HYPOTHALAMIC HYPERTENSIVE FACTOR - AN INHIBITOR OF NITRIC-OXIDE SYNTHASE ACTIVITY

Human and rat plasma and rat hypothalamus contain a cytochemically det ectable substance, the concentration of which rises with an increase i n salt intake. The plasma concentration of this material is also raise d in essential hypertension and in the spontaneously hypertensive rat (SHR), the Milan hypertensive rat, and the reduced renal mass (RRM) hy pertensive rat. In the normal rat, the greatest concentration is found in the hypothalamus of the SHR and the RRM hypertensive rat. The phys icochemical characteristics of this cytochemically detectable hypothal amic hypertensive factor (HHF), including chromatographic behavior and molecular weight range, suggest that it may share features common to a substituted guanidine that is present in established nitric oxide sy nthase (NOS) inhibitors. It was therefore decided to determine the eff ect on NOS activity of the HHF obtained from mature SHR. The ability o f HHF to inhibit NOS activity was studied on (1) NOS extracted from bo vine aorta, rat brain, and human platelets by measuring the conversion of radiolabeled L-arginine to L-citrulline and (2) rat liver NOS meas ured indirectly with a cytochemical technique based on the stimulation of soluble guanylate cyclase activity in hepatocytes by NO. HHF showe d a biphasic inhibitory action on platelet NOS activity that was great er with HHF obtained from SHR than from Wistar-Kyoto rats. HHF also ha d a biphasic inhibitory effect on hepatocyte NOS activity that was mor e potent when obtained from SHR. It is proposed that the increase in H HF, a novel form of NOS inhibitor that is elevated in SHR, may be invo lved in the rise in arterial pressure.