ROLE OF NITRIC-OXIDE SYNTHASE INHIBITION IN THE ACUTE HYPERTENSIVE RESPONSE TO INTRACEREBROVENTRICULAR CADMIUM

1 In the rat, intracerebroventricular (i.c.v.) injection of cadmium, a pollutant with long biological half-life, causes a sustained increase in blood pressure at doses that are ineffective by peripheral route. Since cadmium inhibits calcium-calmodulin constitutive nitric oxide (N O) synthase in cytosolic preparations of rat brain, this mechanism may be responsible for the acute presser action of this heavy metal. 2 To test this possibility, we evaluated the effect of i.c.v. injection of 88 nmol cadmium in normotensive unanaesthetized Wistar rats, which we re i.c.v. pre-treated with: (1) saline (control), (2) L-arginine (L-Ar g), to increase the availability of substrate for NO biosynthesis, (3) D-arginine (D-Arg), (4) 3-[4-morpholinyl]-sydnonimine-hydrochloride ( SIN-1), an NO donor, or (5) CaCl2, a cofactor of brain calcium-calmodu lin-dependent cNOS(I). In additional experiments, the levels of L-citr ulline (the stable equimolar product derived from enzymatic cleavage o f L-Arg by NO synthase) were determined in the brain of vehicle-or cad mium-treated rats. 3 The presser response to cadmium reached its nadir at 5 min (43+/-4 mmHg) and lasted over 20 min in controls. L-Citrulli ne/protein content was reduced from 35 up to 50% in the cerebral corte x, pens, hippocampus, striatus, hypothalamus (P<0.01) of cadmium-treat ed rats compared with controls. Central injection of N-G nitro-l-argin ine-methylester (L-NAME) also reduced the levels of L-citrulline in th e brain. 4 Both the magnitude and duration of the response were attenu ated by 1.21 and 2.42 mu mol SIN-1 (32+/-3 and 15+/-4 mmHg, P<0.05), o r I mu mol CaCl2 (6+/-4 mmHg, P<0.05). Selectivity of action exerted b y SIN-1 was confirmed by the use of another NO donor, S-nitroso-N-acet yl-penicillamine (SNAP). Both L-Arg and D-Arg caused a mild but signif icant attenuation in the main phase of the presser response evoked by cadmium. However, only L-Arg reduced the magnitude of the delayed, pre sser response. Despite their similarity in ability to attenuate the ca dmium-induced pressure effect, L-Arg and its isomer exerted differenti al biochemical changes in brain L-citrulline, as L-Arg normalized cadm ium-induced reduction in L-citrulline levels, whereas i.c.v. D-Arg did not. 5 We conclude that the presser effect of i.c.v. cadmium is due, at least in part, to reduced NO formation, consequent to inhibition of brain NO synthase. Accumulation of cadmium in the central nervous sys tem could interfere with central mechanisms (including NO synthase) im plicated in the regulation of cardiovascular function.