Effect of a tachykinin NK2 receptor antagonist, nepadutant, on cardiovascular and gastrointestinal function in rats and dogs

The effect of the tachykinin NK, receptor antagonist, nepadutant (MEN 11420 or (c{[(beta -D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2 beta -5 beta)})) was as sessed on cardiovascular function (unanaesthetized rats and anaesthetized d ogs) and gastrointestinal motor activity (fasted unanaesthetized dogs). The selective tachykinin NK2 receptor agonist, [beta Ala(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 pres sure and heart rate up to 10 mu mol/kg, whereas saredutant (SR 48968 or ((S )-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)bu tyl] benzamide), a nonpeptide antagonist, produced a transient reduction of mean blood pressure and heart rate. Nepadutant up to 20 mu mol/kg, i.v. ne ither caused changes of cardiovascular and respiratory parameters in anaest hetized dogs nor induced any changes in left ventricular systolic pressure, left ventricular dP/dt or of electrocardiogram (lead II) waveforms. Intrav enous administration of neurokinin A (9 nmol/kg) in unanaesthetized dogs st imulated gastrointestinal motility for 20-25 min. Nepadutant at 0.1 mu mol/ kg suppressed the stimulant effects of neurokinin A but, up to a dose of 10 mu mol/kg, did not produce significant changes in the basal migrating moto r complexes. We conclude that tachykinin NK2 receptors do not participate i n the physiologic regulation of resting cardiovascular and respiratory func tions and that they do not regulate the fasted pattern of gastrointestinal motility. The cardiovascular changes induced by the nonpeptide tachykinin N K2 receptor antagonist, saredutant, likely arise from nonspecific effects u nrelated to tachykinin NK2 receptor blockade. (C) 2001 Elsevier Science B.V . All rights reserved.