1,4-Dihydropyridine Calcium Channel Blockers Inhibit Plasma and LDL Oxidation and Formation of Oxidation-Specific Epitopes in the Arterial Wall and Prolong Survival in Stroke-Prone Spontaneously Hypertensive Rats

Abstract

Background and Purpose-Calcium-channel blockers (CCBs) reduce systolic blood pressure and stroke-related mortality in stroke-prone spontaneously hypertensive rats (SPSHR). Brain ischemia is associated with loss of intracellular antioxidants. Increased formation of oxygen radicals and oxidation of LDL may enhance arterial vasoconstriction by various mechanisms. CCBs that also exert antioxidative properties in vitro may therefore be particularly useful. To investigate such antioxidant effects in vivo, we determined several parameters of LDL oxidation in SPSHR treated with two 1,4-dihydropyridine-type (1,4-DHP) CCBs of different lipophilic properties and compared them with antioxidanttreated and untreated controls. We also tested whether these drugs decrease the formation of oxidation-specific epitopes in arteries. Methods-Five groups of 9 to 14 SPSHR each (aged 8 weeks) were treated with 80 mg/kg body wt per day nifedipine, 1 mg or 0.3 mg/kg body wt per day lacidipine, vitamin E (100 IU/d), or carrier for 5 weeks. A group of Wistar-Kyoto rats was used as normotensive control. Plasma samples were taken, and LDL was isolated by ultracentrifugation. Then LDL was exposed to oxygen radicals generated by xanthine/xanthine oxidase reaction (2 mmol/L xanthineϩ100 mU/mL xanthine oxidase), and several parameters of oxidation were determined. The presence of native apolipoprotein B and oxidation-specific epitopes in the carotid and middle cerebral arteries was determined immunocytochemically. Results-1,4-DHP CCBs completely prevented mortality. Normotensive Wistar-Kyoto rats showed less oxidation than control SPSHR. Plasma lipoperoxide levels were 0.87Ϯ0.27 mol/L in control SPSHR, 0.69Ϯ0.19 and 0.63Ϯ0.20 mol/L in the groups treated with 0.3 and 1 mg lacidipine, respectively, and 0.68Ϯ0.23 mol/L in nifedipine-treated animals (PϽ0.05 versus control SPSHR for all values). Both CCBs significantly decreased formation of conjugated dienes and prolonged the lag time in LDL exposed to oxygen radicals. Similarly, lipoperoxides and malondialdehyde were significantly reduced (PϽ0.05). Reduced relative electrophoretic mobility and increased trinitrobenzenesulfonic acid reactivity of LDL from treated rats (PϽ0.01) also indicated that fewer lysine residues of apolipoprotein B were oxidatively modified in the presence of 1,4-DHP CCBs. Finally, these drugs reduced the intimal presence of apolipoprotein B and oxidized LDL (oxidation-specific epitopes) in carotid and middle cerebral arteries. Conclusions-In the SPSHR model, 1,4-DHP CCBs reduce plasma and LDL oxidation and formation of oxidation-specific epitopes and prolong survival independently of blood pressure modifications. Our results support the concept that the in vivo protective effect of these drugs on cerebral ischemia and stroke may in part result from inhibition of oxidative processes. (Stroke. 1999;30:1907-1915

Benidipine improves oxidized LDL-dependent monocyte and endothelial dysfunction in hypertensive patients with type 2 diabetes mellitus

“…It was previously reported that calcium channel blockers could inhibit the oxidation of LDL. [44][45][46] Benidipine also has the same action, because the concentration of anti-oxLDL antibody decreased significantly after benidipine treatment in the present study.…”

Age-Related Effects on Atherogenesis and Scavenger Enzymes of Intracranial and Extracranial Arteries in Men Without Classic Risk Factors for Atherosclerosis Editorial Comment

“…Recent data in strokeprone hypertensive rats have demonstrated that exogenous administration of the antioxidant, vitamin E, or calcium antagonists with antioxidant properties reduces their long-term mortality. 13 On the other hand, studies in humans have yielded conflicting effects of vitamin E treatment on clinical end points (see review 28 ). However, atherogenesis is a complex disease, 29 and it is possible that the lower susceptibility of intracranial arteries to cholesterol-induced atherogenesis results mainly from the coincidence of lower blood pressure 1 and decreased susceptibility to endothelial dysfunction.…”

“…2,3 Statins reduce the incidence of nonfatal stroke in coronary heart disease patients [1][2][3] but are apparently less effective in reducing the mortality from ischemic stroke. [1][2][3] Although intracranial arteries eventually develop atherosclerotic lesions, the onset of atherogenesis occurs much later in life, and the severity of the lesions at various ages is consistently less than that in extracranial arteries in humans, 2,4 -9 nonhuman primates, 10 rhesus and cynomolgus monkeys, 11 spontaneously hypertensive rats, 12,13 cholesterolSee Editorial Comment, page 2479 fed rabbits, 11 and Watanabe heritable hyperlipidemic rabbits. 14 To date, it is unknown whether the difference in atherosclerosis is due to anatomic differences between intracranial and extracranial arteries, systemic differences (eg, lower local blood pressure), or other differences in atherogenic mechanisms.…”

Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis

“…The gastric damage score was calculated for each stomach by summing the lengths of all erosions (23,24,32,33). Carotid arteries were perfused with phosphate-buffered paraformaldehyde (4%, 0.1 mol͞liter, pH 7.3) for histology or normal saline for immunohistochemistry assessed by computer-assisted imaging analysis (34)(35)(36). Carotid arteries were serially sectioned into 15-20 slices (10 M) with a rotating diamond-coated knife, and sections were stained with toluidine blue.…”