SLC-1 receptor mediates the effect of melanin concentrating hormone on feeding behavior in the rat: a structure activity study. J Pharmacol Exp Ther 299,

ABSTRACT Several studies have shown that melanin-concentrating hormone (MCH) is an orexigenic peptide in rat. In the present study, a structure-activity relationship with MCH analogs was performed in rat, both in vitro and in vivo. On rat recombinant SLC-1 receptor, both cAMP inhibition and [ 125 I]S36057 binding were measured. In vivo, these analogs were injected intracerebroventricularly in rats and their effects were evaluated upon food intake. First, data obtained with the rat recombinant receptor were highly correlated with those obtained from its human counterpart. Second, agonist potencies in the cAMP assay were also highly correlated with binding affinities. These peptides could be classified into several groups according to their potency at the SLC-1 receptor (from subnanomolar activity to complete inactivity). Indeed, there was a strong correlation between their effects upon food intake and the results obtained at the rat SLC-1 receptor. The present report describes for the first time the rat SLC-1 receptor pharmacology and clearly establishes the relevance of the SLC-1 receptor in feeding behavior. The rat/human melanin-concentrating hormone (MCH) consists of a 19 amino acid sequence presenting a high homology with the fish peptide originally describe

Cannabinoid CB(1) receptor and endothelium-dependent hyperpolarization in guinea-pig carotid, rat mesenteric and porcine coronary arteries

1. The purpose of these experiments was to determine whether or not the endothelium-dependent hyperpolarizations of the vascular smooth muscle cells (observed in the presence of inhibitors of nitric oxide synthase and cyclo-oxygenase) can be attributed to the production of an endogenous cannabinoid. 2. Membrane potential was recorded in the guinea-pig carotid, rat mesenteric and porcine coronary arteries by intracellular microelectrodes. 3. In the rat mesenteric artery, the cannabinoid receptor antagonist, SR 141716 (1 μM), did not modify either the resting membrane potential of smooth muscle cells or the endothelium-dependent hyperpolarization induced by acetylcholine (1 μM) (17.3±1.8 mV, n=4 and 17.8±2.6 mV, n=4, in control and presence of SR 141716, respectively). Anandamide (30 μM) induced a hyperpolarization of the smooth muscle cells (12.6±1.4 mV, n=13 and 2.0±3.0 mV, n=6 in vessels with and without endothelium, respectively) which could not be repeated in the same tissue, whereas acetylcholine was still able to hyperpolarize the preparation. The hyperpolarization induced by anandamide was not significantly influenced by SR 141716 (1 μM). HU-210 (30 μM), a synthetic CB(1) receptor agonist, and palmitoylethanolamide (30 μM), a CB(2) receptor agonist, did not influence the membrane potential of the vascular smooth muscle cells. 4. In the rat mesenteric artery, the endothelium-dependent hyperpolarization induced by acetylcholine (1 μM) (19.0±1.7 mV, n=6) was not altered by glibenclamide (1 μM; 17.7±2.3 mV, n=3). However, the combination of charybdotoxin (0.1 μM) plus apamin (0.5 μM) abolished the acetylcholine-induced hyperpolarization and under these conditions, acetylcholine evoked a depolarization (7.7±2.7 mV, n=3). The hyperpolarization induced by anandamide (30 μM) (12.6±1.4 mV, n=13) was significantly inhibited by glibenclamide (4.0±0.4 mV, n=4) but not significantly affected by the combination of charybdotoxin plus apamin (17.3±2.3 mV, n=4). 5. In the guinea-pig carotid artery, acetylcholine (1 μM) evoked endothelium-dependent hyperpolarization (18.8±0.7 mV, n=15). SR 141716 (10 nM to 10 μM), caused a direct, concentration-dependent hyperpolarization (up to 10 mV at 10 μM) and a significant inhibition of the acetylcholine-induced hyperpolarization. Anandamide (0.1 to 3 μM) did not influence the membrane potential. At a concentration of 30 μM, the cannabinoid agonist induced a non-reproducible hyperpolarization (5.6±1.3 mV, n=10) with a slow onset. SR 141716 (1 μM) did not affect the hyperpolarization induced by 30 μM anandamide (5.3±1.5 mV, n=3). 6. In the porcine coronary artery, anandamide up to 30 μM did not hyperpolarize or relax the smooth muscle cells. The endothelium-dependent hyperpolarization and relaxation induced by bradykinin were not influenced by SR 141716 (1 μM). 7. These results indicate that the endothelium-dependent hyperpolarizations, observed in the guinea-pig carotid, rat mesenteric and porcine coronary arteries, are not related to the activation of cannabinoid CB(1) receptors