Systemic Oxidative Stress Is Increased in Postmenopausal Women and Independently Associates with Homocysteine Levels.

Oxidative stress plays a pivotal role in the pathogenesis of cardiovascular diseases (CVD). Postmenopausal women have an increased risk of developing CVD due to decreased estrogen availability, which is accompanied by increased oxidative stress. Serum free thiols (R-SH) provide a robust and powerful read-out of systemic oxidative stress. In this study, we aimed to establish serum levels of free thiols and explore associations between free thiols and demographic, clinical, and biochemical parameters related to obesity and the risk for developing CVD in both pre- and postmenopausal women. Serum free thiols were measured in a cohort consisting of healthy pre- (n = 223) and postmenopausal (n = 118) Omani women. Postmenopausal women had significantly lower levels of serum free thiols as compared to premenopausal women (762.9 ± 85.3 vs. 780 ± 80.9 µM, age-adjusted p < 0.001). Women's age was positively associated with serum free thiol levels in premenopausal women (ß = 0.36, p = 0.002), whereas an inverse association was observed in postmenopausal women (ß = -0.29, p = 0.002). Homocysteine levels were significantly inversely associated with serum free thiol levels in both pre- (ß = -0.19, p = 0.005) and postmenopausal (ß = -0.20, p = 0.032) women, independent from known cardiovascular risk factors. In this study, we show that postmenopausal women are affected by increased systemic oxidative stress, which independently associates with homocysteine levels.

Exercise training attenuates ageing-induced BKCa channel downregulation in rat coronary arteries.

Physical inactivity and ageing are widely recognized as risk factors for development of coronary artery disease. One of the characteristic changes that occurs in aged coronary artery is downregulation of their large-conductance voltage- and calcium-activated K(+) (BK(Ca)) channels. In this study, we investigated the effects of moderate exercise training (ET) on the activity of BK(Ca) channels in coronary arteries of aged rats. Old Fischer 344 rats (23-26 months old) were randomly assigned to sedentary (O-SED, n = 24) or exercise-trained groups (O-ET, n = 28). The O-ET rats underwent a progressive treadmill exercise-training programme for 60 min day(1), 5 days week(1) for 12 weeks. Young animals were used for comparison. Coronary arteries were mounted on a wire myograph, and contractions in response to 1, 10, 30, 50 and 100 nmoll(1) iberiotoxin were compared. Iberiotoxin (100 nmol l(1)) contracted coronary arteries of young, O-SED and O-ET rats by 115 +/- 14, 36 +/- 5.6 and 61 +/- 5% of 5-hydroxytryptamine-induced contractions, respectively. Patch-clamp studies revealed a larger magnitude of BK(Ca) current in young (104 +/- 15.6 pA pF(1)) compared with O-ET (44 +/- 9 pA pF(1)) and least in O-SED coronary smooth muscle cells (8.6 +/- 2 pA pF(1)). Western immunoblotting was performed to study expression levels of BK(Ca) channel proteins. The alpha and beta1 subunits of the BK(Ca) channel were reduced by 40 +/- 3.5 and 30 +/- 2.6%, respectively, in coronary arteries of old compared with young rats, and ET attenuated this reduction in expression level to 28 +/- 2 and 12 +/- 4%, respectively. Our results showed that ageing was associated with a reduction in BK(Ca) channels, and ET partly reversed this reduction. We conclude that low-intensity ET may be beneficial in restoring age-related decline in coronary vasodilatory properties mediated by BK(Ca) channels.

Aging Reduces L-Type Calcium Channel Current and the Vasodilatory Response of Small Mesenteric Arteries to Calcium Channel Blockers.

Calcium channel blockers (CCBs) are widely used to treat cardiovascular disease (CVD) including hypertension. As aging is an independent risk factor for CVD, the use of CCBs increases with increasing age. Hence, this study was designed to evaluate the effect of aging on the sensitivity of small mesenteric arteries to L-type voltage-gated calcium channel (LTCC) blockers and also to investigate whether there was a concomitant change in calcium current density. Third order mesenteric arteries from male F344 rats, aged 2.5-3 months (young) and 22-26 months (old) were mounted on wire myograph to measure the tension during isometric contraction. Arteries were contracted with 100 mM KCl and were then relaxed in a cumulative concentration-response dependent manner with nifedipine (0.1 nM-1 µM), verapamil (0.1 nM-10 µM), or diltiazem (0.1 nM-10 µM). Relaxation-concentration response curves produced by cumulative concentrations of three different CCBs in arteries of old rats were shifted to the right with statistically significant IC50s. pIC50 ± s.e.m: (8.37 ± 0.06 vs. 8.04 ± 0.05, 7.40 ± 0.07 vs. 6.81 ± 0.04, and 6.58 ± 0.07 vs. 6.34 ± 0.06) in young vs. old. It was observed that the maximal contractions induced by phenylephrine and reversed by sodium nitroprusside were not different between young and old groups. However, Bay K 8644 (1 µM) increased resting tension by 23 ± 4.8% in young arteries and 4.7 ± 1.6% in old arteries. LTCC current density were also significantly lower in old arteries (-2.77 ± 0.45 pA/pF) compared to young arteries (-4.5 ± 0.40 pA/pF); with similar steady-state activation and inactivation curves. Parallel to this reduction, the expression of Cav1.2 protein was reduced by 57 ± 5% in arteries from old rats compared to those from young rats. In conclusion, our results suggest that aging reduces the response of small mesenteric arteries to the vasodilatory effect of the CCBs and this may be due to, at least in part, reduced current density of LTCC.

Prehypertension: Underlying pathology and therapeutic options.

Prehypertension (PHTN) is a global major health risk that subjects individuals to double the risk of cardiovascular disease (CVD) independent of progression to overt hypertension. Its prevalence rate varies considerably from country to country ranging between 21.9% and 52%. Many hypotheses are proposed to explain the underlying pathophysiology of PHTN. The most notable of these implicate the renin-angiotensin system (RAS) and vascular endothelium. However, other processes that involve reactive oxygen species, the inflammatory cytokines, prostglandins and C-reactive protein as well as the autonomic and central nervous systems are also suggested. Drugs affecting RAS have been shown to produce beneficial effects in prehypertensives though such was not unequivocal. On the other hand, drugs such as ß-adrenoceptor blocking agents were not shown to be useful. Leading clinical guidelines suggest using dietary and lifestyle modifications as a first line interventional strategy to curb the progress of PHTN; however, other clinically respected views call for using drugs. This review provides an overview of the potential pathophysiological processes associated with PHTN, abridges current intervention strategies and suggests investigating the value of using the "Polypill" in prehypertensive subjects to ascertain its potential in delaying (or preventing) CVD associated with raised blood pressure in the presence of other risk factors.