Hepatocyte growth factor (HGF), a potent mitogen for mature hepatocytes, possesses mitogenic and morphogenic activities for renal epithelial cells. To examine the renotropic function of HGF, we investigated the expression of HGF mRNA and HGF activity in the rat kidney after acute renal failure. When acute renal failure was induced by ischemia or by HgCl2 administration, a DNA synthesis occurred predominantly in the renal tubular cells located in the outer medulla with a peak at 48 h after the treatments. In both renal injuries, HGF mRNA in the kidney increased markedly, reaching a maximum 6 to 12 h after the treatments. HGF activity in the kidney also increased to three- to fourfold higher level than the normal level at 12 h after ischemic treatment or HgCl2 administration. In situ hybridization and immunohistochemical analysis indicated that both HGF mRNA and HGF protein were expressed in renal interstitial cells, presumably endothelial cells and macrophages, but not in tubular epithelial cells. In addition, HGF activity in the plasma of rats with renal ischemia or HgCl2 administration rapidly increased, reaching a maximum at 6 h after the treatment. One week after these injuries, HGF mRNA and HGF activity reverted to normal levels, and renal tubular cell regeneration ceased. Moreover, intravenous injection of human recombinant HGF into mice with acute renal failure caused by HgCl2 administration stimulated DNA synthesis of renal tubular cells in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Background and Purpose-The purpose of this study was to assess individual differences in the pharmacological effects of acetylsalicylic acid (ASA) on bleeding time as measured by in vitro platelet aggregation and to examine the consistency of responses over time. Methods-We measured template IIR bleeding time and platelet aggregation in 8 healthy male volunteers before and 2 hours after ingestion of 324 mg of ASA. An individual was considered a nonresponder if his post-ASA bleeding time was not 2 SDs above his baseline bleeding time, where SD was estimated from the baseline bleeding times of the 8 volunteers. The same experiment was done after a 30-month interval. Results-Five volunteers were identified as ASA responders, and 3 were identified as nonresponders. Bleeding time before and after ingestion of ASA was 408Ϯ121 seconds (meanϮSD) and 720Ϯ225 seconds, respectively, in ASA responders and 330Ϯ30 seconds and 330Ϯ52 seconds, respectively, in ASA nonresponders. The mean ED 50 for collagen-induced platelet aggregation, that is, the mean concentration of collagen that caused a response at 50% of maximum, was 0.91 g/mL (95% CI, 0.73 to 1.14) in ASA responders and 0.48 g/mL (95% CI, 0.38 to 0.60) in nonresponders. When optimum concentrations of collagen, ie, concentrations that yielded 90% maximum aggregation, were used as stimuli, the mean IC 50 for ASA, that is, the mean concentration that yielded 50% inhibition, was 322.5 mol/L (95% CI, 264.8 to 392.6) in ASA responders and 336.1 mol/L (95% CI, 261.0 to 432.8) in nonresponders. The variability in individual responsiveness in the second experiment remained consistent with that in the first experiment. Conclusions-ASA resistance may be caused by an increased sensitivity of platelets to collagen. A platelet aggregation study specific for collagen dose response may be useful for strict selection of ASA responders for low-dose ASA therapy and for identifying ASA nonresponders for high-dose ASA therapy. (Stroke. 2000;31:591-595.)Key Words: aspirin Ⅲ bleeding time Ⅲ collagen Ⅲ platelets A cetylsalicylic acid (ASA) is one of the most commonly used pharmacological substances. Its effectiveness as an antiplatelet agent in preventing cardiovascular events has been clearly demonstrated. [1][2][3][4][5][6][7] Low ASA doses of 300 mg are often recommended because of relatively few associated bleeding and gastrointestinal side effects. 8 However, some patients still suffer a thromboembolic event despite low-dose ASA therapy. The fact remains that low-dose ASA exerts a beneficial effect without side effects in some patients but not in others, 9 -11 ie, different patients require different ASA dosages to achieve complete inhibition of platelet function. Since Duke first described the bleeding time test in 1910, 12 bleeding time has been used to identify disorders of primary hemostasis, indicating risks for bleeding with ASA therapy. Buchanan and Brister 13 reported that an ASA dose of 325 mg prolonged the bleeding time in 60% of volunteers (ASA responders) but not in others (AS...
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