Journal of Cardiovascular Pharmacology and Therapeutics

Background: Reduction of serum cholesterol, most notably low-density lipoprotein choles terol is associated with reductions in cardiovascular morbidity and mortality. Statins have been shown to effectively reduce low-density lipoprotein cholesterol via inhibition of the hydroxymethyl-coenzyme A (HMG-CoA) reductase. Cerivastatin is the most potent HMG- CoA reductase inhibitor currently under study in the United States.

Methods and Results: A parallel group, randomized, placebo-controlled, double-blind, mul ticenter study was conducted to compare the efficacy and safety of three different dosing reg imens of 0.2 mg/day of cerivastatin, a new HMG-CoA reductase inhibitor, in patients with hypercholesterolemia. After a 10-week diet-placebo lead-in period, 319 patients with low- density lipoprotein cholesterol >160 mg/dL were randomized to 4 weeks of treatment with one of the following regimens: cerivastatin 0.1 mg twice daily, cerivastatin 0.2 mg once daily with the evening meal, cerivastatin 0.2 mg once daily at bedtime or placebo. All three active treatment groups produced statistically significant (P < .05) changes compared to baseline and placebo in total cholesterol (0.1 mg twice daily -18.9%; 0.2 mg once daily with the evening meal: -21.9%; 0.2 mg once daily at bedtime: -22.1%; placebo: 0.0%), low-density lipoprotein cholesterol (0.1 mg twice daily: -25.7%; 0.2 mg once daily with the evening meal: -29.4%; 0.2 mg once daily at bedtime: -30.4%; placebo: 1.4%) and high-density lipoprotein cholesterol (0.1 mg twice daily: 5.3%; 0.2 mg once daily with the evening meal: 2.3%; 0.2 mg once daily at bedtime: 3.2%; placebo: -1.2%). Triglycerides, compared to baseline and placebo, were also reduced by all active treatments (0.1 mg twice daily: -11.6% [P = .05]; 0.2 mg once daily with the evening meal: -11.6% [P = .05]; and 0.2 mg at bed time: -10.9% [P = .07]). The percentage change in total cholesterol and low-density lipopro tein cholesterol after 4 weeks of therapy for the once-daily cerivastatin groups was statisti cally significantly greater (P < .05) than the cerivastatin twice daily regimen. A treatment response was seen by 1 week of therapy and was maximal by 3 weeks. The drug was well tolerated in all three dosing regimens and resulted in no significant increase in biochemical or clinical side effects compared to placebo.

Conclusion: Cerivastatin is a novel, highly potent, well-tolerated HMG-CoA reductase inhibitor that produces low-density lipoprotein cholesterol reductions of approximately 30% when administered at 0.2 mg once a day in the evenings.

Background: Pravastatin inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase. It pre vents mevalonate synthesis, reducing endogenous cholesterol production, and reduces cholesterol content in the liver, thus resulting in a down-regulation of low-density lipoprotein receptor production. Gemfibrozil reduces very low-density lipoprotein production and low- density lipoprotein-cholesterol level and increases very low-density lipoprotein catabolism. Therefore, it was suggested that combination therapy with both drugs could effect greater reduction of cholesterol levels as compared to pravastatin alone. The present study was car ried out to evaluate the efficacy and safety of pravastatin as a monotherapy or in combination with gemfibrozil in the treatment of patients with familial type IIb hyperlipoproteinemia or familial combined hyperlipidemia.

Methods and Results: Forty-one patients were included in the study. All patients initially followed 6 weeks of hypolipidemic diet; subsequently they were randomized and received either 20 mg once daily of pravastatin alone (n = 13) or 20 mg of pravastatin together with 600 mg of gemfibrozil twice daily (n = 14). As a control, 14 patients were treated with diet only. The treatment lasted 24 months and clinical evaluation and laboratory tests were done at given time points. Both groups of treated patients showed an early reduction (3 months) of total (about 30% P < .0 vs controls), low-density lipoprotein (about 35%, P < .0 vs con trols) and very low-density lipoprotein cholesterol levels (about 18%, P = NS). In contrast, high-density lipoprotein cholesterol levels increased significantly in patients treated with pravastatin and gemfibrozil (about 20%, P < .05 vs controls). Pravastatin treatment alone reduced the level of serum triglycerides as efficiently as in combination with gemfibrozil. Data showed a sustained normalization of lipid profile until 24 months. However, this effect was achieved in patients that had rather low levels of triglycerides. During the treatment we did not observe any difference in the incidence of possible drug-related side effects. Severe myopathy or rhabdomyolysis was not observed at the doses of the drugs used in our study. Conclusions: Therapy with pravastatin alone and in combination with gemfibrozil resulted in significant and sustained normalization of lipid profile in high-risk patients with familial type lib hyperlipoproteinemia or familial combined hyperlipidemia.

Background: Despite its class III antiarrhythmic actions, experimental and clinical studies have shown that d-sotalol can also be proarrhythmic; a recent clinical trial that evaluated d- sotalol in postmyocardial patients (SWORD) had to be prematurely interrupted because of the excess mortality in the treated group. Previous studies have demonstrated the existence of a marked heterogeneity across the ventricular wall; epicardial, endocardial, and M cells have been shown to display distinct electrophysiologic characteristics and pharmacologic behav ior. The present study was designed to test the hypothesis that M cells are the primary target for the class III actions of d-sotalol in canine ventricular myocardium and may contribute to its proarrhythmic effects.

Methods and Results: We used standard microelectrode techniques to record transmem brane activity from endocardial, epicardial, midmyocardial, and transmural strips isolated from the canine left ventricle. d-Sotalol (100 μM, 60 minutes of exposure, [K+]o = 4 mM) prolongs the action potential in the three cell types, but more so in M than epicardial or endo cardial cells, especially at the slower rates. At a basic cycle length of 2000 ms, action poten tial duration after 90% repolarization increases from 199 ± 20 to 247.5 ± 28 ms in epi cardium (n = 10), from 212 ± 26 to 274 ± 27 ms in endocardium (n = 11), and from 309 ± 65 to 533 ± 207 ms in M cells (n = 13). d-Sotalol produces a marked steepening of action potential duration-rate relationships of M cells and an upward shift of restitution of action potential duration curves, more accentuated in M cells. Early afterdepolarizations were observed at slow rates (basic cycle lengths > 1000 ms) in 7 of 13 M cell preparations (54%) but not in endocardial or epicardial preparations. A sudden acceleration of the rate could also induce a transient prolongation of the action potential and early afterdepolarization activity. Conclusion: In canine ventricular tissues, d-sotalol manifests its class III effects preferen tially in the M cells, leading to the development of early afterdepolarizations and a marked increase in transmural dispersion of repolarization. The data suggest an important role of M cells in the proarrhythmic effects of the drug.

Background: The tendency for the electrophysiologic effect of class III antiarrhythmic agents (action potential prolongation) to be diminished at faster heart rates represents a major drawback of this class of drug and is usually referred to as "reverse use dependence." A novel class III agent, MS-551, has recently been reported to exhibit less reverse use dependence than E-4031. We set out to investigate whether this observation may be due to differential blockade of the inward rectifier current (i_K1) by these drugs.

Methods and Results: We recorded i_K1 using single channel methods and cell attached patch configurations, with standard patch clamp technology. Neither E-4031 nor racemic sotalol in concentrations up to 100 μM had any significant effect on the open probability or kinetics of i_K1 channels. MS-551 produced a concentration-dependent reduction in the open probability of i _K1 without altering the single-channel conductance. Openings to subconductance levels were abolished in three of six patches in which they had been frequently present in the absence of drug. MS-551 had no effect on mean channel open time but increased the slower component of the closed time.

Conclusions: MS-551, unlike E-4031 and sotalol, appears to produce significant blockade of the inwardly rectifying potassium channel at clinically relevant concentrations. We propose that this might provide a partial explanation for the observed differences in their response to rate changes.

Background: The benefits of chronic administration of estrogen to postmenopausal women are well documented; however, the acute effects of exogenous estradiol on myocardium after coronary artery occlusion and reperfusion in male and female animal models are unknown. We tested the influence of acute pretreatment with estradiol on the development of myocar dial necrosis in two protocols, studying intact anesthetized female and male rabbits.

Methods and Results: 17β-estradiol (1 mg) was given 15 minutes before coronary artery occlusion in the treated groups (n = 10 females, 10 males); control rabbits (n = 11 females, 10 males) received water. All rabbits underwent 30 minutes of coronary artery occlusion and 4 hours of reperfusion. Myocardial blood flow was similar between groups at 10 minutes after treatment and during coronary artery occlusion and reperfusion. Thus estradiol did not increase blood flow. Heart rate and systemic pressure were also similar between groups. Estradiol levels during coronary artery occlusion were 1-8 pg/mL in untreated female and male rabbits and 66 ± 28 (male) and 352 ± 273 (female) in treated rabbits. Although the size of the ischemic risk zones was similar in both groups in both protocols, estradiol-treated rab bits of both sexes developed significantly less necrosis. Infarct size as a percent of the risk region was 10 ± 1% in female estradiol-treated rabbits compared with 23 ± 5% in controls (P < .03) and 16 ± 4% in estradiol-treated male rabbits compared with 31 ± 5% in control males (P = .03). Although male rabbits had larger infarcts than female rabbits, sex was not a significant covariate for infarct size.

Conclusions: Estradiol exerts a protective effect on ischemic myocardium that is not associ ated with an increase in myocardial blood flow or alteration in hemodynamics. This study shows that acute administration of estrogen before coronary artery occlusion reduces infarct size in both male and female rabbits.

Background: The clinical usefulness of amiodarone for the treatment of cardiac arrhythmias is limited by multiorgan toxicity, especially pulmonary and hepatic. There are conflicting reports in the literature regarding the role of free radicals in the initiation of amiodarone- induced toxicity. We evaluated the possible oxidative stress in a chronic model that is known to manifest pulmonary toxicity.

Methods and Results: A group of 20 Fischer-344 rats were injected with 60 mg/kg/day of amiodarone for 21 days. A control group of 20 animals received only saline injections. The alveolar macrophages obtained by lung lavage were incubated with hydroethidine and opsonized green fluorescent zymosan particles to measure oxidative and phagocytic activities by flow cytometry. Malondialdehyde levels were measured to assess the extent of lipid per oxidation in lung, liver, spleen, kidney, and heart. Total phospholipid levels in all the col lected tissues and distribution of phospholipid classes in the lung and the liver were mea sured. The levels of amiodarone and its metabolite desethylamiodarone in serum and all collected tissues were measured by high-performance liquid chromatography. The phago cytic activity of the macrophages from treated animals was decreased by 18-22% (P < .03) compared to controls; however, the oxidative activities of control and treated groups were not significantly different. The tissue malondialdehyde levels were not significantly different except in the spleen where they increased after amiodarone treatment (18.2 ± 1.1 vs 23.7 ± 2.8 μM/g tissue, P < .0001). Malondyaldehyde levels were not significantly different when normalized to lipid phosphorous content. Lung, liver, and spleen showed significantly higher phospholipid levels in the treated group. The tissue amiodarone and desethylamiodarone lev els in the treated group were highest in spleen followed by lung, liver, kidney, and heart. Conclusions: The results show that amiodarone-induced pulmonary and hepatic toxicity is not directly mediated by oxidative stress; however, increased lipid peroxidation in the spleen, although secondary to phospholipidosis, may be physiologically significant.

The recent discovery of multiple myocardial cell types in the ventricular wall of most species has prompted a reevaluation of several electrophysiologic and electrocardiographic findings. This review briefly presents the salient electrophysiologic features of myocardial cells in the epicardial, midmyocardial and endocardial regions of the ventricle. The epicardial action potential exhibits a prominent notch between phase I and phase 2 that results in a spike and dome configuration. The notch is smaller in midmyocardial cells and absent in endocardial cells. The action potential notch is due to the presence of a transient outward current (I_to), which diminishes in amplitude from the epicardial to endocardial surfaces. Midmyocardial or "M cells" exhibit electrophysiologic features intermediate between those of myocardial and conducting cells. M cells differ from epicardial and endocardial cells primarily in their response to slowing of the stimulation rate. These cells display an exaggerated prolongation of action potential duration at moderate to slow rates of stimulation. The atypical response in M cells reflects decreased levels of the delayed rectifier K⁺ current (I_K) in this cell type. Another distinguishing feature of M cells is a greater rate of rise of the upstroke of phase 0 (dV/dt) compared to epicardial or endocardial cells. These electrophysiologic distinctions contribute to differences in the responsiveness of the various cell types to pharmacologic agents and disease. Also, the dispersion of repolarization created between epicardium and endocardium in the early phases of the action potential, and between M cells and other ven tricular layers during late repolarization, may explain the J wave and U wave of the electro cardiogram, respectively.