Effect of a tachykinin NK(2) receptor antagonist, nepadutant, on cardiovascular and gastrointestinal function in rats and dogs.
The effect of the tachykinin NK(2) receptor antagonist, nepadutant (MEN 11420 or (c[[(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2beta-5beta)])) was assessed on cardiovascular function (unanaesthetized rats and anaesthetized dogs) and gastrointestinal motor activity (fasted unanaesthetized dogs). The selective tachykinin NK(2) receptor agonist, [betaAla(8)]neurokinin A (4-10), up to 100 nmol/kg, i.v., did not produce changes on mean blood pressure or heart rate in unanaesthetized rats. Nepadutant did not affect blood pressure and heart rate up to 10 micromol/kg, whereas saredutant (SR 48968 or ((S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl] benzamide), a nonpeptide antagonist, produced a transient reduction of mean blood pressure and heart rate. Nepadutant up to 20 micromol/kg, i.v. neither caused changes of cardiovascular and respiratory parameters in anaesthetized dogs nor induced any changes in left ventricular systolic pressure, left ventricular dP/dt or of electrocardiogram (lead II) waveforms. Intravenous administration of neurokinin A (9 nmol/kg) in unanaesthetized dogs stimulated gastrointestinal motility for 20-25 min. Nepadutant at 0.1 micromol/kg suppressed the stimulant effects of neurokinin A but, up to a dose of 10 micromol/kg, did not produce significant changes in the basal migrating motor complexes. We conclude that tachykinin NK(2) receptors do not participate in the physiologic regulation of resting cardiovascular and respiratory functions and that they do not regulate the fasted pattern of gastrointestinal motility. The cardiovascular changes induced by the nonpeptide tachykinin NK(2) receptor antagonist, saredutant, likely arise from nonspecific effects unrelated to tachykinin NK(2) receptor blockade.
Department of Pharmacology, Menarini Ricerche S.p.A., via Rismondo 12A, I-50131, Florence, Italy. sgiuliani@menarini-recherche.it
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Giuliani
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Guelfi
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Toulouse
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Buéno
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Lecci
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Tramontana
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Criscuoli
C A
CA
Maggi
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004064:Digestive System / Q000187:drug effects*; D004068:Digestive System Physiological Phenomena; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013990:Tidal Volume / Q000187:drug effects
D001549:Benzamides; C107754:MEN 11420; D010456:Peptides, Cyclic; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C073839:SR 48968