Carvedilol - Antioxidant activity

Antioxidant activity of carvedilol in cardiovascular disease

Dandona, Paresh; Ghanim, Husam; Brooks, David P

Oxidative and inflammatory stresses are cardinal in the pathogenesis of hypertension and atherosclerosis. Oxidative stress also leads to the induction of inflammation through the activation of proinflammatory transcription factors.
Understanding the mechanisms leading to oxidative stress and the means of suppressing it are important in controlling complications related to atherogenesis, since oxidative and inflammatory stress are important in the pathogenesis of atherosclerosis.
The failure of chemical antioxidants [which scavenge reactive oxygen species (ROS)], such as vitamins E and C, has led to further exploration of the ROS-suppressive effects of drugs used in the treatment of cardiovascular disease.
Carvedilol has been shown to possess both ROS-scavenging and ROS-suppressive effects, and its use is associated with a reduction in oxidative stress. Furthermore, anti-inflammatory effects of carvedilol have now been described.
Although further clinical investigations are required, these properties may contribute to the improvement in clinical outcomes observed with carvedilol.

Journal of Hypertension. 25(4):731-741, April 2007.

Diabetes and hypertension: losartan with atenolol

Effect of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension

Flammer, Andreas J; Hermann, Frank; Wiesli, Peter; Schwegler, Beat

Objective: It has been shown that angiotensin-converting enzyme inhibition or angiotensin receptor blockade may improve endothelial dysfunction, an early manifestation of atherosclerosis, in patients with diabetes. Whether this protective effect is mediated through blood pressure-lowering effects or other specific mechanisms such as a reduction in oxidative stress is not clear. We investigated the influence of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension.

Methods: Thirteen patients were included in this randomized, double-blind, crossover study; they received losartan 50 mg twice daily for 4 weeks followed by atenolol 50 mg twice daily or vice versa. Concomitant medication with renin-angiotensin blocking agents or beta-blockers was withdrawn, whereas other medication remained unchanged. At baseline and after each treatment period, flow-mediated dilation of the brachial artery and oxidative stress were measured in serum samples.

Results: Flow-mediated dilation was increased significantly after 4 weeks' treatment with losartan (3.4 +/- 0.44%) compared with atenolol (2.58 +/- 0.42%; P = 0.01). 8-Isoprostanes, a marker of oxidative stress, were significantly reduced in the losartan group compared with baseline (0.039 +/- 0.007 versus 0.067 +/- 0.006 ng/ml; P = 0.01), but did not differ from baseline with atenolol. Glucose, hemoglobin A1c, highly sensitive C-reactive protein, lipids and systolic blood pressure remained unaltered, whereas diastolic blood pressure tended to be lower in the atenolol group.

Conclusions: This study demonstrates that losartan significantly improved endothelial function in type 2 diabetes patients with hypertension compared with atenolol. This must be independent of the blood pressure-lowering effect of losartan and is probably caused by an antioxidative effect of the angiotensin receptor blocker.

Journal of Hypertension. 25(4):785-791, April 2007.

Triple antiplatelet therapy

Effects of aspirin, clopidogrel and dipyridamole administered singly and in combination on platelet and leucocyte function in normal volunteers and patients with prior ischaemic stroke

Zhao L, Fletcher S, Weaver C, Leonardi-Bee J, May J, Fox S, Willmot M, Heptinstal S, Bath P.
Division of Stroke Medicine, South Block, D Floor, Queen's Medical Centre, Nottingham NG7 2UH UK

The aim of this study was to assess whether triple antiplatelet therapy is superior to dual and mono therapy in attenuating platelet and leucocyte function.
Aspirin (A), clopidogrel (C), and dipyridamole (D) were administered singly and in various combinations (A, C, D,AC,AD, CD,ACD), each for two weeks (without washout) to 11 healthy subjects and to 11 patients with previous ischaemic stroke in two randomised multiway crossover trials. At the end of each two-week period platelet aggregation, platelet-leucocyte conjugate formation and leucocyte activation were measured ex vivo blinded to treatment. Platelets were stimulated with collagen; additional measurements were made with adenosine diphosphate (ADP), platelet activating factor (PAF), adrenaline and the combination of, ADP, PAF and adrenaline.
Results show that in the presence of collagen, ACD was superior to all antagonists or combinations, except AC, in reducing aggregation, platelet-leucocyte conjugate formation, and monocyte activation (all p<0.05). ACD was also more potent than other treatments, except AC, in inhibiting the aggregation and platelet-monocyte conjugate formation induced by the combination of ADP, PAF and adrenaline. The effects were similar in both volunteers and stroke patients. No serious adverse events or major bleeding events occurred.
Triple antiplatelet therapy did not appear to be more effective than combined aspirin and clopidogrel in moderating platelet and leucocyte function. Any additional clinical benefit provided by dipyridamole may be through other mechanisms of action.

Thromb Haemost. 2005 Mar;93(3):527-34.

Ventricular septal defect

What is a ventricular septal defect?
A ventricular septal defect (VSD) is an abnormal opening in the wall (septum) that divides the two lower chambers of the heart (ventricles). This opening allows blood from either side of the heart to cross into the opposite ventricle.

Usually, because the left side of the heart is at a higher pressure than the right side, the blood from the left ventricle flows to the right ventricle and, subsequently, back to the lungs. This abnormal shunting of oxygen-rich blood back to the oxygen-poor right side of the heart is referred to as a left-to-right shunt.
Normally, this will not cause cyanosis (bluish coloration of the skin caused by oxygen-poor blood reaching the general circulation). However, because the right side of the heart and the blood vessels in the lungs are not built to withstand increased volumes and pressures, left-to-right shunting eventually may result in heart failure and pulmonary hypertension (elevated blood pressure in the pulmonary blood vessels).

What are the signs and symptoms of a ventricular septal defect?

Signs and symptoms depend on the VSD’s size and how much blood abnormally flows across the defect. Symptoms may include:
• Breathing difficulties
• Enlarged heart
• Irregular heart rhythm (dysrhythmias), especially atrial dysrhythmias
• Heart failure

What are surgical treatments for VSD?
The surgical option for a VSD is ventricular septal defect closure.
How is the surgery performed?
Ventricular septal defect closure is considered open-heart surgery, meaning the heart will have to be opened and the patient’s blood flow will have to be diverted to a heart-lung bypass machine during the repair.
The chest is opened via a sternotomy incision, and the patient is connected to the heart-lung bypass machine. Depending on the location of the defect, an incision will be made in the right atrium, the pulmonary artery or the outflow tract of the right ventricle (infundibulum). A patch is created by the surgeon from either the patient’s pericardial tissue or a synthetic material such as Dacron. The patch then is sutured into place to close the defect. The atrial, pulmonary artery or infundibular incision is closed with sutures, and the remainder of the operation is completed.
If the patient has no other cardiac defects, this operation usually is considered a cure and no further surgeries should be needed.

Synthetic Pacemaker Channel

Gene Transfer of a Synthetic Pacemaker Channel Into the Heart
A Novel Strategy for Biological Pacing

Yuji Kashiwakura, MD, PhD; Hee Cheol Cho, PhD; Andreas S. Barth, MD; Ezana Azene, PhD; Eduardo Marbán, MD, PhD
From the Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md.

Background— One key element of natural pacemakers is the pacemaker current encoded by the hyperpolarization-activated nucleotide-gated channel (HCN) gene family. Although HCN gene transfer has been used to engineer biological pacemakers, this strategy may be confounded by unpredictable consequences of heteromultimerization with endogenous HCN family members and limited flexibility with regard to frequency tuning of the engineered pacemaker.

Methods and Results— To circumvent these limitations, we converted a depolarization-activated potassium-selective channel, Kv1.4, into a hyperpolarization-activated nonselective channel by site-directed mutagenesis (R447N, L448A, and R453I in S4 and G528S in the pore). Gene transfer into ventricular myocardium demonstrated the ability of this construct to induce pacemaker activity with spontaneous action potential oscillations in adult ventricular myocytes and idioventricular rhythms by in vivo electrocardiography.
Conclusions— Given the sparse expression of Kv1 family channels in the human ventricle, gene transfer of a synthetic pacemaker channel based on the Kv1 family has novel therapeutic potential as a biological alternative to electronic pacemakers.

Circulation. 2006;114:1682-1686.
© 2006 American Heart Association, Inc.