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Local anesthetic blockade of Ca2+ -mediated action potentials in cardiac muscle
Abstract:
The effects of local anesthetic agents (lidocaine, procaine, cocaine) and diphenylhydantoin (DPH) were studied on the slow electrical responses induced by isoproterenol or caffeine in cardiac muscle preparations rendered inexcitable by tetrodotoxin (TTX) or by partial depolarization with elevated K+ (26 mM). In such inexcitable cells, we previously demonstrated that addition of some positive inotropic agents, such as catecholamines, histamine, and methylxanthines, rapidly increase the number of available slow Ca2+--Na+ channels, thus allowing slowly rising electrical responses resembling the plateau component of the cardiac action potential. In embryonic chick (16-20-day-old) myocardial cells (ventricular) studied as intact perfused hearts or as reaggregated cell cultures of trypsin-dispersed cells, high concentrations (10-(3) M) of all of the above drugs blocked the induced slow responses with their associated contractions; low concentrations (10-(5) M) of these agents reduced the maximal rate of rise (+Vmax) of the slow responses and depressed the contractions. For comparison with their effects on the slow response, the actions of these drugs on the normal action potential were also studied. As with the slow response, all of these drugs depressed the rate of rise of the action potential (10-(4) M) or blocked it at higher concentrations (10-(3) M); in contrast, low concentrations (10-(5) M) of lidocaine and DPH increased +V max. These findings suggest that local anesthetics, which interact with the lipid phase of the cell membrane, lead to blockade of the slow Ca2+--Na+ channels as well as of the fast Na+ channels in the myocardial sarcolemma.
Insights
Local anesthetics and diphenylhydantoin block cardiac slow electrical responses by affecting calcium and sodium channels. These drugs also impact normal action potentials, suggesting membrane interactions are key.
Area of Science:
- Cardiovascular Pharmacology
- Electrophysiology
- Cell Membrane Biology
Background:
- Cardiac muscle cells exhibit slow electrical responses dependent on Ca2+--Na+ channels.
- Positive inotropic agents increase available slow channels, enabling these responses.
- Previous work established that certain agents modulate these slow responses.
Purpose of the Study:
- To investigate the effects of local anesthetics (lidocaine, procaine, cocaine) and diphenylhydantoin (DPH) on cardiac slow electrical responses.
- To compare these effects with the drugs' actions on normal cardiac action potentials.
- To elucidate the mechanism of action, particularly channel interactions.
Main Methods:
- Studied embryonic chick ventricular myocardial cells (intact hearts and cell cultures).
- Induced slow responses using isoproterenol or caffeine in cells rendered inexcitable (TTX or high K+).
- Administered local anesthetics and DPH at various concentrations (10^-5 M to 10^-3 M) and assessed electrical responses and contractions.
Main Results:
- High concentrations (10^-3 M) of all tested drugs blocked induced slow responses and contractions.
- Low concentrations (10^-5 M) reduced the maximal rate of rise (+Vmax) of slow responses and depressed contractions.
- All drugs depressed the normal action potential's rate of rise, with higher concentrations causing blockade; low concentrations of lidocaine and DPH increased +Vmax.
Conclusions:
- Local anesthetics and DPH interfere with cardiac slow Ca2+--Na+ channels.
- These drugs also affect fast Na+ channels involved in normal action potentials.
- Findings suggest local anesthetics interact with the myocardial sarcolemma's lipid phase, leading to channel blockade.