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 (σ1 ) 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 20 min before and 60 min 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 (ΔHRmax and ΔSBPmax ) and an area under the curve of changes from baseline over the period 5-20 min postinjection (ΔHR_AUC5-20 min and ΔSBP_AUC5-20 min ) were calculated. Three of the four σ1 agonists (SKF-10,047, dehydroepiandrosterone (DHEAS), Compound 14) significantly reduced ΔHR_AUC5-20 min value without changing ΔHRmax , 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 σ1 agonist on HR increase. In conclusion, we demonstrated for the first time the involvement of σ1 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 σ1 ligands in the cardiovascular sphere.