RESUMO
Sympathetic nervous system (SNS) activity, measured by norepinephrine (NE) turnover rate, was greater in the posterior hypothalamic (PH) nuclei, the paraventricular nuclei (PVN), and the locus coeruleus (LC) of 5/6 nephrectomised (CRF) rats than of control rats. NE secretion from the PH was also greater in CRF than in control rats. These findings demonstrate that SNS activity plays an important role in the genesis of hypertension associated with CRF. The increase in central SNS activity was mitigated by increased local expression of nitric oxide synthase (NOS)-mRNA and nitric oxide (NOx) production. Because angiotensin II may stimulate the central SNS, we tested the hypothesis that losartan, a specific angiotensin II AT(1)-receptor antagonist, may lower blood pressure (BP), at least in part, by central noradrenergic inhibition. To this end, we studied two groups of CRF rats. One group received losartan (10 mg/kg body weight) in drinking water between the 3rd and 4th week after nephrectomy, the second group received drinking water without losartan. SNS activity was measured by NE secretion from the PH using the microdialysis technique. NOS-mRNA gene expression was also measured by RT-PCR in the PH, PVN, and LC of CRF and control rats. Losartan reduced systolic BP from 184+/-3.7 to 152+/-3.1 mmHg and NE secretion from the PH from 340+/-9.7 to 247+/-4.8 pg/ml. CRF rats treated with losartan manifested a significant (p<0.01) increase in the expression of nNOS-mRNA in the PH (from 84+/-1.2 to 99+/-2.6), the PVN (from 44+/-1.5 to 63+/-2.1), and the LC (from 59+/-6.7 to 76+/-2.1). CRF rats also manifested a significant increase (p<0.01) in the expression of IL-1beta the PH (from 41.6+/-2.8 to 54.3+/-1.4), PVN (from 44+/-1.9 to 54+/-1.5), and LC (from 35.5+/-1.6 to 53.5+/-1.9). In conclusion, these studies suggest that the antihypertensive action of losartan in CRF rats may be mediated, at least in part, by inhibition of central SNS outflow. The studies also suggest that the inhibitory action of losartan on the SNS may be mediated by activation of IL-1beta, which, in turn, stimulates nNOS, an important modulator of central SNS activity.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Falência Renal Crônica/fisiopatologia , Losartan/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Antagonistas de Receptores de Angiotensina , Animais , Pressão Sanguínea/efeitos dos fármacos , Hipotálamo Posterior/metabolismo , Interleucina-1/genética , Masculino , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo I , Norepinefrina/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de AngiotensinaAssuntos
Proteínas de Ligação ao GTP/genética , Genes de Protozoários , Proteínas de Membrana , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Fatores de Ribosilação do ADP , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Primers do DNA/genética , DNA de Protozoário/genética , Humanos , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
Recent studies suggest that nitric oxide (NO) may regulate hormone biosynthesis and secretion. This was tested by treating male rats with NG-nitro-L-arginine methyl ester (NAME), a NO synthase inhibitor, and measuring serum and testicular interstitial fluid testosterone and serum corticosterone, luteinizing hormone (LH), and prolactin (PRL). The effect of NG-nitro-L-arginine (NA), a less-soluble form of the same NO synthase inhibitor, on the reproductive suppressant actions of alcohol was also examined. NAME increased testosterone and corticosterone secretion dose-dependently without affecting LH and PRL secretion. The alcohol-induced suppression of testosterone or LH secretion was not altered by treatment with NA. Although effects of NAME and NA on other systems may be involved, these results indicate that testicular and adrenal steroidogenesis are negatively regulated by endogenous NO and that NO does not regulate LH and PRL secretion or inhibit the testicular steroidogenic pathway in the same way as alcohol.
