Catecholamine release mediates pressor effects of adrenomedullin-(15-22) in the rat.
Human adrenomedullin, a novel hypotensive peptide, contains a six-member ring structure similar to that found in calcitonin gene-related peptide and pancreatic amylin. Unlike the full-sequence peptide, human adrenomedullin-(15-22) [hADM-(15-22)], which contains the ring structure, increases systemic arterial pressure in the rat but not the cat. We undertook the present study to investigate the mechanism by which hADM-(15-22) increases systemic arterial pressure in the rat. Injection of hADM-(15-22) in doses of 10 to 300 nmol/kg i.v. increased systemic arterial pressure in a dose-dependent manner and was threefold less potent than norepinephrine when doses were compared on a nanomole basis. However, the ring structures of human calcitonin gene-related peptide and human amylin, human calcitonin gene-related peptide-(1-8) and human amylin-(1-8), respectively, had no significant effect on systemic arterial pressure in the rat. Pressor responses to hADM-(15-22) were reduced significantly after administration of phentolamine or reserpine. Responses to hADM-(15-22) were not altered by the angiotensin type 1 blocking agent DuP 753 or the endothelin-A/endothelin-B receptor blocking agent bosentan, and responses to hADM-(15-22) and the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) were reduced after bilateral adrenalectomy. Pressor responses to DMPP were reduced by hexamethonium, whereas the nicotinic blocking agent had no effect on the pressor response to hADM-(15-22). These data suggest that increases in systemic arterial pressure in response to hADM-(15-22) in the rat are mediated by the activation of alpha-adrenergic receptors by catecholamines released from the adrenal medulla. The present data suggest that hADM-(15-22) releases catecholamines from the adrenal medulla by a noncholinergic mechanism.
Champion
H C
HC
Department of Pharmacology, Tulane University School of Medicine, New Orleans, La 70112, USA.
Fry
R C
RC
Murphy
W A
WA
Coy
D H
DH
Kadowitz
P J
PJ
D000315:Adrenalectomy; D053607:Adrenomedullin; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002395:Catecholamines / Q000502:physiology*; D002415:Cats; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011311:Pressoreceptors / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D002395:Catecholamines; D010446:Peptide Fragments; D010455:Peptides; C102562:adrenomedullin (15-22); D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide