Journal of Cardiovascular Pharmacology and Therapeutics (J CARDIOVASC PHARM T)

Publications in this journal

• Article: Probenecid as a Noninjurious Positive Inotrope in an Ischemic Heart Disease Murine Model.

  Koch SE, Tranter M, Robbins N, Luther K, Singh U, Jiang M, Ren X, Tee T, Smith L, Varma P, Jones WK, Rubinstein J
  Journal of Cardiovascular Pharmacology and Therapeutics 12/2012;
• Article: Platelet function testing and implications for clinical practice.

  Jean-Philippe Collet, Gilles Montalescot
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  ABSTRACT: Platelets are key mediators in the pathophysiology of atherothrombotic disease. Inappropriate platelet activation can lead to thrombosis and ischemic events. Platelet function testing has been used to monitor patient response to antiplatelet therapy. Variability in response to antiplatelet therapy may be due in part to incomplete inhibition of targeted pathways (thromboxane A(2) and adenosine diphosphate [ADP]) by currently available agents (aspirin and P2Y(12) ADP receptor antagonists). Low responsiveness to antiplatelet therapy (as measured in various platelet function assays) correlates with a high rate of ischemic events. However, tailoring treatment based on platelet response remains to be definitively proven in clinical trials, correlations between assays are modest, and concordance in defining suboptimal response is poor. Additional studies are needed to determine whether changes in therapy based on results of platelet function testing improve clinical outcomes, and thus will determine whether broader use of platelet function testing in clinical practice is warranted.
  Journal of Cardiovascular Pharmacology and Therapeutics 10/2009; 14(3):157-69.
• Article: The antiarrhythmic effect and possible ionic mechanisms of pilocarpine on animal models.

  Wei-ming Zhao, Han-ping Qi, Ying Liu, Wei Chen, Jing Xie, Zhen-yu Pan, Hong-mei Han, Li-peng Chen, Dan-lu Li, Li-yan Wang, Hong-li Sun, Yan Liu
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  ABSTRACT: This study was designed to evaluate the effects of pilocarpine and explore the underlying ionic mechanism, using both aconitine-induced rat and ouabain-induced guinea pig arrhythmia models. Confocal microscopy was used to measure intracellular free-calcium concentrations ([Ca(2+)](i)) in isolated myocytes. The current data showed that pilocarpine significantly delayed onset of arrhythmias, decreased the time course of ventricular tachycardia and fibrillation, reduced arrhythmia score, and increased the survival time of arrhythmic rats and guinea pigs. [Ca(2+)](i) overload induced by aconitine or ouabain was reduced in isolated myocytes pretreated with pilocarpine. Moreover, M(3)-muscarinic acetylcholine receptor (mAChR) antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) partially abolished the beneficial effects of pilocarpine. These data suggest that pilocarpine produced antiarrhythmic actions on arrhythmic rat and guinea pig models induced by aconitine or ouabain via stimulating the cardiac M(3)-mAChR. The mechanism may be related to the improvement of Ca(2+) handling.
  Journal of Cardiovascular Pharmacology and Therapeutics 10/2009; 14(3):242-7.
• Article: A salute to our founding editor-in-chief Bramah N. Singh, MD, DPhil, DSc, FRCP.

  Robert A Kloner
  Journal of Cardiovascular Pharmacology and Therapeutics 10/2009; 14(3):154-6.
• Article: Partial hindlimb occlusion reduced the susceptibility to sustained ventricular tachycardia in conscious rats.

  Heidi L Lujan, Stephen E DiCarlo
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  ABSTRACT: Remote conditioning induced by ischemia in distant organs protects the heart from ischemia/reperfusion injury; however, its effect on ischemia-induced ventricular arrhythmias is unknown. Therefore, we tested the hypothesis that partial hindlimb occlusion during coronary artery occlusion increases the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion. Rats (n = 7) were instrumented with a radio-telemetry device for recording arterial pressure, electrocardiogram (ECG), and body temperature. A Doppler ultrasonic flow probe and vascular occluder were placed around the terminal aorta. Finally, a snare was placed around the left main coronary artery. The VAT was determined without and, on an alternate day, during partial hindlimb occlusion (remote conditioning) in conscious rats. Without remote conditioning, the VAT was 4.56 + 0.15 minutes. Importantly, remote conditioning significantly increased the VAT (6.29 + 0.49 minutes), suggesting that ischemia in a distant organ may delay the development of ischemia-induced ventricular arrhythmias.
  Journal of Cardiovascular Pharmacology and Therapeutics 10/2009; 14(3):199-206.
• Article: GAP-134 ([2S,4R]-1-[2-aminoacetyl]4-benzamidopyrrolidine-2-carboxylic acid) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs.

  James K Hennan, Robert E Swillo, Gwen A Morgan, Eric I Rossman, Joel Kantrowitz, John Butera, Jorgen S Petersen, Stephen J Gardell, George P Vlasuk
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  ABSTRACT: The antiarrhythmic dipeptide, GAP-134, ([2S,4R]-1[2-aminoacetyl]-4-benzamido-pyrrolidine-2-carboxylic acid) was evaluated in canine ischemia/reperfusion model. In dogs subjected to 60-minute ischemia and 4-hour reperfusion, GAP-134 was administered 10 minutes before reperfusion as a bolus + intravenous (IV) infusion. The doses administered were 0.25 microg/kg bolus + 0.19 microg/kg per hour infusion; 2.5 microg/kg + 1.9 microg/kg per hour; 25 mg/kg + 19 mg/kg per hour; 75 mg/kg + 57 mg/kg per hour. Ventricular ectopy was quantified during reperfusion, including premature ventricular contractions (PVC) and ventricular tachycardia (VT). Total incidence of VT was reduced significantly with the 2 highest doses of GAP-134 (1.7 + 0.8; 2.2 + 1.4 events; P < .05) compared to controls (23.0 + 6.1). Total PVCs were reduced significantly from 11.1 + 1.6% in control animals to 2.0% + 0.7% and 1.8% + 0.8% after the 2 highest doses of GAP-134. Infarct size, expressed as percentage of left ventricle, was reduced significantly from 19.0% + 3.5% in controls to 7.9% + 1.5% and 7.1% + 0.8% (P < .05) at the 2 highest doses of GAP-134. GAP-134 is an effective antiarrhythmic agent with potential to reduce ischemia/reperfusion injury.
  Journal of Cardiovascular Pharmacology and Therapeutics 09/2009; 14(3):207-14.
• Article: The effect of angiotensin-converting enzyme inhibitor on hemodynamic instability in patients undergoing cardiopulmonary bypass: results of a dose-comparison study.

  Mehran Shahzamani, Zohreh Yousefi, Azam Noori Frootaghe, Elnaz Jafarimehr, Mahnoosh Froughi, Farhood Tofighi, Ali N Azadani, Mohamad Amin Pourhoseingholi, Peyman Nejatbakhsh Azadani
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  ABSTRACT: Recently, hemodynamic instability including hypotension and its effect on the clinical outcome in patients treated with angiotensin-converting enzyme inhibitors (ACEIs) during coronary artery bypass graft (CABG) has been described. However, no analysis has examined the dose of ACEIs and its risk of hypotension. In this study, we tested the hypothesis that a higher dose of ACEIs could lead to increased episodes of hypotension. A total of 300 patients scheduled for CABG were studied prospectively. They were divided into 3 groups according to their preoperative use of different doses of ACEIs. The demographic and medical characteristics were compared between these 3 groups. During CABG and throughout the intensive care unit (ICU), vasoconstrictors were infused in patients undergoing hypotension (mean arterial pressure [MAP] < 65 mm Hg or >30% below baseline). The predictive factors responsible for hypotension were investigated separately using univariate and multivariate logistic regression models. The 3 groups were similar with regard to the patients' demographic and medical characteristics. The patients treated with ACEIs were more likely to develop hypotension (73% of high dose and 47% of low dose) in the operating room than those without ACEIs (30%). However, in the ICU, there was no significant association between hemodynamic changes and ACEIstreated patients. Other independent risk factors identified for hypotension were ejection fraction, history of myocardial infarction, coronary grafting count, and pump time during surgery and/or ICU admission. Hemodynamic changes during CABG were observed to be directly proportional to the dosage of ACEIs prescribed preoperatively.
  Journal of Cardiovascular Pharmacology and Therapeutics 09/2009; 14(3):185-91.
• Article: Heart rate variability increases with reductions in cigarette smoke exposure after 3 days.

  Sagar Munjal, Tamara Koval, Raheema Muhammad, Yan Jin, Valentin Demmel, Hans J Roethig, Paul Mendes, Martin Unverdorben
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  ABSTRACT: Smoking has been shown to influence the tone of the autonomic nervous system as reflected by heart rate variability (HRV). To date, no information is available as to whether 24-hour HRV might differentiate users of different tobacco products. To assess the differences in HRV derived from the 24-hour electrocardiogram (ECG) following the use of 2 tobacco products of potentially different exposures. Thirty adult Caucasian male smokers (mean age: 42.8 + 5.7 years) smoking 20 to 40 cigarettes/ day were randomized in a 3-way crossover study design to either smoke a conventional cigarette (CC, tar: 11 mg, Nic: 0.8 mg), to use the Electrically Heated Cigarette Smoking System (EHCSS: tar: 5 mg, Nic: 0.3 mg, according to the Federal Trade Commission [FTC]), or to stop smoking (NS) for 3 days each. The 24 hours ECGs were recorded during the last 24 hours of each exposure period. A 24-hour ECG showed highest mean values for standard deviation of all normal-to-normal heart beat (NN) intervals (SDNN), standard deviation of all 5-minute averaged NN intervals in a 24-hour period (SDANN), mean of the standard deviations of the NN intervals calculated from all 5-minute segments in a 24-hour period (SDNNI), percentage (P) of all NN intervals that differ by 50 milliseconds of all NN (PNN50%), the square root of the mean of all squared differences between adjacent NN intervals in 24-hour period (RMSSD), and total number of all NN intervals divided by the height of the histogram of all NN intervals measured on a discrete scale with bins of 7 x 8125 ms (1/128 seconds; HRVTI) when participants stopped smoking followed by the use of the reduced exposure product and CC. Heart rate variability tended to increase with reduced smoke exposure.
  Journal of Cardiovascular Pharmacology and Therapeutics 08/2009; 14(3):192-8.
• Article: Dose-related shortening of ventricular tachycardia cycle length after administration of the KATP channel opener bimakalim in a 4-day-old chronic infarct anesthetized pig model.

  Isaac Aidonidis, Aphrodite Poyatzi, Georgia Stamatiou, Maria Lymberi, Nikolaos Stamatoyannis, Paschalis-Adam Molyvdas
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  ABSTRACT: Potassium channel openers are known to act on potassium ATP-dependent channels in cardiac tissue. Such agents may exacerbate acceleration of acute ischemia-induced ventricular repolarization and aggravate arrhythmias. To test whether activation of K( ATP) channels during the healing period of myocardial infarction (MI) can still influence the electrophysiologic properties and the type of inducible arrhythmias, we investigated the effects of bimakalim (BIM) on sustained ventricular tachycardia (VT) 4 days after ligation of the left anterior descending (LAD) coronary artery in pigs. Programmed stimulation was performed to elicit VT prior to and after intravenous (IV) BIM. Combination monophasic action potential (MAP)/PACING catheters were used to enable simultaneous ventricular MAP recording and pacing. Ventricular effective refractory period (ERP) and MAP duration determined at 50% and 90% repolarization were measured prior to and after BIM. After completion of baseline measurements, BIM was consecutively given at 0.5, 1, and 3 mg/kg bolus followed by 0.025, 0.05, and 0.1 mg/kg per minute maintenance infusion, respectively. From a total of 23 pigs subjected to LAD ligation, 4 animals succumbed to infarction and the remaining 19 animals were studied by programmed stimulation. Only animals that exhibited reproducible and hemodynamically stable monomorphic VTs during control stimulation were selected for evaluation (n = 14). After the first, second, and third dose of BIM, the mean VT rate was increased by 6%, 14% (P <. 01), and 47% (P < .001) compared to control values, respectively. Ventricular ERP and repolarization were significantly shortened only by the second and third dose of BIM. Of 14 pigs receiving the highest BIM dosage, 3 revealed polymorphic VTs degenerating into ventricular fibrillation (VF). Our data suggest that high BIM doses may lead to faster and more aggressive pacing-induced reentrant VTs after subacute MI. This is consistent with the drug-induced acceleration of ventricular repolarization with shortening of MAP duration and refractoriness.
  Journal of Cardiovascular Pharmacology and Therapeutics 08/2009; 14(3):222-30.
• Article: Statins reduce appropriate cardioverter-defibrillator shocks and mortality in patients with heart failure and combined cardiac resynchronization and implantable cardioverter-defibrillator therapy.

  Harit Desai, Wilbert S Aronow, Fausan S Tsai, Chul Ahn, Hoang M Lai, Harshad Amin, Kaushang Gandhi, William H Frishman, Martin Cohen, Carmine Sorbera
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  ABSTRACT: Of 209 patients with heart failure treated with combined cardiac resynchronization therapy and implantable cardioverter-defibrillator therapy, appropriate cardioverter-defibrillator shocks occurred at 34-month follow-up in 22 of 121 patients (18%) on statins and in 30 of 88 patients (34%) not on statins (P = .009). Deaths occurred in 3 of 121 patients (2%) on statins and in 9 of 88 patients (10%) not on statins (P = .017). Stepwise Cox regression analysis showed that significant independent prognostic factors for appropriate shocks were use of statins (risk ratio = 0.46), smoking (risk ratio = 3.5), and diabetes (risk ratio = 0.34). Significant independent prognostic factors for the time to mortality were use of statins (risk ratio = 0.05), use of digoxin (risk ratio = 4.2), systemic hypertension (risk ratio = 14.2), diabetes (risk ratio = 4.3), and left ventricular ejection fraction (risk ratio = 1.1).
  Journal of Cardiovascular Pharmacology and Therapeutics 08/2009; 14(3):176-9.
• Article: The effect of intracoronary nicorandil on coronary myocardial bridging.

  Jae-Hun Jung, Pil-Ki Min, Chong Won Sung, Sang-Hak Lee, Seonghoon Choi, Jung Rae Cho, Namho Lee, Kyoung-Ha Park, Min-Kyu Kim, Woo Jung Park, Yangsoo Jang
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  ABSTRACT: Medical treatments of coronary myocardial bridging (CMB) generally include beta-blockers and calcium channel blockers. Nitrates are avoided because symptoms may worsen. Nicorandil is a hybrid of a nitrate and a potassium channel opener. However, the effect of nicorandil on CMB is unknown. We analyzed nicorandil reactivity at the site with CMB in 51 patients. Maximal and minimal diameters of CMB were measured by quantitative angiography at baseline and at 60 seconds after intracoronary administration of 200 mg nicorandil. The maximal diameter during diastole increased from 2.15 + 0.42 mm to 2.34 + 0.44 mm after administration of nicorandil (P < .001), and the minimal diameter during systole increased from 1.24 + 0.63 mm to 1.67 + 0.64 mm (P < .001). Thus, nicorandil reduced the percentage vessel narrowing from 44.0 + 26.1% to 30.3 + 21.2% (P < .001). In 22 patients, we also evaluated the effect of nitroglycerin. The maximal diameter during diastole increased from 2.25 + 0.47 mm to 2.51 + 0.44 mm after administration of nitroglycerin (P < .019), and the minimal diameter during systole decreased from 1.28 + 0.64 mm to 1.14 + 0.60 mm (P = .276). Thus, nitroglycerin augmented the percentage vessel narrowing from 44.9% + 25.0% to 56.0% + 23.5% (P = .023). These results indicate that intracoronary administration of nicorandil could dilate coronary arteries during diastole as well as systole in patients with CMB during coronary angiography.
  Journal of Cardiovascular Pharmacology and Therapeutics 07/2009; 14(3):180-4.
• Article: Vitamin E does not regress hypercholesterolemic atherosclerosis.

  Kailash Prasad
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  ABSTRACT: Suppression of hypercholesterolemic atherosclerosis with vitamin E is associated with reductions in oxidative stress without reductions in serum lipids. The objectives of this study were to determine if (1) vitamin E regresses hypercholesterolemic atherosclerosis; and (2) regression is associated with reductions in serum lipids and aortic oxidative stress. The studies were conducted in 4 groups of rabbits: group I, control, regular diet (2 months); group II, 0.25% cholesterol diet (2 months); group III, 0.25% cholesterol diet (2 months) followed by regular diet (2 months); and group IV, 0.25% cholesterol diet (2 months) followed by regular diet with vitamin E (40 mg/kg body weight/day) (2 months). Blood samples were collected monthly for the measurement of serum lipids and oxidative stress (chemiluminescent activity of white blood cells [WBC-CL]). Aortas were removed at the end of the protocol for assessment of atherosclerotic lesions, and oxidative stress (malondialdehyde [MDA] and CL). Increases in serum lipids in group II were associated with an increase in oxidative stress and development of atherosclerosis. Serum lipids decreased to a similar extent in groups III and IV but the atherosclerotic lesions increased by 63% and 141% compared to group II. Acceleration of atherosclerosis in the rabbits on regular diet with or without vitamin E was associated with practically no change in the oxidative stress. These results suggest that (1) regular diet following a high-cholesterol diet decreased oxidative stress but did not induce regression of atherosclerosis; (2) vitamin E did not produce regression; and (3) regular diet with vitamin E following a high-cholesterol diet was not associated with an increase in oxidative stress but produced acceleration of atherosclerosis.
  Journal of Cardiovascular Pharmacology and Therapeutics 07/2009; 14(3):231-41.
• Article: The mechanism by which ischemic postconditioning reduces reperfusion arrhythmias in rats remains elusive.

  Joan Dow, Anil Bhandari, Robert A Kloner
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  ABSTRACT: We have observed that ischemic postconditioning markedly reduces reperfusion-induced ventricular arrhythmias, but whether the mechanism is related to previously described pathways of preconditioning or postconditioning for infarct size reduction is unknown. The purpose of this study was to determine whether known pathways were involved in postconditioning's protective effect on arrhythmias. Anesthetized female rats were subjected to 5 minutes of proximal coronary artery occlusion and 5 minutes of reperfusion. They were either not postconditioned or subjected to 4 cycles of 20 seconds reperfusion, 20 seconds reocclusion before final reperfusion (postconditioned). Electrocardiogram and blood pressure were monitored throughout. Alleged agonists and antagonists to postconditioning representing a number of mechanisms were evaluated. Nonpostconditioned rats treated with the suppressor of the mitochondrial permeability transition pore, cyclosporine A, did not show a reduction in reperfusion-induced ventricular arrhythmias compared to control nonpostconditioned rats. Neither Wortmannin (p13-kinase inhibitor), 5 hydroxydecanoate (selective inhibitor of mitochondrial K(ATP) channel), nor 8-sulfophenyl theophylline (blocker of adenosine receptors) blocked the reduction in ventricular tachycardia of postconditioning. The mechanism by which postconditioning reduces reperfusion-induced ventricular arrhythmias may be independent of known pathways that have been implicated in the infarct sparing effects of preconditioning and postconditioning--including adenosine, mitochondrial K(ATP) channel, mitochondrial permeability transition pore, and p13-kinase-pAKt pathways. Alternative protective pathways may exist to explain the antiarrhythmic effect of postconditioning.
  Journal of Cardiovascular Pharmacology and Therapeutics 07/2009; 14(2):99-103.
• Article: Lack of association of tegaserod with adverse cardiovascular outcomes in a matched case-control study.

  Jeffrey L Anderson, Heidi T May, Tami L Bair, Joseph B Muhlestein, Benjamin D Horne, John F Carlquist
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  ABSTRACT: Tegaserod is a first-in class selective serotonin 4 receptor agonist approved for the treatment of irritable bowel syndrome. In March 2007, the US Food and Drug Administration (FDA) suspended its use citing increased cardiovascular (CV) events in clinical trials. However, there is no known mechanistic basis for an adverse CV effect. To reassess the CV safety of tegaserod, teagaserod-treated patients (pts) in the Intermountain Healthcare database were identified (n = 2603), matched 1:6 with untreated (n = 15,618) patients by age, sex, and date of tegaserod initiation, and followed for an average of 2.5 years. Age averaged 38.6 +/- 13.5 years, and 94% were female. Cardiovascular event rates were low and similar in patients treated with tegaserod and matched untreated patients. For the primary composite CV endpoint, 54 (0.35%) untreated and 12 (0.46%) treated pts had an event (treated OR = 1.27, 95% CI: 0.68-2.38, P =.46), with 7 and 0 events, respectively, occurring within 3 months. A total of 12 (0.1%) untreated and 1 (<0.1%) treated pts were hospitalized for a myocardial infarction (MI). 36 (0.2%) untreated and 10 (0.4%) treated pts for a cardiovascular accident, and 1 pt in each group for unstable angina. A total of 6 (<0.1%) untreated and no treated pts died from cardiac causes. Event rates were comparable to expected rates in this population of mostly premenopausal women. This large epidemiologic study failed to confirm a reported large event differential for tegaserod that was noted incidentally in a clinical trials database, suggesting that the prior observation may have been due to chance.
  Journal of Cardiovascular Pharmacology and Therapeutics 07/2009; 14(3):170-5.
• Article: Application of zinc-bis-(DL-hydrogensaspartate) does not reduce apoptotic cell death in myocardial infarction in the rat heart.

  Ernst R Schwarz, Tanja Tussing, Erik Skobel, Bernd Klosterhalfen, Damian Domanski, Justin E Fuess
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  ABSTRACT: Early studies in different stress models have shown potential beneficial effects of exogenous zinc application with reduction in the rate of apoptotic cell death. This has not been shown in models of myocardial infarction. Rats were exposed to either brief episodes of acute ischemia followed by reperfusion (phase 1) or chronic coronary occlusion (phase 2). Animals were either treated with zinc or vehicle. Groups 1 and 3 received zinc-bis-(DL-hydrogenaspartate) 10 mg/kg body weight as a single 5-mL bolus administered intraperitoneally 24 hours prior to coronary occlusion, groups 2 and 4 received saline. The infarct sizes were determined by triphenyltetrazolium chloride staining and expressed at relative areas to areas of ischemia. Histological slices of the rat's myocardium at the border zones of the infarcts were stained with the TUNEL method to assess for apoptosis. Animals in groups 5, 7, and 9 received zinc, given once before and then repeated every 4 days after coronary occlusion, whereas groups 6, 8, and 10 received saline. Animals were observed for observation periods of 13 (groups 9 and 10), 16 (groups 7 and 8), or 19 weeks (groups 5 and 6), respectively. Two-dimensional echocardiography was performed to measure ejection fraction (EF) at baseline and at the end of the observation periods. TUNEL staining was used to detect and quantify apoptosis rate in the border zones of infarcts after the hearts were excised. Infarct sizes were 49% + 22% in group 1 (zinc + 30 minutes ischemia + 30 minutes reperfusion); 48% + 10% in group 2 (vehicle + 30 minutes ischemia + 30 minutes reperfusion); 42% + 11% in group 3 (zinc + 60 minutes ischemia + 30 minutes reperfusion); and 41% + 23% in group 4 (vehicle + 60 minutes ischemia + 60 minutes reperfusion). In group 1, 11% + 6% of cells were apoptotic compared to 12% + 4% in group 2, 16% + 9% in group 3, and 17% + 7% in group 4 (P > .05). In phase 2, echocardiography revealed a significant reduction in EF in all groups after coronary occlusion. There were no significant differences in EF between the 5 groups at baseline and at follow-up. TUNEL staining did not reveal any significant apoptosis after 13 to 19 weeks. Application of zinc failed to result in reduction of infarct size after temporary coronary occlusion followed by reperfusion and did not demonstrate any reduction in apoptotic cell death. In chronic coronary occlusion, zinc also did not improve EF compared to controls in the presented model in rats. The mechanisms involved in antiapoptotic effects seem to be more complex and might not be inducible by simple zinc injections.
  Journal of Cardiovascular Pharmacology and Therapeutics 07/2009; 14(3):215-21.
• Article: Modification of epinephrine-induced arrhythmias by N-acetyl-L-cysteine and vitamin E.

  Rajat Sethi, Adriana Adameova, Ken S Dhalla, Mohsin Khan, Vijayan Elimban, Naranjan S Dhalla
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  ABSTRACT: Sprague-Dawley rats were pretreated for 21 days with N-acetyl-L-cysteine (NAC) or vitamin E to investigate their influence on arrhythmias induced by a bolus injection or by cumulative doses of epinephrine. Electrocardiographic analysis revealed that both NAC and vitamin E decreased the duration and increased the time of onset of epinephrine-induced arrhythmias in a dose-dependent manner. The antiarrhythmic effects of NAC were comparable with those seen in the vitamin E-pretreated animals. The lipid peroxidation due to cumulative doses of epinephrine was reduced in both pretreated groups; however, NAC, unlike vitamin E, failed to decrease the basal level of malondialdehyde. Although the plasma concentrations of both norepinephrine and epinephrine were markedly increased, the level of aminochromes on epinephrine administration was decreased by both NAC and vitamin E pretreatments. The results support the view that antioxidants may prevent the catecholamine-induced heart rhythm disorders by reducing the formation of oxidized catecholamines.
  Journal of Cardiovascular Pharmacology and Therapeutics 05/2009; 14(2):134-42.
• Article: The cyclic GMP modulators YC-1 and zaprinast reduce vessel remodeling through antiproliferative and proapoptotic effects.

  Amit N Keswani, Kelly J Peyton, William Durante, Andrew I Schafer, David A Tulis
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  ABSTRACT: Guanosine-specific cyclic nucleotide signaling is suggested to serve protective actions in the vasculature; however, the influence of selective pharmacologic modulation of cyclic guanosine monophosphate- synthesizing soluble guanylate cyclase or cyclic guanosine monophosphate-degrading phosphodiesterase on vessel remodeling has not been thoroughly examined. In this study, rat carotid artery balloon injury was performed and the growth-modulating effects of the soluble guanylate cyclase stimulator YC-1 or the cyclic guanosine monophosphate-dependent phosphodiesterase-V inhibitor zaprinast were examined. YC-1 or zaprinast elevated vessel cyclic guanosine monophosphate content, reduced medial wall and neointimal cell proliferation, stimulated medial and neointimal cellular apoptosis, and markedly attenuated neointimal remodeling in comparable fashion. Interestingly, soluble guanylate cyclase inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one failed to noticeably alter neointimal growth, and concomitant zaprinast with YC-1 did not modify any parameter compared to individual treatments. These results provide novel in vivo evidence that YC-1 and zaprinast inhibit injury-induced vascular remodeling through antimitogenic and proapoptotic actions and may offer promising therapeutic approaches against vasoproliferative disorders.
  Journal of Cardiovascular Pharmacology and Therapeutics 05/2009; 14(2):116-24.
• Article: Modest dietary reductions in blood cholesterol have important public health benefits.

  Charles H Hennekens, Wendy R Schneider, E Joan Barice, Patricia R Hebert
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  ABSTRACT: Large reductions in blood cholesterol produce major clinical and public health benefits. Based on extrapolations from randomized evidence, assuming no threshold, a 3% to 4% reduction in blood cholesterol would decrease risk of coronary heart disease (CHD) by 12%. If so, treating larger numbers of people at lower risk would yield greater reductions in CHD than treating smaller numbers at higher risk. High- and moderate-risk patients require evidence-based doses of high-potency statins, as adjuncts to dietary management and benefits to individuals are large and easily quantifiable in randomized trials. In low-risk patients, however, dietary modifications contribute to a public health benefit while that benefit to any individual is small. Thus, the hypothesis that modest dietary reductions in blood cholesterol have important public health benefits is easily quantifiable by extrapolation from existing data but impossible to test among randomized individuals, as the sample sizes and costs are prohibitively large.
  Journal of Cardiovascular Pharmacology and Therapeutics 05/2009; 14(2):85-8.
• Article: p130 Crk-associated substrate (CAS) in vascular smooth muscle.

  Dale D Tang
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  ABSTRACT: Vascular smooth muscle is a key effector in the wall of blood vessels during the pathogenesis of hypertension. Various factors directly elicit smooth muscle cell contraction, migration, growth, and hypertrophy, which lead to the progression of hypertension. Crk-associated substrate (CAS), the first discovered member of the adapter protein CAS family, has recently emerged as a critical cellular component that regulates smooth muscle functions. In this review, the molecular structure and protein interactions of the CAS family members are summarized. Evidence for the role of CAS in the regulation of vascular smooth muscle contractility, cell migration, hypertrophy, and growth is presented. Regulation of CAS by novel tyrosine kinases/phosphatases and unique downstream signaling partners of CAS are also discussed. These new findings establish the important role for CAS in regulating vascular smooth muscle functions. The CAS-associated processes may be new biological targets for the development of new treatment of cardiovascular diseases such as hypertension.
  Journal of Cardiovascular Pharmacology and Therapeutics 04/2009; 14(2):89-98.
• Article: Time courses of subcellular signal transduction and cellular apoptosis in remote viable myocardium of rat left ventricles following acute myocardial infarction: role of pharmacomodulation.

  Sarah Chua, Li-Teh Chang, Cheuk-Kwan Sun, Jiunn-Jye Sheu, Fan-Yen Lee, Ali A Youssef, Cheng-Hsu Yang, Chiung-Jen Wu, Hon-Kan Yip
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  ABSTRACT: We tested hypothesis that acute myocardial infarction (AMI) induces cellular apoptosis and serial changes of protein kinase C epsilon (PKC-epsilon) and p38 mitogen-activated protein kinase (p38 MAPK), and tested cardio-protective effect of losartan in this condition. The rats were assigned to group A (sacrificed on day 2), group B (sacrificed on day 5), and group C (sacrificed on day 14). Rats in each group were further randomized into the following groups: AMI (ligation of left coronary artery) without losartan (AMI-L0); AMI with losartan 20 mg/ kg/d (AMI-L1); and sham groups (L0 and L1). The PKC-epsilon expression in membrane compartment was increased in AMI-L1 group than in other groups on day 5 and in AMI groups than in sham groups on day 14 (P < .01). Phosphorylated form of cytosolic p38 MAPK level was increased in AMI-L1 than in other groups on day 14 (P < .05). Furthermore, 14-day left ventricular ejection fraction was higher and cellular apoptosis was lower in AMI-L1 group than in AMI-L0 group (P < .0001).
  Journal of Cardiovascular Pharmacology and Therapeutics 04/2009; 14(2):104-15.