Class IV antihypertensives bind LTCC multimer

Stable Identifier
Reaction [binding]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
L-type calcium channels are responsible for the excitation-contraction coupling of skeletal, smooth and cardiac muscles and for aldosterone secretion in endocrine cells of the adrenal cortex. Class IV agents are L-type calcium channel blockers used in the treatment of hypertension. In cardiac muscle, they decrease conduction through the AV node, and shorten phase 2 (the plateau) of the cardiac action potential. There are three main chemical classes of class IV agents: Dihydropyridines (prototype nifedipine), phenylalkylamines (prototype verapamil) and benzothiazepines (prototype diltiazem). Despite their different structures, they all bind within a single overlapping drug binding region close to the pore and to the proposed activation gate of the channel’s α1 subunit (Striessnig et al. 2015). Dihydropyridines (nifedipine, amlodipine, cilnidipine, clevidipine, felodipine, isradipine, nicardipine, nimodipine, nisoldipine, nitrendipine) all block Ca2+-channels and are usually the first-line therapy in hypertension.

nifedipine is the prototypical dihydropyridine used in the treatment of angina and hypertension (Mueller et al. 1981, Snider et al. 2008). Amlodipine blocks Ca2+-channels in peripheral vascular and coronary smooth muscles, producing marked vasodilation. It has an intrinsically long duration of action (Murdoch & Heel 1991). Cilnidipine is a slow-acting Ca2+ antagonist, blocking L-type and N-type Ca2+ channels. It is used in the treatment of mild to moderate essential hypertension (Lohn et al. 2002, Minami et al. 2000). Clevidipine is a short-acting Ca2+-blocking agent given intravenously which is highly selective for vascular, as opposed to myocardial smooth muscle and, therefore, has little or no effect on myocardial contractility or cardiac conduction. It reduces mean arterial blood pressure by decreasing systemic vascular resistance (Prlesi & Cheng-Lai 2009). Felodipine is a vascualr smooth muscle-selective Ca2+-channel blocker used in the treatment of moderate to severe hypertension (Muir & Wathen, Cheung et al. 1998, Walton & Symes 1993).

Isradipine is a Ca2+-channel blocker used in the management of hypertension by producing peripheral vasodilation (Cheung et al. 1998, Walton & Symes 1993). Nicardipine is used in treatment of stable angina and mild to moderate hypertension (Sorkin & Clissold 1987). Nimodipine is mainly used in the control of blood pressure in patients with cerebral hemorrhage (vasospasm) (Li et al. 2015). Nisoldipine is used to treat chronic stable angina pectoris and mild to moderate essential hypertension (Friedel & Sorkin 1988).Nitrendipine is used to treat primary (essential) hypertension (Goa & Sorkin 1987, Santiago & Lopez 1990).

Phenylalkylamine Ca2+ channel blockers are relatively selective for myocardium, reduce myocardial oxygen demand and have minimal vasodilatory effects compared with dihydropyridines and therefore cause less reflex tachycardia, making it appealing for treatment of angina. The prototypical phenylalkylamine drug verapamil is used to treat high blood pressure, angina, supraventricular tachycardia and migraine headaches (Benjamin et al. 1988, Pedersen 1981, Vohra 1982, Sigurd & Hansen 1984, Markley 1991).

Benzothiazepine calcium channel blockers possess both cardiac depressant and vasodilator actions, therefore benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines. The prototypical benzothiazepine diltiazem is used in the treatment of hypertension, angina pectoris and some types of arrhythmia (Chaffman & Borgden 1985, O'Connor et al. 1999). It is also used off-label as a preventive medication for migraine (Kim 1991).

Additional L-type calcium channel blockers of the dihydropyridine class all exhibit antihypertensive activity and are identified by the suffix "-dipine"; aranidipine, azelnidipine, barnidipine, dexniguldipine, efonidipine, lacidipine, lercanidipine, levamlodipine, mandipine and nivaldipine.
Literature References
PubMed ID Title Journal Year
25966690 Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets?

Striessnig, J, Ortner, NJ, Pinggera, A

Curr Mol Pharmacol 2015
Orthologous Events
Cite Us!