Journal of Cardiovascular Pharmacology and Therapeutics

Metabolic support for the heart has been an attractive concept since the pioneering work of Sodi-Pallares et al. four decades ago.* Recently, interest has increased in the use of over-the-counter supplements and naturally occurring nutriceuticals for enhancement of cardiac and skeletal muscle performance. These include amino acids such as creatine, L-carnitine, and L-arginine, as well as vitamins and cofactors such as α-tocopherol and coenzyme Q. Like these other molecules. D-ribose is a naturally occurring compound. It is the sugar moiety of ATP and has also received interest as a metabolic supplement for the heart. The general hypothesis is that under certain pathologic cardiac conditions, nucleotides (particularly ATP, ADP, and AMP) are degraded and lost from the heart. The heart's ability to resynthesize ATP is then limited by the supply of D-ribose. which is a necessary component of the adenine nucleotide structure. In support of this hypothesis, recent reports have used D-ribose to increase tolerance to myocardial ischemia. Its use in patients with stable coronary artery disease improves time to exercise-induced angina and etectrocardiographic changes. In conjunction with thallium imaging or dobutamine stress echocardiography, D-ribose supplementation has been used to enhance detection of hibernating myocardium. In this article, we review the biochemical basis for using supplemental D-ribose as metabolic support for the heart and discuss the experimental evidence for its benefit.

Background: Ibutilide may result in chemical cardioversion of atrial fibrillation and facilitates transthoracic cardioversion by lowering the defibrillation energy requirement. Whether routine pretreatment with ibutilide increases or decreases the cost of cardioversion is unknown. The purpose of this study was to compare the cost of outpatient transthoracic cardioversion of atrial fibrillation with and without ibutilide pretreatment.

Methods: Using a model based on published literature and hospital accounting information, a hypothetical group of 100 patients with atrial fibrillation and a left ventricular ejection fraction >0.30 underwent 2 strategies of outpatient cardioversion: transthoracic cardioversion with and without routine pretreatment with 1 mg ibutilide, and with and without involvement of an anesthesiologist for sedation. If transthoracic cardioversion was unsuccessful in patients who did not receive ibutilide, transthoracic cardioversion was repeated after administration of ibutilide.

Results: If an anesthesiologist was involved, transthoracic cardioversion with ibutilide was associated with incremental cost-savings as the efficacy of ibutilide alone in restoring sinus rhythm increased above the critical values of 20%, 27%, and 35% when the efficacy of transthoracic cardioversion alone was 60%, 80%, and 100%, respectively. In the absence of an anesthesiologist, routine pretreatment with ibutilide increased the cost of cardioversion at all success rates of transthoracic cardioversion.

Conclusions: In the presence of an anesthesiologist, whether or not routine pretreatment with ibutilide lowers the mean cost of cardioversion is determined by the success rates of chemical cardioversion with ibutilide and transthoracic cardioversion. In the absence of an anesthesiologist, ibutilide pretreatment increases the cost of cardioversion.

Background: Cardiovascular collapses, syncopes, and sudden deaths have been observed following the rapid administration of intravenous vitamin K. Our objectives were to characterize the effects of vitamin K on cardiac action potentials and to evaluate effects of vitamin K on sodium and potassium currents, namely I_Na, I _Kr, and I_Ks.

Methods and Results: Guinea pig hearts (n = 21) were paced at a cycle length of 250 msec and exposed to vitamin K at 1.15-4.6 μmol/L (2.5-10 mg/L). Monophasic action potential duration measured at 90% repolarization (MAPD₉₀) was not significantly reduced (-1.6 ± 0.3 msec; P > .05; N.S.) at 1.15 μmol/L, but increased by 6.5 ± 0.4 msec (P < .05) at 2.3 μmol/L. MAPD ₉₀ was not measurable at 4.6 μmol/L, as a result of inexcitability. Patch-clamp experiments in ventricular myocytes demonstrated a' ~50% reduction in I_Na by 10 μmol/L vitamin K and a concentration-dependent reduction of the K⁺ current elicited by short depolarizations (250 msec; I_K250). Estimated IC₅₀ for I_K250, mostly representing I_Kr, was 2.3 μmol/L. Vitamin K was less potent to block the K⁺ current elicited by long depolarizations (5,000 msec; IK₅₀₀₀), mostly representing I_Ks, with an estimated IC₅₀ over 100 μmol/L. Conclusions: Therapeutic concentrations (~1.5 μmol/L) of intravenous vitamin K modulate cardiac action potential by blocking ionic currents involved in cardiac depolarization and repolarization.

Cardiomyopathic hamsters develop heart disease early in life, which leads to congestive heart failure and death as these hamsters age. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to reduce ubiquinone concentrations and to deteriorate myocardial function in humans and in experimental animals. HMG-CoA reductase inhibitors differ regarding their ability to penetrate extrahepatic tissues. As a consequence, lovastatin inhibits cholesterol biosynthesis at least 100-Fold more effectively than pravastatin in extrahepatic cells. We examined the effect of lovastatin and pravastatin (approximately 10 mg per kilogram of body weight and per day mixed in the diet) compared with controls on the lifespan of cardiomyopathic hamsters (BIO 8262 strain) in the heart-failure period. In male hamsters, neither lovastatin nor pravastatin significantly affected survival. In female hamsters, lovastatin reduced median survival time from 89 days (control animals) to 30 days (P < .05); pravastatin (median survival, 115 days) had no statistically significant effect. We conclude that lovastatin, but not pravastatin, at a daily dose of 10 mg per kilogram of body weight significantly increases the mortality of cardiomyopathic hamsters. This effect may be the result of inhibition of myocardial ubiquinone supply.

Objectives: The present study was designed to evaluate the possible effect of the combined administration of both captopril (Cap) and L-arginine (L-a) in the isolated ischemic rat heart model.

Background: Recent studies suggest that L-arginine and angiotensin-converting enzyme (ACE) inhibitors possess independent cardioprotective effects in ischemic hearts. The pharmacological effect of the combination of both drugs has not yet been investigated in the ischemic myocardium.

Methods: Using the modified Langendorf model, rats were perfused with either Cap 360 μmol/L (n = 6) or (L-a) 3mmol/L (n = 6), both captopril and L-arginine (Cap+L-a) (n = 8), or saline control (Con) (n = 8). The study design included 30 minutes of perfusion, 30 minutes of global ischemia, and 30 minutes of reperfusion thereafter.

Results: Hearts treated with both Cap+L-a demonstrated an improved performance in all parameters. After 10 minutes of reperfusion, the P_max in the Cap+L-a group was 98 ± 8 mmHg (P < .001), 59 ± 14 mmHg in the Cap group ( P < .02). and 44.3 ± 10 mmHg in the L-a group (P = NS), compared with only 42 ± 8 mmHg in the control. After 10 minutes of reperfusion the dP/dt_min was: in the Cap+L-a group: -1,650 ± 223 mmHg/s (P < .006); in the Cap group: -1,051 ± 302 mmHb/s (P < .03); in the L-a group: -870 ± 131 mmHg/s (P = NS), compared with only -487 ± 131 mmHb/s in the control. Coronary flow was significantly increased in all 3 groups: Cap+L-a group: 22.3 ± 1.5 mL/min (P < .001); Cap group: 18 ± 1.6 mL/min (P <.01); L-a group : 19.8 ± 0.9 mL/min (P < .02), compared with 12.6 ± 0.9 mL/min in the Con group. Total NO level was significantly increased in the Cap+L-a group: 13.4 ± 2 μmol ( P < .03) vs. 6.1 ± 1 μmol for the L-a group. NO levels of both the Cap group and the Con group were beneath detectable values.

Conclusion: Combined administration of captopril and L-arginine has a synergistic, protective effect on heart function and coronary flow that may be mediated by enhanced NO production.

Background: Past studies have demonstrated that exogenous bradykinin (BK) causes vasodilation and increases coronary blood flow, effects that may be beneficial in the setting of cardiac disease states. An important pathway for BK degradation is through angiotensin-converting enzyme (ACE), which results in the formation of a degradative peptide, BK_(1-7). The goal of this study was to examine the effects of BK, BK_(1-7), and the potential modulation of BK by ACE inhibition on myocyte contractility.

Methods and Results: Contractile function was examined in isolated adult porcine (n = 15) left ventricular (LV) myocyte preparations in the presence or absence of BK (10^-8 mol/L), BK_(1-7) (10^-8 mol/L), and with pretreatment by ACE inhibition (benazaprilat). Myocyte velocity of shortening fell by over 15% in the presence of BK and by 8% with BK_(1-7) ( P < .05 vs basal). ACE inhibition blunted the negative effect of BK on myocyte velocity of shortening by over 60% (P < .05). Furthermore, robust ACE activity coupled with significant BK degradation was demonstrated in LV-isolated myocyte preparations, and BK proteolysis was influenced by ACE inhibition.

Conclusion: These results suggest that BK has a direct effect on LV myocyte contractility, and that this effect may be mediated by proteolysis of BK at the level of the LV myocyte sarcolemma.

Background: We hypothesized that the cardioprotective effect of angiotensin II (AngII) type 1 receptor (AT,R) blockade during in vivo ischemia-reperfusion (IR) might be associated with an increase in AngII type 2 receptor (AT₂R) protein, as well as 1,4,5-inositol trisphosphate type 2 receptor (IP₃R) and protein kinase C _ε , (PKC_ε) proteins and cyclic guanosine 3',5' monophosphate (cGMP).

Methods and Results: We studied the effects of the AT₁R blocker, candesartan, on in vivo left ventricular (LV) systolic and diastolic function and remodeling (echocardiogram/Doppler) and hemodynamics during canine reperfused anterior infarction (90-minute ischemia, 120-minute reperfusion), and ex vivo infarct size and AT₁R/AT₂R, IP₃R, and PKC_ε proteins (immunoblots), and cGMP (enzyme immunoassay). Compared with controls, candesartan (1 mg/kg intravenously over 30-minute preischemia) inhibited the AngII pressor response, decreased preload and afterload, improved LV systolic and diastolic function, limited LV remodeling, decreased infarct size (55% vs 27% risk; P < .000003), markedly increased AT₂R, IP₃R, and PKC_ε proteins in the infarct zone, but not the AT,R protein, and increased infarct more than noninfarct cGMP.

Conclusions: The overall results suggest that cardioprotective effects of AT₁R blockade on acute IR injury might involve AT₂R activation and downstream signaling via IP₃R, PKC_ε, and cGMP.

Background: As many as 47% of chronic cocaine users develop cardiac ventricular hypertrophy. The presence and degree of cocaine-induced ventricular hypertrophy is not correlated with the use of other substances of abuse such as alcohol or cigarettes. Moreover, this hypertrophy occurs in individuals without sustained increases in arterial blood pressure or heart rate, or increases in the plasma concentration of renin, aldosterone, norepinephrine, or cortisol. Therefore, we investigated whether cocaine, in concentrations commonly found in cocaine users, has any direct effects on the protein content in cardiac ventricular myocytes. We compared the effects of cocaine with norepinephrine, which increases the total protein content, especially β-myosin heavy-chain contractile protein (β-MHC), in cardiac ventricular myocytes.

Methods: Experiments were performed on 30-day-old rat ventricular myocytes suspended in culture media and cultured in flasks. In 12 suspension-culture experiments, cocaine or norepinephrine, in doses of 0 (control) or 10^-6 mol/L was added to each culture and the cells were harvested on day 5. In 16 tlask-culture experiments, cocaine or norepinephrine was added to each culture on day 7 in doses of 0 (control-vehicle), 10^-7, or 10^-6 mol/L and the cells were harvested on day 10. The total protein content and the myosin protein expression of the myocytes in each culture were determined. Juvenile and adult rat cardiac myosin protein is predominately α-myosin heavy-chain protein (α-MHC), whereas β-MHC occurs primarily in fetal rat hearts.

Results: In the suspension-culture experiments, cocaine, 10^-6 mol/L, increased the cardiomyocyte total protein concentration by 29% ± 2% (P < .001) and the β-MHC expression by 81% ± 10% (P < .01) in comparison with the control myocytes. Cocaine slightly decreased cardiomyocyte α-MHC. Norepinephrine increased the total protein concentration by 21% ± 3% ( P < .001) and the β-MHC expression by 59% ± 10% (P < .01), but did not increase α-MHC expression. In the flask-culture experiments, cocaine, 10^-6 mol/L, maximally increased the total protein concentration by 28% (P < .001), the protein/cell ratio by 57% ± 10% (P < .01), and the β-MHC expression by 85% ± 8% (P < .01). Cocaine slightly decreased α-MHC. Norepinephrine, 10^-6 mol/L, maximally increased the total protein concentration by 35%, the protein/cell ratio by 63% ± 9% (P < .01), and the expression of β-MHC by 78% ± 11% (P < .01). Norepinephrine did not increase α-MHC expression. In 18 separate flask-culture experiments, cocaine, 10^-6 mol/L, was added to the cardiomyocyte cultures after the addition of phentolamine (n = 9), in concentrations of 10^-7 to 10-5 mol/L, or metoprolol (n = 9), in concentrations of 10^-7 to 10^-5 mol/L. Neither phentolamine nor metoprolol inhibited the cocaine-induced increase in cardiomyocyte total protein content or the expression of β-MHC.

Conclusion: Cocaine, similar to norepinephrine, significantly increases the total protein content and the expression of β-MHC in cardiac ventricular myocytes. In this manner, cocaine may cause cardiac ventricular hypertrophy. This process is not inhibited by α- or β-adrenergic receptor blockade.