pituitrin and luzindole

Melatonin exerts its biological role acting via G protein-coupled membrane receptors - MT1 and MT2, as well as through cytoplasmic and/or nuclear receptors. Melatonin has previously been shown to change vasopressin (AVP) and adrenocorticotropic hormone (ACTH) secretion dependently on its concentration. To determine whether the response of vasopressinergic neurones to different concentrations of melatonin is mediated through the membrane MT1 and/or MT2 receptors, the influence of luzindole - an antagonist of both MT1 and MT2 receptors, and 4-phenyl-2-propionamidotetralin (4-P-PDOT) - a selective MT2 receptor antagonist, on melatonin-dependent AVP release from the rat hypothalamo-neurohypophysial (H-NH) system was studied in vitro (melatonin at the concentrations of 10(-9), 10(-7) and 10(-3) M) and in vivo (melatonin at the concentrations of 10(-9) and 10(-7) M). Moreover, the second goal of this study was to find out whether melatonin receptors MT1 and/or MT2 are involved in the regulation of ACTH and corticosterone secretion into the blood. We have demonstrated that melatonin, at the concentrations of 10(-9) and 10(-7) M, significantly inhibited AVP secretion from isolated rat H-NH explants when antagonists solvent (i.e. 0.1% DMSO) was present in the medium. Neither luzindole, nor 4-P-PDOT, applied without melatonin, did influence AVP release in vitro. Luzindole applied together with melatonin (10(-7) M and 10(-9) M) significantly suppressed melatonin-dependent effect, while 4-PPDOT did not eliminate the inhibitory influence of 10(-7) M and 10(-9) M melatonin on AVP secretion from isolated rat H-NH explants. Melatonin at a concentration of 10(-3) M significantly increased AVP release when the H-NH explants were incubated in the medium containing luzindole or 4-P-PDOT. Under present experimental in vivo conditions, infused intracerebroventricularly (i.c.v.) melatonin, at a concentration close to its physiological level in the blood, significantly diminished AVP secretion into the blood, however, at higher concentration (10(-7) M) it remained inactive in this process. Moreover, melatonin at both concentrations of 10(-9) M and 10(-7) M, was able to inhibit AVP secretion into the blood (and increase its neurohypophysial content) when animals were previously i.c.v. injected with 4-P-PDOT, but not with luzindole. Blood plasma concentration of ACTH was diminished significantly by 10(-7) M melatonin in DMSO-infused, but not in luzindole- or 4-P-PDOT-injected rats

Topics: Adrenocorticotropic Hormone; Animals; Corticosterone; Hypothalamo-Hypophyseal System; Male; Melatonin; Rats, Wistar; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Tetrahydronaphthalenes; Tryptamines; Vasopressins

1. Vasoconstrictor effects of melatonin were examined in isolated rat tail arteries mounted either in an isometric myograph or as cannulated pressurized segments. Melatonin failed by itself to mediate observable responses but preactivation of the arteries with vasopressin (AVP) reliably uncovered vasoconstriction responses to melatonin with maxima about 50% of maximum contraction. Further experiments were conducted with AVP preactivation to 5-10% of the maximum contraction. 2. Responses to melatonin consisted of steady contractions with superimposed oscillations which were large and irregular in isometric but small in isobaric preparations. Nifedipine (0.3 microM) reduced the responses and abolished the oscillations. Charybdotoxin (30 nM) increased the magnitude of the oscillations with no change in the maximum response. 3. Forskolin (0.6 microM) pretreatment increased the responses to melatonin compared to control and sodium nitroprusside (1 microM) treated tissues. The AVP concentration required for preactivation was 10 fold higher than control in both the forskolin and nitroprusside treated groups. 4. In isometrically-mounted arteries treated with nifedipine, melatonin receptor agonists had the potency order 2-iodomelatonin > melatonin > S20098 > GR196429, and the MT2-selective antagonist luzindole antagonized the effects of melatonin with a low pK(B) of 6.1+/-0.1. 5. It is concluded that melatonin elicits contraction of the rat tail artery via an mt1 or mt1-like receptor that couples via inhibition of adenylate cyclase and opening of L-type calcium channels. Calcium channels and charybdotoxin-sensitive K channels may be recruited into the responses via myogenic activation rather than being coupled directly to the melatonin receptors. 6. It is proposed that the requirement of preactivation for overt vasoconstrictor responses to melatonin results from the low effector reserve of the melatonin receptors together with the tail artery having threshold inertia. Potentiative interactions between melatonin and other vasoconstrictor stimuli probably also result from the threshold inertia. A simple model is presented and a general framework for consideration of interactions between weak vasoconstrictor agonists and other vasoconstrictor stimuli is discussed.

Topics: Acetamides; Animals; Anticonvulsants; Arteries; Calcium Channel Blockers; Charybdotoxin; Colforsin; Dose-Response Relationship, Drug; Hypnotics and Sedatives; In Vitro Techniques; Indoles; Male; Melatonin; Nifedipine; Nitroprusside; Potassium Channels; Rats; Rats, Sprague-Dawley; Tail; Tryptamines; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents; Vasopressins