Genetic Variants on Rat Chromosome 8 Exhibit Profound Effects on Hypertension Severity and Survival During Nitric Oxide Inhibition in Spontaneously Hypertensive Rats

BACKGROUND: Hypertension and mortality is aggravated by nitric oxide inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHRs) but not in Munich Wistar Frömter (MWF) rats. MWF rats carry major albuminuria quantitative trait loci on rat chromosome (RNO) 6 and RNO8; susceptibility of SHRs to L-NAME is enhanced by transfer of RNO6 from MWF rats into the SHR background. Here, we tested whether the sensitivity to L-NAME in SHRs is affected by transfer of RNO8 from MWF rats in consomic SHR-8(MWF) rats. METHODS: In study 1, we analyzed survival in male SHR and SHR-8(MWF) rats in response to 18 weeks of treatment with either normal drinking water (vehicle-treated) or water containing 20mg/L L-NAME. In study 2, we analyzed blood pressure and renal damage in both strains in response to 6 weeks of treatment with L-NAME compared with vehicle-treated groups. RESULTS: In study 1, starting after 6 weeks of treatment with L-NAME, mortality reached 90% in SHRs in contrast with the group of L-NAME treated SHR-8(MWF) rats (P < 0.0001) in which all rats survived similar to vehicle-treated rats. In study 2, L-NAME resulted in a more pronounced increase in mean arterial blood pressures in SHRs compared with SHR-8(MWF) rats (216 ± 6 vs. 180 ± 11 mm Hg; P < 0.05). In contrast, tubulointerstitial kidney damage was even lower in SHRs compared with SHR-8(MWF) rats after L-NAME treatment (P < 0.05), whereas albuminuria was not different between strains. CONCLUSIONS: The blood pressure increase and impaired survival of SHRs in response to nitric oxide inhibition is profoundly influenced by genes on RNO8.