Determinants of terminal mesenteric artery resistance during the first postnatal month.

Experiments were conducted to delineate the vascular effector systems that contribute to setting mesenteric vascular tone in swine during the first postnatal month. Terminal mesenteric arteries (TMA), which function as resistance vessels, were studied in vitro with a microvascular perfusion system allowing independent pressure and flow manipulation. When pressure was varied 0-100 mmHg in the absence of flow, TMA from 1-day-old animals demonstrated myogenic vasoconstriction, whereas TMA from 40-day-old animals did not. In 1- but not 40-day-old TMA, the endothelin A (ET(A)) receptor antagonist BQ-610 shifted the pressure-diameter curve upward, whereas the ET(B) receptor antagonist BQ-788 and the L-arginine analog N(G)-monomethyl-L-arginine (L-NMMA) shifted the curve downward; in all instances, myogenic vasoconstriction was preserved. Flow eliminated myogenic vasoconstriction in 1-day-old TMA, i.e., diameter increased as a function of pressure. The effect of BQ-610 was lost under flow conditions; however, BQ-788 and N-acyl-L-Trp-3,5-bis-(trifluoromethyl) benzyl ester, an antagonist specific to the substance P neurokinin-1 (NK(1)) receptor, shifted the pressure-diameter curve downward in the presence of flow, whereas L-NMMA restored myogenic vasoconstriction. Adding flow had no effect on the pressure-diameter relationship in 40-day-old TMA. Other blocking agents, including prazosin, losartan, indomethacin, and charybdotoxin, had no effect on the pressure-diameter relationship in either age group under flow or no-flow conditions. Constitutive production of nitric oxide (NO) and endothelin-1 participates in setting resistance in 1-day-old TMA, and important stimulants to NO production include flow and activation of ET(B) and NK(1) receptors. In contrast, 40-day-old TMA act as passive conduits in which the elastic properties of the vessel are the primary determinant of diameter.

Aging↗
PubMed2000

Role of endothelin-1 in regulation of the postnatal intestinal circulation.

Newborn intestine is uniquely prone to vasoconstriction in response to a wide variety of perturbations. To test the hypothesis that endothelin (ET)-1 is an important factor in this process, we determined the effects of exogenous ET-1 administration and blockade of endogenous ET-1 in vivo and in vitro in 3- and 35-day-old swine. Intramesenteric artery administration of exogenous ET-1 to vascularly isolated in vivo gut loops (10(-9) M/kg bolus) caused vasoconstriction and reduced gut O(2) uptake similarly in these age groups. Selective blockade of ET(A) or ET(B) receptors with BQ-610 or BQ-788, respectively, in vascularly isolated in vivo gut loops had no effect on gut vascular resistance or O(2) uptake in either age group; within in vitro gut loops, BQ-610 significantly increased vasoconstriction when perfusion pressure was reduced below baseline, but only in 3-day-old animals; i.e., it impaired the autoregulatory response to perfusion pressure reduction. Exogenous ET-1 significantly decreased capillary perfusion within in vitro gut loops, as evidenced by a decrease in capillary filtration coefficient, but only in 3-day-old animals; furthermore, blockade of endogenous ET-1 activity with BQ-610 significantly enhanced capillary filtration coefficient in 3-day-old animals and increased O(2) extraction ratio. ET-1 did not depress intestinal metabolic rate, as evidenced by its effect on the O(2) uptake-blood flow relationship; it did compromise tissue oxygenation because of its effects on intestinal O(2) transport. ET-1 concentration in mesenteric venous effluent exceeded arterial concentration, but only in 3-day-old intestine, suggesting production of ET-1 by newborn intestine. We conclude that ET-1 exerts an age-dependent effect on intestinal hemodynamics in postnatal intestine, having a greater impact in 3- than in 35-day-old intestine.

Animals↗
PubMed2000

Endothelin-mediated vasoconstriction in postischemic newborn intestine.

We previously suggested that the profound, sustained vasoconstriction noted in 3-day-old swine intestine after a moderate episode of ischemia-reperfusion (I/R) reflects the unmasking of underlying constrictor tone consequent to a loss of endothelium-derived nitric oxide (NO). In this study, we sought to determine whether endothelin-1 (ET-1) was the unmasked constrictor and whether selective loss of endothelial ET(B) receptors, which mediate NO-based vasodilation, participated in the hemodynamic consequences of I/R in newborn intestine. Studies were performed in innervated, autoperfused intestinal loops in 3- and 35-day-old swine. Selective blockade of ET(A) receptors with BQ-610 had no effect on hemodynamics under control conditions; however, when administered before and during I/R, BQ-610 significantly attenuated the post-I/R vasoconstriction and reduction in arteriovenous O(2) difference in the younger group. In 3-day-old intestine, reduction of intestinal O(2) uptake to a level similar to that noted after I/R by lowering tissue temperature had no effect on the response to BQ-610 or ET-1, indicating that the change in response to BQ-610 noted after I/R was not simply consequent to the reduction in tissue O(2) demand. In studies in mesenteric artery rings suspended in myographs, we observed a leftward shift in the dose-response curve for ET-1 after selective blockade of ET(B) receptors with BQ-788 in 3- but not 35-day-old swine. Rings exposed to I/R in vivo behaved in a manner similar to control rings treated with BQ-788 or endothelium-denuded non-I/R rings.

Animals↗
PubMed1998

Developmental differences in response of mesenteric artery to acute hypoxia in vitro.

Studies were conducted to determine if the response of in vitro mesenteric artery from 3- and 35-day-old swine to acute hypoxia was age dependent. Isometric tension developed by mesenteric artery rings was measured using a standard myograph apparatus. When the buffer aeration gas was changed from 95% O2-5% CO2 to 95% N2-5% CO2, phenylephrine-precontracted rings from both age groups consistently demonstrated a triphasic response, consisting of, in order, an initial, brief dilation, a sharp contraction, and a sustained loss of tone. The only portion of the triphasic response that was age dependent was the constrictor response, hypoxic vasoconstriction (HVC), which was significantly greater in rings from younger animals. HVC appeared to be mediated by a hypoxia-induced loss of constitutive nitric oxide production. Thus HVC was eliminated by endothelial removal, significantly attenuated by pretreatment with NG-monomethyl-L-arginine (L-NMMA), but not with NG-monomethyl-D-arginine, restored by coadministration of L-arginine, and accentuated by pretreatment with superoxide dismutase. Blockade of endothelin A receptors with BQ-610 or inhibition of cyclooxygenase or lipoxygenase activities with indomethacin or phenidone had no effect on HVC in either group. HVC appeared to be dependent on reduction in PO2, not on reduced ATP secondary to hypoxia, as it did not occur in rings administered 2,4-dinitrophenol, an agent that uncouples oxidative phosphorylation. The magnitude of HVC, which appears to be mediated by hypoxia-induced supression of NO production, is greater in mesenteric artery from 3-day-old swine than from 35-day-old swine.

2,4-Dinitrophenol↗
PubMed1995

Role of nitric oxide in regulation of vascular resistance in postnatal intestine.

Studies were conducted to determine whether endothelial production of nitric oxide (NO) participates in the regulation of vascular resistance in postnatal swine intestine. In vivo, intra-arterial infusion of the arginine analogue NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) increased intestinal vascular resistance 34% in 3-day-old animals and 9% in 35-day-old animals (P < 0.01); similar findings were noted during infusion of 10(-3) M L-NMMA. Mechanical augmentation of gut flow rate induced intestinal vasodilation in both age groups; L-NMMA eliminated this flow-induced dilation in intestine of 3- but not 35-day-old animals. In vitro, precontracted mesenteric artery rings from both age groups relaxed to a similar extent in response to the endothelium-independent nitrovasodilator sodium nitroprusside (SNP) and the calcium ionophore A-23187; the effect of A-23187, but not SNP, was eliminated by mechanical disruption of the endothelium. Acetylcholine (ACh) and substance P (SP), agents with vascular effects that are secondary to receptor-mediated activation of NO, caused greater relaxation of rings from younger than from older animals, and this effect was attenuated by L-NMMA or methylene blue. Unstimulated accumulation of guanosine 3',5'-cyclic monophosphate (cGMP) occurred to a similar extent in vessel segments from both groups. ACh and SP increased cGMP accumulation in segments from 3- but not from 35-day-old animals. We conclude that the NO-cGMP axis participates to a greater extent in regulation of intestinal vascular resistance in 3- than in 35-day-old swine.

Aging↗
PubMed1994

The role of the circulation in the pathogenesis of necrotizing enterocolitis.

Early descriptions of necrotizing enterocolitis (NEC) proposed gut ischemia as a primary factor in pathogenesis. Subsequent laboratory and clinical investigations have failed to support these theories, relegating most to positions of historical significance. Presently, the role of the circulation in the pathogenesis of NEC is unclear; however, several lines of ongoing investigation have begun to provide novel insight into the means by which circulatory aberration may initiate or contribute to the development of bowel necrosis.

Animals↗
PubMed1993

Effects of ischemia and reperfusion on intrinsic vascular regulation in the postnatal intestinal circulation.

The purpose of these experiments was to determine the effect of 1 h of total ischemia followed by 2 h of reperfusion on intrinsic vascular regulation within intestine from 3- and 35-d-old swine. Intrinsic vascular regulation was defined as the ability of in vitro segments of small intestine to bring about adjustments of blood flow and the arteriovenous O2 content difference across the intestinal segment of sufficient magnitude to preserve tissue O2 uptake in response to a 35% reduction in arterial perfusion pressure. This response was elicited before (control conditions) and after ischemia-reperfusion (post-I/R). In older subjects, the efficacy of blood flow regulation was attenuated post-I/R, insofar as blood flow fell in response to pressure reduction. However, this group demonstrated a rise in arteriovenous content difference after pressure reduction under control and post-I/R conditions that were of sufficient magnitude to preserve tissue O2 uptake. In younger subjects, blood flow regulation was absent under control conditions and post-I/R. The arteriovenous O2 content difference increased in response to pressure reduction under control conditions but failed to do so post-I/R; consequently, tissue oxygenation decreased in response to arterial pressure reduction post-I/R in 3-d-old intestine. We conclude that ischemia-reperfusion affects intrinsic vascular regulation in postnatal intestine and that this effect is age-dependent. Intestine from older subjects maintains the intrinsic capacity to preserve tissue oxygenation in response to a hypotensive challenge despite the insult of ischemia-reperfusion, whereas intestine from younger subjects does not maintain this capacity.

Animals↗