Signal transduction involving Ras-GTPase contributes to development of hypertension and end-organ damage in spontaneously hypertensive rats-treated with L-NAME

The purpose of this study was to examine the effect of inhibition of Ras-GTPase mediated signalling on the development of hypertension and end-organ damage in spontaneously hypertensive rats chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). Administration of L-NAME in drinking water (80 mg/L) for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223 +/- 4 mmHg) as compared to that of SHR controls (165 +/- 3 mmHg). The administration of Ras-GTPase inhibitor FPTIII (232 ng/min) to SHR-L-NAME during the last 6 days significantly attenuated high blood pressure (192 +/- 4 mmHg). Morphological studies of the kidneys and hearts showed that treatment with FPTIII minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. L-NAME-induced increase in urine volume and protein was also significantly lower in FPTIII-treated animals. The impaired vascular responsiveness to isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly attenuated by FPTIII treatment. In isolated per-fused hearts, recovery of left ventricular function from a 40 min of global ischemia was significantly better in FPTIII-treated SHR-L-NAME. Treatment with FPTIII also significantly reduced expression of cardiac sodium-hydrogen exchanger-1 (NHE-1) which was elevated in SHR-L-NAME. These data indicate that inhibition of Ras-GTPase-mediated signalling can attenuate end-organ damage during severe hypertension and endothelial dysfunction. (c) 2005 Elsevier Ltd. All rights reserved.
The purpose of this study was to examine the effect of inhibition of Ras-GTPase mediated signalling on the development of hypertension and end-organ damage in spontaneously hypertensive rats chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). Administration of L-NAME in drinking water (80 mg/L) for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223+/-4 mmHg) as compared to that of SHR controls (165+/-3 mmHg). The administration of Ras-GTPase inhibitor FPTIII (232 ng/min) to SHR-L-NAME during the last 6 days significantly attenuated high blood pressure (192+/-4 mmHg). Morphological studies of the kidneys and hearts showed that treatment with FPTIII minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. L-NAME-induced increase in urine volume and protein was also significantly lower in FPTIII-treated animals. The impaired vascular responsiveness to isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly attenuated by FPTIII treatment. In isolated perfused hearts, recovery of left ventricular function from a 40 min of global ischemia was significantly better in FPTIII-treated SHR-L-NAME. Treatment with FPTIII also significantly reduced expression of cardiac sodium-hydrogen exchanger-1 (NHE-1) which was elevated in SHR-L-NAME. These data indicate that inhibition of Ras-GTPase-mediated signalling can attenuate end-organ damage during severe hypertension and endothelial dysfunction.