Journal of Cardiovascular Pharmacology and Therapeutics current issue

Clinical Review: Is the Perioperative Use of {beta}-Blockers Still Recommended? A Critical Review of Recent Controversies

Domanski, D., Schwarz, E. R. — Tue, 10 Nov 2009 18:11:41 PST

The optimal role of β-adrenergic receptor blockade in the perioperative period remains unclear in patients at risk for cardiovascular events. Cardiovascular complications continue to be the most common cause of perioperative morbidity and mortality, and cardioprotective properties of β-blockers are widely recognized, yet the results of the clinical trials investigating the use of different β-blockers in the perioperative period are controversial. The discrepancy might be related to differences in the design of studies, use of different agents, administration by different routes, and continuation for different time intervals. Evidently, perioperative mortality and morbidity seem to be related to heart rate, and the majority of complications are related to β-blockers’ side effects. Based on the observations from different studies, we propose an algorithm for perioperative β blockade.

What Is the Optimal Postconditioning Algorithm?

Iliodromitis, E. K., Downey, J. M., Heusch, G., Kremastinos, D. T. — Tue, 10 Nov 2009 18:11:41 PST

Ischemic postconditioning has emerged as a clinically feasible intervention for limiting infarction in the setting of percutaneous intervention. In ischemic postconditioning, a number of cycles of a brief period of reperfusion followed by a brief period of occlusion are applied immediately upon reperfusion of the ischemic heart. Although ischemic postconditioning is protective in both animals and man, the animal studies reveal that the algorithm used in selecting the duration of the occlusion and reperfusion periods is critical to the degree of protection realized and it varies with species. The question then arises what is the best algorithm for man? The available animal and clinical data are examined in an attempt to shed light on this perplexing problem.

Efficacy and Safety of Ezetimibe Plus Orlistat or Rimonabant in Statin-Intolerant Nondiabetic Overweight/Obese Patients With Dyslipidemia

Florentin, M., Kostapanos, M. S., Nakou, E. S., Elisaf, M., Liberopoulos, E. N. — Tue, 10 Nov 2009 18:11:41 PST

Aims: To compare the effects of ezetimibe plus orlistat or rimonabant on anthropometric and lipid parameters in nondiabetic statin-intolerant overweight/obese patients with dyslipidemia.

Methods and results: Thirty participants received a hypocaloric diet and were randomized to open-label combination of ezetimibe (10 mg/day) with orlistat (120 mg, 3 times a day with meals; ezetimibe/orlistat [EO], n = 15) or rimonabant (20 mg/day; ezetimibe/ rimonabant [ER], n = 15). Anthropometric and metabolic variables were assessed at baseline and 3 months posttreatment. Similar reductions in body weight, body mass index, and waist circumference were recorded in both groups (—8.3%, —8.6%, and —5.2% in the EO group and —7.3%, —7.2%, and —7.0% in the ER group, P < .01 vs baseline for all). Low-density lipoprotein cholesterol (LDL-C) levels decreased in both treatment groups, but this reduction tended to be more pronounced in the EO group (28.4% vs 15.3%, respectively; P < .01 vs baseline for both). Triglycerides tended to decrease more in the ER compared with the EO group (—20.4% vs —14.1%, P < .01 vs baseline for both). High-density lipoprotein cholesterol (HDL-C) levels tended to decrease in EO group, but remained unaltered with ER treatment. Apolipoprotein B levels were equally reduced in both treatment groups. Conclusion: For similar body weight reduction, the combination of ezetimibe with orlistat may be more efficient in LDL-C lowering, whereas the combination of ezetimibe with rimonabant may be more potent in terms of improving HDL-C and triglycerides.

Rosuvastatin Attenuates Ang II--Mediated Cardiomyocyte Hypertrophy via Inhibition of LOX-1

Kang, B.-Y., Mehta, J. L. — Tue, 10 Nov 2009 18:11:41 PST

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as statins, have been shown to reduce cardiac remodeling. Angiotensin II (Ang II) type 1 receptor (AT1R) and oxidized low-density lipoprotein (ox-LDL) via its lectin-like ox-LDL receptor (LOX-1) are major stimuli for cardiomyocyte growth. We postulated that rosuvastatin, a potent HMG-CoA reductase inhibitor, may reduce Ang II—mediated cardiomyocyte growth via AT1R and LOX-1 inhibition. HL-1 adult mouse cardiomyocytes were incubated overnight in serum-free medium, and then treated with rosuvastatin, the AT1R inhibitor losartan or anti-LOX-1 antibody for 3 hours. The cells were then stimulated with Ang II. We measured cardiomyocyte growth, and associated intracellular redox signals using reverse transcription— polymerase chain reaction (RT-PCR) and real-time quantitative PCR. Losartan and anti-LOX-1 antibody markedly attenuated Ang II—mediated oxidant stress, and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p40^{pho x} and gp91^phox subunits) and nuclear factor-B (NF-B). Rosuvastatin attenuated the Ang II—mediated upregulation of both subunits of NAPDH oxidase as well as NF-B. Rosuvastatin also reduced Ang II—mediated upregulation of AT1R and LOX-1. In other experiments, LOX-1 was upregulated in cardiomyocytes by transfection with pCI-neo/LOX-1, which also enhanced the expression AT1R messenger RNA (mRNA), and rosuvastatin pretreatment reduced the expression of both LOX-1 and AT1R in this system. Thus, rosuvastatin attenuates Ang II—mediated cardiomyocyte growth by inhibiting LOX-1 and AT1R expression and suppressing the heightened intracellular redox state.

MMP-2 and MMP-9 Alteration in Response to Collaring in Rabbits: The Effects of Endothelin Receptor Antagonism

Tue, 10 Nov 2009 18:11:41 PST

Matrix metalloproteinases (MMPs), and, in particular, gelatinases (MMP-2 and MMP-9), have been implicated in vascular cell proliferation and/or migration, contributing to intimal thickening, an essential stage in the development of atherosclerosis and restenosis following balloon angioplasty. Endothelin, a strong chemoatractant and mitogen, has been shown to promote smooth muscle cell proliferation and migration by activating MMPs via endothelin-A (ETA) receptors. The positioning of a soft silicon collar around the left carotid artery in rabbits results in intimal thickening. In this study, we investigate the possible role of gelatinases and the effect of a nonselective ETA/ETB receptor antagonist, TAK-044 (5 mg/kg body weight/day, subcutaneously [sc]), on these enzymes. Our results demonstrated that both MMP-2 and MMP-9 activities increased in response to collaring in placebo group, while treatment with TAK-044 significantly suppressed both gelatinase activities and proMMP-2 levels, and inhibited intimal thickening in collared arteries. These results suggest that either enhanced MMP expression or endothelin receptor antagonism may be involved in the formation of intimal thickening in this model.

Sodium Ferulate Modified Gene Expression Profile of Oxidized Low-Density Lipoprotein-Stimulated Human Umbilical Vein Endothelial Cells

Zhang, D., Bi, Z., Li, Y., Zheng, H., Li, L., Ouyang, J., Wang, B., Bi, Y. — Tue, 10 Nov 2009 18:11:41 PST

Oxidized low-density lipoprotein (ox-LDL) is known to trigger vascular injury in atherosclerosis development. Sodium ferulate is an effective component from Chinese medicines with various beneficial cardiovascular pharmacological activities. Here, we investigated the effects of sodium ferulate on the gene expression profile of ox-LDL-stimulated endothelial cells. Cultured human umbilical vein endothelial cells (HUVECs) were treated with ox-LDL (50 µg/mL) in the absence or presence of sodium ferulate (5 µmol/L). Sodium ferulate significantly reduced ox-LDL-induced endothelial cell death as evaluated by cell viability assay. Human oligonucleotide microarray analysis demonstrated that a total of 32 ox-LDL-induced genes were significantly downregulated to control levels by sodium ferulate. These genes included members from families of chemokine, inflammatory factor, growth factor, and nuclear receptor. These data provided an overview of the gene expression profile of endothelial cells in response to ox-LDL and sodium ferulate, and demonstrated that sodium ferulate could regulate the expression of inflammation-related genes in endothelial cells and has the potential to benefit endothelial function in the setting of atherosclerosis.

Astaxanthin Reduces Oxidative Stress, but not Aortic Damage in Atherosclerotic Rabbits

Tue, 10 Nov 2009 18:11:41 PST

We evaluated whether carotenoid astaxanthin (ASX) could prevent oxidative and atherosclerotic damage in rabbits. Rabbits received regular chow (control) or an atherogenic diet (1% cholesterol) alone or supplemented with 50, 100, and 500 mg% ASX for 60 days (n = 5-9 per group). The atherogenic diet increased the serum cholesterol levels and the ratio of the intima/media area in the aortic arch. These changes were not prevented by ASX. Atherosclerotic rabbits showed increased aortic lipid peroxidation and nonprotein thiol group (NPSH) levels along with inhibition of glutathione peroxidase (GSH-Px). All ASX doses attenuated lipid peroxidation and the increase in NPSH but not the inhibition of GSH-Px. Aortic superoxide dismutase (SOD), catalase (CAT), and thioredoxin reductase (TrxR) activities were enhanced in atherosclerotic rabbits. Although all ASX doses prevented the increase in SOD activity, only 100 and 500 mg% ASX prevented the increase in CAT activity. Furthermore, these same doses partially prevented the increase in TrxR activity, while 50 mg% ASX completely prevented the effects of the atherogenic diet on this enzyme. However, ASX did not attenuate the hypercholesterolemia or the atherosclerotic lesions caused by the atherogenic diet at any of the doses evaluated. Our results indicate that although ASX did not prevent hypercholesterolemia or atherosclerotic lesions, it could play a beneficial role by preventing lipid peroxidation and changes in antioxidant enzyme activities.

Differential Effects of Oral {beta} Blockade on Cardiovascular and Sympathetic Regulation

Beloka, S.P., Gouveia, S., Gujic, M., Naeije, R., Rocha, A.P., van de Borne, P. — Tue, 10 Nov 2009 18:11:41 PST

In patients with hypertension, β blockade decreases muscle sympathetic nerve activity (MSNA; micrographic technique) expressed in burst frequency (burst/min) but does not affect MSNA expressed in burst incidence (burst/100 heart beats), because reductions in blood pressure (BP) upon each diastole continue to deactivate the arterial baroreceptors, but at a slower heart rate (HR). We studied the effects of oral β blockade on MSNA and baroreflex sensitivity (BRS) in normal participants. Bisoprolol (5 mg, 1 week) was administered in 10 healthy young adults, using a double-blind, placebo-controlled, randomized cross-over study design. The beat-to-beat mean RR interval (RR) and systolic blood pressure (SBP) series were analyzed by power spectral analysis and power computation over the very low frequency (VLF), low frequency, and high frequency (HF) bands. Baroreflex sensitivity was computed from SBP and RR cross-analysis, using time and frequency domain methods.

Bisoprolol increased RR (P < .0005), decreased mean SBP and diastolic blood pressure values (P < .01), did not change the SBP and RR powers, except for RR power in VLF (P < .02) and SBP power in HF (P < .03). The MSNA variability (P > .13) and respiratory pattern (P = .84) did not change from placebo to bisoprolol condition. The bisoprolol-induced bradycardia was associated with higher burst/100 heart beats (P < .05) and bisoprolol did not affect burst/min (P = .80). Time domain BRS estimates were increased after bisoprolol (P < .05), while frequency domain ones did not change (P > .1).

Oral bisoprolol induces differential effects on sympathetic burst frequency and incidence in normal participants. Peripheral sympathetic outflow over time is preserved as a result of an increased burst incidence, in the presence of a slower HR. Unchanged BP and HR and MSNA variability suggests that the larger burst incidence is not due to sympathetic activation.

Neither K + Channels Nor PI3K/Akt Mediates the Vasodilative Effect of Nebivolol on Different Types of Rat Arteries

Wang, Y., Zhang, M., Liu, Y., Li, J., Song, E., Niu, L., Cheng, N. — Tue, 10 Nov 2009 18:11:41 PST

Purpose: Nebivolol is a highly selective β₁-adrenoceptor blocker with additional vasodilating properties. It has been shown that the nebivolol-induced vasorelaxation is nitric oxide (NO) dependent. The serine/ threonine protein kinase Akt phosphorylates endothelial cell NO synthase (eNOS) and enhances the ability of eNOS to generate NO. Previous studies have shown that the release of NO from the endothelium may be ascribed to the modulation of different types of K⁺ channels. The current study was designed to determine whether K⁺ channels or phosphatidylinositol-3-kinase (PI3K)/Akt may affect vasorelaxation induced by nebivolol in different rat arteries.

Methods: Rings of the rat aorta, carotid artery, femoral artery, and renal artery were suspended for isometric force recording. During contraction by KCl (60 mmol/L) or phenylephrine (PE; 10^—6 mol/L; femoral artery and renal artery were precontracted by 10^—5 mol/L), the effect of nebivolol (10^—7-10^{— 5} mol/L) was obtained in the presence of different potassium channel, PI3K/Akt, or NOS inhibitors. Results: Nebivolol (10^{— 7}-10^—5 mol/L) relaxed precontractions induced by KCl and PE in different rat arteries, which was inhibited by the presence of the NOS inhibitor N^G-nitro-L-arginine methyl ester (L-NAME; 100 µmol/ L). The effect of nebivolol was concentration dependent. The exposure of the vessel rings to a selective inhibitor of PI3K wortmannin (5 x 10^—7 mol/L) or a selective inhibitor of Akt (1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-Omethyl-3-O-octadecylcarbonate, 10^—5 mol/L) did not influence nebivolol-induced vasorelaxation. Similarly, K⁺ channels blockers, iberiotoxin (100 nmol/L), glibenclamide (0.1 mmol/L), 4-aminopyridine (1 mmol/L), or BaCl₂ (1 mmol/L) had no influence on the relaxation of nebivolol in arteries precontracted by PE. Conclusion: Nebivolol produced a concentration-dependent vasodilation in different rat arteries precontracted by PE or KCl. In the isolated rat aorta, carotid artery, femoral artery, and renal artery, neither K⁺ channels nor PI3K/Akt pathway was involved in the relaxation induced by nebivolol.

Effect of Targeting Mitogen-Activated Protein Kinase on Cardiac Remodeling in Rats

Baraka, A., Mikhail, M., Guemei, A., El Ghotny, S. — Tue, 10 Nov 2009 18:11:41 PST

Background: Increasing evidence suggests that the activation of p38 mitogen-activated protein kinase (p38MAPK) plays a role in cardiac remodeling. Targeting p38MAPK using drugs reported to interfere with its phosphorylation, namely statins and all-trans retinoic acid (atRA), might play a role in ameliorating this remodeling. Methods and Results: Cardiac remodeling was induced in male albino rats by chronic inhibition of nitric oxide (NO) synthesis by N-nitro L-arginine methyl ester (L-NAME). Daily oral administration of L-NAME for 4 weeks resulted in the elevation of mean arterial blood pressure (MABP) together with cardiac remodeling evidenced by an increase in left ventricular-body weight ratio together with an increase in cardiac hydroxyproline concentration and a decrease in left ventricular papillary muscle-developed tension. An elevation in cardiac phosphorylated p38MAPK concentration, tumor necrosis factor alpha concentration and in cardiac caspase 3 activity was also observed. Administration of either rosuvastatin or all-trans retinoic acid (atRA), starting 4 weeks after L-NAME administration, ameliorated remodeling and improved all studied parameters. Conclusions: Targeting MAPK might represent a useful therapeutic avenue to ameliorate cardiac remodeling and support the notion that atRA and statins are potential candidates for the prevention and therapy of cardiac remodeling.