Philip T Nowicki

Newborn intestinal circulation: Physiology and pathophysiology

The physiologic characteristics of the newborn intestinal circulation are unique when compared with the adult condition. Most important, intestinal vascular resistance across newborn intestine is exceptionally low and this transient reduction is mediated by an increased constitutive and stimulated production of NO. The low vascular resistance characteristic of newborn intestine alters the capacity of this vasculature to respond to systemic circulatory perturbations, such as hypotension and arterial hypoxemia. The essential role of endothelial production of NO in maintaining newborn intestinal hemodynamics might be important in the pathogenesis of NEC, because endothelial dysfunction would limit, or possibly eliminate, NO production, leading to substantial intestinal ischemia.

Alterations in cerebral blood flow and oxygen consumption during prolonged hypocarbia.

ABSTRACT. The effect of prolonged (2 h) hypocarbia on cerebral blood flow, oxygen delivery, extraction, and consumption was studied in eight, 1- to 4-day-old piglets. Hyperventilation to PaCO2 < 20 mm Hg acutely (30 min) decreased cerebral blood flow and oxygen oconsumption. Cerebral oxygen consumption was subsequently restored via increases in cerebral blood flow and thus, cerebral oxygen delivery. Cerebral oxygen extraction rose from a normocarbic baseline of 50 to 75% with acute hypocarbia and was maintained at this level. The percent decrease in blood flow to the cerebrum was greater than that to other brain regions during hypocarbia.

Intestinal ischemia and necrotizing enterocolitis

Early descriptions of necrotizing enterocolitis noted histologic evidence of ischemia in affected intestine and colon. This observation led to the hypothesis that intestinal ischemia played a pivotal role in the pathogenesis of NEC, 1 an hypothesis still widely held, although not yet proved in any definitive manner. This article will summarize the developmental physiology of intestinal vascular regulation and review some of the mechanisms by which intestinal ischemia may occur during early postnatal life. In particular, I will focus on the possible means by which extrinsic and intrinsic vascular regulatory mechanisms might contribute to the development of intestinal ischemia during early postnatal life.

Cerebral blood flow in the newborn lamb with polycythemia and hyperviscosity

We measured hematocrit, whole blood viscosity, arterial oxygen content, and cerebral blood flow in seven newborn lambs in which polycythemia and hyperviscosity were induced by partial exchange transfusion with packed red blood cells from a donor lamb. After the exchange transfusion, the hematocrit, whole blood viscosity, and arterial oxygen content were significantly elevated, whereas cerebral blood flow was reduced from baseline measurements. Sodium nitrite was then infused to reduce the arterial oxygen content to baseline values while the hematocrit and viscosity remained elevated. Under this condition, cerebral blood flow returned to baseline values. Oxygen delivery to the brain remained constant throughout the study. These results indicate that the reduction of cerebral blood flow in neonatal polycythemia and hyperviscosity is a physiologic response to increased arterial oxygen content and not a result of hyperviscosity.

Pressure and flow characteristics of terminal mesenteric arteries in postnatal intestine

The responses of buffer-perfused terminal mesenteric arteries from 3- and 35-day-old swine to manipulation of intravascular pressure and flow rate were determined. Under in vivo conditions, these vessels demonstrated age-dependent differences in resting diameter (182 vs. 301 μm in 3- vs. 35-day-old swine). A proximal-to-distal pressure gradient was present in vessels from both age groups (Δ13 vs. Δ16 mmHg in 3- vs. 35-day-old swine), suggesting their functional role as resistance vessels. Vessels were mounted within an in vitro perfusion apparatus that allowed independent regulation of inflow and outflow pressure. Vessels from both age groups demonstrated the development of active tone in response to an incremental rise in pressure, applied in the absence of flow. However, myogenic vasoconstriction was only observed in younger arterioles. Similarly, both groups demonstrated dilation in response to a flow stimulus generated in the absence of a net change in intravascular pressure, although the magnitude of this response was significantly greater in younger vessels (+27 vs. +7% in 3- vs. 35-day-old swine). The dilatory response to flow was eliminated by N G-monomethyl-l-arginine (10-4 M) but restored by coadministration of l-arginine (10-3 M). Myogenic vasoconstriction was overridden by flow-mediated dilation in terminal mesenteric arteries from 3- but not 35-day-old swine after concomitant application of pressure and flow stimuli. We conclude that the hemodynamic characteristics of terminal mesenteric arteries are age dependent in postnatal swine.The responses of buffer-perfused terminal mesenteric arteries from 3- and 35-day-old swine to manipulation of intravascular pressure and flow rate were determined. Under in vivo conditions, these vessels demonstrated age-dependent differences in resting diameter (182 vs. 301 microns in 3- vs. 35-day-old swine). A proximal-to-distal pressure gradient was present in vessels from both age groups (delta 13 vs. delta 16 mmHg in 3- vs. 35-day-old swine), suggesting their functional role as resistance vessels. Vessels were mounted within an in vitro perfusion apparatus that allowed independent regulation of inflow and outflow pressure. Vessels from both age groups demonstrated the development of active tone in response to an incremental rise in pressure, applied in the absence of flow. However, myogenic vasoconstriction was only observed in younger arterioles. Similarly, both groups demonstrated dilation in response to a flow stimulus generated in the absence of a net change in intravascular pressure, although the magnitude of this response was significantly greater in younger vessels (+27 vs. +7% in 3- vs. 35-day-old swine). The dilatory response to flow was eliminated by NG-monomethyl-L-arginine (10(-4)M) but restored by coadministration of L-arginine (10(-3)M). Myogenic vasoconstriction was overridden by flow-mediated dilation in terminal mesenteric arteries from 3- but not 35-day-old swine after concomitant application of pressure and flow stimuli. We conclude that the hemodynamic characteristics of terminal mesenteric arteries are age dependent in postnatal swine.

The effects of ischemia-reperfusion on endothelial cell function in postnatal intestine.

The goal of these experiments was to determine whether the perturbation of ischemia-reperfusion has an age-dependent effect on subsequent endothelial cell production of nitric oxide. Three-and 35-d-old swine in the experimental group were exposed to 1-h partial ischemia (90% flow reduction) and 2-h reperfusion in vivo by creation and then removal of a mesenteric artery coarctation. Control subjects underwent exposure of the mesenteric artery only. After reperfusion, gut vascular resistance had increased 44± 6% in 3-d-old, but had decreased 41 ± 4% in 35-d-old subjects. At the completion of the in vivo portion of the protocol mesenteric artery was removed, and nitric oxide production was estimated in vitro, by measuring cGMP production by vessel segments or by measuring relaxation of phenylephrine-precontracted rings, both after stimulation of nitric oxide production by substance P or the calcium ionophore A23187. Compared with control, mesenteric artery segments from 3-d-old subjects demonstrated reductions in basal, substance P-stimulated (10-8 M) and A23187-stimulated (10-7 M) cGMP accumulation of 50 ± 7%, 66± 6% and 78 ± 7%. Mesenteric artery segments from 35-d-old subjects demonstrated increases in basal, substance P-stimulated, or A23187-stimulated cGMP accumulations of 114 ± 14%, 92 ± 8%, or 78 ± 9%. Compared with control, I/R rings from 3-d-old subjects demonstrated reductions in substance P-induced (10-8 M) or A23187-induced (10-7 M) relaxations of 56 ± 7% or 30 ± 7%. In contrast, 35-d-old ischemia-reperfusion rings demonstrated increases in substance P- or A23187-induced relaxation of 36 ± 8% or 98 ± 11%. It is concluded that ischemia-reperfusion has an age-dependent effect on endothelial production of NO within in vitro postnatal mesenteric artery and that these changes mirror the effects of ischemia-reperfusion on gut vascular resistance in vivo.

Gastrointestinal Blood Flow and Oxygen Consumption in the Newborn Lamb: Effect of Chronic Anemia and Acute Hypoxia

Summary: The purpose of this study was to investigate the compensatory change in circulation and oxygenation of the newborn Iamb gastrointestinal (GI) tract in response to anemic and hypoxic hypoxemia. Radiolabeled microspheres were used to measure blood flow. We subjected the newborn lamb to a 30-35% reduction in hematocrit 4 d before study and to a 10% oxygen environment for 30 min during the study to induce chronic anemic and acute hypoxic hypoxemia, respectively. The circulatory and oxygenation responses were measured 1 h after a standard milk feeding in all cases. During the experimental periods, no change in total GI blood flow was observed. Because of a failure to augment blood flow during hypoxemia, O2 delivery to the GI tract decreased significantly. Despite this, GI O2 consumption was not compromised because tissue O2 extraction by the GI tract rose significantly. The response of the newborn lamb GI tract to hypoxemia after feeding is augmentation of O2 extraction. The newborns GI tract did not regulate local GI blood flow.

Flow-Induced Dilation in Newborn Intestine

ABSTRACT: The goal of these experiments was to determine the presence and mechanistic basis of flow-induced dilation in mesenteric artery from 3-d-old swine. In the first experiment, in vitro gut loops were perfused from a blood-filled reservoir under controlled-flow conditions, and flow was progressively increased from ∼40% to ∼170% in six increments by manipulation of pump speed. Under control conditions, vascular resistance significantly decreased after each step increase in flow rate. NG-Monomethyl-L-arginine (LNMMA; 10-4 M), an arginine analog that blocks nitric oxide production, eliminated this flow-induced dilation, but only for the step increases in flow at rates above the baseline flow rate. For step increases below the baseline rate, LNMMA caused a simple parallel shift of the resistance-flow rate curve upward. Phenylephrine (10-6 M), an α1-agonist which has no effect on nitric oxide production or half-life, did not eliminate flow-induced dilation, but instead caused a simple parallel shift of the resistance-flow rate curve upward across the entire range of flows studied. In the second experiment, a 3-cm segment of mesenteric artery was perfused with Krebs buffer at two flow rates: 10 and 25 mL/min. The effluent from the mesenteric artery segment was suffused onto a deendothelialized, phenylephrine-precontracted ring of swine carotid artery; relaxation of this bioassay vessel served as an index of release of relaxing factors from the mesenteric artery segment. Under control conditions, increase in the mesenteric artery flow rate caused a 60% relaxation of the bioassay vessel. This effect was eliminated by the addition of LNMMA to the buffer (10-4 M), but not by the addition of indomethacin (10-5 M). Flow-induced dilation occurs in the mesenteric artery of 3-d-old swine. This vascular phenomenon appears to be mediated by nitric oxide, but only at flows above the baseline flow rate. The mechanism(s) responsible for this phenomenon at lower flow rates is not clear.

Effects of Ischemia and Reperfusion on Intrinsic Vascular Regulation in the Postnatal Intestinal Circulation

ABSTRACT: 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 ofin 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.

Effects of sustained low-flow perfusion on the response to vasoconstrictor agents in postnatal intestine.

This laboratory has previously reported that sustained reduction of blood flow in newborn intestine causes a triphasic increase in vascular resistance that occurs over 3-4 h and that these changes are mediated, in part, by loss of endothelial nitric oxide (NO) production. This study examines the effects of exposure to sustained low-flow perfusion on the subsequent response to three contractile agonists: ANG II, norepinephrine (NE), and endothelin-1 (ET-1). Gut loops from 3- and 35-day-old swine were exposed to low-flow conditions in vivo (i.e., reduction of flow to approximately 50% of baseline) for 30 min or 5 h. Thereafter, they were removed to an extracorporeal perfusion circuit for in vitro hemodynamic assessment; alternatively, the mesenteric artery perfusing the gut loop was removed and cut into rings for assessment of isometric tension development. Gut loops from 3-day-old subjects exposed to low-flow conditions demonstrated significantly increased contractile responses to ANG II, NE, and ET-1; also, mesenteric artery rings from these gut loops demonstrated a significant reduction of the ED50 for all three agonists. Similar changes were not observed in intestine or mesenteric artery rings from older subjects. Sustained blockade of endogenous NO synthesis with NG-monomethyl- L-arginine duplicated the effects of exposure to sustained low-flow perfusion. It appears that sustained reduction of blood flow in newborn intestine decreases constitutive NO production, which in turn causes a generalized enhancement of the contractile efficacy of ANG II, NE, and ET-1.