h-89 and alpha-methylserotonin

Serotonin (5-hydroxytryptamine [5-HT]) receptors are located in peripheral tissues as well as in the central nervous system. Serotonin receptors mediate positive inotropic and chronotropic effects in atria. The aim of this study was to investigate physiological role of endogenous serotonin on the regulation of atrial natriuretic peptide (ANP) secretion from the atria.. An isolated perfused nonbeating rat atrial model was used. Changes in atrial volume induced by increasing intra-atrial pressure were measured. The concentration of ANP was measured by radioimmunoassay and the translocation of ECF was measured by [3H]-inulin clearance.. Serotonin, an endogenous 5-HT receptor agonist, caused concentration-dependent suppressions of stretch-induced ANP secretion, which were less pronounced than those caused by alpha-methyl-5-HT maleate, a 5-HT(2) receptor selective agonist. The suppression of stretch-induced ANP secretion due to serotonin and alpha-methyl-5-HT maleate was attenuated by ketanserin, a 5-HT(2) receptor antagonist, and accentuated by RS23597-190, a 5-HT(4) receptor antagonist. The suppressive effect of serotonin on ANP secretion was attenuated by neomycin, staurosporine, and chelerythrine. In contrast, 2-[1-(4-piperonyl)piperazinyl]benzothiazole, a 5-HT(4) receptor selective agonist, caused an accentuation of stretch-induced ANP secretion, which was completely blocked by RS23597-190 and SB203186 HCl but not by ketanserin. This effect was not affected by MDL12330, KT-5720, or H-89. The intracellular Ca(2+) concentration in single atrial myocytes was not changed by serotonin and agonist for either 5-HT(2) or 5-HT(4) receptor.. These results suggest that atrial 5-HT(2) and 5-HT(4) receptor agonists have opposite actions on the regulation of ANP secretion and the suppressive effect of serotonin on the ANP secretion may act through 5-HT(2) receptor and phospholipase C pathway.

Topics: Adenylyl Cyclase Inhibitors; Alkaloids; Aminobenzoates; Animals; Atrial Natriuretic Factor; Benzophenanthridines; Benzothiazoles; Calcium; Carbazoles; Cyclic AMP-Dependent Protein Kinases; Depression, Chemical; Dose-Response Relationship, Drug; Heart; Heart Atria; Imines; Indoles; Isoquinolines; Ketanserin; Male; Myocytes, Cardiac; Neomycin; para-Aminobenzoates; Perfusion; Phenanthridines; Piperazines; Piperidines; Protein Kinase C; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Staurosporine; Sulfonamides; Thiazoles; Type C Phospholipases

Intracellular recordings were obtained from rat presumed jaw-closing motoneurons in slice preparations to investigate the involvement of the serotonin(7) (5-HT(7)) receptors in serotonergic inhibition of the postspike medium-duration afterhyperpolarization (mAHP) and enhancement of the afterdepolarization (ADP). 5-HT-induced suppression of the mAHP and enhancement of the ADP were mimicked by application of the 5-HT(1A/7) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and antagonized by the 5-HT(2/6/7) receptor antagonist clozapine, whereas the 5-HT(2) receptor agonist alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT) did not affect the mAHP and ADP. 8-OH-DPAT-induced attenuation of the mAHP and enhancement of the ADP were also antagonized by clozapine and another 5-HT(2/6/7) receptor antagonist ritanserin, whereas the 5-HT(1A) receptor antagonist pindolol failed to block the 8-OH-DPAT-induced effects on the mAHP and ADP. 8-OH-DPAT-induced suppression of the mAHP and enhancement of the ADP were also antagonized by a protein kinase A (PKA) inhibitor H89, whereas 8-OH-DPAT could inhibit the mAHP and enhance the ADP in the presence of a protein kinase C (PKC) inhibitor chelerythrine. The 8-OH-DPAT-induced suppression of the mAHP was enhanced under raised [Ca(2+)](o) and this enhancement was reduced by chelerythrine. It is suggested that the 5-HT(7) receptors are involved in 5-HT-induced attenuation of the mAHP and enhancement of the ADP through activation of PKA, and the attenuation of mAHP through the 5-HT(7) receptors is enhanced under raised [Ca(2+)](o) by PKC activation.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Action Potentials; Alkaloids; Animals; Benzophenanthridines; Brain Stem; Calcium; Clozapine; Cyclic AMP-Dependent Protein Kinases; Electrophysiology; Enzyme Inhibitors; Isoquinolines; Jaw; Membrane Potentials; Motor Neurons; Phenanthridines; Pindolol; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides