Hypothalamic hypertensive factor: an inhibitor of nitric oxide synthase activity

Human and rat plasma and rat hypothalamus contain a cytochemically detectable substance, the concentration of which rises with an increase in salt intake. The plasma concentration of this material is also raised in essential hypertension and in the spontaneously hypertensive rat (SHR), the Milan hypertensive rat, and the reduced renal mass (RRM) hypertensive rat. In the normal rat, the greatest concentration is found in the hypothalamus of the SHR and the RRM hypertensive rat. The physicochemical characteristics of this cytochemically detectable hypothalamic 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 synthase (NOS) inhibitors. It was therefore decided to determine the effect on NOS activity of the HHF obtained from mature SHR. The ability of HHF to inhibit NOS activity was studied on (1) NOS extracted from bovine aorta, rat brain, and human platelets by measuring the conversion of radiolabeled L-arginine to L-citrulline and (2) rat liver NOS measured indirectly with a cytochemical technique based on the stimulation of soluble guanylate cyclase activity in hepatocytes by NO. HHF showed a biphasic inhibitory action on platelet NOS activity that was greater with HHF obtained from SHR than from Wistar-Kyoto rats. HHF also had a biphasic inhibitory effect on hepatocyte NOS activity that was more potent when obtained from SHR. It is proposed that the increase in HHF, a novel form of NOS inhibitor that is elevated in SHR, may be involved in the rise in arterial pressure.