Related Experiment Videos
Histaminergic mechanisms involved in the centrally mediated effects of ouabain
Insights
Central histamine, acting via H2 receptors, enhances cardiac glycoside toxicity by increasing sympathetic activity. This suggests a new target for managing ouabain cardiotoxicity.
Area of Science:
- Neuropharmacology
- Cardiovascular Toxicology
- Autonomic Nervous System
Background:
- Cardiac glycosides like ouabain are potent cardiotoxic agents.
- The central nervous system's role in mediating cardiac glycoside toxicity is not fully understood.
- Histaminergic pathways are involved in various physiological and pathological processes.
Purpose of the Study:
- To investigate the role of central histaminergic mechanisms in cardiac glycoside toxicity.
- To determine the specific histamine receptor subtype involved in ouabain cardiotoxicity.
- To explore the link between central histaminergic activity and sympathetic nervous system activation in toxicity.
Main Methods:
- Experiments were conducted on chloralose-urethane anesthetized cats.
- Cardiac rhythm, blood pressure, and sympathetic nerve activity were monitored during ouabain infusion.
- Histamine, H2 receptor agonist (dimaprit), H2 receptor antagonist (cimetidine), and H1 receptor antagonist (diphenhydramine) were administered intracerebroventricularly.
Main Results:
- Central histamine administration significantly reduced the ouabain dose required to induce ventricular arrhythmias and fibrillation.
- Toxicity potentiation by histamine was linked to enhanced sympathetic efferent activity.
- H2 receptor agonist dimaprit mimicked and slightly amplified histamine's effect.
- H2 receptor antagonist cimetidine dose-dependently protected against ouabain toxicity.
- H1 receptor antagonist diphenhydramine had no significant effect.
Conclusions:
- Central histaminergic mechanisms, specifically through H2 receptors, play a significant role in mediating cardiac glycoside (ouabain) cardiotoxicity.
- Ouabain appears to stimulate central histaminergic neurons, leading to hypothalamic activation and subsequent centrogenic sympathetic stimulation, which underlies cardiotoxicity.
- Targeting central H2 receptors may offer a protective strategy against cardiac glycoside toxicity.
Abstract:
The role of central histaminergic mechanisms in cardiac glycoside toxicity was evaluated in chloralose-urethane anesthetized cats. Cardiac rhythm, blood pressure and sympathetic nerve activity were monitored during continuous i.v. infusion of ouabain (1 microgram/kg/min). Histamine administered into the fourth cerebral ventricle decreased significantly the dose of ouabain necessary to produce ventricular arrhythmias and fibrillation. Toxicity potentiation was associated with enhancement of sympathetic efferent activity. Dimaprit, a specific H2 receptor agonist, produced a similar, but slightly greater, potentiation of ouabain activity than histamine when similarly administered. Intracerebroventricular (i.c.v.) pretreatment of cats with cimetidine, an H2 receptor antagonist, provided a dose-dependent protective effect against ouabain-induced toxicity. Central administration of diphenhydramine, an H1 receptor antagonist, had no effect on cardiotoxic actions. These results suggest a role for central histaminergic mechanisms in cardiac glycoside toxicity which is mediated through an H2 receptor process. Furthermore, it is suggested that ouabain stimulates central histaminergic neurons which impinge on hypothalamic areas and such excitement results in a centrogenic activation of sympathetic centers which is responsible for cardiac glycoside cardiotoxicity.