Proadrenomedullin NH2-terminal 20 peptide has direct vasodilator activity in the cat.
The mechanism by which proadrenomedullin NH2-terminal 20 peptide (PAMP) decreases vascular resistance was investigated in the hindlimb vascular bed in the cat. Injections of PAMP, a shortened form of the peptide PAMP-(12-20), and adrenomedullin (ADM) into the hindlimb perfusion circuit elicit dose-related decreases in perfusion pressure. The order of potency was ADM > PAMP > PAMP-(12-20), and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) had no effect on vasodilator responses to PAMP or ADM. Vasodilator responses to PAMP were increased in duration by the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor Rolipram, whereas inhibitors of nitric oxide synthase and guanosine 3',5'-cyclic monophosphate phosphodiesterase had no effect. Vasodilator responses to PAMP were not altered by treatment with alpha-receptor or adrenergic nerve terminal blocking agents and were similar in innervated and denervated hindlimb preparations. Responses to PAMP were similar when vasoconstrictor tone was increased by stimulation of the sympathetic nerves or infusion of phenylephrine and were not altered by the passage of time. These data suggest that PAMP dilates the hindlimb vascular bed by a direct cAMP-dependent mechanism and that inhibition of norepinephrine release plays little if any role in mediating responses to the peptide in the regional vascular bed of the cat.
Champion
H C
HC
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Murphy
W A
WA
Coy
D H
DH
Kadowitz
P J
PJ
D053607:Adrenomedullin; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002415:Cats; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010646:Phentolamine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D020889:Rolipram; D014655:Vascular Resistance / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D011498:Protein Precursors; D011506:Proteins; D011688:Purinones; D011760:Pyrrolidinones; D011942:Receptors, Adrenergic, alpha; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C088633:proadrenomedullin; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D000242:Cyclic AMP; C011145:zaprinast; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide; D020889:Rolipram; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine; D010646:Phentolamine