Substance P (SP) Causes Bradycardia and Affects the Negative Chronotropic Response to Vagal Stimulation in Reserpinized Guinea Pigs

Previous work demonstrated that SP causes bradycardia in isolated guinea pig hearts by stimulating cholinergic neurons. The present study was initiated to determine if SP could evoke bradycardia in vivo and affect the chronotropic response to vagal stimulation (VS). Male Hartley guinea pigs were treated with reserpine (5 mg/kg, i.p.) to deplete norepinephrine and neuropeptide Y from sympathetic nerves. After 24 h, they were anesthetized with urethane (1.5 g/kg, i.p.) for measurement of blood pressure and heart rate. Both vagal nerves were cut and animals artificially respired. Saline or SP was given by bolus i.v. injection in a volume of 50 1. SP (3.3-33 nmol) caused a dose-dependent bradycardia that was sometimes followed by a slight tachycardia. It also evoked a prolonged decrease in blood pressure. The right vagus was stimulated at l min intervals to cause bradycardia of about 20 to 40 beats per min. Saline had no effect on the response to VS. Effects of SP and VS on heart rate were initially additive or synergistic. The bradycardia evoked by the second VS after injection of SP was less than that to the first and frequently less than pre-SP control values. Responses subsequently returned to the pre-SP control level within two trials or increased above this level for several trails before returning to baseline. These observations support the concept that endogenous tachykinins may have important effects on neurotransmission in the intrinsic cardiac ganglia