Using a high-frequency linear transducer (15L8), we studied 1) the feasibility of performing echocardiography in nonanesthetized mice compared with mice given pentobarbital sodium (Pento) or a mixture of ketamine and xylazine and 2) the feasibility of echocardiographic evaluation of left ventricular (LV) hypertrophy, dilatation, and function in mice with two-kidney, one-clip hypertension or myocardial infarction (MI). Heart rate (HR) in awake mice was 658 +/- 9 beats/min; Pento and ketamine plus xylazine reduced HR to 377 +/- 11 and 293 +/- 19 beats/min, respectively, associated with a significant decrease in shortening fraction (SF), ejection fraction (EF), and cardiac output (CO) and an increase in LV end-diastolic (LVEDD) and end-systolic dimensions (LVESD). Mice with 4 wk of two-kidney, one-clip hypertension had increased LV mass (15.62 +/- 0. 62 vs. 22.17 +/- 1.79 mg) without altered LV dimensions, SF, EF, or CO. Mice studied 4 wk post-MI exhibited obvious LV dilatation and systolic dysfunction, as evidenced by increased LVEDD and LVESD and decreased SF, EF, and CO. Our findings clearly show the adverse impact of anesthesia on basal cardiac function and the difficulty in interpreting data obtained from anesthetized mice. We believe this is the first study to demonstrate the feasibility of using echocardiography to assess cardiovascular function in the nonanesthetized mouse.

Abstract-The role of neural nitric oxide synthase (nNOS) in regulating blood pressure (BP) remains uncertain. Recently it was reported that in mice lacking functional endothelial NOS (eNOS) genes (Ϫ/Ϫ), acute administration of a nonselective NOS inhibitor, N w -nitro-L-arginine, decreased mean BP, suggesting that NO released by non-eNOS isoforms increases BP. Because the inducible NOS isoform is not constitutively expressed and when induced causes hypotension, we hypothesize that it is NO produced by nNOS that increases BP in the absence of eNOS activity. To test this hypothesis, we studied the acute effect of selective and nonselective nNOS inhibitors on BP and cerebellar NOS activity in eNOS (Ϫ/Ϫ), wild-type (ϩ/ϩ), and heterozygous (ϩ/Ϫ) mice as well as in ϩ/ϩ mice with renovascular hypertension. Because it is not known whether the decrease in BP caused by acute NOS inhibition in Ϫ/Ϫ mice can occur chronically, we also studied the effect of chronic NOS inhibition on both BP and cerebellar NOS activity. eNOS (Ϫ/Ϫ) mice had higher BP than ϩ/ϩ or ϩ/Ϫmice, and acute administration of the selective nNOS inhibitor 7-nitroindazole (7-NI) decreased their mean BP from 137Ϯ13 to 124Ϯ12 mm Hg (PϽ0.01). In ϩ/ϩ, ϩ/Ϫ, or renovascular hypertensive ϩ/ϩ mice, 7-NI caused a small but insignificant rise from 105Ϯ5 to 110Ϯ6 mm Hg, from 115Ϯ9 to 119Ϯ13 mm Hg, and from 146Ϯ6 to 150Ϯ6 mm Hg, respectively. Fifteen minutes after administration of 7-NI, cerebellar NOS activity decreased by 70%; however, this inhibitory effect was brief, since 2 hours after 7-NI administration NOS returned toward control values. Chronic oral or intraperitoneal administration of 7-NI did not inhibit cerebellar NOS activity, whereas the nonselective NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME) decreased this activity by 50%. Therefore, we studied the effect of chronic L-NAME administration (4 weeks) on BP. In Ϫ/Ϫ mice, chronic L-NAME administration decreased BP from 135Ϯ4 to 120Ϯ3 mm Hg (PϽ0.05), whereas in ϩ/ϩ and ϩ/Ϫmice, as expected, it increased BP from 109Ϯ2 to 125Ϯ3 mm Hg (PϽ0.001) and from 107Ϯ6 to 119Ϯ5 mm Hg (PϽ0.02), respectively. After L-NAME administration was stopped, BP returned to baseline. These results suggest that in eNOS Ϫ/Ϫ mice, NO derived from nNOS increases BP both acutely and chronically. (Hypertension. 1998;32:856-861.) Key Words: nitric oxide Ⅲ blood pressure Ⅲ nitric oxide synthase, neural Ⅲ nitric oxide synthase, endothelial I t is well known that nitric oxide (NO) plays an important role in regulating blood pressure (BP).1-4 Three isoforms of the enzyme responsible for NO formation, nitric oxide synthase (NOS), have been identified: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS).4,5 eNOS is expressed in endothelial cells and produces NO, which dilates blood vessels. It is stimulated by a variety of receptor agonists and by shear stress produced by flowing blood.3,4 Recently, 2 groups acting independently developed mice lacking functional eNOS genes (eNOS Ϫ/Ϫ mice).6,7 These mutant mice showed elevated B...

It remains controversial whether silica is a human lung carcinogen. In this study, we estimated the relative risks of lung cancer due to silica and silicosis by meta-analysis. We collected papers published from 1966-2001 which epidemiologically reported on the relationship between silica/silicosis and lung cancer. We removed papers which did not exclude the effects of asbestos and radioactive materials including radon. We selected the most recent one if some papers were based on the same cohort. Based on the selected papers, we summarized the lung cancer risks from silica, silicosis and non-silicosis with exposure to silica, by meta-analysis using a random effects model. The pooled relative risks were 1.32 (95% confidence interval (CI), 1.23-1.41) for silica, 2.37 (95% CI, 1.98-2.84) for silicosis and 0.96 (95% CI, 0.81-1.15) for non-silicosis with exposure to silica. Since some papers on silica did not exclude silicosis, the risk due to silica itself may be smaller than 1.32. It was less possible that silica exposure directly increases lung cancer risk. On the other hand, the relative risk, 2.37 for silicosis suggested that silicosis increases lung cancer risk. Meta-analysis also revealed that cigarette smoking strongly increased the lung cancer risk in silicotic patients (relative risk, 4.47; 95% CI, 3.17-6.30). Thus, the present study suggested the great importance of preventing silicosis and smoking cessation in reducing lung cancer incidence in silica-exposed workers.

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1. Zinc deficiency (ZD) induces many kinds of pathological states. However, the effects of ZD on haemodynamics remain unclear. In the present study, we measured mean blood pressure (BP) and renal blood flow (RBF) under anaesthesia and calculated renal vascular resistance (RVR) from these parameters in rats maintained on a ZD diet (0.5 p.p.m. zinc) for 4 weeks. 2. Zinc deficiency did not change mean BP, but significantly reduced RBF and increased RVR (each P < 0.01). In addition, these effects of ZD were reversible. 3. Because Cu/Zn superoxide dismutase (SOD) is a zinc-containing enzyme and superoxide is a potent scavenger of nitric oxide (NO), a vasodilator, we hypothesized that one of the mechanisms by which ZD increases RVR is by decreasing NO bioavailability by the enhanced formation of superoxide due to low Cu/Zn SOD activity. To test this hypothesis, we observed the roles of NO and superoxide in the mechanism, after having confirmed the low activity of Cu/Zn SOD in the kidneys of ZD rats. 4. Administration of the SOD mimetic tempol (5 mg/kg per min) decreased RVR to a significantly greater extent in ZD rats compared with control, suggesting that superoxide was responsible for the mechanism. Low doses of the NO donor sodium nitroprusside (SNP; 2.0 micro g/kg per min, continuous) decreased RVR to a significantly smaller extent in ZD rats compared with control, whereas a high dose of SNP (0.75 mg/kg, bolus) decreased RVR to a significantly greater extent in ZD rats compared with control, suggesting that the mechanism includes an inhibition of NO activity in ZD, which is most likely to be a scavenging of NO by the activated superoxide. 5. In summary, ZD may increase RVR. The mechanism probably includes changes in NO and superoxide activities.