Journal of Cardiovascular Pharmacology and Therapeutics

The present study was designed to determine the efficacy and safety of Niaspan (Kos Pharmaceuticals, Inc, Hollywood, FL), a new controlled-release formulation of niacin, in the treatment of primary hyperlipidemia, the occurrence and severity of flushing events, and potential adverse effects, particularly hepatotoxicity.

The study was conducted as a multicenter, randomized, double-blind, placebo-controlled, parallel comparison of Niaspan in doses of 1000 mg/day and 2000 mg/day, administered once a day at bedtime. One hundred twenty-two patients with low-density lipoprotein cholesterol levels > 4.14 mM/L (160 mg/dL) with dietary intervention and high-density lipoprotein cholesterol ≤ 1.81 mM/L (70 mg/dL) were randomized to one of three treatment groups: placebo, and 1000 mg/day or 2000 mg/day of Niaspan. Safety and efficacy measures included 12-hour serum fasting lipid and lipoprotein concentrations, serum analyte levels for major organ function, flushing diaries, and adverse event records. The placebo group demonstrated no significant changes in serum lipoprotein concentrations over the treatment period of 12 weeks, except for a slight 4% increase in high-density lipoprotein cholesterol. Niaspan significantly lowered low-density lipoprotein cholesterol levels by 6% and 14% for the 1000 mg/day and 2000 mg/day doses, respectively. High-density lipoprotein cholesterol levels rose significantly, with a 17% increase occurring at the 1000 mg/day dose and a 23% increase occurring at the 2000 mg/day dose. Niaspan (2000 mg/day) produced significant decreases of 27% and 29%, respectively, for serum lipoprotein(a) and triglyceride concentration. Although the incidence of flushing was significant, these episodes were generally well tolerated.

Niaspan administered in doses of 1000 mg/day and 2000 mg/day at bedtime were well tolerated with few side effects and produced favorable effects on the major circulating lipoproteins of patients with primary dyslipidemias as specified by the enrollment criteria.

To investigate the effects of dipyridamole, a drug with phosphodiesterase-, adenosine reuptake-inhibiting, and prostacyclin-stimulating activity on the biological actions of nitric oxide, 30 norepinephrine-precontracted subcutaneous arterioles were prepared from specimens removed during surgery.

Specimens were mounted on a myograph and relaxed through either acetylcholine, a muscarinic agonist that stimulates endothelial nitric oxide production, or sodium nitroprusside, an endothelium-independent vasodilator. Studies were performed under control conditions and after dipyridamole which potentiated in a concentration-dependent manner the vasorelaxation induced both by acetylcholine and sodium nitroprusside, indicating an endothelium-independent mechanism of action. The contribution of nitric oxide to the relaxation produced by acetylcholine was confirmed by N-monomethyl-L-arginine, a nitric oxide synthase inhibitor. In contrast, indomethacin, a cyclo-oxygenase inhibitor, was ineffective, indicating that prostacyclin stimulation could not explain the effect of dipyridamole. CGS 21680 C, an A₂-selective adenosine receptor agonist insensitive to tissue deaminase, did not influence the relaxations induced by acetylcholine, suggesting that interference with adenosine metabolism was not implicated in the potentiating action of dipyridamole.

Dipyridamole potentiated the vasorelaxing effect of acetylcholine and sodium nitroprusside in human subcutaneous arterioles; neither prostacyclin stimulation nor A₂ adenosine receptor stimulation could explain this effect. The data are consistent with an increase in intracellular cyclic 3’ 5'-guanosine monophosphate levels secondary to the phosphodiesterase-inhibiting properties of the drug.

Although oxygen free radicals have been shown to induce myocardial cell damage and cardiac dysfunction, the exact mechanism by which these radicals affect the heart function is not clear. Since the occurrence of intracellular Ca²⁺ overload is critical in the genesis of cellular damage and cardiac dysfunction, and since the sarcolemmal Na⁺–Ca²⁺ exchange is intimately involved in Ca²⁺ movements in myocardium, this study was undertaken to examine the effects of oxygen free radicals on the relationship between changes in cardiac contractile force development and sarcolemmal Na⁺–Ca²⁺ exchange activity.

Isolated rat hearts were perfused with a medium containing xanthine plus xanthine oxidase for different times, and changes in contractile force as well as sarcolemmal Na⁺–Ca²⁺ exchange activity were monitored. Perfusion of the heart with xanthine plus xanthine oxidase resulted in a transient increase followed by a marked decrease in contractile activity; the resting tension was markedly increased. The xanthine plus xanthine oxidase-induced depression in developed tension, rate of contraction, and rate of relaxation, except the transient increase in contractile activity, was prevented by the addition of catalase, but not by superoxide dismutase, in the perfusion medium. A time-dependent depression in sarcolemmal Na⁺–Ca²⁺ was also evident upon perfusing the heart with xanthine plus xanthine oxidase. This depression in Na⁺-dependent Ca²⁺ uptake was associated with a decrease in the maximal velocity of reaction without any changes in the affinity of Na⁺–Ca²⁺ exchanger for Ca²⁺. The presence of catalase, unlike superoxide dismutase, prevented the decrease in sarcolemmal Na⁺–Ca²⁺ exchange activity in hearts perfused with xanthine plus xanthine oxidase.

The results support the view that a depression in the sarcolemmal Na⁺–Ca²⁺ exchange activity may contribute to the occurrence of intracellular Ca²⁺ overload and subsequent decrease in contractile activity. Furthermore, these actions of xanthine plus xanthine oxidase in the whole heart appear to be a consequence of H₂O₂ production rather than the ‘ generation of superoxide radicals.

We determined if a single administration of heparin or nonanticoagulant N-acetylheparin could reduce myocardial injury resulting from a 90-minute occlusion of the left circumflex coronary artery (LCX) and 6 hours of reperfusion in the anesthetized canine.

Heparin (2 mg/kg), N-acetylheparin (2 mg/kg), or vehicle, 0.9% sodium chloride (control), was administered intravenously to separate groups of animals 2 hours before LCX occlusion. To ensure parity of LCX ischemia, only animals with ischemic zone regional blood flow < 0.16 mL/min/g tissue were included in the final analysis. Hemodynamics did not differ among the three study groups. Infarct size as a percentage of the left ventricular area at risk was obtained for each group. Myocardial infarct size was 43.0 ± 3.9% in the vehicle, 28.8 ± 5.8% in the heparin (P < .05 vs vehicle) and 24.7 ± 4.6% (P < .05 vs vehicle) in the N-acetylheparin-treated animals.

Pretreatment with heparin or its nonanticoagulant derivative, N-acetylheparin, provides significant protection to the regionally ischemic and reperfused canine myocardium independent of either plasma glycosaminoglycan concentration or alterations in the coagulation system.

Dofetilide is a new class III antiarrhythmic agent with demonstrated efficacy in ventricular and atrial tachyarrhythmias. We investigated its class HI actions and their modulation by stimulation rate in rabbit atrial myocardium.

Standard microelectrode techniques were used to record action potentials from rabbit atrial tissue at varying stimulation rates. Dofetilide produced a dose-dependent prolongation of action potential duration at concentrations from 1 nM to 1 μM at an interstimulus interval of 1000 ms. Action potential duration at 90% repolarization (action potential duration) was prolonged from 116 ± 11.7 ms in control solutions to 148 ± 13.9 ms at 1nM dofetilide and 186 ± 49.3 ms at 1 μM dofetilide (P < .05 for 1 nM vs control; P < .01 for 1 μM vs control). Reduction of interstimulus interval to 500 ms had no significant effect on action potential duration prolongation by dofetilide. At faster rates than this, and particularly at an interstimulus interval less than 330 ms, a marked “reverse rate dependence” of the class III effect was observed. Specifically, the high therapeutic concentration of 10 nM showed no effect on action potential duration at interstimulus interval of 250 ms or 200 ms, and even at a concentration of 30 nM, the small class III effect was no longer statistically significant at these rates.

Dofetilide prolongs action potential duration in rabbit atrial myocardium, but this effect is significantly attenuated at stimulation rates above 2 Hz.

3-(2,2,2-trimethylhydrazinium) propionate (THP or mildronate) is an inhibitor of carnitine biosynthesis. This study was carried out to determine whether feeding of guinea pigs with THP results in decreased myocardial-free carnitine content and, as a result, attenuates hypoxic damage in isolated and paced work-performing hearts.

Guinea pigs were administered either distilled water or 100 mg THP/kg/day orally for 10 days. The treatment resulted in about a 50% decline in myocardial-free carnitine content, from 11.1 ± 0.2 (n = 5) to 5.6 ± 0.2 (n = 5) μM/g dry weight of the heart. The left ventricular contractile function of the hearts was measured during normoxic perfusion (PO₂ = 590 mmHg), hypoxic perfusion (PO₂ = 149 mmHg), and reperfusion (PO₂ = 590 mmHg). In both untreated and THP-treated groups, the rate of development of intraventricular pressure (+dP/dt) under normoxic perfusion was similar; however, +dP/dt declined to about 10% of the initial rate within 20 minutes of hypoxic perfusion. In the THP-treated group of hearts, the initial decline was slower than that of the untreated animal hearts. After 20 minutes of normoxic reperfusion following 60 minutes of hypoxic perfusion, the recovery of +dP/dt and -dP/dt was greater in the THP-treated group than in the untreated group. The elevation of end-diastolic pressure during hypoxia was completely reversed by normoxic reperfusion of the THP-treated group but not in the untreated group. Mitochondria isolated from hearts from the THP-treated group after normoxic reperfusion following hypoxic perfusion exhibited better respiratory function than those from untreated hearts.

The data suggest that feeding guinea pigs with THP results in reduced myocardial-free carnitine content and attenuation of hypoxic and reperfusion injury in isolated hearts.

Recently, intravenous magnesium therapy has been used for the treatment of ventricular arrhythmias, but data to establish a causal link between the electrophysiological properties and the antiarrhythmic actions are lacking.

The acute antiarrhythmic effect of magnesium sulfate was assessed using epinephrine-, digitalis-, and coronary ligation-induced canine ventricular arrhythmia models. The intravenous administration of magnesium sulfate (100 mg/kg) reduced the incidence of the ventricular arrhythmias of all models. The antiarrhythmic effect on the epinephrine-induced arrhythmia was potent and long-lasting, while those on the other arrhythmia models were weak and transient. The direct cardiovascular effects were assessed using the canine isolated, blood-perfused sinus node, papillary muscle, and atrioventricular node preparations. The intracoronary administration of magnesium sulfate (0.1–30 mg) suppressed sinoatrial automaticity and ventricular contraction, while it increased atrio-His and His-ventricular conduction time, coronary blood flow, and the duration of monophasic action potential in a dose-dependent manner. The effects on His-ventricular conduction and monophasic action potential duration were less potent compared with the other cardiovascular effects.

These results suggest that magnesium sulfate possesses multiple electrophysiological properties and that the effects related to the calcium channel inhibition may be the most relevant for the antiarrhythmic actions.