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© Copyright 2004 The British Pharmacological Society

008P GKT, University of London
Winter Meeting December 2003

Effects of chronic nitric oxid inhibition on endothelin-induced increase in cardiac inositol phosphate formation in uremic rats


Barbara Miletzki, Kirsten Leineweber, O.-E. Brodde Depts. of Pathophysiology and Nephrology, University of Essen School of
Medicine, D-45147 Essen/Germany.

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Miletzki B
Leineweber K
Brodde OE

Endothelin (ET) receptors, coupled via the Gq/11-protein with the phospholipase C (PLC)/inositol phosphate (IP)/ diacyl glycerol (DAG) system, exert a positive inotropic effect on the heart. On the other hand, growing evidence has accumulated that in the myocardium nitric oxide (NO) can inhibit contractility. The aim of the study was to investigate the effects of nitric oxide synthase inhibition with the L-arginine analog NG-nitro-L-arginine methyl ester (L-NAME) on the endothelin (ET)-induced increase in inositol phosphate (IP) formation in right (RV) and left ventricles (LV) of control (SOP) and uremic rats (SNX). Renal failure was induced by a two-stage 5/6 nephrectomy. SOP and SNX rats were studied separately and subdivided into two groups: SOP (A), SOP + L-NAME (B) and SNX (C), SNX + L-NAME (D), respectively. After two weeks L-NAME treatment (SOP 65±0.2 and SNX 62±2 mg/kg/day) systolic blood pressure measured by a tail-cuff method was significantly increased in SOP (A: 114±1.7 vs. B: 157±5.6 mmHg; n=10/6, p<0.05) as well as SNX rats (C: 127±7.2 vs. D: 176±8.2 mmHg; n=6/10, p<0.05). Accordingly, LV/body weight-ratio was significantly increased in SOP (A: 2.0±0.04 vs. B: 2.3±0.01 mg/g; n=10/6, p<0.05) and SNX rats (C: 2.2±0.07 vs. D: 2.5±0.06 mg/g; n=6/10, p<0.05). On the other hand, plasma noradrenaline level was not affected in SOP (A: 281±26 vs. B: 275±35 pg/ml; n=9/10), but significantly attenuated in SNX rats after L-NAME treatment (C: 436±46 vs. D: 310±25 pg/ml; n=6/10, p<0.05). ET (1 nM-1µM) caused in tissue slices obtained from RV and LV of SOP and SNX rats concentration-dependent increases in IP formation.

Whereas in RV slices L-NAME treatment had no influence on Emax-values for ET-induced IP formation in SOP (1 µM ET, A: 175±17 vs. B: 156±19 % above basal; n=8/6) and SNX rats (C: 185±27 vs. D: 229±18 % above basal; n=6/8), Emax-values for ET-induced IP formation were significantly decreased in LV slices of SOP rats (A: 179±9 vs. B: 128±22 % above basal; n=8/6, p<0.05), but significantly increased in LV slices of SNX-rats (C: 126±17 vs. 192±20 % above basal; n=6/8, p<0.05).

In conclusion: These results show that NO inhibition affects ET-induced IP-formation in a tissue-dependent manner.