Effect of adrenomedullin on cAMP levels along the rat nephron: comparison with CGRP.
Adrenomedullin (ADM) is a recently discovered hypotensive peptide that has been detected in the kidney. Recent studies have shown that intrarenal administration of ADM produces natriuresis without changes in glomerular filtration rate. Although ADM stimulates adenosine 3',5'-cyclic monophosphate (cAMP) synthesis in some tissues, the site of action and signal transduction pathway in the kidney are unknown. In the present study, we examined the effects of ADM and calcitonin gene-related peptide (CGRP) on cAMP levels in glomeruli and tubules dissected from rat kidney. ADM (1 microM) stimulated cAMP formation in glomeruli (4-fold), cortical thick ascending limb (CTAL, 6-fold), and in the distal convoluted tubule (DCT, 16-fold). In glomeruli, ADM was more potent than CGRP [50% effective concentration (EC50) = 33.7 vs. 156 nM], whereas the opposite was true in the DCT (CGRP, EC50 = 55 vs. 327 nM for ADM). In both glomeruli and DCT, the responses to maximum concentrations of ADM and CGRP were not additive. In glomeruli, the CGRP antagonist, CGRP-(8-37), had no effect on ADM-induced increases in cAMP and inhibited CGRP activity only at concentrations > 1 microM. However, in the DCT and CTAL, CGRP-(8-37) inhibited both ADM- and CGRP-induced increases in cAMP. We conclude that in the kidney, as in other tissues, ADM and CGRP stimulate cAMP accumulation. Our results suggest that ADM and CGRP may be important in the regulation of glomerular and distal tubule function and are consistent with the view that glomeruli have "ADM-like" receptors that have a high affinity for ADM but a low affinity for CGRP and CGRP-(8-37), whereas the DCT has "CGRP-like" receptors with high affinity for CGRP and CGRP-(8-37) but a lower affinity for ADM.
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
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Edwards
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Trizna
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Stack
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Aiyar
D053607:Adrenomedullin; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D009399:Nephrons / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000959:Antihypertensive Agents; D010446:Peptide Fragments; D010455:Peptides; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide