Inhibitors of Na(+)-H+ exchange block stimulus-provoked pineal melatonin synthesis.
In rat pinealocytes, amiloride can modulate adrenergic-stimulated cyclic nucleotide accumulation. In this study, the effect of amiloride on melatonin production was characterized. Addition of 5-(N,N-hexamethylene)amiloride, a potent inhibitor of the Na(+)-H+ antiport, dose dependently inhibited norepinephrine- and isoproterenol-stimulated N-acetyltransferase (NAT) activity and melatonin production. Similar inhibition was also observed when pineal melatonin synthesis was stimulated directly with forskolin or dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP), suggesting that the site of inhibition is distal to cAMP accumulation. Similarities between the inhibitory potencies of amiloride derivatives on the Na(+)-H+ antiport and pineal melatonin synthesis indicate that the observed inhibition on pineal melatonin synthesis by amilorides may be secondary to their actions on the Na(+)-H+ antiport. Further studies also indicate that the inhibitory effect of amilorides was not secondary to its cytotoxic actions and that amilorides had no direct antagonistic action on NAT activity. Our findings, therefore, suggest that, in addition to their effects on cyclic nucleotide accumulation, the Na(+)-H+ antiport also plays an important role in the cAMP-mediated melatonin synthesis in the rat pineal gland.
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Department of Physiology, University of Alberta, Edmonton, Canada.
Chik
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CL
D000584:Amiloride / Q000031:analogs & derivatives*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008297:Male; D008550:Melatonin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010870:Pineal Gland / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers; D013566:Sympathomimetics / Q000494:pharmacology
D002352:Carrier Proteins; D017923:Sodium-Hydrogen Exchangers; D013566:Sympathomimetics; D005576:Colforsin; D003994:Bucladesine; D000584:Amiloride; D000242:Cyclic AMP; D001191:Arylamine N-Acetyltransferase; D008550:Melatonin