Dihydropyridine And Cardiac Muscle: What's The Connection?

Dihydropyridine (DHP) receptors are critical for excitation-contraction coupling in both skeletal and cardiac muscle. In cardiac muscle, the DHP-sensitive L-type calcium channel is the major entry pathway for extracellular Ca2+, which is essential for contraction. Voltage-gated calcium channels in cardiac muscle are activated by dihydropyridines, a class of drugs that includes BayK 8644, nitrendipine, nisoldipine, and nifedipine. These drugs affect the L-type Ca2+ channel current in ventricular cardiomyocytes, with BayK 8644 acting as an agonist and the other three as inhibitors. The cardiac dihydropyridine receptor has been extensively studied, and its structure and function have been elucidated through techniques such as cloning, sequencing, and photoaffinity-labelling. Exercise training has also been shown to regulate dihydropyridine receptor levels in cardiac muscle.

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Dihydropyridine and ryanodine receptors

Dihydropyridine receptors (DHPRs) are voltage-dependent but are not functional calcium channels. They are critical elements in excitation-contraction (e-c) coupling in both skeletal and cardiac muscle. However, the mechanism for calcium release differs in these muscles. In cardiac muscle, the DHP receptor functions as a rapidly activated calcium channel.

Ryanodine receptors (RyRs) are calcium release channels that are closely associated with DHPRs. RyR1 is present on the terminal cisternae of the sarcoplasmic reticulum (SR) and is directly activated by DHPRs. The opening of RyR1 is triggered by the depolarization of the sarcolemmal membrane, which is sensed by DHPRs. This results in the release of Ca2+ from the SR into the myoplasm, initiating muscle contraction.

In cardiac myocytes, coupling between L-type Ca2+ channels (DHPRs) and RyRs plays a crucial role in excitation-contraction coupling. The L-type Ca2+ channel agonist BayK 8644 (BayK) has been found to alter RyR gating via a functional linkage between DHPR and RyR, independent of Ca2+ influx. BayK increases resting Ca2+ spark frequency in ferret ventricular myocytes, which is not influenced by depolarization.

BayK may also cause depolarization-independent SR Ca2+ release in skeletal muscle. It is hypothesized that BayK binding to DHPRs could facilitate protein conformational changes, altering L-type Ca2+ channel gating. While BayK can have direct effects on RyRs, it does not appear to affect single-channel RyR current amplitude or open probability in lipid bilayer experiments. The effect of BayK on RyRs is likely mediated by DHPRs and a Ca2+-independent connection between the receptors.

Dihydropyridine's role in excitation-contraction coupling

Dihydropyridine (DHP) receptors are critical in excitation-contraction (e-c) coupling in both skeletal and cardiac muscle. However, the mechanism for calcium release differs between the two muscle types. In cardiac muscle, the DHP receptor functions as a rapidly activated calcium channel, while in skeletal muscle, the DHP receptor acts as a voltage sensor.

In cardiac muscle, the coupling between L-type Ca2+ channels (dihydropyridine receptors, DHPRs) and ryanodine receptors (RyRs) is essential for excitation-contraction coupling. The influx of Ca2+ through the DHPR triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) via the RyRs, leading to muscle contraction. This process is known as calcium-induced calcium release (CICR).

The L-type Ca2+ channel agonist BayK 8644 (BayK) has been found to alter RyR gating independently of Ca2+ influx. BayK increases the resting Ca2+ spark frequency (CaSpF), which indicates an increase in the opening of the RyR channels and a subsequent release of Ca2+ from the SR. This effect is dose-dependent, with even low concentrations of BayK causing a rapid increase in CaSpF.

Additionally, BayK has been shown to alter gating charge movement attributed to cardiac Ca2+ channels. However, the effect of BayK on CaSpF is maximal during rest when no charge movement occurs, suggesting that its impact on CaSpF is not mediated by gating charge movement. Furthermore, depolarization did not alter CaSpF, indicating that it did not trigger the release of Ca2+ from the SR under the experimental conditions.

Exercise training has also been found to regulate DHP receptor levels in skeletal and cardiac muscle. For example, studies have shown that training increases the concentration of [3H]ouabain-binding sites in rat skeletal muscle, suggesting that exercise can influence the expression of DHP-sensitive Ca2+ channels.

Dihydropyridine receptor levels in cardiac muscle

Dihydropyridine receptors (DHPRs) are voltage-gated Ca2+ channels that play a critical role in excitation-contraction (e-c) coupling in both skeletal and cardiac muscles. However, the mechanism of calcium release differs between these two muscle types. In cardiac muscle, the DHPR functions as a rapidly activated calcium channel, and its interaction with the ryanodine receptor (RyR) is essential for excitation-contraction coupling.

The DHPR in cardiac muscle is a high-voltage-activated, long-lasting L-type Ca2+ channel. It is a heterotetrameric complex composed of α1, β, and α2/δ subunits, with the α1C subunit forming the channel pore. This subunit has receptor sites that can be blocked by dihydropyridines, a class of Ca2+ channel drugs. The cardiac DHPR appears to lack the γ subunit found in skeletal muscle, which likely contributes to the differences in excitation-contraction coupling mechanisms between the two muscle types.

The coupling between L-type Ca2+ channels (DHPRs) and ryanodine receptors (RyRs) is crucial for excitation-contraction coupling in cardiac myocytes. The DHPR senses the depolarization of the T-tubule membrane and opens its Ca2+ channel, allowing Ca2+ to enter the cell. This influx of Ca2+ triggers the release of additional Ca2+ from the sarcoplasmic reticulum (SR) through the activation of the RyR. This process is known as Ca2+-induced Ca2+ release (CICR) and is essential for cardiac muscle function.

The regulation of DHPR levels in cardiac muscle has been studied in the context of exercise training. Exercise training can influence the expression of DHPR-sensitive Ca2+ channels in cardiac muscle. For example, training has been shown to increase the concentration of [3H]ouabain-binding sites in rat skeletal muscle, which may impact DHPR levels. Additionally, biomechanical unloading has been found to regulate skeletal muscle DHPR gene expression.

In summary, dihydropyridine receptors (DHPRs) are essential for excitation-contraction coupling in cardiac muscle, and their interaction with ryanodine receptors (RyRs) plays a pivotal role in this process. The regulation of DHPR levels in cardiac muscle can be influenced by factors such as exercise training and biomechanical unloading.

Dihydropyridine-sensitive calcium channels

The dihydropyridine receptor is a protein complex composed of multiple subunits, including alpha, beta, and gamma. The alpha 1 subunit contains the dihydropyridine binding site, making it the primary target for dihydropyridine drugs. These drugs, known as calcium channel blockers (CCBs) or calcium antagonists, can either activate or block the DHPRs, leading to various physiological effects.

One example of a dihydropyridine drug is BayK 8644 (BayK), which acts as an agonist at the L-type Ca2+ channel (the dihydropyridine receptor) and has been shown to alter RyR gating. This results in an increased calcium spark frequency (CaSpF) and subsequent calcium release, even in the absence of extracellular calcium. This effect of BayK on CaSpF is dose-dependent and can occur independently of calcium influx.

Dihydropyridine calcium channel blockers are a class of medications derived from the molecule dihydropyridine. They work by blocking calcium channels located in the muscle cells of the heart and arterial blood vessels, reducing the entry of calcium ions into these cells. This blockage leads to vasodilation and changes in heart function, including reduced heart rate, contractility, and speed of conduction, ultimately resulting in lowered blood pressure and decreased oxygen demand by the heart.

Due to their effects on calcium channels and subsequent cardiovascular effects, dihydropyridine calcium channel blockers have important clinical applications. They are commonly used to treat hypertension (high blood pressure) and other heart-related issues such as angina (chest pain due to reduced oxygen supply to the heart) and cardiac arrhythmias (irregular heart rhythms). Additionally, they can be used to treat Raynaud's syndrome, a condition caused by narrowed arteries in the fingertips triggered by cold temperatures or stress.

Dihydropyridine receptor binding

The dihydropyridine receptor is a voltage-dependent, L-type calcium channel that is activated by depolarization of the T-tubule membrane. This activation opens the calcium channel, allowing calcium to enter the cell. The influx of calcium through the dihydropyridine receptor triggers the release of calcium from the sarcoplasmic reticulum, which in turn activates muscle contraction.

The cardiac dihydropyridine receptor (DHPR) appears to lack the γ subunit found in skeletal muscle. This difference likely explains the different mechanisms of excitation-contraction coupling in these two types of muscle. The cardiac DHPR is composed of α1, β, and α2/δ subunits, with the α1 subunit forming the channel pore and containing receptor sites.

The L-type Ca2+ channel agonist BayK 8644 has been shown to alter ryanodine receptor (RyR) gating via a functional linkage with the DHPR. BayK increases the resting Ca2+ spark frequency, which may be due to protein conformational changes that alter L-type Ca2+ channel gating.

Exercise training has also been found to regulate dihydropyridine receptor levels in skeletal and cardiac muscle. In addition, hybrid molecules incorporating the 1,4-dihydropyridine moiety have been designed to possess both calcium channel blocking ability and cardiotonic activity, with potential applications in treating myocardial heart failure or hypertensive disorders.

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