These data demonstrate that ROS mediate signal transduction of cardiac hypertrophy induced by ET-1 or PE in adult rat cardiac myocytes.

The pharmacokinetics of a new, potent H2-receptor antagonist, famotidine, 20 mg i.v. was studied in 7 subjects with normal renal function and in 24 patients with varying degrees of renal impairment. The volume of distribution at steady state was 1.141/kg in normal subjects and was not altered in renal failure. The half-life of elimination was 2.59 h in normal subjects and was unchanged in mild renal failure (creatinine clearance, CLCR 90-60 ml/min/1.48 m2) but was increased to 4.72 h in moderate renal failure (CLCR 60-30 ml/min/1.48 m2), and to 12.07 h in severe renal failure (CLCR below 30 ml/min/1.48 m2). The cumulative urinary excretion and renal clearance of famotidine were correspondingly reduced in patients with impaired kidney function. In normal subjects and in patients with mild to moderate renal failure, about 70% of famotidine was excreted through the kidney, mainly by tubular secretion. In patients with a CLCR above 60 ml/min/1.48 m2 the normal daily dose of famotidine can be employed, but in those with a CLCR between 60 and 30 ml/min/1.48 m2 the dose should be reduced by half, and in patients with a CLCR below 30 ml/min/1.48 m2 a reduction by three quarters of the normal dose is recommended.

We evaluated the effect of acute unilateral renal denervation (DNX) on the tubuloglomerular feedback (TGF) mechanism in Inactin-anesthetized hydropenic male 8- to 10-wk-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). SHR had higher mean arterial pressure (MAP, 28%) and renal vascular resistance (RVR, 35%), whereas renal blood flow (RBF), glomerular filtration rate (GFR), urine flow, and sodium excretion were similar. DNX in SHR did not change MAP but decreased RVR (26%) and increased RBF (29%), GFR (16%), urine flow (52%), and sodium excretion (431%). DNX did not affect these in WKY. Loop of Henle perfusion with Ringer solution reduced early proximal flow rate (EPFR) in SHR more than in WKY; significantly different at a loop flow of 20 nl/min (9.8 +/- 0.7 vs. 6.5 +/- 0.7 nl/min). DNX in SHR increased the nonperfused EPFR from 25.6 +/- 1.1 to 31.7 +/- 1.3 nl/min and reduced TGF responses during perfusion at both 20 nl/min (9.8 +/- 0.7 vs. 4.4 +/- 0.7 nl/min) and 40 nl/min (14.2 +/- 1.1 vs. 10.4 +/- 0.7 nl/min). TGF sensitivity was attenuated by DNX, as indicated by reduced maximum reactivity (-0.89 +/- 0.14 to -0.36 +/- 0.07) and increased turning point (16.5 +/- 0.9 to 25.2 +/- 2.9 nl/min). TGF responses in WKY were not influenced by DNX. Sham denervation did not alter renal hemodynamics and TGF. These results indicate that renal nerves exert a tonic influence on the renal vasculature and the TGF system in SHR but not in WKY. Enhanced TGF responsiveness may be involved in volume retention and in the maintenance of hypertension in SHR.

Expression of MHC-class II molecules (HLA-DR and -DQ), serum gamma-interferon (gamma-IFN) and soluble interleukin-2 receptor (sIL-2R) levels were studied in 35 Japanese patients with lupus nephritis (LN) to clarify intraglomerular cellular activation and cytokine involvement in human LN. In 11 normal kidney specimens, HLA-DR(Ia1) was noted in glomerular tufts, but HLA-DQ was either not or was faintly detected in glomeruli by the indirect immunofluorescence technique. HLA-DR and -DQ were observed mainly on the surface of glomerular endothelial cells in 100% and 50% of 28 lupus kidney specimens except for necrotic or sclerotic lesions. HLA-DQ was expressed in a high incidence of 67%, 86% in patients with proliferative LN (WHO Class III-IV) and active lesions, respectively. Serum gamma-IFN and sIL-2R levels were 1.2 +/- 0.2 U/ml and 190 +/- 24 U/ml (mean +/- SEM; N = 30) in normal controls, and elevated in patients with proliferative LN (4.1 +/- 1.0 U/ml, 383 +/- 81 U/ml, N = 25), especially with active lesions (6.2 +/- 1.5 U/ml, 500 +/- 110 U/ml, N = 14). Overall, glomerular lesions such as HLA-DQ expression, the activity index and leukocyte infiltration correlated positively with serum gamma-IFN levels (r = 0.55; P less than 0.01 for HLA-DQ, r = 0.68; P less than 0.001 for activity index, r = 0.38; P less than 0.05 for leukocyte infiltration), but not with serum sIL-2R levels, anti-DNA antibody titers and CH50 titers.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to clarify intraglomerular cellular activation and cytokine involvement in IgA nephropathy, the glomerular expression of MHC class II antigens (HLA-DR and DQ) and cellular proliferative nuclear antigen (Ki-67), and serum γ-interferon (γ-IFN) levels were evaluated in 49 patients with IgA nepropathy. HLA-DR was detected in all but 4 patients in whom glomerular sclerosis was present. HLA-DQ and Ki-67 were observed in 51 and 38% of the patients, respectively. Proteinuria, recent macroscopic hematuria, mesangial proliferation, and extracapillary and endocapillary lesions were more frequent and more severe in HLA-DQ-positive than in HLA-DQ-negative patients. In 10 patients with acute exacerbation, endocapillary lesions and HLA-DQ and Ki-67 expression were present in 70,80 and 88%, respectively. Serum γ-IFN levels were high in the patients (2.0 ± 0.3 U/ml, n = 40), especially during acute exacerbation (3.4 ± 1.1 U/ml, n = 9). Glomerular HLA-DQ and Ki-67 expression correlated with serum γ-IFN levels (r = 0.73, p < 0.01 for HLA-DQ; r = 0.75, p < 0.01 for Ki-67). Renal biopsy specimens taken before and after prednisolone and/or urokinase therapy were available from 4 patients. There was strong reactivity to HLA-DQ in the glomerular tufts of all 4 pretreatment samples. However, HLA-DQ reactivity disappeared after treatment in 3 samples, concomitant with normalization of serum γ-IFN levels. We conclude that serum γ-IFN levels are related to glomerualr HLA-DQ and Ki-67 expression and acute exacerbation in patients with IgA nephropathy. These data suggest that γ-IFN and MHC class II antigens play an important role in the immune-mediated glomerular injury of IgA nephropathy.