Background Testing for the susceptibility of vasodepressor reaction in humans involves the combination of restriction of venous return by passive upright tilting and the administration of isoproterenol.We developed an experimental rat model in which vasodepressor reactions are induced when the inferior vena cava is occluded during an infusion of isoproterenol. The reactions are characterized by the development of paradoxical bradycardia during the period of inferior vena cava occlusion.Methods and Results Inferior vena cava occlusion was performed for 60 seconds, and the maximal changes in RR interval were measured during seven states as follows:(1) when inferior vena cava occlusion was performed under control conditions in 40 rats, the rate accelerated in all 40 rats (Delta RR, -15.6+-1.9 milliseconds in 25 rats, P<.001; Delta RR, -13.3+-1.7 milliseconds in 10 rats, P<.001); (2) when inferior vena cava occlusion was performed in 25 rats during an infusion of isoproterenol, a vasodepressor reaction was observed in all rats as the heart rate slowed (Delta RR, +92.7+-8.3 milliseconds, P<.001); (3) when inferior vena cava occlusion was performed in 10 rats during an infusion of dobutamine, a selective beta1-agonist, a vasodepressor reaction was observed in all rats as the heart rate slowed (Delta RR, +63.3+-10.6 milliseconds, P<.001); (4) when inferior vena cava occlusion was performed in 5 rats during an infusion of salbutamol, a selective beta2-agonist, vasodepressor reaction was not observed as the heart rate accelerated in all rats (Delta RR, -11.4+-2.8 milliseconds, P<.002); (5) the vasodepressor reaction induced by either dobutamine or isoproterenol was inhibited by atenelol, a selective beta1-adrenergic receptor antagonist; (6) the vasodepressor reaction induced by isoproterenol was inhibited by propranolol (lipophilic) and sotalol (nonlipophilic) beta -blockers and there was a dose-dependent attenuation by propranolol of the maximal RR interval slowing during inferior vena cava occlusion; and (7) butoxamine, a selective beta2-adrenergic receptor antagonist, attenuated but did not block the vasodepressor reaction observed during an infusion of isoproterenol.Conclusions Reduced cardiac volume combined with beta1-adrenergic stimulation can stimulate a vasodepressor reaction in rats. beta (2) -Adrenergic receptors play little or no role in the reaction. The vasodepressor reaction can be blocked by selective or nonselective beta1-adrenergic antagonists independent of the drug's ability to penetrate the central nervous system. The application of these findings to humans remains to be elucidated. (Circulation. 1994;89:2401-2411.)