The hemodynamic link between insulin resistance and hypertension.
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Aging↗
Biomedical subjects
S Julius
Publications and source records attributed to S Julius.
Platelet function during antihypertensive treatment with quinapril, a novel angiotensin converting enzyme inhibitor.
The effect of various antihypertensive medications on platelet function is of increasing interest. Conflicting effects of captopril on platelet function are reported and the impact of angiotensin converting enzyme (ACE) inhibitors not containing a sulfhydryl group such as enalapril, lisinopril, and quinapril on platelet function remains unstudied. Therefore, the aim of the present study was to examine the effect of antihypertensive treatment with quinapril, a novel ACE inhibitor not containing a sulfhydryl group, on platelet function. Ten white men (age range of 32-61 years) with untreated mild-to-moderate essential hypertension (supine diastolic blood pressure greater than 95 mm Hg) were treated with 4 weeks each of placebo and quinapril in a double-blind, randomized, crossover design. Quinapril (20 mg twice a day) significantly lowered systolic (p less than 0.01) and diastolic blood pressure (p less than 0.01) without any significant effect on heart rate or plasma catecholamines. No significant change was noted for in vitro platelet aggregation induced by epinephrine, ADP, or collagen. Plasma concentrations of the platelet release factors beta-thromboglobulin and platelet factor 4 did not change, nor did the platelet content of norepinephrine, platelet weight (mg/10 ml of blood), circulating platelet count, or platelet size. Thus, as assessed by a broad spectrum of platelet parameters, we found that antihypertensive treatment with quinapril has no significant effect on platelet function in patients with mild-to-moderate essential hypertension. These "platelet-neutral" properties of quinapril suggest that quinapril, both from a thromboembolic and a hemostatic point of view, may be a rather safe agent for treatment of hypertension.
Adenosine Diphosphate↗
Independence of pressure reactivity from pressure levels in Tecumseh, Michigan.
The relation between blood pressure level and reactivity to mental arithmetic and isometric exercise was investigated in 169 men and 120 women (average age, 32.3 years) from the village of Tecumseh, Mich. In the entire population, the correlation between baseline blood pressure and blood pressure response to both stressors was not significant. Blood pressure reactivity to both stressors was not increased in participants with borderline hypertension (one clinic reading of more than 140 mm Hg systolic and/or 90 mm Hg diastolic). When subjects were classified according to blood pressure response (below and above the 80th percentile), the hyperreactors to mental and physical stress had normal baseline blood pressure values. The hyperreactors also had clinic-to-home blood pressure differences similar to those of the rest of the population. Participants who had borderline hypertension at age 32 years had significantly elevated blood pressures at ages 5, 8, 12, 21, and 22 years. Those who were hyperreactors at age 32 years had normal blood pressures as children and young adults. Results of the present study lend no support to an association between higher blood pressures and blood pressure hyperreactivity. Study participants in Tecumseh will be recalled for future examinations. The independence of blood pressure levels from blood pressure reactivity offers a unique opportunity to prospectively evaluate their separate effects on cardiovascular morbidity.
Adolescent↗
Red blood cell lithium-sodium countertransport in the tecumseh blood pressure study.
Human essential hypertension has more than one cause, but to dissect out subtypes, markers are required. The maximal activity of red blood cell lithium-sodium countertransport has been shown to be increased in hypertensive patients in case-control and population-based studies; in the latter, its distribution is a mixture of two overlapping but distinguishable subpopulations. In the present study, we classified 705 participants in the Tecumseh Blood Pressure Study as having either normal (mean, 0.234 mmol/l cells/hr; n = 614) or high (mean, 0.463 mmol/l cells/hr; n = 91) red blood cell lithium-sodium countertransport to determine if the red blood cell marker is associated with distinctive physiological characteristics. We found that subjects with elevated lithium-sodium countertransport have higher average blood pressure and a greater prevalence of hypertension than those with normal countertransport and that elevated blood pressure had been present since youth. Hemodynamically, the high countertransport group is characterized by elevated vascular resistance, whereas sympathetic nervous system activity appears to be slightly depressed. Subjects with increased lithium-sodium countertransport, compared with those with normal countertransport, have significantly lower average left ventricular mass index and only very infrequently demonstrate left ventricular hypertrophy. Our results support the usefulness of measurements of the maximal activity of red blood cell lithium-sodium countertransport as a way of distinguishing subgroups in the population. Our data are consistent with the idea that subjects with an elevated maximal activity for red blood cell lithium-sodium countertransport are a subset of the population with a genetic lesion that predisposes them to the development of essential hypertension.
Adolescent↗
Quinapril, an angiotensin converting enzyme inhibitor, prevents cardiac hypertrophy during episodic hypertension.
Six control dogs, six dogs treated with 1.5 mg/kg b.i.d. quinapril, and six dogs treated with 8 mg/kg q.d. minoxidil underwent 6 hours daily of hindquarter compression for 9 weeks. Minoxidil significantly decreased baseline blood pressure (-17 mm Hg; p less than or equal to 0.01), whereas quinapril decreased baseline blood pressure 11 mm Hg but not significantly (p = 0.15). Hindquarter compression elicited blood pressure increases in all three groups (control +18, quinapril +13, minoxidil +19 mm Hg). After 9 weeks, left ventricular mass in control dogs increased 22% (p less than 0.004); a similar increase was seen in minoxidil-treated dogs (+22%, p less than 0.0001) but not in the quinapril-treated group (+4%, p less than 0.15). The increase in left ventricular mass in control dogs was concentric (increased epicardial volume only), whereas in the minoxidil group, the hypertrophy was eccentric (both epicardial and endocardial volumes increased). The minimal hypertrophy in the quinapril group was concentric (no change in epicardial, but a decrease in endocardial volume). Quinapril had little hypotensive effect, but prevented the development of left ventricular hypertrophy, whereas minoxidil did not prevent hypertrophy in spite of its hypotensive effect. The mechanism of this differential effect of direct vasodilation versus converting enzyme inhibition on left ventricular hypertrophy is not fully elucidated. The results with quinapril suggest that some antihypertensive agents may positively affect left ventricular hypertrophy in spite of the absence of a large effect on baseline blood pressure or on blood pressure reactivity.
Angiotensin-Converting Enzyme Inhibitors↗
Linkage of MN locus and erythrocyte lithium-sodium countertransport in Tecumseh, Michigan.
Human essential hypertension is a family of diseases; one subtype has an increased maximum velocity for red blood cell lithium-sodium countertransport activity. To begin the localization of the gene or genes responsible for this phenotype, we examined the association of blood pressure, lithium-sodium countertransport, and two genetic markers previously associated with hypertension--the MN blood group antigen (chromosome 4) and the plasma protein haptoglobin (chromosome 18)--in a population-based sample of 592 young adults from Tecumseh, Mich., the site of an ongoing cardiovascular epidemiological investigation. Our results suggest that the relation between MN phenotype and systolic blood pressure is significantly different and oppositely directed in men and women. Analysis of data available from previous examinations revealed that similar blood pressure differences related to MN phenotype had been present at least a decade earlier in both men and women. There also was a significant relation between systolic blood pressure and haptoglobin phenotype for the combined group of men and women. In addition to having high systolic blood pressure, men with the MM phenotype had significantly elevated red blood cell lithium-sodium countertransport activity. In studies of brother-brother pairs, we found evidence for significant genetic linkage between the MN locus and red blood cell lithium-sodium countertransport activity.
Adolescent↗
Autonomic nervous dysfunction in essential hypertension.
Borderline hypertension, a condition in which the blood pressure oscillates between normal and high values, is a predictor of future more severe hypertension. Pathophysiologically, borderline hypertension is different from established hypertension. A large proportion of such patients have elevated cardiac output and a normal vascular resistance. In established hypertension, the output is normal and resistance is elevated. The elevation of cardiac output in borderline hypertension is neurogenic; it can be abolished by an autonomic blockade of the heart. In addition to an increased cardiac sympathetic drive, increased sympathetic tone to the kidney, arterioles, and veins has also been found. In parallel with the hypersympathetic state, patients with borderline hypertension also show decreased parasympathetic tone. The enhanced sympathetic tone leads to a decreased cardiac responsiveness, and eventually, the cardiac output returns to the normal range. High blood pressure causes vascular hypertrophy, and hypertrophic vessels are hyperresponsive to vasoconstriction. These secondary changes in the responsiveness of the heart and blood vessels are the basis of transition from a high cardiac output to high-resistance hypertension. These hemodynamic changes are associated with a downregulation of the sympathetic tone. A picture of an apparently nonneurogenic high-resistance hypertension emerges. Nevertheless, when assessed in regard to the enhanced pressor responsiveness, the sympathetic drive in such patients is still excessive. Despite the apparently normal tone, the sympathetic nervous system continues to play an important pathophysiological role in established hypertension. Borderline hypertension is associated with numerous metabolic abnormalities including obesity and insulin resistance. It is tempting to view all these abnormalities as a common expression of the increased sympathetic drive in hypertension. Explanation of the basis of the association of hypertension and metabolic abnormalities promises to bring new insights into the pathophysiology of two common diseases of civilization: hypertension and diabetes mellitus.
Autonomic Nervous System↗
Home blood pressure monitoring: advantages and limitations.
Home blood pressure monitoring is a useful tool for clinical management of patients with hypertension. Its major advantages are the ease with which the techniques can be learned, reproducibility of values, sensitivity of measurement and availability of normotensive data. In spite of the ability to tell whether a subject has normal or abnormal values, because of the lack of prospective mortality/morbidity data, home blood pressure monitoring cannot be used to decide whether treatment is indicated. The treatment decision must be based on repeated clinic blood pressure readings. After that the home blood pressure monitoring can be used to exclude individuals who are at risk for side effects due to low out-of-office blood pressure readings and to precisely monitor the blood pressure response to therapy. Home blood pressure monitoring is frequently used to find subjects with 'white-coat' hypertension. In our study of borderline hypertension in Tecumseh, white-coat hypertension is present in 7.1% of the whole population and in 58% of all subjects with elevated blood pressures in the clinic. Subjects with white-coat hypertension in Tecumseh appear to be at an increased risk for coronary heart disease: they show repeated elevated clinic readings throughout their life time, their parents have higher blood pressure, their high-density lipoprotein is decreased and insulin, cholesterol and triglycerides are elevated. Whereas subjects with white-coat hypertension should not be treated with antihypertensive agents, they must be followed and managed through non-pharmacologic means.
Blood Pressure Determination↗
The association of borderline hypertension with target organ changes and higher coronary risk. Tecumseh Blood Pressure study.
The Tecumseh project investigates the evolution of hypertension in a healthy population. Of 946 subjects aged 18 through 38 years, 124 had clinic blood pressure readings higher than 140/90 mm Hg (the mean for borderline hypertensive subjects was 130/94 mm Hg). Compared with normotensive subjects, borderline hypertensive subjects had higher home blood pressures (mean, 12/7 mm Hg higher). Their childhood and postpubertal blood pressures were elevated (6/4 mm Hg higher than normal at age 6 years and 12/7 mm Hg higher than normal at age 21 years), and hypertensive target organ changes were detected. Borderline hypertensive subjects also had elevated minimal forearm resistance (0.22 U higher than normal), decreased stroke index (1.8 mL/m2 lower than normal), and impaired ventricular diastolic relaxation (mitral Doppler peak early diastolic blood flow [E] to peak late diastolic blood flow [A] ratio 0.13 lower than normal). Borderline hypertensive subjects had significant abnormalities in other coronary risk factors (cholesterol levels were 0.39 mmol/L higher, triglyceride levels were 0.45 mmol/L higher, high-density lipoprotein levels were 0.08 mmol/L lower, insulin levels were 38 pmol/L higher, and 16.5% more of them were overweight). Borderline hypertension is neither transient nor innocuous. Its association with other predictors of atherosclerosis calls for clinical attention.
Adolescent↗
Disease entities, mixed multi-normal distributions, and the role of the hyperkinetic state in the pathogenesis of hypertension.
This paper concerns the theory and relevance of finite mixtures of univariate and multivariate normal distributions in medical research and suggests that multivariate normal mixture analysis, hitherto not extensively explored, is an appealing approach to the investigation of etiologically obscure, multifactorial diseases such as hypertension. We elaborate a statistical strategy to resolve and test for a normal mixture distribution in a seemingly heterogenous population actually comprising homogenous subpopulations. We use this strategy to validate the hypothesis that in the population at large there is a subgroup of individuals with the characteristic of a hyperkinetic circulatory state, defined as the association of an elevated cardiac index or heart rate with high blood pressure. This subgroup may have implications for the pathogenesis of hypertension. We discuss directions and implications for future research into the pathogenesis of hypertension.
Cluster Analysis↗
Are different hemodynamic patterns of antihypertensive drugs clinically important?
Since vascular resistance is elevated in hypertension, it is suggested that vasodilators lower the blood pressure by a physiologic mechanism and therefore must be more useful than cardiac output-lowering drugs. This is not entirely correct. Drugs that lower cardiac output are also relative vasodilators, but the vasodilation occurs at a lower level of cardiac output. It is also not necessarily true that all vasodilators are good antihypertensive agents. The clinical profile of a vasodilator depends on its effect on the venous return, cardiac output, regional blood flow, renin-angiotensin system, and sympathetic reflexes. From the viewpoint of hemodynamics, an ideal antihypertensive drug is a vasodilator that does not excessively increase cardiac output, causes no fluid retention, does not induce a great deal of venodilation, and does not elicit substantial neurohumoral counterregulation. Angiotensin-converting-enzyme inhibitors, some calcium antagonists, and some combined alpha/beta-blocking agents come close to satisfying the hemodynamic definition of an ideal antihypertensive drug.
Animals↗
Hemodynamic effects of quinapril, a novel angiotensin-converting enzyme inhibitor.
The hemodynamic effects of quinapril, a novel nonsulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, were assessed in 10 patients with mild-to-moderate essential hypertension. Compared with placebo, quinapril (20 mg) administered twice daily for 4 weeks significantly lowered blood pressure by decreasing total peripheral resistance without producing tachycardia, an increase in cardiac output, or a rise in plasma catecholamines. Quinapril significantly reduced renal, but not forearm, vascular resistance. Renal blood flow, glomerular filtration rate, and filtration fraction remained unchanged. Left ventricular wall stress was markedly reduced by quinapril, but during the relatively short treatment period, only a nonsignificant trend toward reduction in left ventricular mass was observed. These findings suggest that quinapril is an effective antihypertensive agent that lowers peripheral resistance without increasing cardiac output or disturbing autoregulation of renal hemodynamics.
Adult↗
Validation of non-invasive measurement of cardiac output. The Ann Arbor experience.
In an assessment of non-invasive methods for the clinical measurement of cardiac output, both M-mode echocardiography and the CO2 rebreathing technique were found to be unreliable. However, the echo-Doppler method appeared for population studies.
Carbon Dioxide↗
"White coat" versus "sustained" borderline hypertension in Tecumseh, Michigan.
During a survey of young subjects not receiving treatment for hypertension in Tecumseh, Michigan, clinic and self-monitored blood pressures taken at home (14 readings in 7 days) were obtained in 737 subjects (387 men, 350 women, average age 31.5 years). Hypertension in the clinic was diagnosed if the clinic blood pressure exceeded 140 mm Hg systolic or 90 mm Hg diastolic. In the absence of firm criteria for what constitutes hypertension at home, subjects whose average home blood pressure was in the upper decile of the whole population were considered to have hypertension at home. By these criteria, 7.1% of the whole population had "white coat" hypertension (i.e., high clinic but not elevated home readings). The prevalence of "sustained" hypertension (i.e., high readings in the clinic and at home) was 5.1%. Subjects with white coat and sustained borderline hypertension in Tecumseh were very similar. Both groups showed, at previous examinations (at ages 5, 8, 21, and 23 years), significantly higher blood pressure readings than the normotensive subjects. As young adults (average age 33.3 years), the parents of both hypertensive groups had significantly higher blood pressure readings than the parents of normotensive subjects. Both hypertensive groups had faster heart rates, higher systemic vascular resistance, and higher minimal forearm vascular resistance. Both hypertensive groups were more overweight, had higher plasma triglycerides, insulin, and insulin/glucose ratios than normotensive subjects. The white coat hypertensive group also had lower values of high density lipoprotein than the normotensive group. White coat hypertension is a frequent condition.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Predictors of blood pressure and hypertension in Tecumseh, Michigan.
Correlates of present blood pressure status are analyzed in 576 subjects (271 males, average age 32 years) in Tecumseh, Michigan. In addition to the current values, anthropometric and blood pressure data are available when the subjects were, on average, 6.9 and 22.2 years of age. Data on 351 fathers and 368 mothers when they were, on average, 32 years old are also available. Moderate, but significant correlations were found between present and past blood pressure and between past weight or skinfold thickness and the present blood pressure. These correlations were much weaker for childhood values than for values at age 22. When multiple regression techniques were used with blood pressure values at age 22 and parental values as independent variables, 40% of the present systolic blood pressure variance could be explained. Prediction of present hypertension status (blood pressure greater than 140 and/or 90 mm Hg) was evaluated by discriminant analysis. Three variables (weight at age 22, systolic blood pressure at age 22, and father's diastolic blood pressure) entered the model and accurately predicted the present blood pressure classification in 89% of the sample. When current blood pressure status was assessed with respect to previous blood pressure classification (upper 20%), family background, and overweight, a gradient of risk for hypertension was found. On the low end of risk was high childhood pressure (risk 19.1% versus 12.1% in the overall population). The highest risk occurred for those with high pressure and overweight at 22 years who also had a family background of high blood pressure (44% versus 12.1%). The prediction of hypertension from young adulthood to the early fourth decade of life is feasible and permits delineation of populations targeted for primary prevention.
Adult↗
A new dimension in hypertension: role of insulin resistance.
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Humans↗
Hemodynamic and neurohumoral evidence of multifaceted pathophysiology in human hypertension.
As hypertension advances, secondary pathophysiologic changes are induced in multiple organs. Consequently, we investigated the pathophysiology of the earliest forms of hypertension--e.g., borderline hypertension. Borderline hypertension is associated with abnormal autonomic control of the circulation; sympathetic drive to the heart, blood vessels, and kidney is increased, cardiac parasympathetic inhibition is decreased, and plasma norepinephrine is increased. The hemodynamic picture is one of increased cardiac output not met by adequate vasodilation. The condition of "hyperkinetic" borderline hypertension is a precursor of more severe hypertension. In due course, a transition from high cardiac output to high vascular resistance occurs, while the enhanced sympathetic tone recedes toward normal values. The mechanism of hemodynamic transition is easily understood: cardiac output decreases due to structural changes and receptor downregulation, whereas ensuing vascular hypertrophy increases vascular resistance. The apparent regression of plasma norepinephrine values is explained in the framework of our hypothesis of the "blood pressure-seeking properties of the central nervous system." Large body mass and overweight are a consistent feature of borderline hypertension. A recent study in Tecumseh, Michigan shows that weight, plasma norepinephrine, a hyperkinetic state, and plasma insulin values are correlated in the general population. The explanation of this interrelationship will greatly advance our understanding of hypertension. From the pathophysiological viewpoint, the paradoxical outcome of clinical trials involving older antihypertensive medication is not surprising. The complexity of pathophysiologic interrelationships and the fact that risk factors for atherosclerosis are increased in hypertension suggest that reduction of blood pressure cannot be expected to ameliorate all consequences of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Hemodynamics↗
Changing role of the autonomic nervous system in human hypertension.
Pathophysiological effects of the autonomic nervous system are clearly seen in young patients with a high cardiac output and borderline hypertension. As the hypertension progresses, there is a change from the hyperkinetic circulation in borderline hypertension to the increased vascular resistance seen in established hypertension. This hemodynamic transition is caused by decreased beta-adrenergic responsiveness and decreased end-diastolic distension of the heart combined with an increased alpha-adrenergic responsiveness of the resistance vessels. In parallel, the sympathetic tone decreases in the course of hypertension. This transition in sympathetic tone can be explained by the hypothesis of the 'blood pressure seeking properties of the brain'. The central nervous system 'seeks' to maintain a higher pressure. When vascular overresponsiveness sets in, less sympathetic drive is needed to maintain a neurogenic hypertension. Sympathetic overactivity in borderline hypertension is associated with overweight subjects, insulin resistance and dyslipidemia. This suggests a new area of research to investigate the basis of metabolic abnormalities in hypertension.
Adult↗