Compound 48/80 induces endothelium-dependent and histamine release-independent relaxation in rabbit aorta.
Compound 48/80 (C48/80) is a synthetic condensation product of N-methyl-p-methoxyphenethylamine with formaldehyde and is an experimental drug used since the 1950s to induce anaphylactic shock through histamine release. This study was carried out to further elucidate the mechanism by which this drug induces nitric oxide (NO) release. Our specific goals were: (a) to verify if C48/80's relaxation occurs through the stimulation of histamine receptors; (b) to evaluate the endothelium-dependent relaxation induced by C48/80; (c) to identify NO as the endothelium-relaxing factor released by C48/80; (d) to identify the NO synthase (NOS) responsible for NO release; and (e) to verify if the relaxation induced by C48/80 is calcium and cyclic guanidine monophosphate (cGMP) dependent. Rabbit aorta segments, with and without endothelium, were suspended in organ chambers (25ml) filled with Krebs solution maintained at 37 degrees C, bubbled with 95% O(2)/5% CO(2) (pH 7.4). Phenylephrine was used to contract the segments. Other protocol drugs included H(1)- and H(2)-receptor antagonists, cyclooxygenase, NOS, guanylyl cyclase and phospholipase C (PLC) inhibitors. Endothelium-dependent relaxation induced by C48/80 was also studied in calcium-free Krebs solution associated with a calcium chelator. In summary, our investigation demonstrated that the C48/80 vasodilating action: (a) does not depend on H(1) and H(2) histamine receptors; (b) is NO endothelium-dependent; (c) is dependent on the endothelial constitutive NOS (NOS-3) isoform activation; (d) is cGMP-dependent; and that NOS-3 activation by C48/80: (a) is independent of PLC up to 25mug/ml and (b) is partially dependent of this lipase in higher doses.
Viaro
Fernanda
F
Department of Surgery and Anatomy, Ribeirão Preto Medical School, São Paulo University, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, SP, Brazil.
Celotto
Andréa Carla
AC
Capellini
Verena Kise
VK
Baldo
Caroline Floreoto
CF
Rodrigues
Alfredo José
AJ
Vicente
Walter V A
WV
Evora
Paulo Roberto B
PR
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D002927:Cimetidine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D011738:Pyrilamine / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011817:Rabbits; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology*
D004963:Estrenes; D006634:Histamine H1 Antagonists; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D009569:Nitric Oxide; D003189:p-Methoxy-N-methylphenethylamine; D002927:Cimetidine; D011738:Pyrilamine; D019331:NG-Nitroarginine Methyl Ester