bluuebunny/crossref_metadata_2025 huggingface dataset:
Diuretic agents versus beta-blockers. Comparison of effects on mortality, stroke, and coronary events.
Authors: Furberg C D , Cutler J A
Published: August 2012

Three recently concluded large randomized clinical trials have compared the preventive effects of diuretic agents and beta-blockers in the treatment of approximately 22,000 subjects with hypertension. In the Medical Research Council trial, bendrofluazide (10 mg daily) was compared with a dose of propranolol (as much as 240 mg daily), a nonselective beta-blocker without intrinsic sympathomimetic activity. Two selective beta-blockers, atenolol (100 mg daily) and metoprolol (200 mg daily), were compared with bendrofluazide (5-10 mg daily) and hydrochlorothiazide (50-100 mg daily) in the Heart Attack Primary Prevention in Hypertension trial. In the International Prospective Primary Prevention Study in Hypertension, 160 mg of slow-release oxprenolol, a beta-blocker with intrinsic sympathomimetic activity, was compared with a diuretic-based regimen not containing beta-blockers. In each trial, similar reductions in mean diastolic blood pressure were achieved with diuretic and beta-blocker treatment that lasted for several years. All-cause mortality and fatal and nonfatal stroke and coronary event rates were also similar in the treatment groups. Thus, it appears that beta-blockers are as effective as diuretic agents in improving survival and in preventing major morbid events. Regarding cigarette smoking and stroke incidence, observations based on post hoc subgroup analyses of the Medical Research Council trial were not supported by subgroup findings in the Heart Attack Primary Prevention in Hypertension and the International Prospective Primary Prevention Study in Hypertension trials, and these observations should not form the basis for any treatment recommendations.
Diuretic agents and beta-blockers in the treatment of hypertension.
Authors: Dollery C
Published: August 2012

Benzothiadiazine diuretic agents and beta-adrenergic receptor-blocking drugs are two of the main groups of drugs used to treat mild hypertension. Recently, questions have been raised about their relative efficacy in preventing morbidity and mortality from vascular disease in addition to their effect on lowering blood pressure. Attention has been focused on the unfavorable metabolic effects of diuretic drugs and the proven value of beta-adrenergic receptor blockade in secondary prevention after myocardial infarction. Four randomized controlled trials comparing drugs in these two classes have been published: the Medical Research Council trial, the International Prospective Primary Prevention Study in Hypertension, the Heart Attack Primary Prevention in Hypertension trial, and the Metoprolol Atherosclerosis Prevention in Hypertension study. These trials, especially that of the Medical Research Council, have raised some questions about the relative efficacy of these two classes of drugs in preventing stroke in smokers and nonsmokers. Overall, there is little evidence of a reduction in morbidity and mortality after myocardial infarction. The predicted advantage of beta-adrenergic receptor blockade over diuretic therapy has not been realized although there are sufficient hints of a differential benefit to encourage the performance of further trials.
Potential impact of exclusion criteria on results of hypertension trials.
Authors: Remington R D
Published: August 2012

Recent trials of antihypertensive therapy, including the Veterans Administration trials, the Hypertension Detection and Follow-up Program, the Multiple Risk Factor Intervention Trial, the Australian Mild Hypertension Trial, and the British Medical Research Council Trial, are reviewed with a particular emphasis on the criteria leading to the exclusion of potentially eligible participants. The observation of all-cause and cause-specific mortality rates in the group ultimately selected to participate in the trial is suggested as an index to the general applicability of trial results. Because end-point rates are fundamental for determining sample size, substantial reduction in these end-point rates by patient exclusion should be taken into account by the trial design. Some recent trials may have generated end-point-event rates so low that the power of the trial to detect reasonable treatment effects was substantially reduced. Future trials should attempt to take this important factor into account at the design stage.
Epidemiology of blood pressure and predictors of hypertension.
Authors: Horan M J , Lenfant C
Published: August 2012

Hypertension is a clinical disease with a prevalence sufficiently high in acculturated societies to warrant it being designated a serious public health problem. In population studies, blood pressure has been found to be a continuously distributed risk variable with mortality directly related to the level of blood pressure. Thus, hypertension is both a disease and a risk factor. Classic genetic studies suggest that the predisposition for the development of hypertension is an inherited trait that becomes manifest when coupled with one or more environmental insults. Risk factors for hypertension include age, weight, sedentary lifestyle, excessive dietary sodium intake, and excessive alcohol intake. Current and future research is being directed toward the identification of predictors of hypertension that can be conceptualized according to demographic, clinical, genetic, challenge-response, and laboratory predictors. The intent is to identify subjects with a high probability for the development of hypertension in advance of the rise in blood pressure so that appropriate interventions can be implemented as early as possible.
Hypertension research. The next five years.
Authors: Horan M J , Mockrin S C
Published: August 2012

Hypertension is both a disease and a risk factor. Long-term research objectives are to understand blood pressure homeostasis and the pathogeneses of the various forms of hypertension. Short-term research objectives center around enhancing methods for detection, evaluation, treatment, and control of high blood pressure because, even in the absence of precise knowledge of the etiology of hypertension, its control results in substantial reductions in morbidity and mortality. Therefore, a multifaceted national research strategy has been developed that includes basic science, applied research, clinical research, clinical trials, and demonstration and education research approaches. Complementing this research strategy is a congressionally mandated program to facilitate the application of the products of research to the clinical care setting by promoting educational activities aimed at health care providers, patients, and consumers.
Rapid resetting of the baroreceptors in renal hypertensive rats.
Authors: Moreira E D , Ida F , Oliveira V L , Krieger E M
Published: August 2012

The characteristics and extent of rapid or acute resetting of the aortic baroreceptors were studied in long-term renal hypertensive rats during 30 minutes of sustained hypertension produced by phenylephrine infusion. The aortic baroreceptors of hypertensive rats exhibited complete resetting to hypertension because during the control period the systolic threshold pressure for activation of the baroreceptors was similar (137 +/- 5 vs. 142 +/- 4 mm Hg) to the control diastolic pressure. Five minutes after onset of hypertension, a resetting of 32% (percent change of mean pressure threshold divided by total change of mean pressure) was demonstrable. The extent of resetting was 39%, 38%, and 41% after 10, 20, and 30 minutes of hypertension, respectively. When the percent change of systolic threshold pressure divided by total change of control diastolic pressure was used to calculate the extent of resetting, similar results were obtained. The extent of displacement of the entire baroreceptor pressure-response curves was similar to that of pressure thresholds. Reversibility of the resetting process was not complete within 30 minutes of pressure normalization after the administration of phenylephrine was interrupted. These data indicate that the characteristics and extent of rapid resetting of the baroreceptors of renal hypertensive rats, which were reset to operate at hypertensive levels, are similar to those previously described in normotensive rats.
Angiotensin II as a modulator of baroreceptor reflexes in the brainstem of conscious rats.
Authors: Michelini L C , Bonagamba L G
Published: August 2012

The effect of microinjection into the nucleus tractus solitarii (NTS) of angiotensin II (Ang II) on baroreceptor control of heart rate (HR) in conscious, freely moving rats was evaluated with a new method of long-term cannulation of the dorsal brainstem areas. Reflex changes in HR were produced by intravenous bolus injections of either phenylephrine or sodium nitroprusside (0.2-25.6 micrograms/kg) both after saline and after unilateral microinjection of Ang II into the NTS (24 ng, 0.2 microliter) and compared with those produced after administration of Ang II into the fourth ventricle (24 ng, 0.2 microliter) or intravenously (1-2 ng/kg/min). Baseline levels of mean arterial pressure (MAP) and HR were not affected by the route of Ang II application but reflex bradycardia during MAP increase was significantly attenuated after injections of Ang II into the NTS. Both the slope and the intercept of the regression line function between delta HR and delta MAP were reduced by 43% from the control value of -1.55 +/- 0.13 beats/min/mm Hg (p less than 0.01) and -14 +/- 5 beats/min (p less than 0.05), respectively. Similar reductions were observed after Ang II administration into the fourth ventricle or intravenously, although microinjections into the cerebellum produced no effect. Endogenous blockade of Ang II by saralasin (22 ng) in the NTS facilitated the bradycardic response (-2.29 +/- 0.91 beats/min/mm Hg). Nitroprusside-induced tachycardia was not altered by Saralasin microinjection into the NTS or by Ang II application to the NTS, fourth ventricle, or intravenously.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of enalaprilic acid on cardiac contractile response to beta-adrenergic stimulation.
Authors: Gomez Llambi H , Taquini C M , Mazzadi A , Gallo A , Fontan M , Taquini A C
Published: August 2012

Studies in two-kidney--one clip hypertensive rats have demonstrated that long-term treatment with enalapril induced regression of cardiac hypertrophy, but the cardiac contractile response to beta-adrenergic stimulation remained depressed. In the present study, we evaluate the contractile response to beta-adrenergic stimulation of isolated papillary muscle in normal rats with isoproterenol (10(-11) M to 10(-4) M) in the presence of enalaprilic acid (10(-6) M or 10(-4) M) or enalaprilic acid (10(-4) M) and angiotensin II (10(-6) M). Myocardial contractility was characterized by maximal developed tension and maximal rate of rise of tension (+T), and the relaxant effect of isoproterenol by the ratio of (+T), and the maximal velocity of relaxation (-T)(+T/-T ratio). The rest tension (g/mm2) and the cross-sectional area (mm2) were similar in all the muscles studied. Enalaprilic acid (either 10(-6) M or 10(-4) M) in the bath did not induce any change in contractile and relaxation parameters. The increment in +T and -T (expressed as percentage) in response to cumulative doses of isoproterenol (10(-11) M to 10(-4) M) was significantly depressed in the presence of enalaprilic acid (10(-4) M) when compared with control hearts in which only vehicle was added before isoproterenol (p less than 0.05). The addition of angiotensin II after enalaprilic acid (10(-4) M) did not normalize the response in +T and -T. Enalaprilic acid diminishes the contractile response of the papillary muscle to beta-adrenergic stimulation. The inhibition of the local angiotensin II does not seem to be involved in this result.
Effects of systemic hypertension, antidiuretic hormone, and prostaglandins on remnant nephrons.
Authors: Bregman R , Boim M A , Santos O F , Ramos O L , Schor N
Published: August 2012

Renal function was evaluated in normal and after 30 days of 5/6 renal mass reduction (CRF) in Munich-Wistar (MW) rats, spontaneously hypertensive rats with superficial glomeruli (EPM), and in Brattleboro rats with congenital diabetes insipidus (DI). Mean arterial pressure was higher in EPM-Control and EPM-CRF rats as compared with MW and DI rats. MW and EPM rats with CRF showed increases of 120% and 196%, respectively, in single nephron glomerular filtration rate as compared with their controls. However, DI rats with CRF did not show any increase in single nephron glomerular filtration rate as compared with the control group. Therefore, the data suggest that the presence of hypertension enhances the adaptive mechanisms on remnant kidney's function. Conversely, in the absence of antidiuretic hormone, adaptive mechanisms of remnant nephrons did not occur. In addition, it was observed that rats with CRF submitted to prostaglandin blockade with indomethacin showed for MW rats a 55% and 20% reduction in ultrafiltration coefficient and in single nephron glomerular filtration rate, respectively. Decreases of 60% and 30% in ultrafiltration coefficient and single nephron glomerular filtration rate, respectively, were observed for EPM rats. In contrast, DI rats did not show any alteration on renal function after indomethacin. It seems, therefore, that prostaglandins play a role in remnant nephron function of MW and EPM rats, but in the absence of antidiuretic hormone, prostaglandins do not affect remnant glomerular hemodynamics.
Methodology of sodium sensitivity assessment. The example of age and sex.
Authors: Grobbee D E
Published: August 2012

This article addresses the methodology of sodium sensitivity assessment. There have been reports to suggest that a high sodium intake is a cause of elevated blood pressure and trials to indicate that a reduction in sodium intake may reduce blood pressure that is already high; the implications of these findings are discussed. Many studies on sodium sensitivity suffer from what could be called the "normal probability fallacy"; without appropriate control conditions, an intervention such as sodium restriction may incorrectly be assigned to a more pronounced response in a subgroup of the study population. As an example, findings are reviewed of age and sex as determinants of a response of blood pressure to variations in sodium intake. The limited data available suggest that subjects that are older and have higher blood pressure levels seem to benefit more from a reduction in sodium intake. In addition, elderly subjects at a high dietary sodium intake may have a higher risk of developing hypertension. Findings in both nonexperimental and experimental studies tend to support this view. Findings on sex differences are less consistent. A systematic approach to the assessment of factors and mechanisms responsible for sodium sensitivity in some subjects is needed to determine who might benefit most. Until more data are available, there is little basis to discriminate sodium-sensitive from sodium-resistant hypertensive subjects.
Behavioral aspects of intervention strategies to reduce dietary sodium.
Authors: Kumanyika S
Published: August 2012

This article addresses general and specific aspects of dietary sodium interventions from the perspective of behavioral change. Changing dietary behavior requires relearning a range of habitual behaviors involved in day-to-day eating situations in the context of a diverse and complex food supply and in consideration of numerous factors, other than health concerns, that influence habitual eating patterns. Potential obstacles to dietary sodium reduction relate to the wide distribution of sodium in foods, the strong cultural values for salt, and the difficulty of assessing success in sodium reduction. A review of sodium interventions reported in the literature suggests that state-of-the-art behavioral change strategies can be effective in achieving reductions in sodium intake to around 3,000 mg/day but that this level is achieved only with highly motivated individuals and when a high level of intervention (i.e., intensive and multifaceted) is provided. Thus, in regard to sodium reduction in the general population, either the goal will have to be modest or the food supply will have to change so that substantial decreases in sodium intake can be accomplished with less intensive and less costly interventions.
Salt and hypertension--future directions.
Authors: Cowley A W
Published: August 2012

The comments that follow reflect the personal views of this author regarding some useful directions of research in the field of salt and hypertension. From a physiological perspective, salt sensitivity is defined, and the merits and limitations of certain animal models of hypertension used to study this issue are discussed. The need to more clearly define the mechanisms that detect sodium intake and control the renal excretion of sodium is discussed. Additionally, the need to better understand the relation between sodium homeostasis, volume regulation, and the consequences of dysfunction in these regulatory system on the arterial vasculature and interstitial matrix is emphasized. The necessity for the application of new tools and approaches in a number of investigative areas is discussed. Finally, the necessity of equally imaginative whole animal and cell/molecular research and efforts to merge and integrate the data obtained at the cellular level with that of intact systems is emphasized.
Sodium chloride raises blood pressure in normotensive subjects. The study of sodium and blood pressure.
Authors: Mascioli S , Grimm R , Launer C , Svendsen K , Flack J , Gonzalez N , Elmer P , Neaton J
Published: August 2012

The effects of dietary sodium on blood pressure in normotensive adults is not well characterized. The Study of Sodium and Blood Pressure (SNaP) is a randomized, double-blind crossover trial using a placebo or 96 meq sodium in 4-week treatment periods separated by a 2-week washout period. Before capsule treatment periods, participants were instructed in a low sodium diet for 10 weeks to reduce urinary sodium excretion to less than 35 meq/8 hr. The low sodium diet was continued throughout the capsule treatment periods. Participants (n = 48; 47 white, 1 black) were 79% male and had an average age of 52 years, a body mass index of 27.6, and a baseline blood pressure of 131/84 mm Hg. Baseline overnight urinary sodium excretion was 51 meq/8 hr and 19 meq/8 hr after the low sodium diet run-in period, before the capsule treatment periods began. Resting, seated blood pressure was measured twice at each visit in a standard fashion. Differences between sodium and placebo treatment periods were as follows: systolic blood pressure, 123.9 versus 120.3 mm Hg, respectively (p less than 0.001); diastolic blood pressure, 78.7 versus 76.4 mm Hg, respectively (p = 0.005); and sodium excretion, 51.3 versus 30.9 meq/8 hr, respectively (p less than 0.001). Both systolic and diastolic blood pressures increased significant amounts in normotensive adults on a low sodium diet supplemented with 96 meq/day sodium. Long-term effects and dose-response relations need further study.
An overview of randomized trials of sodium reduction and blood pressure.
Authors: Cutler J A , Follmann D , Elliott P , Suh I
Published: August 2012

To test for effects on systolic and diastolic blood pressure and to provide precise estimates of their magnitude, we conducted an overview of randomized clinical trials that aimed to reduce the intake of sodium in human subjects. We excluded from pooled analyses trials with confounded designs, those that compared intake levels beyond the usual range in the population, and those without published reports. Two reviewers abstracted information in duplicate and differences were reconciled. Twenty-three trials with outcome data from an aggregate of 1,536 subjects were included. Data were pooled both separately for hypertensive and normotensive subjects and for all trials combined. With the use of sample size weighting, blood pressure reductions (net of controls) were 4.9 +/- 1.3/2.6 +/- 0.8 mm Hg (systolic and diastolic, respectively, with 95% confidence limits) in hypertensive subjects and 1.7 +/- 1.0/1.0 +/- 0.7 mm Hg in normotensive subjects. The combined blood pressure reductions were 2.9 +/- 0.8/1.6 +/- 0.5 mm Hg. These changes were associated with mean reduction of urinary sodium excretion ranging from 16 to 171 mmol/24 hr for individual trials. A dose-response relation across trials was found, both in normotensive and in hypertensive subjects. These results indicate that sodium reduction lowers mean blood pressure in both hypertensive and normotensive individuals for periods of at least several months. The findings are highly consistent with results of observational epidemiological studies and have implications for preventive strategies of blood pressure control.
Observational studies of salt and blood pressure.
Authors: Elliott P
Published: August 2012

The observational data relating salt and blood pressure (excluding INTERSALT) are reviewed. Important methodological difficulties and biases are inherent to both across- and within-population studies and confuse their interpretation. Across-population studies are positive but rely on data drawn from the international literature based on a variety of unstandardized field methods; they are prone to unmeasured (ecological) confounding. Within-population studies generally lack statistical power and are subject to major regression-dilution bias (because of considerable day-to-day variation in sodium intake), which could conceal true correlations between sodium and blood pressure. Nevertheless, an overview of reported studies that used 24-hour urine excretion to quantify intake shows positive and highly significant correlations between sodium and blood pressure for both men and women and for systolic and diastolic blood pressures. These results are consistent with the INTERSALT findings and those from trials of sodium restriction.
Neurovascular mechanisms and sodium balance in the pathogenesis of hypertension.
Authors: Brum J M , Tramposch A F , Ferrario C M
Published: August 2012

Physiological studies have clarified the role that the brain has in the interplay between salt balance and hypertension. Neural mechanisms and endocrine secretions play a pivotal role in the adaptation of mammals to changes in the intake and excretion of sodium. Maneuvers that alter the concentration of sodium in the plasma modify the sensitivity of baroreceptor reflexes and alter vascular reactivity. These changes may be mediated in part by the release of vasopressin. The research also suggests that the brain indirectly modulates the ability of the vascular endothelium to release vasoactive factors. Collectively, these studies illustrate the multiple effects of the sodium ion on the peripheral neural and central endocrine mechanisms that participate in the regulation of arterial pressure.
Findings of the International Cooperative INTERSALT Study.
Authors: Stamler J , Rose G , Elliott P , Dyer A , Marmot M , Kesteloot H , Stamler R
Published: August 2012

INTERSALT, an international cooperative study on electrolytes and other factors related to blood pressure, found, in within-population analyses involving 10,079 persons, a significant positive association between 24-hour urinary sodium excretion and systolic blood pressure and between the sodium/potassium ratio and systolic blood pressure. These significant findings were derived from analyses for individuals from all 52 centers and from the 48 centers remaining when persons from four low sodium centers were excluded. Potassium excretion of individuals was significantly and independently related inversely to their systolic blood pressure. For men and women, both separate and combined, the relation between sodium and systolic blood pressure was stronger for older than younger adults, perhaps reflecting the result of longer exposure with age or diminished capacity to handle a sodium load. Relations between electrolyte excretion and diastolic blood pressure in individuals were weaker than for systolic blood pressure. Body mass index and heavy alcohol consumption of individuals were strongly and independently related to blood pressure. In cross-population analyses with n = 52 or n = 48, sample median sodium excretion was significantly and independently related to the slope of systolic blood pressure and diastolic blood pressure with age. Other ecological analyses yielded inconsistent results. Four isolated populations showed low sodium excretion, low sodium/potassium excretion, low body mass index, and low alcohol consumption; sample median blood pressures were low, there was little or no upward slope of blood pressure with age, and high blood pressure was rare or nonexistent.
Dietary salt and blood pressure. A perspective.
Authors: Pecker M S , Laragh J H
Published: August 2012

Although dietary salt restriction is often valuable as sole or adjunctive therapy of hypertensive disorders, it is abundantly clear that hypertensive patients comprise a heterogeneous group with regard to salt sensitivity of blood pressure. This is apparent despite the many methodological obstacles to defining salt sensitivity in an individual patient. Currently, dietary trial is the only sure means of defining a given patient as responsive to salt restriction. Easily definable markers of salt sensitivity would allow appropriate targeting of this rather ponderous therapy. Promising leads include the assessment of membrane ion transporters such as sodium-lithium exchange and of the activity of the renin-angiotensin system, including the phenomenon of "non-modulating" hypertension and other volume regulatory hormones such as atrial natriuretic factor. Although less intensively studied than in hypertensive patients, the blood pressure response of normal subjects to salt restriction is also marked by great variability. Given the possibility of deleterious consequences of population-wide salt restriction for at least some people in a setting such as the United States, it seems imprudent to recommend such a policy before its proven worth has been demonstrated by clinical trial. Pending such evidence and the development of markers, salt restriction should be reserved for those in whom it is of demonstrated efficacy.
Systolic Hypertension of the Elderly Program (SHEP). Part 10: Analysis.
Authors: Wittes J , Davis B , Berge K , Cohen J D , Grimm R H , Hawkins C M , Kuller L
Published: August 2012

The SHEP is a randomized, placebo-controlled trial that will follow standard clinical trial principles in analyzing data relating to its proposed hypotheses. The protocol has stated a priori the main objective as well as the secondary subgroup hypotheses. Sample size calculations for SHEP have accounted for dropins to and drop-outs from active therapy as well as for the risk of nonstroke death. The sample size achieved (4,736 participants) should be adequate to address the proposed questions. Monitoring procedures have been described and established. A data and safety monitoring board that uses these procedures is closely following the data from the trial. The board will periodically examine the data to determine whether termination of the study is warranted.
Biochemical evidence of sympathetic hyperactivity in human hypertension.
Authors: Esler M , Ferrier C , Lambert G , Eisenhofer G , Cox H , Jennings G
Published: August 2012

Radiotracer measures of norepinephrine overflow to plasma are well suited for studying both human sympathetic nervous system responses to mental stress and sympathetic nervous pathophysiology in human hypertension. With an experimental laboratory stressor (cognitive challenge), we noted a preferential activation of the cardiac sympathetic outflow; however, in fainting reactions ("vasovagal syncope"), which occur infrequently during the course of central venous catheter placement under local anesthesia, the converse was seen--an almost total withdrawal of cardiac sympathetic activity. In primary human hypertension (particularly in younger patients), a differentiated activation of the sympathetic outflow to the heart and kidneys is present, based on measurements of norepinephrine spillover to plasma. It is uncertain whether this is attributable to behavioral factors and represents a component of the defense reaction. We previously reported overflow of norepinephrine into the cerebrovascular circulation (with high internal jugular venous sampling) in humans. Because this is resistant to ganglion blockade, brain neurons--not the cerebrovascular sympathetics--are the presumed source. In a preliminary study, we found higher rates of norepinephrine spillover into the cerebrovascular circulation in patients with essential hypertension than in healthy subjects, suggesting that an underlying increase in central nervous system norepinephrine turnover may be the basis for the increased sympathetic outflow.
Stress management in the treatment of mild primary hypertension.
Authors: Johnston D W
Published: August 2012

The use of simple relaxation-based stress management procedures in the treatment of mild primary hypertension has been the subject of extensive study. Stress management appears to lead to reliably greater reductions in pressure than a variety of control procedures. The mechanisms underlying these effects are obscure, and research has not identified which patients will benefit most from treatment. Preliminary data suggest that stress management may reduce the risk of coronary heart disease, but much research must be done if this is to be confirmed. It is suggested that such research should take into account the possibility that stress management may have beneficial effects on more than just hypertension-related aspects of the cardiovascular disease process.
Hemodynamic determinants of vascular changes in hypertension and atherosclerosis.
Authors: Heistad D D , Lopez J A , Baumbach G L
Published: August 2012

Several new concepts are reviewed concerning structural and functional changes in atherosclerotic and hypertensive blood vessels. First, in regard to modulation of vascular changes, atherosclerosis appears to progress more slowly during hypotension than during normotension. This finding may have implications for the optimal level of blood pressure. Second, structural "remodeling" of the vessel wall occurs in both atherosclerosis and hypertension. Remodeling helps to preserve the arterial lumen despite intimal proliferation in atherosclerosis. In contrast, remodeling (which differs from vascular hypertrophy) reduces the vascular lumen in chronic hypertension. Third, functional changes impair active vasodilator responses in both atherosclerotic and hypertensive vessels, in part by endothelium-dependent mechanisms. Finally, we propose that leukocytes as well as platelets may be important cellular mediators of spasm in atherosclerotic arteries.
Insulin resistance and hypertension.
Authors: Slater E E
Published: August 2012

While clinicians have long recognized the apparent increased prevalence of hypertension among diabetics, sophisticated epidemiological analyses begun in the early 1970s have established that hypertensive individuals are more prone to hyperinsulinemia and glucose intolerance than normotensive individuals. Subsequently, the several hypertensinogenic effects of insulin were carefully studied in a number of laboratories. Most recently, the association of these two relatively common cardiovascular risk factors, hypertension and insulin resistance, was broadened to include lipid abnormalities, namely, increased concentrations of very low density lipoprotein triglycerides and decreased concentrations of high density lipoprotein cholesterol. These abnormalities, all of which appear in association more commonly than would be expected by chance, clearly predispose affected individuals to increased cardiovascular risk. This review summarizes our current understanding of the mechanisms underlying the relations between insulin resistance and hypertension and focuses discussion on the role of insulin as a common link between them. It concludes with recommendations, based on today's knowledge, for behavioral and therapeutic interventions aimed at the prevention of increased cardiovascular risk.
Hypertension and coronary artery disease. Can the chain be broken?
Authors: Dunn F G , Pringle S D
Published: August 2012

Hypertension is an established risk factor for all the clinical sequelae of coronary artery disease. Despite this, individual therapeutic trials of antihypertensive therapy have not demonstrated the expected reduction in coronary morbidity and mortality. This apparent failure is perhaps not surprising when one considers the multifactorial nature of coronary artery disease and the different ways in which hypertension may affect the coronary circulation. Much debate has also centered on the antihypertensive therapy used in major trials in that it may in some way prevent the reduction in coronary mortality. However, thus far no clear evidence of a harmful effect has emerged. Reducing coronary mortality in hypertensive patients is a major challenge but one that can be effectively surmounted by approaching these different factors in a concerted manner. The ultimate goal must be to prevent the development of hypertension and left ventricular hypertrophy, but until such time as that can be achieved, the early detection of hypertension is mandatory. The optimal levels of systolic and diastolic blood pressures must be established. Studies on the more recent antihypertensive agents hold promise for a more specific effect on the atherosclerotic process as well as sustained control of arterial blood pressure. In this regard, it would seem essential to develop more precise ways of quantifying atherosclerosis and thus clarifying the nature of its relation to hypertension. Finally, management of hypertension must include precise assessment of the patient's overall cardiovascular risk status and appropriate and aggressive management of all risk factors for coronary artery disease.
Long-term effectiveness of nonpharmacological treatment of hypertension.
Authors: Kaplan N M
Published: August 2012

Various nonpharmacological therapies reduce the blood pressure of a significant portion of both patients with established hypertension and people who are considered to be at high risk for the development of hypertension; that is, they are secondary and primary preventions. Of the various therapies, weight reduction, sodium restriction, moderation of alcohol intake, and regular aerobic exercise have been shown to be most effective, whereas the effectiveness of other practices has been less uniform or smaller in degree. Changes in lifestyle, mainly involving diet and physical activity, should be widely used to treat and, hopefully, to prevent hypertension.
Dissecting the primary causes of genetic hypertension in rats.
Authors: Rapp J P
Published: August 2012

Blood pressure has a genetic component influenced by several to many genetic loci in both humans and animals; that is, blood pressure is a polygenic trait. Ultimately, the primary causes of genetic hypertension can only be established with genetic techniques. The primary tools for this analysis in animals are inbred strains of rodents selectively bred for differences in blood pressure and the genetic analysis of these strains by cosegregation techniques. This analysis determines whether it is possible to separate specific alleles at a candidate genetic locus from a component of blood pressure in genetically segregating populations. If the candidate alleles cosegregate with a component of blood pressure, these alleles must be the cause of the blood pressure differences or be linked on the same chromosome to alleles at other loci that cause blood pressure differences. If, on the other hand, the candidate alleles do not cosegregate with blood pressure, they cannot be the cause of the blood pressure differences. This analysis is straightforward in the case of a single-locus Mendelian candidate trait but is less informative if a candidate trait is itself polygenic. In this case, genetic analysis yields either 1) results that are compatible with, but not definitive proof for, a genetic role of the trait in causing blood pressure differences or 2) results that eliminate the trait as a cause of genetic differences in blood pressure. A complete listing of all the traits that have undergone genetic cosegregation analysis in rodents is given.
Are there interactions and relations between genetic and environmental factors predisposing to high blood pressure?
Authors: Williams R R , Hunt S C , Hasstedt S J , Hopkins P N , Wu L L , Berry T D , Stults B M , Barlow G K , Schumacher M C , Lifton R P
Published: August 2012

An overview of published observations suggests that both genetic predisposition and environment work together to produce hypertension in most persons. High blood pressure before age 55 occurs 3.8 times more often among persons with a strong positive family history of high blood pressure. Much of the total variability in blood pressure in modern populations seems attributable to genetic factors. Estimates of the proportion of the variance attributable to all genetic factors (heritability [H2]) vary from 25% in pedigree studies to 65% in twin studies for sitting diastolic blood pressure. Several biochemical traits associated with high blood pressure are highly genetic (H2, 78-84%) and may help elucidate the pathophysiology of high blood pressure. While pertinent environmental factors such as salt intake, alcohol use, and amount of exercise also correlate significantly among relatives, only 7% of the total variance of diastolic blood pressure seems attributable to all shared environmental factors in family households. Thus most familial aggregation of high blood pressure appears to be due to genes rather than shared family environment. Practical benefit may result from identifying familial predisposition in multiple siblings with high blood pressure before age 55 and lipid abnormalities (labeled "familial dyslipidemic hypertension"). About 12% of high blood pressure patients have familial dyslipidemic hypertension and also have high risk of early coronary heart disease. Hyperinsulinemia and central obesity as well as high triglycerides and low high density lipoprotein cholesterol are prominent features of familial dyslipidemic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Childhood predictors of future blood pressure.
Authors: Lauer R M , Burns T L , Clarke W R , Mahoney L T
Published: August 2012

Blood pressure in infants and children is much lower than that in adults. It is suspected that children whose blood pressures are greatest for their age or body size may be destined for future hypertension. However, it is apparent that some children with lower blood pressures are also destined for hypertension as adults. Children with a family history of hypertension demonstrate greater blood pressure and heart rate responses to mental challenge. These responses are enhanced when a high salt diet is consumed. Increased maximal exercise systolic blood pressure and increased left ventricular wall mass in childhood add significantly to the prediction of future high blood pressure. In addition, the acquisition of excess weight for height from childhood to young adult life adds to the prediction of future blood pressure elevations. Both children and adults who are obese have significantly higher blood pressures than those who are lean. Approximately 34% of the variability in body mass index is explained by genotype differences at a single recessive locus, 41% by genotype differences at polygenic loci, and 25% by nongenetic factors. Thus, the genetic influence of obesity may be an important factor responsible for elevated blood pressure in both children and adults.
Can essential hypertension be subclassified with respect to mechanism?
Authors: Weinberger M H
Published: August 2012

Hypertension may result from a variety of abnormalities. The rise in blood pressure may trigger other secondary events that further influence cardiovascular homeostasis. The ability to measure some markers associated with hypertension or the responsiveness of blood pressure to nutritional interventions or to specific therapeutic agents may also have pathogenetic implications. The ultimate goal of further knowledge in this area should be to understand the fundamental abnormalities responsible for hypertension. Such insight would permit more effective treatment and, perhaps, primary prevention of this ubiquitous and multifaceted disorder.
Molecular mechanisms of vascular renin-angiotensin system in myointimal hyperplasia.
Authors: Dzau V J , Gibbons G H , Pratt R E
Published: August 2012

Angiotensin II has been shown by many investigators to be a potent growth factor for vascular smooth cells in culture as well as in vivo. Depending on the conditions, the response of these cells is either hypertrophy or hyperplasia. These observations have important clinical implications, because it has been shown that angiotensin II participates in the hypertrophic response of the vessel wall during hypertension and the hyperplastic response after balloon angioplasty. Thus, an understanding of the molecular mechanism of these responses is important in the development of potential treatment strategies. This review examines the evidence for the growth-promoting properties of angiotensin II, concentrating on these molecular mechanisms. Hypotheses are presented that may explain the bifunctional effects (hypertrophy versus hyperplasia) of angiotensin II. These hypotheses revolve around the interaction of angiotensin with endothelium- and smooth muscle cell-derived products. These autocrine and paracrine interactions play important roles in the modulation of vascular structure.
Mechanism of action of angiotensin converting enzyme inhibitors on endothelial function in hypertension.
Authors: Clozel M
Published: August 2012

Hypertension is associated with an endothelial dysfunction characterized by an increased endothelium-dependent contraction and a decreased endothelium-dependent relaxation. Angiotensin converting enzyme (ACE) inhibition with cilazapril or captopril can remarkably improve the endothelial function in spontaneously hypertensive rats (SHRs). The goal of the present study was to investigate whether ACE inhibitors were acting by decreasing endothelium-dependent contraction or by increasing endothelium-dependent relaxation. Endothelial function was estimated by calculating the ratio of maximal contraction to serotonin on isolated aortic rings with endothelium to maximal contraction on paired rings without endothelium, termed the serotonin ratio. The serotonin ratio was greater than 1 in SHRs, indicating the release of a vasoconstrictor substance by the endothelium. This substance was identified as prostaglandin (PG) H2, because the serotonin ratio was significantly decreased by thromboxane (TX) A2/PGH2 receptor antagonists but not by TXA2 synthetase inhibitors. Two weeks of treatment of SHRs with cilazapril led to a marked decrease in the serotonin ratio, although acute administration of cilazaprilat was without any effect. However, after 2 weeks of treatment, the serotonin ratio still could be lowered further by TXA2/PGH2 receptor antagonists, indicating that cilazapril did not act by inhibition of PGH2 synthesis. In contrast, the effect of a 4-week treatment with cilazapril could be completely reversed by inhibiting the action of endothelium-derived relaxing factor with methylene blue. The same result was found after treatment with captopril. We speculate that ACE inhibitors improve endothelial function in SHRs not by inhibiting the synthesis of PGH2 but by increasing the release or the action of endothelium-derived relaxing factor.
Effects of angiotensin converting enzyme inhibition with cilazapril on intimal hyperplasia in injured arteries and vascular grafts in the baboon.
Authors: Hanson S R , Powell J S , Dodson T , Lumsden A , Kelly A B , Anderson J S , Clowes A W , Harker L A
Published: August 2012

To determine the importance of angiotensin converting enzyme (ACE) activity in the development of arterial proliferative lesions in a primate model, the response to vascular injury was studied in five baboons treated with oral cilazapril (20 mg/kg/day) and in five untreated control animals. Each animal underwent three procedures: 1) carotid artery endarterectomy, 2) balloon catheter deendothelialization of the superficial femoral artery, and 3) surgical placement of bilateral aorto-iliac expanded polytetrafluoroethylene (Gore-Tex) vascular grafts. Cilazapril therapy was initiated 1 week preoperatively and continued throughout the study interval. At 1 and 3 weeks postoperatively, plasma ACE activity was inhibited by more than 96% versus control values. After animals were killed at 3 months, injured vessel and graft segments were evaluated morphometrically. Although the response between animals was variable, average cross-sectional areas of neointima did not differ between the cilazapril-treated and control groups at sites of carotid endarterectomy (0.26 +/- 0.12 versus 0.34 +/- 0.17 mm2, respectively; p greater than 0.5), femoral artery ballooning (0.15 +/- 0.08 versus 0.11 +/- 0.01 mm2; p greater than 0.5), or at graft anastomoses (1.86 +/- 0.50 versus 1.72 +/- 0.50 mm2; p greater than 0.5). Thus, cilazapril did not reduce intimal thickening over 3 months in these primate arterial injury models. However, a possible beneficial effect of cilazapril, which might be apparent at earlier time points or with larger animal groups, cannot be excluded.
Effects of two angiotensin converting enzyme inhibitors and hydralazine on coronary circulation in hypertensive rats.
Authors: Clozel J P , Véniant M , Hess P , Sprecher U
Published: August 2012

The goal of the present study was to compare the effects of cilazapril, a new long-acting angiotensin converting enzyme inhibitor, to those of captopril and hydralazine on the coronary vascular bed. For this purpose, spontaneously hypertensive rats were treated for 4 months with either placebo, 10 mg/kg/day cilazapril, 100 mg/kg/day captopril, or 10 mg/kg/day hydralazine. At the end of treatment, maximal coronary blood flow was measured during maximal coronary vasodilation with adenosine in isolated perfused hearts. Cilazapril was the most effective drug in increasing maximal coronary blood flow. Captopril was less effective in improving maximal coronary blood flow but was as effective as cilazapril in reducing cardiac hypertrophy. Hydralazine had an extremely small effect on cardiac hypertrophy and maximal coronary flow reserve. The ranking of efficacy was similar for the reduction of vessel wall hypertrophy in the coronary arteries and arterioles. Because of the higher efficacy of cilazapril compared with captopril, a second experiment was performed in which 10 mg/kg/day cilazapril was compared with 100 mg/kg/day captopril and 300 mg/kg/day captopril after 1 month of treatment. Captopril increased maximal coronary flow and decreased cardiac hypertrophy to the same level as cilazapril only at the highest dose. We conclude that angiotensin converting enzyme inhibitors, in contrast to hydralazine, can increase markedly maximal coronary flow in spontaneously hypertensive rats but that this increase does not always parallel the decrease of cardiac hypertrophy and is closely dose dependent.