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Simplified view of the pharmacological action of L-type Ca²⁺ channel blockers in arterial smooth muscle: In contrast to cardiomyocytes action potentials are not carried by fast sodium channels in smooth muscle and depolarzations are more long lasting. Contraction requires the binding of Ca²⁺ to calmodulin, which then activates myosin light chain kinase (MLCK). MLCK phosphorylates the light chain of myosin which turns on contraction. The Ca²⁺ for activation of this pathway can enter through L-type Ca²⁺ channels in response to depolarization. Ca²⁺ channel blockers inhibit this pathway through concentration-dependent block of Ca²⁺ entry. Alternatively, Ca²⁺ can be released from intracellular stores after activation of membrane receptors (e.g. of angiotensin II AT1 or a1 -adrenergic receptors) coupled to IP₃ production. IP₃ opens IP₃ receptor channels, RyR related Ca²⁺ release channels in the SR. This process does not involve L-type Ca²⁺ channels and is not inhibited by Ca²⁺ channel blockers. Store-depletion also triggers the activation of "store-operated channels" (SOC) in the plasma membrane which are also not sensitive to Ca²⁺ channel blockers. Receptor-mediated activation of cAMP-dependent protein kinase (cAMP-PK) results in muscle relaxation through different mechanisms. D1-R, dopamine1 receptor; AR, adrenergic receptor; PLC, phospholipase C.

By blocking L-type channels in arterial smooth muscle they reduce Ca²⁺ influx during depolarisation. Thus less Ca²⁺ is available for activation of calmodulin which activates myosin-light chain kinase and thereby turns on actin-myosin interaction. Note that smooth muscle also contracts after stimulation of receptor-activated pathways. Agonists of angiotensin AT1 (e.g. angiotensin II) and a1 -adrenergic receptors (e.g. noradrenaline) release Ca²⁺ from intracellular IP₃-sensitive stores. Noradrenaline-induced contractions are much less sensitive to Ca²⁺ channel blockers. The differential contribution of depolarization-induced and receptor-activated contraction in different types of smooth muscle and under different pathophysiological conditions is one of the explanations why Ca²⁺ channel blockers are not effective relaxants in other diseases (such as e.g. of bronchial muscle in asthma or uretral spasms).

Simplified view of the pharmacological action of L-type Ca²⁺ channel blockers in cardiac myocytes: In cardiac myocytes L-type Ca²⁺ channels open when the plasma membrane is depolarised by an action potential carried along the muscle cells by the opening of voltage-gated sodium-channels (Na-Ch). The action potential is terminated (an its duration is determined) by the opening of potassium channels (K-Ch). Ca²⁺ influx triggers massive release of Ca²⁺ from intracellular stores by opening ryanodine-sensitive Ca²⁺ channels (ryanodine receptors, RyR) in the sarcoplasmic reticulum, resulting in an intracellular Ca²⁺ transient. Ca²⁺ influx and released Ca²⁺ directly initiate contraction. Contraction is terminated by the rapid uptake into the SR by SR Ca²⁺ ATPases (SERCA). b-adrenergic receptor stimulation increases inotropy by phosphorylation (P) of phospholamban (PLN) and L-type channels through cAMP-dependent protein kinase (cAMP-PK). The resulting stimulation of Ca²⁺ influx and Ca²⁺ - pump activity increases the load of Ca²⁺ in the SR stores. This leads to enhanced Ca²⁺ transients upon depolarization. Inhibition of Ca²⁺ influx through L-type Ca²⁺ channels by Ca²⁺ channel blockers causes decreased Ca²⁺ entry and SR load. Less Ca²⁺ influx and release result in smaller Ca²⁺ transients and a decrease in contractile force.

In the heart calcium entering through L-type channels during the action potential serves as a trigger ("trigger calcium") for further calcium release from the sarcoplasmic reticulum which initiates contraction. b-adrenergic receptor activation increases inotropy at least in part by cAMP-dependent phosphorylation of L-type channels thereby increasing calcium entry.

Chemical classes of organic Ca²⁺ channel blockers: Three different chemical classes: Dihydropyridines (DHPs; prototype nifedipine), phenylalkylamines (prototype verapamil) and benzothiazepines (prototype diltiazem). Despite their different structure they all bind within a single drug binding region close to the pore of the channel. All these drugs reversibly interact with this binding domain in a stereoselective manner and with dissociation constants in the nanomolar range (0.1 -50 nM).

DHPs: Widely used DHPs are nifedipine, amlodipine, nitrendipine, nisoldipine, nicardipine and isradipine. They directly bind to and stabilize the inactivated state of the channel and do not require the channel to open in order to access the binding domain. Inactivated channels are more likely to exist in arterial vascular smooth muscle because depolarizations are longer lasting than in cardiac muscle. Moreover, the arterial smooth muscle channel differs slightly from the cardiac isoform (alternative splicing of a1 subunits) which facilitates channel block. As a consequence, DHPs block the channels in arterial smooth muscle at lower concentrations than cardiac muscle. Their clinical use is therefore related to their vasodilating properties in arterial smooth muscle (inlcuding the coronary arteries) and not to direct actions on the myocardium and the conduction system (i.e. antiarrhythmic and cardiodepressive effects) which are observed at higher concentrations in vitro or at toxic plasma levels.

Phenylalkylamines: Verapamil is the most widely used phenylalkylamine. The more active methoxyverapamil (gallopamil) is also licensed for clinical use in some countries. Verapamil mainly gets access to the binding domain when the channel is open. As an organic cation it blocks the channel by interfering with Ca²⁺ ion binding to the extracellular mouth of the pore. Once bound to the open state it can promote the inactivated channel conformation. Verapamil also slows the recovery of channels from inactivation. This increases the refractory period of the drug bound channel. As a consequence, the number of channels available for Ca²⁺ influx decreases when the time between depolarizations shortens (i.e. stimulation frequency increases). The open channel block and slowing of recovery explains why inhibition by a given verapamil concentration increases at higher heart rates. Like lidocain block of voltage-gate sodium channels, verapamil block of Ca²⁺ channels becomes more pronounced during tachyarrhythmias. These antiarrhythmic effects are exploited in addition to its vasodilating and cardiodepressive actions.

Benzothiazepines: Diltiazem is the only benzothiazepine in clinical use. Its molecular mechanism of action as well as its pharmacological effects closely resemble those of phenylalkylamines.

All three classes also inhibit depolarisation-induced contraction of venous smooth muscle in vitro. However, venous relaxation does not contribute to the hemodynamic actions of Ca²⁺ channel blockers.

Clinical Use: DHPs are potent arterial vasodilators. They act on resistance vessels and therefore reduce peripheral vascular resistance, lower arterial blood pressure and antagonize vasospasms in coronary or peripheral arteries. By reducing afterload DHPs also reduce cardiac oxygen demand. Together with their antivasospastic effect this explains most of the beneficial actions of DHPs in angina pectoris. Most DHPs are only licensed for the therapy of hypertension, some of them also for the treatment of angina pectoris and vasospastic (Prinzmetal) angina.

The DHP-induced lowering of blood pressure can result in compensatory sympathetic activation and a subsequent increase in heart rate and cardiac oxygen demand. This unfavourable effect has been mainly associated with the use of short-acting DHPs, such as non-retarded formulations of nifedipine, nitrendipine or nicardipine. The use of such formulations which cause fluctuations in plasma levels is discouraged. Instead, formulations with slower onset and longer duration of action (e.g. slow release nifedipine, nisoldipine, amlodipine) are recommended. Due to their vasodilating properties in the absence of negative inotropic actions, DHPs have also been evaluated as vasodilators for the treatment of congestive heart failure in addition to standard therapy. Although long acting DHPs seem to be save in these patients, no clear benefit could be established for this indication.

In addition to the vasodilatory and antispastic properties therapeutic doses of verapamil and diltiazem also exert negative inotropic, dromotropic and chronotropic actions. As a consequence, compensatory tachycardia does not occur and heart rate may even decrease. Similar to b-adrenergic antagonists, verapamil and diltiazem also inhibit exercise-induced increases in heart rate and myocardial oxygen consumption. Due to their cardiodepressive effects they are more suitable for the treatment of angina pectoris than DHPs. Both drugs are licensed for the treatment of angina, vasospastic angina and hypertension. Their negative dromotropic and antiarrhythmic properties (see above) can be expoited to slow AV-conduction and to treat supraventricular arrhythmias. In patients with normal contractile function, the negativ inotropic action of verapamil is partially compensated by the decreased afterload and improved myocardial perfusion. However, verapamil may decrease left ventricular function in patients with congestive heart failure. Unlike b-adrenergic blockers, Ca²⁺ antagonists are not recommended for early treatment or secondary prevention of myocardial infarction.
DHPs are also used to treat Raynaud's phenomenon and pulmonary hypertension.

Side effects: Many unwanted effects are related to the vasodilatory effects of Ca²⁺ channel blockers, such as flushing, headache, dizziness, and hypotension. DHPs frequently cause edema and ankle swelling upon chronic use. Constipation is a frequent side effect of verapamil due to its inhibitory action on intestinal smooth muscle. Bradycardia, atrioventricular block or a decrease in left ventricular function are observed with verapamil (and to a lesser degree diltiazem) especially in patients taking b-adrenergic blockers or who have preexisting cardiac disease (impaired left ventricular function, atrioventricular block). Worsening of angina has also been observed with DHPs. This is most likely due to their pronounced effect on coronary resistance resulting in coronary steal in the presence of hypoperfused regions. It may also be caused by the reactive sympathetic activation with increase in heart rate and cardiac oxygen consumption.

Epidemiological and case-control studies suggested that Ca²⁺ channel blockers cause increased risk for myocardial infarction, cancer and gastrointestinal bleeding. The increased cardiovascular morbidity was again associated with short-acting DHPs and fast release forms of verapamil and diltiazem. It was explained by the unfavourable hemodynamic effects of short-acting drugs. Enhanced cardiovascular morbidity has not been consistently shown for long-acting formulations. The increased risk of cancer and gastrointestinal bleeding was not confirmed in other large trials. Although Ca²⁺ channel blockers are not considered first-line agents for the treatment of angina and hypertension, they can be savely used in such patients when they are clearly indicated.

L-type Ca²⁺ channels are not tightly coupled to fast phasic neurotransmitter release from nerve terminals in most neurons but they do so in sensory (cochlear hair cells, retinal photoreceptors) and endocrine cells (insulin secretion in pancreatic b-cells). In contrast to the cardiovascular system where mainly the Cav1.2 isoform is expressed (with the exception of the sinoatrial node), neurotransmitter release from sensory cells in controlled by Cav1.3 (cochlea, retinal cells) or Cav1.4 (retinal cells). These isoforms are an order of potency less sensitive to voltage-dependent block by DHPs. This may be one of the reasons why therapeutic concentrations of these drugs only causes pharmacological effects in the cardiovascular system. A decreased glucose-tolerance may be observed from block of pancreatic b-cell Cav1.2 channels which can decrease insulin secretion. However, this side effect plays a minor role in clinical practice.

Other pharmacological actions of Ca²⁺ antagonists: Some DHPs (such as nifedipine) and verapamil inhibit p-glycoprotein-mediated drug transport. P-glycoprotein is a drug efflux pump which can confer multidrug resistance to tumor cells. Structural analogues with potent p-glycoprotein but weak Ca²⁺ channel blocking activity were therefore developed but are of no clinical benefit for the treatment of cancer. However, inhibition of transport (and excretion) of other p-glycoprotein substrates, such as digoxin, explains the decrease of their body clearance by Ca²⁺ channel blockers.

In vitro nifedipine inhibits proliferation of colon cancer cells with a DNA mismatch repair defect which are resistant to 5-fluorouracil. Whether this also translates into clinical efficacy in such tumors remains to be determined.

Nimodipine, but not other DHPs, is also a potent inhibitor of nucleoside transport with actions similar to known nucleoside transport inhibitors such as dipyridamol. It is likely that this mechanism also contributes to the potent vasodilating properties of this DHP.

BAYK8644 is a DHP with calcium channel activating properties. Although some therapeutic effects can be envisaged for such drugs (such as stimulation of insulin secretion, positive inotropy) severe side effects are also predicted from animal studies (dystonic neurobehavioural syndrome, hypertension, arrhythmias) which prevents their clinical development.

References:

Abernethy DR, Schwartz JB (1999) Ca²⁺-antagonist drugs. N Engl J Med 341: 1447-1457.

Betkowski AS, Hauptman PJ (2000) Update on recent clinical trials in congestive heart failure. Curr Opin Cardiol 15: 293-303

Cutler JA (1998) Ca²⁺-channel blockers for hypertension--uncertainty continues. N Engl J Med 338: 679-681

Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Cavazzini C, Furberg CD (2000) Health outcomes associated with Ca²⁺ antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet 356: 1949-1954

Striessnig J, Grabner M, Mitterdorfer J, Hering S, Sinnegger MJ, Glossmann H (1998) Structural basis of drug binding to L Ca²⁺ channels. Trends Pharmacol Sci 19: 108-115