Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K+ channel-dependent decrease in blood pressure in freely moving rats.

Hydrogen sulfide (H2S) is a naturally occurring gas that may act as an endogenous signaling molecule. In the brain, H2S is mainly produced by cystathionine beta-synthase (CBS) and its cellular effects have been attributed to interactions with N-methyl-D-aspartate (NMDA) receptors and cyclic adenosine 3',5'-monophosphate (cAMP). In contrast, direct vasodilator actions of H2S are most probably mediated by opening smooth muscle ATP-sensitive K+ (K(ATP)) channels. In the hypothalamus, K(ATP) channel-dependent mechanisms are involved in CNS-mediated regulation of blood pressure. In this report, we investigated the hypothesis that H2S may act via K(ATP) channels in the hypothalamus to regulate blood pressure. Mean arterial blood pressure (MAP) and heart rate were monitored in freely moving rats via a pressure transducer placed in the femoral artery. Drugs were infused via a cannula placed in the posterior hypothalamus. Infusion of 200 microM sodium hydrogen sulfide (NaHS), an H2S donor, into the hypothalamus of freely moving rats reduced MAP and heart rate. Infusion of 300 nM to 3 microM gliclazide dose-dependently blocked the effect of 200 microM NaHS. Infusion of the CBS activator, s-adenosyl-L-methionine (0.1 mM and 1 mM), likewise decreased MAP. Infusion of the CBS inhibitors aminooxyacetic acid (10 mM) and hydroxylamine (20 mM) increased MAP but did not block the effects of infusion of 200 microM NaHS. These data indicate that actions of H2S in the hypothalamus decrease blood pressure and heart rate in freely moving rats. This effect appears to be mediated by a K(ATP) channel-dependent mechanism and mimicked by endogenous H2S.

L-NG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse.

1. L-NG-nitro arginine methyl ester (L-NAME, 1-75 mg kg-1) administered intraperitoneally (i.p.) elicits dose-related antinociception in the mouse assessed by the formalin-induced paw licking procedure. Antinociceptive activity is still present 24 h after injection. L-NAME (75 mg kg-1, i.p.) is also antinociceptive in the acetic acid-induced abdominal constriction and hot plate procedures. 2. L-NAME additionally produces a dose-related inhibition of formalin-induced paw licking following intracerebroventricular (i.c.v., 0.1-100 microgram per mouse) and oral (p.o., 75-150 mg kg-1) administration. 3. L-Arginine (600 mg kg-1, i.p.) but not D-arginine (600 mg kg-1) or naloxone (5 mg kg-1) reverses the antinociceptive effect of L-NAME in the formalin test. 4. High doses of L-NAME (37.5-600 mg kg-1) but not D-NAME (75 mg kg-1) administered i.p. produce dose-related increases in blood pressure of the urethane-anaesthetized mouse whilst i.c.v. injected L-NAME (0.1 and 100 microgram per mouse) in inactive. 5. L-NAME (75 mg kg-1, i.p.) did not inhibit oedema formation in the formalin-injected mouse hindpaw. 6. L-NAME (75 mg kg-1) did not produce any overt behavioural changes in treated mice and failed to influence locomotor activity or the incidence of dipping, crossing, rearing or circling behaviour assessed by a modified 'head-dipping' board procedure. A high dose of L-NAME (600 mg kg-1) reduced dipping behaviour and locomotor activity suggesting a possible sedative effect. D-NAME (600mgkg 1) was inactive. 7. These results suggest that L-NAME produces an opioid-independent and long-lasting antinociception in the mouse most probably by a direct effect within the central nervous system.