Antioxidant effects and the therapeutic mode of action of calcium channel blockers in hypertension and atherosclerosis

Abstract

Drugs currently known as calcium channel blockers (CCB) were initially called calcium antagonists because of their ability to inhibit calcium-evoked contractions in depolarized smooth muscles. Blocking the entry of calcium reduces the active tone of vascular smooth muscle and produces vasodilatation. This pharmacological property has been the basis for the use of CCBs in the management of hypertension and coronary heart disease. A major question is whether drugs reducing blood pressure have other effects that help prevent the main complications of hypertension, such as atherosclerosis, stroke, peripheral arterial disease, heart failure and end-state renal disease. Experimental studies that focus on this question are reviewed in the present paper.

Figure 1

Chemical structures of the major families of calcium channel blockers as represented by their lead compound.

Figure 2

The effect of cinnarizine on contractions evoked by Ca²⁺ in K⁺-depolarized rabbit mesenteric arteries. Arterial preparations were pre-incubated in Ca²⁺-free physiological solution depolarized in a Ca²⁺-free, KCl-rich solution and then further incubated with increasing Ca²⁺ concentrations. Cumulative concentration–effect curves were obtained before (circle) and after (triangle) addition of cinnarizine (C) at the concentrations indicated. Responses are expressed as the percentage of maximal contraction evoked before the addition of cinnarizine. The inhibitory effect of cinnarizine is observed at concentrations as low as 1 nM and resembles the action of antagonists in receptor studies. In view of this similarity, the term ‘calcium antagonist’ was suggested to describe the action of cinnarizine. From Godfraind & Kaba (1969a).

Figure 3

Specific binding of +isradipine (+PN 200-110) in an intact aorta isolated from a WKY (circle) and a SHR (triangle) bathed in physiological solutions at various KCl concentrations shown on the abcissa. Note the higher binding in SHR arteries that illustrates the higher affinity of the hypertensive arteries' binding sites compared with normotensive ones. Data from Morel & Godfraind (1994).

Figure 4

Left upper panel and right lower panel: Effects of salt diet without and with lacidipine (Lac) on endothelium-dependent (acetylcholine) and endothelium-independent (SNAP) NO-vasorelaxation of arteries isolated from SHRSPs exposed or not exposed to a salt diet with or without lacidipine. Left lower panel: note that salt-evoked over-expression of ET-1 mRNA is prevented by lacidipine. Right upper panel: note increased levels of eNOS mRNA in vessels isolated from SHRSPs treated with lacidipine. Data from Krenek et al. (2001).

Figure 5

Response of rat isolated basilar artery to acetylcholine (ACh) and serotonin (5-HT). Upper panel: basilar artery isolated from normotensive WKY rat. Left: artery pre-contracted by 5-HT and relaxed by ACh. Right: artery exposed to increasing concentrations of 5-HT. Lower panel: basilar artery isolated from hypertensive SHRSP rat. Left: artery pre-contracted by 5-HT and relaxed by ACh. Right: artery exposed to increasing concentrations of 5-HT. Note the difference in responses between the WKY and the SHRSP, indicating a reduced production of NO in the SHRSP. Data from Salomone et al. (1997).

Figure 6

The response of the basilar artery, isolated from a SHRSP exposed to a salt diet, to the calcium channel activator Bay K8644 is reversed by bosentan, an endothelin antagonist. Lower panel left: note ET-1 mRNA over-expression in the vessel wall showing that functional ET-1 was produced locally. Higher panel right: note the increased response to 5HT in the basilar artery isolated from WKY and bathed with ET-1 (10⁻⁹ M). Data from Salomone et al. (1996) and unpublished experiments.

Figure 7

Left panel: salt-evoked over-expression of ET-1 mRNA in a basilar artery from a SHRSP is prevented by lacidipine treatment. Right panel: salt-evoked accumulation of LDL and ox-LDL in the cerebral arteries of a SHRSP is prevented by CCBs and vitamin E. Data from Napoli et al. (1999) and unpublished experiments.

Figure 8

Gross appearance of the atherosclerotic lesions in the aorta of apoE-deficient mouse exposed to a Western-type diet for 20 weeks without (upper panel) or with lacidipine (lower panel). Whole aortas (from heart to iliac bifurcation) were placed into cold (4 °C) physiological solution. They were photographed against a black background in a standard fashion, allowing plaques and even minor fatty streaks to appear whitish in contrast to the darker, opaquely transparent normal tissue. Note the reduced number of fatty streaks in an aorta from a mouse treated with lacidipine.