Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms

We compared detailed efficacy of efonidipine and nifedipine, dihydropyridine analogues, and mibefradil using recombinant T- and L-type Ca2+ channels expressed separately in mammalian cells. All these Ca2+ channel antagonists blocked T-type Ca2+ channel currents (I(Ca(T))) with distinct blocking manners: I(Ca(T)) was blocked mainly by a tonic manner by nifedipine, by a use-dependent manner by mibefradil, and by a combination of both manners by efonidipine. IC50s of these Ca2+ channel antagonists to I(Ca(T)) and L-type Ca2+ channel current (I(Ca(L))) were 1.2 micromol/l and 0.14 nmol/l for nifedipine; 0.87 and 1.4 micromol/l for mibefradil, and 0.35 micromol/l and 1.8 nmol/l for efonidipine, respectively. Efonidipine, a dihydropyridine analogue, showed high affinity to T-type Ca2+ channel.     

Pathophysiological significance of T-type Ca2+ channels: T-type Ca2+ channels and drug development

T-type Ca(2+) channels are present in cardiovascular, neuronal, and endocrine systems; and they are now receiving attention as novel therapeutic targets. Many drugs and compounds non-specificaly block T-type Ca(2+) channels. Certain dihydropyridine compounds, such as efonidipine, have blocking activity on both L-type and T-type Ca(2+) channels which possibly underlies their excellent clinical profiles such as minimum reflex tachycardia and renal protection. Selective inhibitors of T-type Ca(2+) channels, such as non-hydrolyzable mibefradil and R(-)-efonidipine, are powerful pharmacological tools for further studies and may lead to the development of novel therapeutic strategies.     

Pathophysiological significance of T-type Ca2+ channels: role of T-type Ca2+ channels in renal microcirculation

Since conventional Ca(2+) antagonists, with predominant blockade of L-type voltage-dependent Ca(2+) channels, elicit preferential dilation of afferent arterioles, they might ostensibly aggravate glomerular hypertension. Recently, novel Ca(2+) antagonists, with inhibitory action on L-/T-type Ca(2+) channels, have been reported to dilate both afferent and efferent arterioles. The present review attempted to characterize the renal action of these Ca(2+) antagonists and evaluated the consequences following the treatment with these agents. In contrast to conventional Ca(2+) antagonists (e.g., nifedipine), novel antagonists (e.g., benidipine, efonidipine) potently dilated afferent and efferent arterioles; their action on efferent arterioles appeared to be mediated by the T-type Ca(2+) channel blockade, probably through the inhibition of the intracellular Ca(2+) release. The comparison of the anti-proteinuric action in subtotally nephrectomized rats showed that efonidipine exerted more prominent action than nifedipine. Furthermore, Ca(2+) antagonists with T-type Ca(2+) inhibitory action inhibited renin/aldosterone release and proinflammatory process. Finally, patients with chronic renal disease given a 48-week efonidipine treatment showed reduced proteinuria, and this effect was seen even when mean arterial blood pressure failed to become less than 100 mmHg. Collectively, T-type Ca(2+) channel blockade provides beneficial action in renal injury. Various mechanisms serve to protect against renal injury, including systemic/glomerular hemodynamic action and non-hemodynamic mechanisms.     

Identification of R(-)-isomer of efonidipine as a selective blocker of T-type Ca2+ channels

Efonidipine, a derivative of dihydropyridine Ca(2+) antagonist, is known to block both L- and T-type Ca(2+) channels. It remains to be clarified, however, whether efonidipine affects other voltage-dependent Ca(2+) channel subtypes such as N-, P/Q- and R-types, and whether the optical isomers of efonidipine have different selectivities in blocking these Ca(2+) channels, including L- and T-types. To address these issues, the effects of efonidipine and its R(-)- and S(+)-isomers on these Ca(2+) channel subtypes were examined electrophysiologically in the expression systems using Xenopus oocytes and baby hamster kidney cells (BHK tk-ts13). Efonidipine, a mixture of R(-)- and S(+)-isomers, exerted blocking actions on L- and T-types, but no effects on N-, P/Q- and R-type Ca(2+) channels. The selective blocking actions on L- and T-type channels were reproduced by the S(+)-efonidipine isomer. By contrast, the R(-)-efonidipine isomer preferentially blocked T-type channels. The blocking actions of efonidipine and its enantiomers were dependent on holding potentials. These findings indicate that the R(-)-isomer of efonidipine is a specific blocker of the T-type Ca(2+) channel.     

Mibefradil (Ro 40-5967): the first selective T-type Ca2+ channel blocker

Mibefradil is a novel Ca2+ antagonist acting on both L- and T-type Ca2+ channels, with a ten-fold selectivity for T-type Ca2+ channels. It belongs to a chemical class different from other Ca2+ antagonists (tetralol derivative), and binds to a new receptor site on the L-type Ca2+ channel, where it does not affect dihydropyridine (DHP) binding but appears to overlap the verapamil and fantofarone sites. In vitro and in vivo studies indicate that mibefradil has a high selectivity for the coronary vasculature over the peripheral vasculature and the myocardium. It has no relevant negative inotropic effects in various animal models, in normotensive patients, and patients with hypertension or angina pectoris. Instead, treatment with mibefradil slightly decreases heart rate and improves cardiac function. Clinical studies confirm that mibefradil is an effective antihypertensive and anti-ischaemic drug, which may be beneficial in the treatment of heart failure. Its excellent pharmacological and safety profile combined with high bioavailability makes it a promising new drug. Many of the unique pharmacological properties of mibefradil may derive from its selective block of T-type Ca2+ channels.     

Inhibitory effect of efonidipine on aldosterone synthesis and secretion in human adrenocarcinoma (H295R) cells

Targeting aldosterone synthesis and/or release represents a potentially useful approach to the prevention of cardiovascular disease. Aldosterone production is stimulated by angiotensin II (Ang II) or extracellular K+ and is mediated mainly by Ca2+ influx into adrenal glomerulosa cells through T-type calcium channels. We therefore examined the effects of efonidipine, a dual T-type/L-type Ca2+ channel blocker, on aldosterone secretion in the H295R human adrenocarcinoma cell line; 100 nmol/L Ang II and 10 mmol/L K+ respectively increased aldosterone secretion from H295R cells 12-fold and 9-fold over baseline. Efonidipine dose-dependently inhibited both Ang II- and K+-induced aldosterone secretion, and nifedipine, an L-type Ca2+ channel blocker, and mibefradil, a relatively selective T-type channel blocker, similarly inhibited Ang II- and K+-induced aldosterone secretion, but were much less potent than efonidipine. Efonidipine also lowered cortisol secretion most potently among these drugs. Notably, efonidipine and mibefradil also significantly suppressed Ang II- and K+-induced mRNA expression of 11-beta-hydroxylase and aldosterone synthase, which catalyze the final two steps in the aldosterone synthesis, whereas nifedipine reduced only K+-induced enzyme expression. These findings suggest that efonidipine acts via T-type Ca2+ channel blockade to significantly reduce aldosterone secretion, and that this effect is mediated, at least in part, by suppression of 11-beta-hydroxylase and aldosterone synthase expression.     

钙通道不同分型与亚基和抗高血压药物的关系

该文阐述电压依赖性钙通道不同分型与亚型和抗高血压药物的关系。(1)传统的L型电压依赖性钙通道阻断剂舒张肾入球小动脉,但对肾出球小动脉无作用。第3代新的双氢吡啶类钙通道阻断剂(manidipine,nilvadipine,benzin-damine和efonidipine)能同时作用L及T型钙通道,对肾出球小动脉也能舒张,故对肾性高血压有效,并起保护肾脏作用。(2)L型钙通道的主要组成α1c亚基,在高血压时表达增加,使钙通道数量增多,从而加速高血压的发展,故能使α1c亚基数目恢复正常的药物,有望用于临床治疗高血压。     

Vascular effects of calcium channel antagonists: new evidence

Calcium channel antagonists have a well-established role in the management of cardiovascular diseases. L-type calcium channels in vascular cells are a key therapeutic target in hypertension and are the preferred molecular target of the initial calcium channel antagonists. However, third-generation dihydropyridine (DHP) calcium channel antagonists, including manidipine, nilvadipine, benidipine and efonidipine, appear to have effects in addition to blockade of the L-type calcium channel. Voltage-gated calcium channels are widely expressed throughout the cardiovascular system. They constitute the main route for calcium entry, essential for the maintenance of contraction. Cardiac and vascular cells predominantly express L-type calcium channels. More recently, T-type channels have been discovered, and there is emerging evidence of their significance in the regulation of arterial resistance. A lack of functional expression of L-type channels in renal efferent arterioles may be consistent with an important role of T-type channels in the regulation of efferent arteriolar tone. Although the exact role of T-type calcium channels in vascular beds remains to be determined, they could be associated with gene-activated cell replication and growth during pathology. The three major classes of calcium channel antagonists are chemically distinct, and exhibit different functional effects depending on their biophysical, conformation-dependent interactions with the L-type calcium channel. The DHPs are more potent vasodilators, and generally have less cardiodepressant activity than representatives of other classes of calcium channel antagonist such as diltiazem (a phenylalkylamine) and verapamil (a benzothiazepine). In contrast to older calcium channel antagonists, the newer DHPs, manidipine, nilvadipine, benidipine and efonidipine, dilate not only afferent but also efferent renal arterioles, a potentially beneficial effect that may improve glomerular hypertension and provide renoprotection. The underlying mechanisms for the heterogenous effects of calcium channel antagonists in the renal microvasculature are unclear. A credible hypothesis suggests a contribution of T-type calcium channels to efferent arteriolar tone, and that manidipine, nilvadipine and efonidipine inhibit both L and T-type channels. However, other mechanisms, including an effect on neuronal P/Q-type calcium channels (recently detected in arterioles), the microheterogeneity of vascular beds, and other types of calcium influx may also play a role. This article presents recent data about the expression and physiological role of calcium channels in arteries and the molecular targets of the calcium channel antagonists, particularly those exhibiting distinct renovascular effects.     

Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R

Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca2+ channels. More recently, it has been demonstrated that benidipine inhibits T-type Ca2+ channels in addition to L-type Ca2+ channels. Therefore, effect of calcium channel blockers, including benidipine, on aldosterone production and T-type Ca2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that benidipine concentration-dependently inhibited T-type Ca2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-beta-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca2+ influx inhibitory activities of benidipine for aldosterone production. T-type Ca2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca2+ channels.     

A selective T-type Ca2+ channel blocker R(−) efonidipine

Recently, novel compound R(-) efonidipine was reported to selectively block low-voltage-activated (LVA or T-type) Ca(2+) channels in peripheral organs. We examined how R(-) efonidipine acts on T-type and high-voltage-activated (HVA) Ca(2+) channels in mammalian central nervous system (CNS) neurons. Furthermore, we compared the effects of R(-) efonidipine with those of flunarizine and mibefradil on both T-type and HVA Ca(2+) channels in rat hippocampal CA1 neurons by using the nystatin perforated-patch clamp technique. Flunarizine and mibefradil nonselectively inhibited both T-type and HVA Ca(2+) channels, though the dose-dependent blocking potency of flunarizine on T-type Ca(2+) channels was slightly stronger than that of mibefradil. In contrast, R(-) efonidipine inhibited only T-type Ca(2+) channels and did not show any effect on HVA Ca(2+) channels. The inhibitory actions of R(-) efonidipine or flunarizine were similar on both Ba(2+) and Ca(2+) current components passing through T-type Ca(2+) channels. In addition, flunarizine but not R(-) efonidipine inhibited voltage-dependent Na(+) channels and Ca(2+)-activated K(+) channels. Thus, it appears that R(-) efonidipine is a selective blocker for T-type Ca(2+) channels. It could be used as a pharmacological tool in future studies on T-type Ca(2+) channels.     

Ca2+ channel inhibition in a rat osteoblast-like cell line, UMR 106, by a new dihydropyridine derivative, S11568.

UMR 106 rat osteogenic sarcoma cells were studied with the whole cell patch clamp technique to investigate the presence of voltage-gated inward currents. In barium (Ba2+)-containing medium, depolarizing jumps revealed both transient (T-type) and sustained (L-type) Ba2+ currents. The L-type component was dihydropyridine-sensitive: the agonist Bay K 8644 increased the amplitude of the L-type Ba2+ current. A new dihydropyridine calcium channel blocker, S 11568 ((+/-)-2(2-[2-(aminoethoxy)ethoxyl]methyl)4-(2',3'- dichlorophenyl)3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4- dihydropyridine, and its enantiomers, S 12967 ((+)-S 11568) and S 12968 ((-)-S 11568), inhibited the L-type Ba2+ current. IC50 values at a holding potential (VH) of -50 mV were 90 nM for S 11568, 800 nM for S 12967 and 45 nM for S 12968. At VH = -80 mV, S 12968 was less potent (IC50 near 500 nM). In contrast, S 12968 was without appreciable effect on the T-type component of the inward current through Ca2+ channels. Our results indicate that UMR 106 cells express both T-type and L-type Ca2+ channels and could be used to study the modulation by Ca2+ channel blocking agents, such as S 12968, of the hormonal regulation of Ca2+ fluxes across the osteoblast membrane.     

Inhibition of T-type and L-type calcium channels by mibefradil: physiologic and pharmacologic bases of cardiovascular effects

Ca2+ channel antagonists of the dihydropyridine, benzothiazepine, and phenylalkylamine classes have selective effects on L-type versus T-type Ca2+ channels. In contrast, mibefradil was reported to be more selective for T-type channels. We used the whole-cell patch-clamp technique to investigate the effects of mibefradil on T-type and L-type Ca2+ currents (I(CaT) and I(CaL)) recorded at physiologic extracellular Ca2+ in different cardiac cell types. At a stimulation rate of 0.1 Hz, mibefradil blocked I(CaT) evoked from negative holding potentials (HPs) (-100 mV to -80 mV) with an IC50 of 0.1 microM in rat atrial cells. This concentration had no effect on I(CaL) in rat ventricular cells (IC50: approximately3 microM). However, block of I(CaL) was enhanced when the HP was depolarized to -50 mV (IC50: approximately 0.1 microM). Besides a resting block, mibefradil displayed voltage- and use-dependent effects on both I(CaT) and I(CaL). In addition, inhibition was enhanced by increasing the duration of the step-depolarizations. Similar effects were observed in human atrial and rabbit sinoatrial cells. In conclusion, mibefradil combines the voltage- and use-dependent effects of dihydropyridines and benzothiazepines on I(CaL). Inhibition of I(CaL), which has probably been underestimated before, may contribute to most of the cardiovascular effects of mibefradil.     

Effects of Ca channel blockers on Ca loading induced by metabolic inhibition and hyperkalemia in cardiomyocytes

The effects of the L-type (nifedipine and verapamil) and the T-type (mibefradil) Ca²⁺ channel blockers on the increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) induced by NaCN metabolic inhibition and hyperkalemia were examined in chicken cardiomyocytes using fluorescence imaging with Fura-2. NaCN induced a slow and sustained rise in [Ca²⁺]_i, which was not affected by pretreating the cells for 5 min with nifedipine, verapamil, or mibefradil at 100 nM or 10 μM. Pretreatment of the cells with 10 μM nifedipine, verapamil, or mibefradil for 5 min remarkably inhibited the K⁺-induced increase in [Ca²⁺]_i. These inhibitory effects diminished after 48-h pretreatment with nifedipine or verapamil but not with mibefradil. Ryanodine also induces an increase in [Ca²⁺]_i, and this effect was enhanced by 48-h pretreatment of the cells with 10 μM verapamil but not with 10 μM mibefradil. We conclude that the NaCN-induced increase in [Ca²⁺]_i is independent of the Ca²⁺ influx though the L-type or T-type Ca²⁺ channels. Chronic inhibition of the L-type Ca²⁺ channels but not T-type channels may enhance the ryanodine receptor-mediated Ca²⁺ release, which may be responsible for the development of tolerance to their inhibitory effects on K⁺-induced increase in [Ca²⁺]_i.     

Pharmacological properties of Cav3.2, a low voltage-activated Ca2+ channel cloned from human heart

Three genes encoding T-type Ca2+ channels have been described but their correspondence to the various native T-type Ca2+ currents remains uncertain. In particular, Ca(V)3.2 (or alpha1H) was cloned from a human heart library, its message was found abundantly in cardiac tissue, and expressed Ca(V)3.2 was shown to conduct low voltage-activated currents, which inactivate rapidly and are sensitive to Ni2+ and mibefradil. These observations suggested that Ca(V)3.2 might encode native cardiac T-type Ca2+ channels but more information on the pharmacology of Ca(V)3.2 was needed to confirm this hypothesis. In the present study, we compare the pharmacology of Ca(V)3.2 expressed in HEK293 cells and of native T-type Ca2+ channels in guinea pig atrial myocytes ("native-T"). (1) Ca(V)3.2 and native-T are insensitive to TTX and to toxins selective for N-, P-, or Q-type Ca2+ channels (omega-CTx-GVIA, omega-Aga-IVA, omega-CTx-MVIIC). (2) The half-maximal blocking concentration (IC50) of mibefradil on Ca(V)3.2 is near that on native-T and the block is similarly voltage-dependent. (3) Ca(V)3.2 is five- to sixfold less sensitive than native-T to the 1,4-dihydropyridine (DHP) amlodipine, suggesting a difference in the DHP binding site. (4) Both channels display similar (but not identical) sensitivities to the inorganic blockers Ni2+ and Cd2+ and the IC50s are in the range of values found for T-type Ca2+ currents in other cell types. (5) Ni2+ shifts the voltage dependence of Ca(V)3.2 activation but not that of native-T. The many similarities between the two channels support the contention that Ca(V)3.2 encodes cardiac T-type Ca2+ channels. The slight differences may be due to species variations and/or to the choice of splice variant.     

Contrasting the effects of nifedipine on subtypes of endogenous and recombinant T-type Ca2+ channels

There is evidence that nifedipine (Nif) - a dihydropyridine (DHP) Ca(2+)-channel antagonist mostly known for its L-type-specific action--is capable of blocking low voltage-activated (LVA or T-type) Ca(2+) channels as well. However, the discrimination by Nif of either various endogenous T-channel subtypes, evident from functional studies, or cloned Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3 T-channel alpha 1 subunits have not been determined. Here, we investigated the effects of Nif on currents induced by Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3 expression in Xenopus oocytes or HEK-293 cells (I(alpha 1G), I(alpha 1H) and I(alpha 1I), respectively) and two kinetically distinct, "fast" and "slow", LVA currents in thalamic neurons (I(LVA,f) and I(LVA,s)). At voltages of the maximums of respective currents the drug most potently blocked I(alpha 1H) (IC(50)=5 microM, max block 41%) followed by I(alpha 1G) (IC(50)=109 microM, 23%) and I(alpha 1I) (IC(50)=243 microM, 47%). The mechanism of blockade included interaction with Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3 open and inactivated states. Nif blocked thalamic I(LVA,f) and I(LVA,s) with nearly equal potency (IC(50)=22 microM and 28 microM, respectively), but with different maximal inhibition (81% and 51%, respectively). We conclude that Ca(v)3.2 is the most sensitive to Nif, and that quantitative characteristics of drug action on T-type Ca(2+) channels depend on cellular system they are expressed in. Some common features in the voltage- and state-dependence of Nif action on endogenous and recombinant currents together with previous data on T-channel alpha 1 subunits mRNA expression patterns in the thalamus point to Ca(v)3.1 and Ca(v)3.3 as the major contributors to thalamic I(LVA,f) and I(LVA,s), respectively.     

Effect of an homologous series of aliphatic alcohols on neuronal and smooth muscle voltage-dependent Ca2+ channels.

The acute inhibitory actions of alcohol on K(+)-stimulated 45Ca2+ uptake into synaptosomes shows regional variation in sensitivity throughout the brain, suggesting the possibility of a selective action on a specific Ca2+ channel subtype. This was examined by comparing the effects of a homologous series of aliphatic alcohols on synaptosomal Ca2+ channels with their actions on K(+)-stimulated Ca2+ channels in guinea-pig intestinal longitudinal muscle, which have been demonstrated to be of the L-type. K(+)-stimulated contraction of and [3H]nitrendipine binding to smooth muscle were both inhibited by the alcohols at similar concentrations, with the potency increasing with chain length. In synaptosomes, however, K(+)-stimulated 45Ca2+ uptake was 5-30 times more sensitive to the inhibitory actions of alcohol than were [3H]nitrendipine and [125I]omega-conotoxin binding. These observations suggest that K(+)-stimulated 45Ca2+ uptake is mediated by a non-L non-N type channel which is more sensitive to the acute effects of alcohols. This is supported by the observation that K(+)-stimulated 45Ca2+ uptake which is insensitive to L- and N-channel antagonists was inhibited by funnel web spider venom.     

The Ca2+ channel blockade changes the behavioral and biochemical effects of immobilization stress.

We investigated how the effects of chronic immobilization stress in rats are modified by Ca2+ channel blockade preceding restraint sessions. The application of nifedipine (5 mg/kg) shortly before each of seven daily 2 h restraint sessions prevented the development of sensitized response to amphetamine as well as the stress-induced elevation of the densities of L-type Ca2+ channel in the hippocampus and significantly reduced the elevation of the densities of [3H]nitrendipine binding sites in the cortex and D1 dopamine receptors in the limbic forebrain. Neither stress, nor nifedipine affected the density of alpha 1-adrenoceptors and D1 receptors in the cerebral cortex nor D2 dopamine receptors in the striatum. A single restraint session caused an elevation of blood corticosterone level that remained unaffected by nifedipine pretreatment, but the reduction of this response during the eighth session was significantly less expressed in nifedipine-treated rats. We conclude that L-type calcium channel blockade prevents development of several stress-induced adaptive responses.     

Sites of action of Ca2+ channel inhibitors

Ca2+ channel inhibitors are viewed as a subgroup of Ca2+ antagonists. Most of the currently used Ca2+ channel inhibitors are thought to act by reducing Ca2+ entry into the cell through Ca2+ channels. There is substantial electrophysiological evidence that the major site of action of verapamil, nifedipine and diltiazem in cardiac cells is a sarcolemmal Ca2+ channel. Cytosolic sites of action may contribute to their effects but probably only at higher than therapeutic concentrations. The recent ligand binding studies also tend to support the view that the sarcolemma is the site of action of Ca2+ channel inhibitors in smooth muscle. High affinity binding sites for 1,4-dihydropyridines without any established function are found in fast skeletal muscle and some neuronal membranes. The binding of [3H]nitrendipine to membranes from cardiac, skeletal and smooth muscle, and from brain is saturable, reversible and of high affinity; it is sensitive to cations and other drugs that interact with Ca2+ channels. Inhibition of [3H]nitrendipine binding and blockade of K+ responses in guinea pig ileum by 1,4-dihydropyridines are well correlated, supporting the view that the observed binding is to Ca2+ channel. In contrast, blockade of Ca2+ channels in cardiac and skeletal muscle and in brain synaptosomes occurs only at higher concentrations than needed to saturate the high affinity binding sites. The therapeutic success of Ca2+ channel inhibitors in the treatment of angina pectoris, hypertension, peripheral vascular diseases, and many other disease entities is based on selective inhibition of Ca2+ entry into smooth muscle cells. The specificity of some of these drugs for Ca2+ channels in different cell types, organs, or vascular beds is probably determined by receptor modulation and the effect of reflex mechanisms, which in turn determine the indications for their therapeutic use.     

Molecular pharmacology of T-type Ca2+ channels

Over the past few years increasing attention has been focused on T-type calcium channels and their possible physiological and pathophysiological roles. Efforts toward elucidating the exact role(s) of these calcium channels have been hampered by the lack of T-type specific antagonists, resulting in the subsequent use of less selective calcium channel antagonists. In addition, the activity of these blockers often varies with cell or tissue type, as well as recording conditions. This review summarizes a variety of compounds that exhibit varying degrees of blocking activity towards T-type Ca2+ channels. It is designed as an aid for researchers in need of antagonists to study the biophysical and pathological nature of T-type channels, as well as a starting point for those attempting to develop potent and selective antagonists of the channel.     

Efonidipine hydrochloride: a dual blocker of L- and T-type ca(2+) channels

T-type Ca(2+) channels have properties different from those of the L-type and are involved in cardiac pacemaking and regulation of blood flow, but not in myocardial contraction. Efonidipine is an antihypertensive and antianginal drug with dihydropyridine structure that was recently found to block both L- and T-type Ca(2+) channels. In isolated myocardial and vascular preparations, efonidipine has potent negative chronotropic and vasodilator effects but only a weak negative inotropic effect. In experimental animals and patients, reduction of blood pressure by the drug was accompanied by no or minimum reflex tachycardia leading to improvement of myocardial oxygen balance and maintenance of cardiac output. Efonidipine increased glomerular filtration rate without increasing intraglomerular pressure. By relaxing both the afferent and efferent arterioles, efonidipine markedly reduced proteinuria. Thus, efonidipine, an L- and T-type dual Ca(2+) channel blocker, appears to have an ideal profile as an antihypertensive and antianginal drug with organ-protective effects in the heart and kidney.