Hypertension

Abstract —The contributions of increases in circulating catecholamines, changes in central command, and muscle afferents on baroreflex control of the sinus node during exercise are unclear. We used a dobutamine infusion to induce hemodynamic changes comparable to those of moderate physical exercise in the absence of changes in central command and muscle afferents in 13 healthy subjects. Dobutamine (up to 9 μg/kg body weight per minute) increased systolic blood pressure, shortened the RR interval, increased systolic blood pressure variability, but blunted RR interval variability ( P <0.05 versus placebo). Consequently, dobutamine decreased the coherence between variations in systolic blood pressure and RR interval and decreased arterial baroreflex sensitivity from 12±2 to 3±1 ms/mm Hg ( P <0.01). The largest increases in systolic blood pressure with dobutamine were paralleled by the greatest impairments in arterial baroreflex sensitivity (0.50< r <0.56, P <0.01). The chronotropic effects of dobutamine prevented a reflex bradycardia in response to the blood pressure increase. However, less predominant low-frequency oscillations in systolic blood pressure ( P <0.0001) suggested preserved sympathetic withdrawal in response to the blood pressure increase induced by dobutamine. In conclusion, this study revealed that a shift in the operating point of the arterial baroreceptors and the chronotropic effects of adrenergic stimulation impair baroreflex control of the sinus node during dobutamine exercise stress testing. Baroreflex control of the sinus node is not reset when hemodynamic characteristics of exercise are reproduced in the absence of modifications in central command and muscles afferents.

We investigated the relation between morning blood pressure (BP) variations, sympathetic activity, and QT intervals in 156 never-treated subjects with essential hypertension and different patterns of morning BP increase. The morning BP peak (MP) was defined as a rise in systolic BP ≥50 mm Hg and/or diastolic BP ≥22 mm Hg during early morning (6:00 to 10:00 am ) compared with mean BP during the night. Clinical characteristics of patients with morning BP peak (MP+, n= 69, morning systolic BP=+54±4, diastolic BP=+32±5 mm Hg) did not differ from patients without BP peak (MP−, n= 87, morning systolic BP=+24±5, diastolic BP=+19±3 mm Hg). The daytime (10:00 am to 10:00 pm ) and the nighttime (10:00 pm to 6:00 am ) BP profile did not differ between the two groups. During daytime and nighttime ECG monitoring, the corrected QT (QTc) interval, and QTc dispersion did not differ significantly between the two groups, whereas during the morning period the QT values were significantly broader in the MP+ group compared with the MP− group ( P ≤0.001). Morning LF/HF ratio was significantly higher in MP+ patients than in MP− patients ( P ≤0.02). Both systolic and diastolic morning BP, in combination with ratio LF/HF power, were significant predictors of QTc dispersion (adjusted R ² =0.59, P ≤0.01) and QTc interval (adjusted R ² =0.41, P ≤0.01), whereas inclusion of physical activity and echocardiographic parameters did not add explanatory information. The prolongation of cardiac repolarization times and morning sympathetic overactivity coexist in hypertensive patients with morning BP peaks, and they might contribute to raised cardiovascular risk in these patients.

Chronic increases in blood flow increase arterial diameter and NO-dependent dilation in resistance arteries. Because endothelial dysfunction accompanies metabolic syndrome, we hypothesized that flow-mediated remodeling might be impaired in obese rat resistance arteries. Obese and lean Zucker rat mesenteric resistance arteries were exposed to chronic flow increases through arterial ligation in vivo: arteries exposed to high flow were compared with normal flow arteries. Diameter was measured in vitro in cannulated arteries using pressure arteriography. After 7 days, outward remodeling (diameter increased from 346±9 to 412±11 μm at 100 mm Hg) occurred in lean high-flow arteries. Endothelium-dependent tone was reduced in high-flow arteries from obese rats by contrast with lean animals. On the other hand, diameter enlargement occurred similarly in the 2 strains. The involvement of NO in endothelium-dependent dilation (evidenced by NO blockade) and endothelial NO synthase phosphorylation was smaller in obese than in lean rats. Superoxide anion and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunit expression (p67phox and gp91phox) increased in obese rats and were higher in high-flow than in control arteries. Acute Tempol (a catalase mimetic), catalase plus superoxide dismutase, and l -arginine plus tetrahydrobiopterin restored endothelium-dependent dilation in obese rat normal and high-flow arteries to the level found in lean control arteries. Thus, flow-induced remodeling in obese resistance arteries was associated with a reduced endothelium-mediated dilation because of a decreased NO bioavailability and an excessive superoxide production. This dysfunction might have negative consequences in ischemic diseases in patients with obesity or metabolic syndrome.

Heme oxygenase 1 is induced by hemodynamic forces in vascular smooth muscle and endothelial cells. We investigated the involvement of heme oxygenase 1 in flow (shear stress)-dependent remodeling. Two or 14 days after ligation of mesenteric resistance arteries, vessels were isolated. In rats, at 14 days, diameter increased by 23% in high-flow arteries and decreased by 22% in low-flow arteries compared with normal flow vessels. Heme oxygenase activity inhibition using Tin-protoporphyrin abolished diameter enlargement in high-flow arteries and accentuated arterial narrowing in low-flow arteries (32% diameter decrease versus 22% in control). Two days after ligation, heme oxygenase 1 expression increased in high-flow and low-flow vessels, in association with a reduced mitochondrial aconitase activity (marker of oxidative stress) in high-flow arteries only. Inhibition of macrophage infiltration (clodronate) decreased heme oxygenase 1 induction in low-flow but not in high-flow arteries. Similarly, inhibition of NADPH oxidase activity (apocynin) decreased heme oxygenase 1 induction in low-flow but not high-flow arteries. However, dihydroethidium staining was higher in high-flow and low-flow compared with normal flow arteries. In arteries cannulated in an arteriograph, heme oxygenase 1 mRNA increased in a flow-dependent manner and was abolished by N ^G -nitro- l -arginine methyl ester, catalase, or mitochondrial electron transport chain inhibition. Furthermore, heme oxygenase 1 induction using cobalt-protoporphyrin restored altered high-flow remodeling in endothelial NO synthase knockout mice. Thus, in high-flow remodeling, heme oxygenase 1 induction depends on shear stress–generated NO and mitochondria-derived hydrogen peroxide. In low-flow remodeling, heme oxygenase 1 induction requires macrophage infiltration and is mediated by NADPH oxidase–derived superoxide.

Angiotensin II is a potent growth factor involved in arterial wall homeostasis. In resistance arteries, chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy. Nevertheless, the role of angiotensin II in this remodeling is unknown. We investigated the effect of blocking angiotensin II production or receptor activation on flow-induced remodeling of mesenteric resistance arteries. Arteries were ligated in vivo to generate high-flow arteries compared with normal flow (control) vessels located at a distance. Arteries were isolated after 1 week for in vitro analysis. Arterial diameter, media surface, endothelial NO synthase expression, superoxide production, and extracellular signal–regulated kinase 1/2 phosphorylation were higher in high-flow than in control arteries. Angiotensin-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) prevented arterial wall hypertrophy without affecting diameter enlargement. The nonselective vasodilator hydralazine had no effect on remodeling. Although perindopril and candesartan increased endothelial NO synthase expression in high-flow arteries, hypertrophy remained in rats treated with N ^G -nitro- l -arginine methyl ester and mice lacking endothelial NO synthase. Perindopril and candesartan reduced oxidative stress in high-flow arteries, but superoxide scavenging did not prevent hypertrophy. Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high-flow vessels. Extracellular signal–regulated kinase 1/2 activation in high-flow arteries was prevented by perindopril and candesartan and not by hydralazine. Extracellular signal–regulated kinase 1/2 inhibition in vivo (U0126) prevented hypertrophy in high-flow arteries. Thus, a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide, whereas hypertrophy was associated with extracellular signal–regulated kinase 1/2 activation by angiotensin II.

Blood flow through healthy human vessels releases NO to produce vasodilation, whereas in patients with coronary artery disease (CAD), the mediator of dilation transitions to mitochondria-derived hydrogen peroxide ( _mt H ₂ O ₂ ). Excessive _mt H ₂ O ₂ production contributes to a proatherosclerotic vascular milieu. Loss of PGC-1α (peroxisome proliferator–activated receptor γ coactivator 1α) is implicated in the pathogenesis of CAD. We hypothesized that PGC-1α suppresses _mt H ₂ O ₂ production to reestablish NO-mediated dilation in isolated vessels from patients with CAD. Isolated human adipose arterioles were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the presence of PEG (polyethylene glycol)–catalase (H ₂ O ₂ scavenger) or L-NAME ( N ^G -nitro- l -arginine methyl ester; NOS inhibitor). In contrast to the exclusively NO- or H ₂ O ₂ -mediated dilation seen in either non-CAD or CAD conditions, respectively, flow-mediated dilation in CAD vessels was sensitive to both L-NAME and PEG-catalase after PGC-1α upregulation using ZLN005 and α-lipoic acid. PGC-1α overexpression in CAD vessels protected against the vascular dysfunction induced by an acute increase in intraluminal pressure. In contrast, downregulation of PGC-1α in non-CAD vessels produces a CAD-like phenotype characterized by _mt H ₂ O ₂ -mediated dilation (no contribution of NO). Loss of PGC-1α may contribute to the shift toward the _mt H ₂ O ₂ -mediated dilation observed in vessels from subjects with CAD. Strategies to boost PGC-1α levels may provide a therapeutic option in patients with CAD by shifting away from _mt H ₂ O ₂ -mediated dilation, increasing NO bioavailability, and reducing levels of _mt H ₂ O ₂ . Furthermore, increased expression of PGC-1α allows for simultaneous contributions of both NO and H ₂ O ₂ to flow-mediated dilation.

Abstract —Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 receptor developed for the treatment of hypertension. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the β-blocker atenolol on the reduction of cardiovascular morbidity and mortality. Patients with essential hypertension, aged between 55 and 80 years, and ECG-documented left ventricular hypertrophy (LVH) were included. Altogether, 9223 patients in Scandinavia, the United Kingdom, and the United States were randomized from June 1995 through April 1997, and 9194 remain after exclusion of a study center at which irregularities were discovered. This population of hypertensives (mean systolic/diastolic blood pressure, 174.4/97.8 mm Hg) with LVH comprises women (54.1%) and men, mostly retired from active work (mean age, 66.9 years), with a high prevalence of overweight (mean body mass index, 28.0 kg/m ² ), diabetes mellitus (12.3%), lipid disorders (18.0%), and symptoms or signs of coronary heart disease (15.1%). There were fewer current smokers (<17%) than in the general population, and ≈7% were nonwhite. Almost 30% of participants had been untreated for at least 6 months when screened for the study. Only 1557 persons who entered the placebo run-in period of 14 days were excluded, predominantly because of sitting blood pressures above or below the predetermined range of 160-200/95-115 mm Hg and ECG-LVH criteria not met. By application of simple 12-lead ECG criteria for LVH (Cornell voltage QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory), hypertensive patients with LVH with an average 5-year coronary heart disease risk of 22.3% according to the Framingham score were identified. This population is now being treated (goal, <140/90 mm Hg) in adherence with the protocol for at least 4 years after final enrollment (ie, through April 2001) and until at least 1040 patients suffer myocardial infarction, stroke, or cardiovascular death.

Abstract —Progression to failure in hypertension is associated with ventricular dilation, excessive myocyte lengthening, and an increase in myocyte length/width ratio. The temporal development of these changes in relation to impaired pump performance is unknown. We examined isolated myocytes from 1- to 12-month-old spontaneously hypertensive heart failure (SHHF) rats who develop heart failure at approximately 24 months of age. Left ventricular myocyte cross-sectional area reached a maximum of ≈350 to 400 μm ² at 3 months of age and did not change significantly thereafter. Nonetheless, LV systolic wall stress, a known stimulus for myocyte transverse growth, increased progressively between 3 and 12 months of age. Unlike the situation in normally aging rats with stable body mass, myocyte length in SHHF rats continued to increase with aging ( P <0.05 from 9 to 12 months of age). In summary, (1) left ventricular myocyte transverse growth reaches an upper limit by 3 months of age although systolic wall stress continues to rise; and (2) cell length is significantly increased by 12 months of age. This study suggests that maladaptive remodeling of cardiac myocyte shape begins long before pump failure in hypertension. Additionally, it appears that the left ventricle may be robbed of an important adaptive mechanism to normalize wall stress (eg, myocyte transverse growth) early in the progression to failure.

Cardiovascular disease is frequent in chronic kidney disease and has been related to angiotensin II, endothelin-1 (ET-1), thromboxane A ₂ , and reactive oxygen species (ROS). Because activation of thromboxane prostanoid receptors (TP-Rs) can generate ROS, which can generate ET-1, we tested the hypothesis that chronic kidney disease induces cyclooxygenase-2 whose products activate TP-Rs to enhance ET-1 and ROS generation and contractions. Mesenteric resistance arterioles were isolated from C57/BL6 or TP-R+/+ and TP-R−/− mice 3 months after SHAM-operation (SHAM) or surgical reduced renal mass (RRM, n=6/group). Microvascular contractions were studied on a wire myograph. Cellular (ethidium: dihydroethidium) and mitochondrial (mitoSOX) ROS were measured by fluorescence microscopy. Mice with RRM had increased excretion of markers of oxidative stress, thromboxane, and microalbumin; increased plasma ET-1; and increased microvascular expression of p22 ^phox , cyclooxygenase-2, TP-Rs, preproendothelin and endothelin-A receptors, and increased arteriolar remodeling. They had increased contractions to U-46,619 (118±3 versus 87±6, P <0.05) and ET-1 (108±5 versus 89±4, P <0.05), which were dependent on cellular and mitochondrial ROS, cyclooxygenase-2, and TP-Rs. RRM doubled the ET-1-induced cellular and mitochondrial ROS generation ( P <0.05). TP-R−/− mice with RRM lacked these abnormal structural and functional microvascular responses and lacked the increased systemic and the increased microvascular oxidative stress and circulating ET-1. In conclusion, RRM leads to microvascular remodeling and enhanced ET-1-induced cellular and mitochondrial ROS and contractions that are mediated by cyclooxygenase-2 products activating TP-Rs. Thus, TP-Rs can be upstream from enhanced ROS, ET-1, microvascular remodeling, and contractility and may thereby coordinate vascular dysfunction in chronic kidney disease.

Sodium transport in epithelial tissues is regulated by the physiological mineralocorticoid aldosterone. The response to aldosterone is mediated by the mineralocorticoid receptor (MR), for which the crystal structure of the ligand-binding domain has recently been established. The classical mode of action for this receptor involves the regulation of gene transcription. Several genes have now been shown to be regulated by aldosterone in epithelial tissues. Of these, the best characterized is serum- and glucocorticoid-regulated kinase, which increases sodium influx through the epithelial sodium channel. Turnover of these channels in the cell membrane is mediated by Nedd4–2, a ubiquitin protein ligase; serum- and glucocorticoid-regulated kinase interacts with and phosphorylates Nedd4–2, thereby rendering it unable to bind the sodium channels. In nonepithelial tissues, particularly the cardiovascular system, aldosterone also has direct effects, activating an inflammatory cascade, leading to cardiac fibrosis. A critical role for the MR in cardiovascular disease has now been demonstrated by the beneficial response to MR blockade in 2 large clinical trials in patients with cardiac failure. It is these nonepithelial actions of MR activation that need to be exploited for the development of antagonists that target the cardiovascular system while avoiding the undesirable side effects of renal MR blockade.