ABSTRACT
Intravenous administration of serotonin inhibits the nociceptive tail-flick (TF) reflex, partially through activation of vagal afferents. The present study examined the role of the rostral ventral medulla (RVM) in i.v. serotonin-produced inhibition of the TF reflex. In Experiment 1, the effects of anesthetic blockade of the RVM on serotonin-produced inhibition of the TF were determined. Lidocaine attenuated the serotonin-produced inhibition of the TF reflex, but had no effect on the cardiovascular effects of serotonin. In Experiment 2, the effects of i.v. serotonin on neural activity in the RVM in intact and cardiopulmonary deafferented rats were determined. Neurons in the RVM were classified as ON and OFF cells, where ON cells were excited by noxious heat, and OFF cells were inhibited. The effects of i.v. serotonin on TF latency, blood pressure, and ON or OFF cell activity were then determined. In intact rats, serotonin produced a dose-dependent increase in TF latency, triphasic changes in blood pressure, and bi- or triphasic changes in ON or OFF cell activity. The changes in blood pressure included an initial sharp decrease in blood pressure (Bezold-Jarisch reflex), followed by a brief pressor response, followed by a delay depressor response. ON cells were generally excited, although there was a period during which the excitation decreased. OFF cells were initially excited, followed by a period of inhibition, followed by a second period of excitation. Bilateral cervical vagotomy attenuated the increase in TF latency, the Bezold-Jarisch reflex, and the excitation of OFF cells, and potentiated the excitation of ON cells and the pressor response. Bilateral sinoaortic deafferentation attenuated the Bezold-Jarisch reflex and potentiated the pressor response. These findings indicate that i.v. serotonin inhibits the TF reflex through at least two distinct mechanisms, one of which requires the RVM. In addition, serotonin produces a vagally mediated excitation of OFF cells and inhibition of ON cells that may mediate some of the antinociception.
Subject(s)
Blood Pressure/physiology , Medulla Oblongata/physiology , Neurons, Afferent/physiology , Nociceptors/physiology , Serotonin/pharmacology , Vagus Nerve/physiology , Anesthetics, Local/administration & dosage , Anesthetics, Local/pharmacology , Animals , Blood Pressure/drug effects , Heart Rate/drug effects , Injections, Intravenous , Lidocaine/administration & dosage , Lidocaine/pharmacology , Male , Medulla Oblongata/cytology , Microinjections , Nociceptors/drug effects , Pain Measurement/drug effects , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Serotonin/administration & dosage , Vagus Nerve/cytologyABSTRACT
We investigated the effects of 5-(N-ethyl-N-isopropyl)amiloride (EIPA) on infarction in isolated rabbit hearts and cardiomyocytes. Thirty min of regional ischemia caused 29.6 +/- 2.8% of the risk zone to infarct in untreated Krebs buffer-perfused hearts. Treatment with EIPA (1 microM) for 20 min starting either 15 min before ischemia or 15 min after the onset of ischemia significantly reduced infarction to 5.4 +/- 2.0% and 7.0 +/- 1.0%, respectively (p < 0.01 versus untreated hearts). In both cases salvage was very similar to that seen with ischemic preconditioning (PC) (7.1 +/- 1.5% infarction). Unlike the case with ischemic preconditioning, however, protection from EIPA was not blocked by 50 microM polymyxin B, a PKC inhibitor, or 1 microM glibenclamide, a KATP channel blocker. Forty-five min of regional ischemia caused 51.0 +/- 2.9% infarction in untreated hearts. Ischemic preconditioning reduced infarction to 23.4 +/- 3.1% (p < 0.001 versus untreated hearts). In these hearts with longer periods of ischemia pretreatment with EIPA reduced infarction similarly to 28.8 +/- 2.1% (p < 0.01 versus untreated hearts). However, when EIPA was combined with ischemic PC, no further reduction in infarction was seen (23.8 +/- 3.5% infarction). To further elucidate the mechanism of EIPA's cardioprotective effect, this agent was also examined in isolated rabbit cardiomyocytes. Preconditioning caused a delay of about 30 min in the progressive increase in osmotic fragility that occurs during simulated ischemia. In contrast, EIPA had no effect on the time course of ischemia-induced osmotic fragility. Furthermore, EIPA treatment did not alter the salutary effect of ischemic preconditioning when the two were combined in this model. We conclude that Na+/H+ exchange inhibition limits myocardial infarction in the isolated rabbit heart by a mechanism which is quite different from that of ischemic preconditioning. Despite the apparently divergent mechanisms, EIPA's cardioprotective effect could not be added to that of ischemic or metabolic preconditioning in these models.
