Vascular Function In Hypertension Research Articles

Chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats

Epidemiologic studies indicate that ingestion of vegetables and fruit inhibits the development of cardiovascular disease. Chlorogenic acids are abundant phenolic compounds contained in vegetables and fruits, but the impact of dietary chlorogenic acids on vascular function in hypertension is not known. We therefore examined the effects of 5-caffeoylquinic acid (CQA), a representative chlorogenic acid, on blood pressure and vascular function in age-matched normotensive Wistar-Kyoto rats and spontaneously hypertensive rats. A single ingestion of CQA (30-600 mg/kg) reduced blood pressure in spontaneously hypertensive rats, an effect that was blocked by administration of a nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester. When spontaneously hypertensive rats were fed diets containing 0.5% CQA for 8 weeks (approximately 300 mg/kg per day), the development of hypertension was inhibited compared with the control diet group. CQA ingestion increased urinary excretion of nitric oxide metabolites and decreased urinary excretion of hydrogen peroxide; decreased NADPH-dependent superoxide anion production in the aorta, suggesting that dietary CQA inhibited vascular NADPH oxidase activity; significantly improved acetylcholine-induced endothelium-dependent vasodilation in the aorta; and markedly reduced the degree of immunohistochemical staining for nitrotyrosine and media hypertrophy in aorta sections. In contrast, CQA had no effects in Wistar-Kyoto rats. Dietary CQA reduces oxidative stress and improves nitric oxide bioavailability by inhibiting excessive production of reactive oxygen species in the vasculature, and leads to the attenuation of endothelial dysfunction, vascular hypertrophy, and hypertension in spontaneously hypertensive rats.

Salt intake and depletion increase circulating levels of endogenous ouabain in normal men

High-salt diets elevate circulating Na+ pump inhibitors, vascular resistance, and blood pressure. Ouabain induces a form of hypertension mediated via the alpha2-Na+ pump isoform and the calcium influx mode of the vascular sodium calcium exchanger (NCX). Whereas elevated levels of an endogenous ouabain (EO) and NCX have been implicated in salt-sensitive hypertension, acute changes in sodium balance do not affect plasma EO. This study investigated the impact of longer-term alterations in sodium balance on the circulating levels and renal clearance of EO in normal humans. Thirteen normal men consumed a normal diet, high-salt diet, and hydrochlorothiazide (HCTZ), each for 5-day periods to alter sodium balance. EO and other humoral and urinary variables were determined daily. On a normal diet, urinary sodium excretion (140 +/- 16 meq/day), plasma EO (0.43 +/- 0.08 nmol/l) and urinary EO excretion (1.04 +/- 0.13 nmol/day) were at steady state. On the 3rd day of a high-salt diet, urine sodium excretion (315 +/- 28 meq/day), plasma EO (5.8 +/- 2.2 nmol/l), and the urinary EO excretion (1.69 +/- 0.27 nmol/day) were significantly increased, while plasma renin activity and aldosterone levels were suppressed. The salt-evoked increase in plasma EO was greater in older individuals, in subjects whose baseline circulating EO was higher, and in those with low renal clearance. During HCTZ, body weight decreased and plasma renin activity, aldosterone, and EO (1.71 +/- 0.77 nmol/l) rose, while urinary EO excretion remained within the normal range (1.44 +/- 0.31 nmol/day). Blood pressure fell in one subject during HCTZ. HPLC of the plasma extracts showed one primary peak of EO immunoreactivity with a retention time equivalent to ouabain. High-salt diets and HCTZ raise plasma EO by stimulating EO secretion, and a J-shaped curve relates sodium balance and EO in healthy men. Under normal dietary conditions, approximately 98% of the filtered load of EO is reabsorbed by the kidney, and differences in the circulating levels of EO are strongly influenced by secretion and urinary excretion of EO. The dramatic impact of high-salt diets on plasma EO is consistent with its proposed role as a humoral vasoconstrictor that links salt intake with vascular function in hypertension.

Sex Hormones as Potential Modulators of Vascular Function in Hypertension

The greater incidence of hypertension in men and postmenopausal women compared with premenopausal women has suggested gender differences in vascular function. Vascular effects of the female sex hormones estrogen and progesterone and the male hormone testosterone have been described. Sex steroid receptors have been identified in vascular endothelium and smooth muscle. Interaction of sex hormones with cytosolic/nuclear receptors initiates long-term genomic effects that stimulate endothelial cell growth but inhibit smooth muscle proliferation. Activation of sex hormone receptors on the plasma membrane triggers nongenomic effects that stimulate endothelium-dependent vascular relaxation via NO-cGMP, prostacyclin-cAMP, and hyperpolarization pathways. Sex hormones also cause endothelium-independent inhibition of vascular smooth muscle contraction, [Ca2+]i, and protein kinase C. These vasorelaxant/vasodilator effects suggested vascular benefits of hormone replacement therapy (HRT) during natural and surgically induced deficiencies of gonadal hormones. Although some clinical trials showed minimal benefits of HRT in postmenopausal hypertension, the lack of effect should not be generalized because it could be related to the type/dose of sex hormone, subjects' age, and other cardiovascular conditions. The prospect of HRT relies on continued investigation of the molecular mechanisms underlying the vascular effects of sex hormones and identification of compounds that specifically target the vascular sex hormone receptors. Naturally occurring hormones and phytoestrogens may be more beneficial HRT than synthesized compounds. Also, the type/dose, time of initiation, and duration of HRT should be customized depending on the subject's age and preexisting cardiovascular condition, and thereby enhance the outlook of sex hormones as potential modulators of vascular function in hypertension.

Markers of Vascular Function in Hypertension due to Cushing’s Syndrome

There are limited data regarding the role of vascular endothelial growth factor (VEGF) in arterial hypertension. The aim of the study was to determine some markers of vascular function, including VEGF, active renin and prostaglandin E (2) (PGE (2)) in patients with endocrine hypertension resulting from Cushing's syndrome. The study comprised 32 patients with active Cushing's syndrome, 22 patients with essential hypertension, and 24 healthy volunteers. VEGF was significantly elevated in the groups of patients compared to controls. VEGF levels in the patients with Cushing's syndrome were significantly higher than in patients with essential hypertension. We did not find significant differences in VEGF levels between patients with Cushing's disease and Cushing's syndrome due to adrenal tumor. Active renin and PGE (2) levels did not differ significantly among groups. VEGF levels were significantly elevated in endocrine hypertension due to glucocorticoid excess. Higher VEGF levels were detected in patients with Cushing's syndrome compared to patients with essential hypertension. Based on our results, we could not judge the extent to which this VEGF elevation in the patients with Cushing's syndrome was due to the hypertension itself and/or to the presence of adrenal tumor/hyperplasia.

Recent advances in intracellular signalling in hypertension.

Transmission of external signals from the cell surface to the internal cellular environment occurs via tightly controlled complex transduction pathways. Alterations in these highly regulated signalling cascades in vascular smooth cells may play a fundamental role in the structural, mechanical and functional abnormalities that underlie vascular pathological processes in hypertension. The present review focuses on recent developments relating to two novel signalling pathways: angiotensin II signalling through tyrosine kinases; and oxidative stress and redox-dependent signal transduction. These pathways are emerging as critical mediators of hypertensive vascular disease because they influence multiple cellular responses that are involved in structural remodelling, vascular inflammation and altered tone. A recent advance in the field of angiotensin II signalling was the demonstration that, in addition to its vasoconstrictor properties, angiotensin II has potent mitogenic-like and proinflammatory-like characteristics. These actions are mediated through phosphorylation of both nonreceptor tyrosine kinases and receptor tyrosine kinases. It is also becoming increasingly apparent that many signalling events that underlie abnormal vascular function in hypertension are influenced by changes in intracellular redox status. In particular, increased bioavailability of reactive oxygen species (oxidative stress) stimulates growth-signalling pathways, induces expression of proinflammatory genes, alters contraction-excitation coupling and impairs endothelial function. A better understanding of the molecular pathways that regulate vascular smooth muscle cell function will provide further insights into the pathophysiological mechanisms that contribute to vascular changes and end-organ damage associated with high blood pressure, and could permit identification of potential novel therapeutic targets in the prevention and management of hypertension.

Pulse waveform analysis of arterial compliance: relation to other techniques, age, and metabolic variables

T o assess the physiologic and clinical relevance of newer noninvasive measures of vascular compliance, computerized arterial pulse waveform analysis (CAPWA) of the radial pulse was used to calculate two components of compliance, C1 (capacitive) and C2 (oscillatory or reflective), in 87 normotensive (NlBP, n = 20), untreated hypertensive (HiBP, n = 21), and treated hypertensive (HiBP-Rx, n = 46) subjects. These values were compared with two other indices of compliance, the ratio of stroke volume to pulse pressure (SV/PP) and magnetic resonance imaging (MRI)–based aortic distensibility; and were also correlated with demographic and biochemical values. The HiBP subjects displayed lower C1 (1.34 ± 0.09 v 1.70 ± 0.11 mL/mm Hg, significance [sig] = .05) and C2 (0.031 ± 0.003 v 0.073 ± 0.02 mL/mm Hg, sig = .005) than NlBP subjects. This was not true for C1 (1.64 ± 0.08 mL/mm Hg) and C2 (0.052 ± 0.005 mL/mm Hg) values in HiBP-Rx subjects. The C1 (r = 0.917, P < .0001) and C2 (r = 0.677, P < .0001) were both closely related to SV/PP, whereas C1 (r = 0.748, P = .002), but not C2, was significantly related to MRI-determined aortic distensibility. Among other factors measured, age exerted a strong negative influence on both C1 (r = −0.696, P < .0001) and C2 (r = −0.611, P < .0001) compliance components. Positive correlations were observed between C1 (r = 0.863, P = .006), aortic distensibility (r = 0.597, P = .19) and 24-h urinary sodium excretion, and between C1- and MR spectroscopy-determined in situ skeletal muscle intracellular free magnesium (r = 0.827, P = .006), whereas C2 was inversely related to MRI-determined abdominal visceral fat area (r = −0.512, P = .042) and fasting blood glucose (r = −0.846, P = .001). Altogether, the close correspondence between CAPWA, other compliance techniques, and known cardiovascular risk factors suggests the clinical relevance of CAPWA in the assessment of altered vascular function in hypertension.

Abnormal proliferative response of the carotid artery of spontaneously hypertensive rats after angioplasty may be related to the depolarized state of its smooth muscle cells.

Hypertension is one of the major precursors of atherosclerotic vascular disease, and vascular smooth muscle abnormal cell replication is a key feature of plaque formation. The present study was conducted to examine the relationship between hypertension and smooth muscle cell proliferation after balloon injury and to correlate neointima formation with resting membrane potential of uninjured smooth muscle cells, since it has been suggested that altered vascular function in hypertension may be related to the resetting of the resting membrane potential in spontaneously hypertensive rats (SHR). Neointima formation was induced by balloon injury to the carotid arteries of SHR and renovascular hypertensive rats (1K-1C), as well as in their normotensive controls, i.e., Wistar Kyoto (WKY) and normal Wistar (NWR) rats. After 14 days the animals were killed and the carotid arteries were submitted to histomorphometric and immunohistochemical analyses. Resting membrane potential measurements showed that uninjured carotid arteries from SHR smooth muscle cells were significantly depolarized (-46.5 +/- 1.9 mV) compared to NWR (-69 +/- 1.4 mV), NWR 1K-1C (-60.8 +/- 1.6 mV), WKY (-67.1 +/- 3.2 mV) and WKY 1K-1C (-56.9 +/- 1.2 mV). The SHR arteries responded to balloon injury with an enhanced neointima formation (neo/media = 3.97 +/- 0.86) when compared to arteries of all the other groups (NWR 0.93 +/- 0.65, NWR 1K-1C 1.24 +/- 0.45, WKY 1.22 +/- 0.32, WKY 1K-1C 1.15 +/- 0.74). Our results indicate that the increased fibroproliferative response observed in SHR is not related to the hypertensive state but could be associated with the resetting of the carotid smooth muscle cell resting membrane potential to a more depolarized state.