Inhibitory effects of sigma-1 ligands on handling-induced tachycardia in conscious tethered rats.

We used conscious tethered Sprague-Dawley rats to evaluate the cardiovascular effects of four sigma-1 (sigma 1) agonists and five antagonists, given alone or in combination. All drugs were administered as a single intraperitoneal dose. The agonists were given at doses reported as efficacious in rodent cognition models, while the antagonists were administered at doses neutralizing agonist effects in vivo. Systolic blood pressure (SBP) and heart rate (HR) were continuously recorded for 20min before and 60min postadministration. Immediately after injection, a sudden, transitory increase in HR and SBP was noted in all animals, because of the stress induced by handling. For both parameters, a peak value (HRmax and SBPmax) and an area under the curve of changes from baseline over the period 5-20min postinjection (HR_AUC5-20min and SBP_AUC5-20min) were calculated. Three of the four sigma 1 agonists (SKF-10,047, dehydroepiandrosterone (DHEAS), Compound 14) significantly reduced HR_AUC5-20min value without changing HRmax, while the fourth one, SA-4503, had no significant effect. None of the antagonists (haloperidol, rimcazole, NE-100, and BD1047) reduced, and even one (progesterone) enhanced the stress-induced effects on HR. No changes in SBP were noted with any compound. When the antagonist NE-100 was administered just before SKF-10,047, it completely reversed the inhibitory effects of the sigma 1 agonist on HR increase. In conclusion, we demonstrated for the first time the involvement of sigma 1 receptors in the regulation of handling-induced tachycardia in the conscious rat. Although additional investigations are needed to fully understand this role, it might offer new therapeutic perspectives to sigma 1 ligands in the cardiovascular sphere.