Disease relevance of Dihydropyridine

• Dihydropyridine receptor mutations cause hypokalemic periodic paralysis [1].
• The new generation of dihydropyridine calcium entry blockers exhibits more specific vasodilatory actions with a less negative inotropic effect, which may affect their use in patients with congestive heart failure [2].
• OBJECTIVE: To compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a beta-blocker (metoprolol) on hypertensive renal disease progression [3].
• The major component of whole-cell Ca2+ current in differentiated, neuron-like rat pheochromocytoma (PC12) cells and sympathetic neurons is carried by dihydropyridine-insensitive, high-threshold-activated N-type Ca2+ channels [4].
• We have used the chicken ciliary ganglion calyx synapse to test the effect of the dihydropyridine nifedipine on Ca current recorded directly from a cholinergic presynaptic nerve terminal [5].

Psychiatry related information on Dihydropyridine

• CONCLUSION: The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension [6].
• Unaltered hippocampal dihydropyridine and omega-conotoxin GVIA binding sites after repeated electroconvulsive shock in rats [7].
• The conclusions suggest that dihydropyridine calcium channel antagonists may offer a new therapeutic approach to the treatment of ethanol and opiate dependence [8].
• OBJECTIVE: To investigate the association between use of calcium channel blockers (CCB), dihydropyridine (DHP) or nondihydropyridine (nonDHP) type CCB and risk of developing Alzheimer's Disease (AD) or mortality [9].
• Sub-analyses indicated differences between groups of calcium-channel blockers, as use of non-dihydropyridine drugs was associated with a larger risk reduction than use of dihydropyridine drugs [10].

High impact information on Dihydropyridine

• Genetic linkage analysis has localized the hypoKPP gene to chromosome 1q31-q32 near a dihydropyridine (DHP) receptor gene [1].
• The source of calcium for BK channel activation is unknown, but the slow AHP is blocked by dihydropyridine antagonists, indicating that L-type calcium channels provide the calcium for activation of SK channels [11].
• Here we report that the beta-subunit binds to the cytoplasmic linker between repeats I and II of the dihydropyridine-sensitive alpha 1-subunits from skeletal (alpha 1S) and cardiac muscles (alpha 1C-a), and also with the more distantly related neuronal alpha 1A and omega-conotoxin GVIA-sensitive alpha 1B-subunits [12].
• The skeletal muscle dihydropyridine (DHP) receptor serves dual functions, as a voltage sensor for excitation-contraction coupling and as an L-type calcium channel [13].
• The available number of drug receptor sites increases 10-fold with an alpha 1 beta combination, whereas the affinity of the dihydropyridine binding site remains unchanged [14].

Chemical compound and disease context of Dihydropyridine

• Intravenous nitroglycerin and dihydropyridine calcium antagonists promptly relieved the spasms [15].
• Nimodipine, a dihydropyridine-type calcium channel blocker, prevents alcoholic hepatitis caused by chronic intragastric ethanol exposure in the rat [16].
• Vitamin D3 metabolites modulate dihydropyridine-sensitive calcium currents in clonal rat osteosarcoma cells [17].
• In 10 patients with moderate to severe hypertension, the hemodynamic effects of ergometric exercise and nicardipine, a dihydropyridine calcium channel antagonist, were characterized under basal conditions and after 1 week of therapy [18].
• CONCLUSIONS: In elderly patients with isolated systolic hypertension, stepwise antihypertensive drug treatment, starting with the dihydropyridine calcium channel blocker nitrendipine, improves prognosis [19].

Biological context of Dihydropyridine

• Repeat I of the dihydropyridine receptor is critical in determining calcium channel activation kinetics [20].
• The complete amino-acid sequence of the receptor for dihydropyridine calcium channel blockers from rabbit skeletal muscle is predicted by cloning and sequence analysis of DNA complementary to its messenger RNA [21].
• Microinjection of an expression plasmid that carries complementary DNA encoding the receptor for dihydropyridine calcium channel blockers of skeletal muscle restores both excitation-contraction coupling and slow calcium current in cultured skeletal muscle cells from mice with muscular dysgenesis [22].
• By contrast, a second calcium current, which is rapidly inactivating and dihydropyridine-insensitive, contributes to release elicited by the transient depolarization of an action potential and to the other three forms of plasticity [23].
• A slowly inactivating, dihydropyridine-sensitive calcium current does not contribute either to normal synaptic transmission or to any of three different forms of plasticity: presynaptic inhibition, homosynaptic depression, and presynaptic facilitation [23].

Anatomical context of Dihydropyridine

• Structural and sequence similarities to the voltage-dependent sodium channel suggest that in the transverse tubule membrane of skeletal muscle the dihydropyridine receptor may act both as voltage sensor in excitation-contraction coupling and as a calcium channel [21].
• The purified dihydropyridine-receptor complex has also been incorporated into phospholipid bilayer membranes [24].
• As 3H-dihydropyridine binding to cortical membrane preparations resembles the binding in heart and smooth muscle where there are good functional correlates we conclude that the dihydropyridine binding sites in the brain represent functional Ca2+ channels that can be unmasked under certain circumstances [25].
• There are dihydropyridine (DHP)-sensitive calcium currents in both skeletal and cardiac muscle cells, although the properties of these currents are very different in the two cell types (for simplicity, we refer to currents in both tissues as L-type) [26].
• It is thought that in skeletal muscle excitation-contraction (EC) coupling, the release of Ca2+ from the sarcoplasmic reticulum is controlled by the dihydropyridine (DHP) receptor in the transverse tubular membrane, where it serves as the voltage sensor [27].

Associations of Dihydropyridine with other chemical compounds

• Apparently, nifedipine and the novel compounds bind to the same specific dihydropyridine binding sites in or near the calcium channel [28].
• Yet the dihydropyridine calcium antagonists (for example, nitrendipine) bind stereospecifically with high affinity to a recognition site on brain-cell membranes thought to represent the Ca2+ channel and consequently, the physiological relevance of these sites has been questioned [25].
• Functional dihydropyridine-sensitive Ca2+ channels (L-type) are maintained in the vesicle, and their gating is inhibited by thyrotropin-releasing hormone [29].
• Opening of dihydropyridine calcium channels in skeletal muscle membranes by inositol trisphosphate [30].
• Muscle biopsies excised from three patients with HOPP carrying the R528H mutation of the dihydropyridine receptor showed a reduced sarcolemma KATP current that was not stimulated by magnesium adenosine diphosphate (MgADP; 50-100 microM) and was partially restored by cromakalim [31].

Gene context of Dihydropyridine

• In this study we show that the CACNL1A3 gene encoding the alpha 1-subunit of the human skeletal muscle dihydropyridine-sensitive L-type voltage-dependent calcium channel (VDCC) represents a new MHS locus and is responsible for the disease in a large French family [32].
• Exclusion of malignant hyperthermia susceptibility (MHS) from a putative MHS2 locus on chromosome 17q and of the alpha 1, beta 1, and gamma subunits of the dihydropyridine receptor calcium channel as candidates for the molecular defect [33].
• Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil [34].
• Blockade of L-type voltage-sensitive Ca2+ channels with nimodipine, a dihydropyridine drug, had the same effect as Ca2+e removal on both the initial spike and sustained plateau phases of the response to AVP [35].
• Reversal by a dihydropyridine derivative of non-P-glycoprotein-mediated multidrug resistance in etoposide-resistant human prostatic cancer cell line [36].

Analytical, diagnostic and therapeutic context of Dihydropyridine

• Increasing [Mg2+]i from 0.3 to 3.0 mM in cardiac cells by internal perfusion has only small effects on the basal voltage-gated calcium current (ICa) or on ICa elevated by dihydropyridine calcium channel agonists [37].
• Oxo-M depresses dihydropyridine-augmented tail currents in whole-cell recordings, whereas NE does not [38].
• They also immunoprecipitate 64% of rabbit brain dihydropyridine-sensitive calcium channels followed by immunoprecipitation reveals alpha 1-, alpha 2 delta-, and beta-like subunits that have apparent molecular masses of 175, 142, and 57 kd, respectively [39].
• We have studied the subcellular distribution of the alpha 1 and alpha 2 subunits of the dihydropyridine (DHP) receptor and ankyrin in rat skeletal muscle with immunofluorescence and immunogold labeling techniques [40].
• Dihydropyridine receptor gene expression is regulated by inhibitors of myogenesis and is relatively insensitive to denervation [41].

References