Impaired hypotensive responses induced by intrathecally injected drugs in fructose-fed rats.

Blood pressure responses to intrathecal (i.t.) injection of neurochemicals were examined in the fructose-fed rat, an experimental model of metabolic syndrome.Sprague-Dawley rats receiving either tap water or water containing 10% fructose during 8 weeks were anesthetized with sodium pentobarbital. The endocannabinoid anandamide (100 nmol; i.t.) decreased mean blood pressure in control rats (-21.2 ± 6.3 mm Hg), but had no effect in fructose-fed animals. Similarly, calcitonin gene-related peptide (CGRP; 0.125 nmol; i.t.) decreased mean blood pressure in control, but not in treated rats. The high fructose diet did not cause significant changes in the pressor effects of i.t. administered noradrenaline (100 nmol) and N-methyl-d-aspartate (30 nmol). The nitric oxide donor sodium nitroprusside (500 nmol, i.t.) induced a brief hypotension followed by a sustained increase in mean blood pressure in control rats; however, this drug only produced pressor effects in fructose-fed animals. The GABAA-receptor agonist muscimol (8.8 nmol, i.t.) and the GABAB-receptor agonist baclofen (100 nmol, i.t.) decreased mean blood pressure 30-35 mm Hg, both in control and in fructose-fed rats. Fructose potentiated the pressor effect of i.v. injected noradrenaline, but did not modify the hypotensive responses to i.v. administered sodium nitroprusside and acetylcholine.These results could suggest that, in pentobarbital-anesthetized rats, fructose feeding could alter spinal mechanisms of regulation of preganglionic sympathetic nerve activity. It is proposed that the spinal cord could be involved in the sympathetic dysfunction associated with the metabolic syndrome.

Sex-linked differences in the vasorelaxant effects of anandamide in vascular mesenteric beds: role of oestrogens.

Anandamide (0.01 to 10 microM) caused greater concentration-dependent reductions of the contractile-induced responses to noradrenaline in female than in male mesenteric vascular beds isolated from adult Sprague-Dawley rats. Greater relaxant responses in females were also induced by the vanilloid TRPV1 receptor agonist capsaicin (0.01 to 10 microM), whereas no sex differences were observed for the relaxations caused by either acetylcholine or sodium nitroprusside. The effect of anandamide in either sex was reduced by the vanilloid TRPV1 receptor antagonist capsazepine but not by the cannabinoid CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR141716A). In males, the anandamide-induced relaxations were potentiated by in vitro exposure during 5 min to 0.5 microM 17beta-oestradiol and unmodified by the protein synthesis inhibitor cycloheximide. The vasorelaxant effects of anandamide in female rats were decreased by ovariectomy. This decrease was prevented by in vivo treatment with 17beta-oestradiol-3-benzoate (450 microg/kg i.m., once a week during 3 weeks) and counteracted by in vitro exposure to oestrogen. In vivo treatment with 17beta-oestradiol also potentiated anandamide-induced responses in males. In conclusion, this study shows an oestrogen-dependent sensitivity to the vanilloid TRPV1 receptor-mediated vasorelaxant effects of anandamide in the mesenteric vasculature of Sprague-Dawley rats, that could be mediated by both genomic and non-genomic mechanisms.

Potentiation of anandamide effects in mesenteric beds isolated from endotoxemic rats.

The aim of the present experiments was to study the effects of exogenously added anandamide on transient norepinephrine (NE)-induced contractions in mesenteric beds isolated from adult male Sprague-Dawley rats 6 h after the i.p. administration of 5 mg kg(-1) lipopolysaccharide (LPS). LPS treatment induced a 3-fold increase in total nitric-oxide synthase (NOS) activity without modifying either the systolic blood pressure or the vascular reactivity to NE of the isolated mesenteric bed. The endocannabinoid anandamide (0.01-10 microM) caused concentration-dependent reductions of the contractile responses to NE in the isolated mesenteric bed. This effect was significantly potentiated after LPS treatment compared with the controls. Anandamide-induced reductions of the contractile responses to NE in mesenteric beds isolated from LPS-treated rats were unmodified by endothelium removal but significantly diminished by either the anandamide amidase inhibitor phenylmethylsulfonyl fluoride (200 microM) or the vanilloid receptor antagonist capsazepine (1 microM). The vanilloid receptor agonist capsaicin (0.01-100 nM) also caused concentration-dependent relaxations that were potentiated in mesenteric beds from LPS-treated rats. Nevertheless, they were unmodified by 1 microM capsazepine. It is concluded that the potentiation of anandamide relaxations after LPS treatment, which are evident at early stages of endotoxic shock, could involve the participation of an anandamide metabolite and might be mediated, at least in part, through a vanilloid receptor.