We investigated the role of nitric oxide (NO) in the control of myocardial O2 consumption in Fischer 344 rats. In Fischer rats at 4, 14, and 23 mo of age, we examined cardiac function using echocardiography, the regulation of cardiac O2 consumption in vitro, endothelial NO synthase (eNOS) protein levels, and potential mechanisms that regulate superoxide. Aging was associated with a reduced ejection fraction [from 75 +/- 2% at 4 mo to 66 +/- 3% (P < 0.05) at 23 mo] and an increased cardiac diastolic volume [from 0.60 +/- 0.04 to 1.00 +/- 0.10 ml (P < 0.01)] and heart weight (from 0.70 +/- 0.02 to 0.90 +/- 0.02 g). The NO-mediated control of cardiac O2 consumption by bradykinin or enalaprilat was not different between 4 mo (36 +/- 2 or 34 +/- 3%) and 14 mo (29 +/- 1 or 25 +/- 3%) but markedly (P < 0.05) reduced in 23-mo-old Fischer rats (15 +/- 3 or 7 +/- 2%). The response to the NO donor S-nitroso-N-acetyl penicillamine was not different across groups (35%, 35%, and 44%). Interestingly, the eNOS protein level was not different at 4, 14, and 23 mo. The addition of tempol (1 mmol/l) to the tissue bath eliminated the depression in the control of cardiac O2 consumption by bradykinin (25 +/- 3%) or enalaprilat (28 +/- 3%) in 23-mo-old Fischer rats. We next examined the levels of enzymes involved in the production and breakdown of superoxide. The expression of Mn SOD, Cu/Zn SOD, extracellular SOD, and p67phox, however, did not differ between 4- and 23-mo-old rats. Importantly, there was a marked increase in gp91phox, and apocynin restored the defect in NO-dependent control of cardiac O2 consumption at 23 mo to that seen in 4-mo-old rats, identifying the role of NADPH oxidase. Thus increased biological activity of superoxide and not decreases in the enzyme that produces NO are responsible for the altered control of cardiac O2 consumption by NO in 23-mo-old Fischer rats. Increased oxidant stress in aging, by decreasing NO bioavailability, may contribute not only to changes in myocardial function but also to altered regulation of vascular tone and the progression of cardiac or vascular disease.

When the dialkylacetamide side chain of the ET(A)-selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ET(B) over ET(A). By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ET(B) and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ET(B) receptor in modulating blood pressure; the observed hypertensive response to persistent ET(B) blockade is consistent with previous postulates and indicates that ET(B)-selective antagonists may not be suitable as agents for long-term systemic therapy.

Background/Aims: Microalbuminuria is a marker for early kidney disease and cardiovascular risk. The purposes of this study were to determine the prevalence of microalbuminuria in an HIV-infected clinic population, to test the predictive value of a single urine albumin/creatinine ratio (ACR) to identify persistent microalbuminuria and to examine covariates of microalbuminuria. Methods: We conducted a prospective cohort study of HIV-infected subjects (n = 182) without proteinuria (urine protein/creatinine ratio ≥0.5 g/g), elevated serum creatinine, diabetes, or chronic inflammatory conditions. Subjects completed three research visits within 9 months. Microalbuminuria was defined as the geometric mean ACR of 25-355 mg/g for females and 17-250 mg/g for males. Results: The prevalence of microalbuminuria was 14%. The negative predictive value of a single urine ACR determination was 98%, whereas the positive predictive value was only 74%. Microalbuminuria was similar among Black (15%) and non-Black (14%) subjects (p = 0.8). Subjects with microalbuminuria were more likely to have hypertension (p = 0.02) and metabolic syndrome (p = 0.03). While duration of HIV infection and the level of HIV viremia were similar between groups, those with microalbuminuria were more likely to have a CD4 count <200 cells/μl (p = 0.0003). In a multivariate logistic regression analysis, the only significant independent predictors of microalbuminuria were low CD4 count (p = 0.018) and current ritonavir exposure (p = 0.04). Conclusion: The prevalence of microalbuminuria in an HIV-infected clinic population was similar to earlier reports, and was associated with hypertension and impaired immune function. A single normal ACR determination effectively excludes microalbuminuria, whereas an elevated ACR requires confirmation.

Background: In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on growth and the cardiovascular system. Glucocorticoid excess promotes free radical overproduction and vascular dysfunction. Objectives: We hypothesized that the adverse effects of postnatal glucocorticoid therapy are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects. Methods: Male rat pups received a clinically relevant course of dexamethasone (Dex), or Dex with vitamins C and E (DexCE), on postnatal days 1–6 (P1–6). Controls received saline (Ctrl) or saline with vitamins (CtrlCE). Results: At P21, Dex reduced survival (Ctrl: 96 vs. Dex: 70%) and promoted asymmetric growth restriction (ponderal index, Ctrl: 6.3 ± 0.1 g · mm^–3 × 10^–5 vs. Dex: 7.4 ± 0.2 g · mm^–3 × 10^–5), both p < 0.05. Dex increased cardiac oxidative stress (protein expression: 4-HNE +20%, Hsp90 –42% and eNOS –54%), induced left ventricle (LV) wall thinning (LV wall volume: Ctrl: 47.2 ± 1.2 mm³ vs. Dex: 38.9 ± 1.7 mm³) and decreased the ratio of the aortic lumen:total vessel area (Ctrl: 0.74 ± 0.01 vs. Dex: 0.66 ± 0.02), all p < 0.05. DexCE restored towards control values survival, growth symmetry the aortic lumen:total vessel area, and increased the cardiac expression of Hsp90 relative to Dex. In addition, relative to controls, the decrease in the cardiac expression of eNOS was no longer significant in DexCE animals (–20.3 ± 14.4%, p > 0.05). However, DexCE did not prevent growth retardation, cardiac 4-HNE upregulation (DexCE: +29%) or LV thinning (DexCE: 40.1 ± 1.1 mm³). Treatment of neonates with vitamins alone affected somatic growth and promoted thinner LV walls (CtrlCE: 39.9 ± 0.5 mm³, p < 0.05). Conclusions: Combined glucocorticoid and antioxidant therapy in premature infants may be safer than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended.

In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on long-term neurological function. Glucocorticoid excess promotes free radical overproduction. We hypothesised that the adverse effects of postnatal glucocorticoid therapy on the developing brain are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects. Male rat pups received a clinically-relevant tapering course of dexamethasone (DEX; 0.5, 0.3, and 0.1 mg.kg−1.day−1), with or without antioxidant vitamins C and E (DEXCE; 200 mg.kg−1.day−1 and 100 mg.kg−1.day−1, respectively), on postnatal days 1–6 (P1–6). Controls received saline or saline with vitamins. At weaning, relative to controls, DEX decreased total brain volume (704.4±34.7 mm3 vs. 564.0±20.0 mm3), the soma volume of neurons in the CA1 (1172.6±30.4 µm3 vs. 1002.4±11.8 µm3) and in the dentate gyrus (525.9±27.2 µm3 vs. 421.5±24.6 µm3) of the hippocampus, and induced oxidative stress in the cortex (protein expression: heat shock protein 70 [Hsp70]: +68%; 4-hydroxynonenal [4-HNE]: +118% and nitrotyrosine [NT]: +20%). Dexamethasone in combination with vitamins resulted in improvements in total brain volume (637.5±43.1 mm3), and soma volume of neurons in the CA1 (1157.5±42.4 µm3) and the dentate gyrus (536.1±27.2 µm3). Hsp70 protein expression was unaltered in the cortex (+9%), however, 4-HNE (+95%) and NT (+24%) protein expression remained upregulated. Treatment of neonates with vitamins alone induced oxidative stress in the cortex (Hsp70: +67%; 4-HNE: +73%; NT: +22%) and in the hippocampus (NT: +35%). Combined glucocorticoid and antioxidant therapy in premature infants may be safer for the developing brain than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended.