Thromboxane (Tx) A2 is a platelet agonist, smooth muscle cell constrictor, and mitogen1. Urinary Tx metabolite (Tx-M) excretion is increased in syndromes of platelet activation and early in both normal pregnancies and in pregnancy-induced hypertension2,3. A further increment occurs in patients presenting with severe preeclampsia, in whom Tx-M correlates with other indices of disease severity4. TxA2 exerts its effects through a membrane receptor (TP), of which two isoforms (α and β; refs. 5,6) have been cloned. Overexpression of TP in the vasculature under the control of the pre-proendothelin-1 promoter7 results in a murine model of intrauterine growth retardation (IUGR), which is rescued by timed suppression of Tx synthesis with indomethacin. IUGR is commonly associated with maternal diabetes or cigarette smoking, both conditions associated with increased TxA2 biosynthesis8,9.

OBJECTIVES:Hemoglobin-based oxygen carriers are designed to replace blood volume and to increase oxygen delivery to tissues after blood loss. The goals of the present study were two-fold: a) to determine the systemic and regional vascular effects of resuscitation with recombinant human hemoglobin (rHb1.1) in rats during controlled hemorrhage; and b) to determine whether nitric oxide (NO) or prostaglandins were involved in the observed responses.DESIGN:Paralyzed, ventilated rats were hemorrhaged (18 mL blood/kg body weight) during halothane anesthesia and allowed to stabilize for 30 mins. Systemic and regional hemodynamics and oxygen delivery were monitored at three time points, using the radioactive microsphere method. Microspheres were first infused at the end of the hemorrhage stabilization period (t=0 min). rHb1.1 (1 g/kg body weight) or rHb1.1 diluent (phosphate buffered saline, 36 mL/kg body weight) were infused over 20 mins and microspheres were administered again, 30 mins later (t=50 mins). Saline (0.5 mL), indomethacin (5 mg/kg to inhibit cyclooxygenase), or NG-monomethyl-L-arginine (L-NMMA, 100 mg/kg, to inhibit NO synthase) were then infused in rHb1.1-treated rats and microspheres injected once more (t=80 mins).SETTING:Research laboratory.SUBJECTS:Male Wistar rats (n=37).INTERVENTIONS:Recombinant human hemoglobin (rHb1.1), rHb1.1 diluent (phosphate buffered saline) resuscitation of hemorrhaged rats. Saline, L-NMMA, or indomethacin treatment after resuscitation.MEASUREMENTS AND MAIN RESULTS:Resuscitation with rHb1.1 increased mean arterial pressure (MAP), cardiac output, and systemic oxygen delivery significantly when compared with diluent. After rHb1.1 resuscitation, regional blood flows were significantly increased in skin, kidney, spleen, and heart compared with diluent resuscitation. Compared with saline treatment after rHb1.1 resuscitation, L-NMMA increased MAP and regional resistances in virtually all tissues; indomethacin did not alter MAP, but increased resistance in the brain.CONCLUSIONS:These data indicate that rHb1.1 resuscitation was more effective than diluent in improving systemic and regional hemodynamics and oxygen delivery, suggesting that rHb1.1 may be of benefit in the treatment of acute blood loss. Increased resistance after L-NMMA in the presence of rHb1.1 indicated that rHb1.1 resuscitation did not eliminate NO dependent circulatory control. Increased resistance after indomethacin in brain indicated that vasodilator prostanoids were important in regulating vascular resistance in these tissues after rHb1.1 resuscitation.

Objectives Hemoglobin-based oxygen carriers are designed to replace blood volume and to increase oxygen delivery to tissues after blood loss. The goals of the present study were two-fold: a) to determine the systemic and regional vascular effects of resuscitation with recombinant human hemoglobin (rHb1.1) in rats during controlled hemorrhage; and b) to determine whether nitric oxide (NO) or prostaglandins were involved in the observed responses. Design Paralyzed, ventilated rats were hemorrhaged (18 mL blood/kg body weight) during halothane anesthesia and allowed to stabilize for 30 mins. Systemic and regional hemodynamics and oxygen delivery were monitored at three time points, using the radioactive microsphere method. Microspheres were first infused at the end of the hemorrhage stabilization period (t = 0 min). rHb1.1 (1 g/kg body weight) or rHb1.1 diluent (phosphate buffered saline, 36 mL/kg body weight) were infused over 20 mins and microspheres were administered again, 30 mins later (t = 50 mins). Saline (0.5 mL), indomethacin (5 mg/kg to inhibit cyclooxygenase), or NG-monomethyl-L-arginine (L-NMMA, 100 mg/kg, to inhibit NO synthase) were then infused in rHb1.1-treated rats and microspheres injected once more (t = 80 mins). Setting Research laboratory. Subjects Male Wistar rats (n = 37). Interventions Recombinant human hemoglobin (rHb1.1), rHb1.1 diluent (phosphate buffered saline) resuscitation of hemorrhaged rats. Saline, L-NMMA, or indomethacin treatment after resuscitation. Measurements and Main Results Resuscitation with rHb1.1 increased mean arterial pressure (MAP), cardiac output, and systemic oxygen delivery significantly when compared with diluent. After rHb1.1 resuscitation, regional blood flows were significantly increased in skin, kidney, spleen, and heart compared with diluent resuscitation. Compared with saline treatment after rHb1.1 resuscitation, L-NMMA increased MAP and regional resistances in virtually all tissues; indomethacin did not alter MAP, but increased resistance in the brain. Conclusions These data indicate that rHb1.1 resuscitation was more effective than diluent in improving systemic and regional hemodynamics and oxygen delivery, suggesting that rHb1.1 may be of benefit in the treatment of acute blood loss. Increased resistance after L-NMMA in the presence of rHb1.1 indicated that rHb1.1 resuscitation did not eliminate NO dependent circulatory control. Increased resistance after indomethacin in brain indicated that vasodilator prostanoids were important in regulating vascular resistance in these tissues after rHb1.1 resuscitation. (Crit Care Med 1998; 26:1071-1080)

Chronic cocaine abuse by pregnant women results in chronic neonatal drug exposure. In adults, chronic cocaine use alters neurotransmitter concentrations and receptor dose-response relationships. Similar changes may also occur in the neonatal cerebrovasculature after in utero cocaine exposure. This study examined the effect of chronic cocaine exposure on internal carotid artery reactivity to norepinephrine, serotonin, acetylcholine, sodium nitroprusside, adenosine, and cocaine in neonatal rabbits. Internal carotid artery rings were isolated from 16 to 20 day old rabbits that had received cocaine (20 mg/kg IP BID, n = 8) or saline (n = 8) from 5 days of age and were studied in organ baths using standard in vitro techniques. Chronic treatment with cocaine decreased the half-maximal relaxant response (ED50) to adenosine (control 6.9 +/- 1.8 vs cocaine 3.5 +/- 0.99 microM, p = 0.05). The half-maximal contractile responses (EC50) to norepinephrine and serotonin and the half-maximal relaxant responses (ED50) to acetylcholine and sodium nitroprusside were similar between groups. The threshold concentration of cocaine that induced vessel contraction was altered by chronic cocaine exposure (control group 10(-6) M vs chronic cocaine group 10(-4) M). We conclude that chronic cocaine exposure sensitizes carotid arteries to the relaxant effects of adenosine. In addition, chronic cocaine exposure desensitizes carotid arteries to the contractile effects of acute cocaine. These vasoreactivity changes may underlie altered cerebrovascular responses to asphyxia and play a role in the pathogenesis of postnatally acquired brain injury in critically ill "crack" babies.

Several studies have suggested that halothane and isoflurane modify responses to endothelium-dependent vasodilators, indicating that the differing circulatory effects of these anesthetics may be, in part, attributable to alterations in endothelial cell control of vascular tone. This study was designed to determine the contribution of endothelium-derived relaxing factor (EDRF/NO) to circulatory control in indomethacin-treated rats anesthetized with equipotent concentrations (1 MAC) of either isoflurane (n = 6) or halothane (n = 8). Using radiolabelled microspheres, systemic and regional hemodynamics were measured in cerebrum, cerebellum, heart, kidney, gastrointestinal tract, spleen, liver, skeletal muscle, skin, ear, and white and brown fat. Cardiac output, mean arterial pressure (MAP), systemic vascular resistance (SVR), regional blood flows, and regional vascular resistances were determined before (control) and after administration of NG-monomethyl-L-arginine (L-NMMA, 100 mg/kg) to inhibit EDRF/NO synthesis, and following L-arginine (300 mg/kg) to reverse the effects of L-NMMA. In both anesthetic groups, L-NMMA decreased cardiac output and increased MAP, SVR, and regional resistances in brain, heart, kidney, spleen, gastrointestinal tract, hepatic artery, skeletal muscle, skin, and white fat. L-arginine returned SVR and MAP to or below control values in both groups, although cardiac output remained decreased. During isoflurane as compared to halothane anesthesia, L-NMMA caused significantly greater increases in blood pressure (54 +/- 7% vs. 24 +/- 2%) and SVR (143 +/- 22% vs. 79 +/- 11%). In addition, rats anesthetized with isoflurane had significantly greater increases in vascular resistance in heart, kidney, gastrointestinal tract, hepatic artery, and skin after L-NMMA than did rats anesthetized with halothane.(ABSTRACT TRUNCATED AT 250 WORDS)