Interactions between the heme oxygenase, cyclooxygenase and nitric oxide synthase pathways in the regulation of the resting hypothalamic blood flow

Abstract

The heme-oxgenase (HO) – carbon monoxide (CO) pathway has been reported to evoke direct vascular effects and to influence other vasoregulatory mechanisms like the cyclooxygenase (COX) and nitric oxide synthase (NOS) systems. Since the hypothalamus expresses relatively high HO, COX and NOS levels compared to other brain regions, we have hypothesized interactions among these pathways in the regulation of the resting local hypothalamic tissue blood flow (HBF). Therefore, we have investigated whether inhibition of the COX and NOS pathways influences the alterations of the HBF that develop after HO blockade. Adult male Wistar rats were anaesthetized with 1.3 g/kg urethane. The femoral arteries were cannulated for measurement of the mean arterial pressure (MAP) and for blood sampling. HBF was measured by use of the hydrogen gas-clearance method. HO-blockade was induced by ip. injection of 45 imol/kg zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG). In the first group of the animals HBF, MAP and blood gas measurements were performed under physiological conditions. In the second and third experimental groups the animals received diclofenac (10 mg/kg iv.) or NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg iv.) pretreatment in order to inhibit prostanoid- or NO-synthesis, respectively. In the fourth group the animals received combined diclofenac and L-NAME pretreatment. In all groups HBF values were determined before and after the pretreatment as well as after the induction of HO-blockade. Baseline arterial pO2, pCO2 and pH values were within the physiological range and did not change throughout the experiments. In animals pretreated with L-NAME or with diclofenac+L-NAME the MAP was significantly higher (1435 mmHg and 1386 mmHg, respectively) than in controls (995 mmHg) or after diclofenac pretreatment alone (957 mmHg). ZnDPBG administration, however, did not influence the MAP in any of the experimental groups. L-NAME and diclofenac+L-NAME pretreatments markedly reduced the HBF (from 0.900.10 to 0.550.09 ml/g/min and from 0.790.11 to 0.440.11 ml/g/min, respectively) while diclofenac alone had no significant effect (0.840.09 vs. 0.880.10 ml/g/min). ZnDPBG administration in control animals did not influence the HBF (-0.34.1 %), but significantly increased it by 15.52.9 % after diclofenac pretreatment. In contrast, ZnDPBG induced a marked reduction (-20.65.6 %) of the HBF in animals pretreated with L-NAME. In animals receiving both diclofenac and L-NAME pretreatment the HBF remained unchanged after ZnDPBG administration (+5.95.4 %). Our observations indicate that the HO pathway interacts with both the COX and the NOS systems in the regulation of the hypothalamic circulation. Endogenous CO production appears to increases the HBF via a COX-dependent mechanism, but at the same time suppresses NOS activity which leads to the reduction of HBF. These effects of CO may neutralize each other under physiological conditions. In pathophysiological states, however, which are associated with altered COX or NOS activity, the HO pathway may significantly influence the resting CBF.