Endothelium-Dependent GenderDifferences inthe Response of the Rat Pulmonary Arteryto theThromboxane Mimic(U46619)1

ABSTRACT The pulmonaryarteriesof ratswere studiedinorderto determine the existence of sexual dimorphism. Gender differences, in the sensitivity (EC@)and maximum contractility (T,,,@) of ring prepa rations of the main pulmonary arteries of adult male and female rats, were evaluated with the syntheticendoperoxideanalog [(15S)-hydroxy-11a,9a-(epoxymethano)-prosta-5Z, I 3E-dienoic acid,] (U46619) and norepinephrine. There were no significant gender differences in the T@ values obtained with either U46619 or norepinephnne. However, when the intimal surface of vessel segments from female rats was rubbed, U46619 but not norep inephnne elicited a significantly lower T@. In contrast, no change inT@ was observedwithdenudedvesselsegmentsfrommales. Removal of the endothelium did not significantly affect the ECse of U46619 or norepinephnne in segmentsfrom either sex. The inhibitory effect of verapamil on the U46619-induced contractile responsewas studiedon both intactand denudedvesselsfrom rats of both gender. The T@ of intact vesselsfrom males but not femaleswas significantly attenuatedby verapamil(P < .05). The ECrevalues with verapamil were not significantly different in any of the vessel preparations. We suggest that the endothelium of the pulmonaryartery of female rats significantly potentiates the contractile response to U46619 and attenuates the inhibitory effectof verapamil. Sexual dimorphism in the vascular reactivity of isolated pulmonary blood vessels is of considerable interest owing to the reported gender differences in the incidence of primary pulmonary hypertension. After sexual maturation, women pres ent with this disease three times more frequently than men (Wagenvoort and Wagenvoort, 1970). Recent studies demonstrate that the endothelium mediates the response of the underlying smooth muscle to several ago nists (DeMey and Vanhoutte, 1982; Singer and Peach, 1983) and may be involved in the development of pulmonary hyper tension (Molteni et at., 1984). An EDRF was reported by Furchgott and Zawadski (1980) and has subsequently been verified in various vascular preparations including the human pulmonary artery In addition to EDRF, the pulmonary endothelium may also release a contractile substance. Exuded lung surface fluid and lymph fluid collected during vasoconstriction, caused by bilat eral and unilateral hypoxia, elicited contractile responses of isolated helical strip preparations of the canine pulmonary artery (Benumofet at., 1978). In addition, hypoxic vasoconstric tion of porcine pulmonary artery rings requires the presence of the endothelium and may involve the release of an endothe lium-dependent contractile factor The purpose of this study was to investigate in pulmonary this drug is currently used in the clinic for treating primary pulmonary hypertension Methods Animals. A total of 51 mature(12 weeksof age)Sprague-Dawley rats from the Charles River Breeding Laboratories (Wilmington, MA) were housed in a controlled environment with food and water ad libitum. The females and males weighed 234.2 ±6.42 and 260.83 Â

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

DISPOSITION AND TISSUE DISTRIBUTION OF ANGIOPEPTIN IN THE RAT

ABSTRACT: Th

914-74 Estradiol 17βProtects Against Homocysteine-induced Vascular Injury in Rat Thoracic Aorta

Hyperhomocysteinemia produces atherosclerotic lesions with characteristic endothelial desquamation and intimal smooth muscle cell (VSMC) proliferation. In vitro, homocysteine is cytotoxic to endothelial cells and recent observations suggest that it may directly stimulate VSMC proliferation. Estrogen, on the other hand, inhibits VSMC proliferation both in vivoand in vitro. We evaluated the effect of estradiol 17β(E2β) on homocysteine-induced VSMC proliferation in arterial segments from the rat thoracic aorta. Segments were placed overnight in Dulbecco's Minimum Essential Medium, supplemented with gentamycin(25 μg/ml), glutamine (2mM) and 0.4% fatal bovine serum, before incubation for 30 hours with DL-homocysteine thiolactone (0.1–5.0mM). Radiolabelled thymidine uptake was assessed in intact and deendothelialized arterial segments, in presence of E2β(30nM) or vehicle (1% ethanol). In deendothelialized segments homocysteine elicited a concentration-dependent increase in 3H-thymidine uptake, expressed as cpm/mg protein. Thymidine uptake increased from a basal value of 8694±1465 to 36338±2025, at 5mM homocysteine concentration (p&lt;0.01). Intact arterial segments showed a significantly attenuated response to homocysteine stimulation. On the other hand, incubation of deendothelialized segments with E2β(30nM) caused a significant inhibition of homocysteinestimulated response, without affecting basal 3H-thymidine incorporation. These results provide evidence for a direct stimulatory effect of homocysteine on VSMC proliferation in rat aortic segments. Further, our data show estradiol 17βprotects against homocysteine-induced vascular injury, possibly via a direct effect on VSMC

) and Hypertension-Endocrine Branch, National Heart, Lung and Blood Institute

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