Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. We have used the isolated, buffer-perfused, superior mesenteric arterial bed of male and female rats to assess the relative contributions of nitric oxide (NO) and the endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxations to carbachol. 2. Carbachol caused dose-related relaxations of methoxamine-induced tone in mesenteric vascular beds from male rats described by an ED50(M) of 0.43+/-0.15 nmol and a maximum relaxation (Rmax(M) of 89.6+/-1.2% (n=28) which were not significantly different from those observed in mesenteries from female rats (ED50(F)=0.72+/-0.19 nmol and Rax(F)=90.7+/-0.9%; n=22). 3. In the males, the addition of 100 microM NG-nitro-L-arginine methyl ester (L-NAME) caused the dose-response curve to carbachol to be significantly (P<0.001) shifted to the right 15 fold (ED50(M)=6.45+/-3.53 nmol) and significantly (P<0.01) reduced Rmax(M) (79.7+/-2.8%, n=13). By contrast, L-NAME had no effect on vasorelaxation to carbachol in mesenteries from female rats (ED50(f)= 0.89+/-0.19 nmol, Rmax(F)=86.9+/-2.3%, n=9). 4. Raising tone with 60 mM KCl significantly reduced the maximum relaxation to carbachol in mesenteries from male rats 2 fold (Rmax(M)=40.3+/-9.2%, n=4; P<0.001) and female rats by 1.5 fold (Rmax(F)=55.3+/-3.3%, n=6; P<0.001), compared with methoxamine-induced tone. The potency of carbachol was also significantly reduced 1.2 fold in preparations from males (ED50(M)=0.87+/-0.26 nmol; P<0.01) but not the females (ED50(F)=4.04+/-1.46 nmol). In the presence of both 60 mM KCl and L-NAME, the vasorelaxation to carbachol was completely abolished in mesenteries from both groups. 5. The cannabinoid receptor antagonist SR141716A (1 microM), which is also a putative EDHF antagonist, had no significant effect on the responses to carbachol in mesenteries from males or females (ED50(M)=1.41+/-0.74 nmol, Rmax(M)=89.4+/-2.5%, n=7; ED50(F)=2.17+/-0.95 nmol, Rmax(F)=89.9+/-1.8%, n=9). In mesenteries from male rats, in the presence of 100 microM L-NAME, SR141716A significantly (P<0.05) shifted the dose-response curve to carbachol 8 fold further to the right than that seen in the presence of L-NAME alone (ED50(M)= 53.8+/-36.8 nmol) without affecting Rmax(M) (72.4+/-4.8%, n=10). In mesenteries from female rats, the combined presence of L-NAME and SR141716A, significantly (P < 0.01) shifted the dose-response curve to carbachol 7.5 fold, (ED50(F)=6.66+/-2.46 nmol), as compared to L-NAME alone and significantly (P<0.001) decreased Rmax(F) (70.1+/-5.5%, n=8). 6. Vasorelaxations to the nitric oxide donor sodium nitroprusside (SNP), to the endogenous cannabinoid, anandamide (a putative EDHF) and to the ATP-sensitive potassium channel activator, levcromakalim, did not differ significantly between male and female mesenteric vascular beds. 7. The continuous presence of sodium nitroprusside (SNP; 20-60 nM) had no effect on vasorelaxation to carbachol in mesenteries from either males or females. In the presence of L-NAME, SNP significantly (P<0.05) reduced the potency of carbachol 6 fold, without affecting the maximal relaxation in mesenteries from male rats (ED50(M)=40.9+/-19.6 nmol, Rmax(M)=79.4+/-2.5%, n=11). Similarly in mesenteries from female rats, the ED50(F) was also significantly (P<0.01) increased 7 fold (6.24+/-2.02 nmol), while the Rmax(F) was unaffected (81.9+/-11.0%; n=4). 8 The results of the present investigation demonstrate that the relative contributions of agonist-stimulated NO and EDHF to endothelium-dependent relaxations in the rat isolated mesenteric arterial bed, differ between males and females. Specifically, although both NO and EDHF appear to contribute towards endothelium-dependent relaxations in males and females, blockade of NO synthesis alone has no effect in the female. This suggests that EDHF is functionally more important in females; one possible explanation for this is that in the absence of NO, the recently identified ability of EDHF to compensate for the loss of NO, is functio
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PMID:Sex differences in the relative contributions of nitric oxide and EDHF to agonist-stimulated endothelium-dependent relaxations in the rat isolated mesenteric arterial bed. 960 78

The agonist-stimulated guanosine 5'-(gamma-[(35)S]thio)triphosphate binding assay was used to anatomically localize receptor-activated G-proteins by autoradiography in post mortem human brain. The optimal conditions for guanosine 5'-(gamma-[(35)S]thio)triphosphate binding to human brain sections were established in post mortem samples of the prefrontal cortex, hippocampus, basal ganglia, brainstem and cerebellar cortex. An excess of GDP (2mM) was required to decrease basal activity and obtain effective stimulation by specific agonists. guanosine 5'-(gamma-[(35)S]Thio)triphosphate binding was increased after stimulation with specific agonists of different G-protein-coupled receptors. They include cannabinoid (WIN55212-2), mu-opioid ([D-Ala(2),N-Me-Phe(4), Gly(5)-ol]enkephalin), serotonin-1A [(+/-)-8-hydroxy-2-(di-n-propylamino)tetralin] and serotonin-1B/1D (sumatriptan), cholinergic muscarinic receptors (carbachol) and alpha(2)-adrenoceptors (UK14304). Such stimulation reached 1458%, 440%, 188%, 219%, 61% and 339%, respectively, over the basal levels. In tissue sections, the use of the above-mentioned agonists (10(-4)M) showed patterns of anatomical distribution similar to those already described by receptor autoradiography, with high densities over the hippocampus (serotonin-1A receptors), cortex (alpha(2)-adrenoceptors) and striatum (mu-opioid receptors). The highest binding levels were reached with the cannabinoid receptor agonist in most of the analysed brain regions. Carbachol produced only moderate stimulation of those same regions. The blockage of agonist-stimulated guanosine 5'-(gamma-[(35)S]thio)triphosphate binding by selective antagonists verified that the effect was receptor mediated. This technique provides a method to identify modifications of the receptor-mediated activation of G-proteins in post mortem human brain with anatomical resolution. It also provides valuable information on the level of drug efficacy in the human species.
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PMID:Autoradiography of receptor-activated G-proteins in post mortem human brain. 1068 21