C. Tissa Kappagoda

Mechanism of the endothelium-dependent relaxation evoked by a grape seed extract

GSEs (grape seed extracts) which contain polyphenolic compounds cause an endothelium-dependent relaxation of blood vessels. The aim of the present study was to examine the mechanisms involved in this response. A well-characterized GSE was applied to rabbit aortic rings suspended in organ baths containing Krebs-Henseleit buffer maintained at 37 degrees C. In aortic rings pre-contacted with noradrenaline (norepinephrine), the extract produced a dose-dependent relaxation. The maximum relaxations elicited by the extract (71.9+/-1.0%) were similar to those elicited by acetylcholine (64.2+/-1.5%) (n=12 for each). As expected, the relaxations were abolished by removal of the endothelium and by prior incubation with L-NAME (N(G)-nitro-L-arginine methyl ester), confirming the essential role of eNOS (endothelial NO synthase) in the response. The responses to the GSE were also abolished by incubation with wortmannin and LY294002, which are inhibitors of PI3K (phosphoinositide 3-kinase). These compounds had no effect on the responses to acetylcholine. Using immunoblotting, we also demonstrated that the GSE induced the phosphorylation of both Akt and eNOS in HUVECs (human umbilical vein endothelial cells). Finally, the extract was modified by methylation of the hydroxy groups in the polyphenolic groups and was applied to the aortic rings. The modified extract failed to cause a relaxation. Taken together, these findings suggest that the endothelium-dependent relaxation induced by the GSE was mediated by activation of the PI3K/Akt signalling pathway through a redox-sensitive mechanism, resulting in phosphorylation of eNOS.

Effect of fatty acids on endothelium-dependent relaxation in the rabbit aorta

The metabolic syndrome, Type II (non-insulin-dependent) diabetes and obesity are associated with endothelial dysfunction and increased plasma concentrations of NEFAs (non-esterified fatty acids; free fatty acids). The present study was undertaken to define the inhibitory effects of saturated NEFAs on EDR (endothelium-dependent relaxation). Experiments were performed in rings of rabbit aorta to establish (i) dose-response relationships, (ii) the effect of chain length, (iii) the effect of the presence of double bonds, (iv) reversibility and time course of inhibition, and (v) the effect on nitric oxide production. Aortic rings were incubated (1 h) with NEFA-albumin complexes derived from lauric (C(12:0)), myristic (C(14:0)), palmitic (C(16:0)), stearic (C(18:0)) and linolenic (C(18:3)) acids. EDR induced by acetylcholine (0.1-10 mumol/l) was measured after pre-contraction with noradrenaline. Inhibition of EDR was dose-dependent (0.5-2 mmol/l NEFA), and the greatest inhibition (51%) was observed with stearic acid (2 mmol/l). Lauric acid had the smallest inhibitory effect. The inhibitory effects were always reversible and were evident after 15 min of incubation. Linolenic acid caused a significantly lower inhibition of EDR than stearic acid. SOD (superoxide dismutase) restored the inhibitory effect caused by NEFAs, suggesting the involvement of ROS (reactive oxygen species) in removing nitric oxide. The nitric oxide concentration measured after exposure of the rings to acetylcholine was lower after incubation with NEFAs than with Krebs buffer alone. This finding is consistent with removal of nitric oxide by ROS. This claim was supported by the demonstration of increased concentrations of nitrated tyrosine in the rings incubated with NEFAs.

Lifestyle modification program in management of patients with coronary artery disease : the clinical experience in a tertiary care hospital.

OBJECTIVES The authors examined clinical outcomes in 71 male and female patients with coronary atherosclerosis who enrolled in a 2-year, independent-living, lifestyle modification program. The findings in 43 patients who completed the program were compared with those in 28 patients who dropped out of the program. BACKGROUND Clinical studies suggest that lifestyle modification of risk factors for coronary atherosclerosis reduces subsequent cardiac events but there are very few reports of the effect of these programs in patients living independently. METHODS Patients with diagnosed coronary atherosclerosis were managed for a 2-year period in a structured multidisciplinary program by a team that included two cardiologists, a nurse, a dietitian, an exercise physiologist, and a clinical psychologist. The overall aim of the program was to normalize or control all major reversible cardiovascular risk factors. Patients were required to participate in several weekly sessions for exercise, meditation/stress reduction training, dietary education and counseling, and participatory dinners. There was a strong emphasis on patients self care, inclusion of support members, and regular monitoring of and feedback to patients. RESULTS Data comparing baseline and 2-year outcomes showed a significant reduction in body weight, dietary intake of total/saturated fat and cholesterol, serum low- and high-density lipoprotein concentration, and an increase in exercise capacity. In the compliant group, the incidence of cardiac events was 2.3% over 2 years. CONCLUSION Multidisciplinary lifestyle modification programs addressing cardiovascular risk factors are known to have a significant impact upon cardiac risk factors in patients with coronary atherosclerosis. Data show that these changes can be accomplished in independent-living patients in a program offered through a routine cardiology service. However, compliance is an important issue in these self-regulated programs.

Exercise testing after myocardial infarction: Relative values of the low level predischarge and the postdischarge exercise test

This study was undertaken to compare the relative values of the low level predischarge exercise test and the postdischarge (6 weeks) symptom-limited test in 518 consecutive patients admitted with an acute myocardial infarction. Of the patients who did not develop significant ST segment depression or angina during the predischarge test, the symptom-limited test also remained negative in 91.5 and 91.9% of the patients, respectively. Similar results were obtained with ST segment elevation and the systolic blood pressure response during the two exercise tests with only 2.1 and 11.4% changing from normal to abnormal, respectively. Discriminant function analysis was done to predict the occurrence of coronary events (unstable angina, reinfarction, cardiac failure, cardiac death) with use of the data from the exercise tests together with other clinical and investigational data. The jackknife method correctly classified 71.9 and 71.4% of the patients with the data from the predischarge exercise test and symptom-limited test, respectively. Combining the data from the two tests improved the overall predictive accuracy to only 75.0%. It is concluded that the routine performance of a symptom-limited test 6 to 8 weeks after infarction does not reveal any significant additional information in those patients who have undergone a predischarge low level exercise test. Thus the 6 to 8 week test should be restricted to selected patients after myocardial infarction.

The rapidly adapting receptors in mammalian airways and their responses to changes in extravascular fluid volume

In this short review, we shall focus on some recent findings on the physiological stimulus for the rapidly adapting receptors (RAR) of the airways. They are readily activated by a sustained inflation of the lungs and they are usually identified by their rapid adaptation to this stimulus. They are also activated by both tactile stimuli and irritant gases applied to the epithelium of the airways. The investigations reviewed here suggest that these receptors are activated by changes in extravascular fluid volume. The principal factors governing fluid flux from the microcirculation are identified in the Starling equation. These are the hydrostatic pressure, plasma oncotic pressure and capillary permeability. Findings from recent studies suggest that all these factors increase the activity of RAR. In addition, these receptors are also activated by obstruction of lymph drainage from the lung. Evidence is presented to show that manipulation of Starling forces also increases the extravascular fluid volume of the airways in areas where the RAR are located. On the basis of these findings, it is suggested that, along with mechanosensitivity to stimuli such as stretch, inflation and deflation, another physiological stimulus to the RAR is a change in extravascular fluid volume in the regions of the airways where these receptors are located.

Responses of bronchial C-fiber afferents of the rabbit to changes in lung compliance

Rapidly adapting receptors (RAR) in the lung are stimulated when the lung compliance is reduced. The present investigation was undertaken to determine whether bronchial C-fibers are also activated when lung compliance is decreased since both RAR and bronchial C-fibers are influenced by extra-vascular fluid in the airways. Action potentials (AP) were recorded from bronchial C, pulmonary C, RAR and slowly adapting receptor (SAR) afferents in the cervical vagus in open chest New Zealand White rabbits ventilated at a constant rate and tidal volume. AP were recorded during (a) positive end-expiratory pressure (PEEP) of 2-3 cmH2O (control), (b) zero end-expiratory pressure (ZEEP), (c) negative end-expiratory pressure (NEEP) of -4 cmH2O, (d) restoration of PEEP and (e) final control after hyper-inflation. Both RAR and bronchial C-fiber activity increased significantly compared with control when lung compliance was decreased (bronchial C-fibers: 35 +/- 5 vs. 66 +/- 13 impulses per 30 sec and RAR: 3 +/- 1 vs. 94 +/- 14 impulses per 30 sec).

Rapidly adapting receptors in a rabbit model of mitral regurgitation.

1 Unlike in normal rabbits, pulmonary rapidly adapting receptors (RARs) in rabbits with chronic mitral regurgitation (MR) do not respond to small changes in extravascular fluid (EVF) volume in major airways. The present study examined the effect of shrinking the EVF volume in rabbits with chronic MR by infusing hypertonic albumin, to see whether this response of RARs is restored. The effect of raising the left atrial pressure (LAP) acutely above 25 mmHg (to cause pulmonary oedema) on RARs was also investigated. 2 Mean RAR activities in rabbits with MR (n= 6) at initial control, LAP +5 mmHg, LAP +10 mmHg and final control periods were 20·9 ± 9·5, 18·8 ± 11·3, 27·0 ± 11·2 and 17·2 ± 9·8 action potentials min−1, respectively (P> 0·05, ANOVA). After infusion of 35 % bovine serum albumin i.v. these values were 9·4 ± 3·2, 30·6 ± 14·6, 48·9 ± 10·1 and 18·4 ± 7·3 action potentials min−1, respectively (P < 0·01, ANOVA). In rabbits with chronic MR (n= 7) raising the LAP above 25 mmHg stimulated RARs. 3 EVF content of the airways and lungs was measured in rabbits with MR and in control rabbits, at baseline and after elevation of the LAP by 10 or 25 mmHg for 20 min. In control rabbits the EVF contents in the lower trachea, carina and bronchi at baseline and at LAP +10 mmHg were 52·1 ± 1·2 and 57·8 ± 1·7 %, respectively (P < 0·05, Students t test). In rabbits with MR these values were 58·3 ± 1·5 and 56·9 ± 1·9 %, respectively. When the LAP was elevated by 25 mmHg the EVF content increased to 62·4 ± 1·1 % (P < 0·05, ttest compared with baseline and LAP +10 mmHg). 4 We concluded that in rabbits with chronic MR, RARs are unable to respond to acute, small elevations of LAP because there is no concomitant increase in EVF content in the vicinity of these receptors. Furthermore, these receptors can be activated in these animals by elevating the LAP above 25 mmHg or can be made sensitive to acute small elevations of LAP by shrinking the chronically expanded EVF compartment.

Assessment of risk for developing coronary heart disease in asymptomatic individuals.

The assessment of risk for developing coronary heart disease (CHD) in asymptomatic individuals continues to be an important challenge for clinicians. We suggest that the Framingham risk score provides a pragmatic basis for assessing global 10-year CHD risk in this population. The Framingham risk score should be supplemented with additional information pertaining to diabetes, metabolic syndrome, family history, and peripheral arterial disease before a final decision is made with respect to individual risk. In terms of additional investigations, it is suggested that measurement of the ankle brachial index and a stress test that focuses on functional capacity be incorporated into the evaluation of asymptomatic subjects for CHD. The role of emerging risk factors remains unresolved as is the value of attempting to routinely diagnose subclinical disease with measurements such as the coronary calcium score.

Nonpharmacologic therapy for coronary artery atherosclerosis: results of primary and secondary prevention trials.

The association between abnormal serum lipoprotein levels and coronary atherosclerosis has been established by extensive clinical, experimental, and epidemiologic evidence. Recent angiographic trials in patients with coronary artery disease have demonstrated that improvement in serum lipids and other risk factors has a favorable effect on coronary lesions and reduces coronary events and interventions. Most trials of coronary disease prevention have used intensive pharmacologic therapy, but several have involved only nonpharmacologic intervention. The latter investigations include both primary and secondary prevention studies. Three controlled, nonpharmacologic primary prevention trials with long-term follow-up used dietary management aimed at lowering serum cholesterol levels; one trial also included smoking cessation, and one used a comprehensive approach to risk-factor modification. Serum cholesterol levels and other risk factors were significantly decreased in the intervention groups but were unaltered in the control populations. After periods of 5 to 10 years, reductions of 20% to 45% in coronary events were observed in the intervention groups compared with controls. Four secondary intervention trials examined the effect of nonpharmacologic therapy alone on coronary artery disease regression; three of these trials included control groups. All of the trials focused on reduction of elevated serum cholesterol levels with a low-fat diet, and several included interventions for other risk factors. Serum cholesterol levels fell by 14% to 24% in treated patients compared with 4% to 9% in controls. Although these trials were of relatively short duration (1 to 3 years) and included small numbers of patients (36 to 90), each demonstrated favorable effects on coronary lesions and three revealed clinical benefits.(ABSTRACT TRUNCATED AT 250 WORDS)

Benefits of Exercise in the Elderly

There is an abundance of evidence supporting the claim that physical activity enhances the quality of life in both elderly men and women. These benefits extend well beyond the cardiovascular system and are not limited to those who get into the habit of exercise on a regular basis at a young age. It is apparent that physical exercise not only reduces the functional deterioration associated with ageing but also helps to reverse some of these trends in those who start an exercise program late in life. In this chapter, we have reviewed some of the physiological concepts associated with exercise training in the elderly together with some of the evidence supporting health benefits that are likely to follow in patients with common non-communicable diseases associated with ageing, such as coronary atherosclerosis, hypertension, diabetes, obesity, and osteoporosis.