GENE-EXPRESSION OF BRAIN NITRIC-OXIDE SYNTHASE AND SOLUBLE GUANYLYL CYCLASE IN HYPOTHALAMUS AND MEDULLA OF 2-KIDNEY, ONE-CLIP HYPERTENSIVE RATS

Nitric oxide may act at autonomic sites in the brain to regulate arterial blood pressure. Our goal was to determine whether gene expressions of the brain isoform of nitric oxide synthase and of the beta subunit of soluble guanylyl cyclase, the target of nitric oxide, were altered in discrete autonomic brain regions after induction of hypertension in rats. The two-kidney, one clip model was used to induce hypertension, and measurements were made 3 and 6 weeks after the left renal artery was clipped. Only experimental rats with blood pressures elevated by at least 25 mm Hg were used. Total RNA was purified from microdissected tissue blocks containing hypothalamus, dorsal medulla, rostral ventrolateral medulla, and caudal ventrolateral medulla. Changes in nitric oxide synthase and guanylyl cyclase mRNA were semiquantified in each region by use of reverse transcription-polymerase chain reactions in which known concentrations of deletion mutants of the two genes were coampiified as internal standards. Compared with controls, significant decreases and increases in nitric oxide synthase mRNA were found in the hypothalamus (x2.2) and caudal ventrolateral medulla (X6.4), respectively, of hypertensive rats 3 weeks after clipping. These alterations were reversed in hypertensive rats at 6 weeks; levels increased (x4.6) in the hypothalamus and decreased (x5.5) in the caudal ventrolateral medulla. Changes in guanylyl cyclase expression paralleled those for nitric oxide synthase in some but not all areas at both time points. Changes in nitric oxide synthase gene expression in the hypothalamus and the so-called depressor caudal ventrolateral medulla support the hypothesis that nitric oxide participates in the response of the central nervous system to increases in blood pressure. Reversal of responses at 6 weeks after clipping may be related to the different phases of hypertension that occur in this model. Finally, while guanylyl cyclase is thought to be the primary target of nitric oxide, regional differences in expression of nitric oxide synthase and soluble guanylyl cyclase suggest that the two genes are differentially regulated in some parts of the brain.