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Positive inotropic responses of the sodium channel modulator BDF 9148 in diseased rat myocardium
1Department of Physiology and Pharmacology, University of Queensland, Brisbane, Australia.
Insights
The sodium channel modulator BDF 9148 effectively increases heart muscle contraction in various disease states. Its potency is maintained in ventricles across hypertension, diabetes, and dwarfism, unlike other agonists.
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Electrophysiology
- Pharmacology of Ion Channels
Background:
- Sodium channel modulators represent a therapeutic target for cardiovascular diseases.
- Understanding drug responses in disease states is crucial for effective treatment.
- Previous studies have not fully elucidated the inotropic effects of BDF 9148 in various pathological conditions.
Purpose of the Study:
- To define the positive inotropic responses to the sodium channel modulator BDF 9148.
- To evaluate these responses in rat models of hypertension, thyroid dysfunction, diabetes, and dwarfism.
- To compare BDF 9148 responses with calcium chloride and other receptor agonists.
Main Methods:
- Isolated left atria and left ventricular papillary muscles were used.
- Concentration-response curves for BDF 9148 and calcium chloride were determined.
- Experiments were conducted on tissues from rats with induced hypertension, thyroid dysfunction, diabetes, and dwarfism.
Main Results:
- BDF 9148 significantly increased the force of contraction in left ventricular papillary muscles across all disease states.
- Maximal responses to BDF 9148 were comparable to those of calcium chloride.
- BDF 9148 potency was only significantly decreased in muscles from diabetic rats.
- Left atria showed similar responses, except in hyperthyroid rats where negative inotropic effects were observed.
Conclusions:
- The positive inotropic effect of BDF 9148 on ventricular contractility is preserved in models of hypertension, diabetes, and dwarfism.
- Left atrial preparations may not accurately reflect ventricular responsiveness, as seen in hyperthyroid models.
- Sodium channel modulation by BDF 9148 offers a potential therapeutic strategy with sustained efficacy in diseased hearts, unlike alpha- or beta-adrenoceptor agonists.
Abstract:
1. This study has defined the positive inotropic responses to the sodium channel modulator BDF 9148 in rats with hypertension, thyroid dysfunction, diabetes or dwarfism. Concentration-response curves to BDF 9148 and calcium chloride were determined in isolated left atria and left ventricular papillary muscles. 2. BDF 9148 increased force of contraction in left ventricular papillary muscles in all disease states with maximal responses comparable to calcium chloride. BDF 9148 potency was significantly decreased in muscles from diabetic rats only. 3. BDF 9148 produced similar responses in left atria except from hyperthyroid rats where negative inotropic responses only were measured. This exception confirms that the left atria is an imperfect model for ventricular responsiveness. 4. Thus, the increase in force of contraction in the ventricles as a consequence of sodium channel modulation by BDF 9148 is maintained in these disease states unlike responses to alpha-or beta-adrenoceptor agonists.