kb-r7943 and Acute-Disease

Recent evidence suggests that the sodium calcium exchanger (NCX) may contribute to the etiology of pentylenetetrazol-induced seizures. Here we further investigated the role of NCX in the etiology of seizures by quantifying the effects of KB-R7943 and SN-6, potent inhibitors of the reverse mode of NCX subtypes 3 (NCX3) and 1 (NCX1), respectively, on the occurrence of acute seizures and status epilepticus induced by intraperitoneal administration of pilocarpine, a muscarinic acetylcholine receptor agonist. Pretreatment with KB-R7943 significantly reduced the incidence of pilocarpine-induced seizures and status epilepticus in 22-56% of treated animals. In the remaining animals that exhibited seizures, KB-R7943 pretreatment delayed the onset of seizures and status epilepticus, and reduced seizure severity. Delayed onset of seizures and reduced seizure severity also were seen following pretreatment with SN-6. These findings suggest that altered NCX activity may contribute to the pathophysiology of pilocarpine-induced seizures and status epilepticus.

Topics: Acute Disease; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Male; Muscarinic Agonists; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures; Sodium-Calcium Exchanger; Thiourea

To test the hypothesis that Ca2+ influx via Na+/Ca2+ exchange (NCX) underlies atrial fibrillation (AF)-induced shortening of atrial effective refractory period (AERP), we examined the potential of KB-R7943 (KB), a selective inhibitor of Ca2+-influx mode NCX, to attenuate this effect.. Studies were performed in 41 isoflurane-anesthetized dogs. In sinus rhythm dogs, peak AERP changes resulting from intravenous KB infusion ranged from (mean+/-SEM) 4.4+/-0.4% (1 mg/kg) to 14.8+/-2.6% (5 mg/kg; ED50=1.9 mg/kg). AERP was maximally prolonged between 5 and 10 minutes after beginning of KB infusion and returned to baseline values within 30 minutes thereafter. Rapid atrial pacing-induced AF reversibly shortened AERP (P<0.001) in 5 dogs, averaging 14.9+/-2.1% after 90 minutes of AF. Both the time course and magnitude of mean AERP changes in 5 AF dogs receiving 5 mg/kg KB were indistinguishable from those in 5 sinus rhythm dogs receiving an equivalent KB dose (P>0.05). We measured cardiac tissue and arterial plasma KB concentrations produced by intravenous infusion (1 mg x kg(-1) x min(-1)) of 5 mg/kg KB. Plasma drug concentration peaked at the end of KB infusions (30.86+/-3.26 nmol/L; n=4 dogs) and declined to 0.56+/-0.19 nmol/L after 100 minutes. The cardiac tissue-to-plasma drug concentration gradient averaged approximately 40 at 100 minutes after start of KB infusion. KB at concentrations achieved in vivo irreversibly blocked NCX-mediated Ca2+ influx in isolated canine right atrial myocytes by approximately 60%, but had no significant effect on NCX-dependent Ca2+ extrusion.. NCX-mediated Ca2+ influx plays an important role in acute, AF-induced AERP shortening.

Topics: Acute Disease; Anesthesia; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Calcium; Cells, Cultured; Dogs; Female; Heart Atria; Heart Conduction System; Ion Transport; Kinetics; Male; Myocardium; Periodicity; Refractory Period, Electrophysiological; Sodium-Calcium Exchanger; Thiourea