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Biomedical subjects

A B Weder

Publications and source records attributed to A B Weder.

At least 37 records · Page 2Linked to original sources
PubMed1994

Adaptation, allometry, and hypertension.

Essential hypertension is a "disease of civilization" but has a clear genetic component. From an evolutionary perspective, persistence in the human genome of elements capable of raising blood pressure presupposes their adaptive significance. Recently, two hypotheses that explicitly appeal to selectionist arguments, the "slavery" and "thrifty gene" theories, have been forwarded. We find neither completely successful, and we advance an alternative explanation of the adaptive importance of genes responsible for hypertension. We propose that blood pressure rises during childhood and adolescence to subserve homeostatic needs of the organism. Specifically, we contend that blood pressure is a flexible element in the repertoire of renal homeostatic mechanisms serving to match renal function to growth. The effect of modern diet and lifestyle on human growth stimulates earlier and more vigorous development, straining biologically necessary relationships between renal and general somatic growth and requiring compensation via homeostatic mechanisms preserved during evolution. Prime among such mechanisms is blood pressure, which rises as a compensation to maintain renal function in the face of greater growth. Since virtually all members of acculturated societies share in the modern lifestyle, the demands imposed by accelerated growth and development result in a populational shift to higher blood pressures, with a consequent increase in the prevalence of hypertension. We propose that hypertension is the product of maladaptation of highly genetically conserved mechanisms subserving important biological homeostatic needs. Elucidation of the mechanisms underlying hypertension will require approaches that examine the developmental processes linking growth to blood pressure.

Adaptation, Physiological↗
PubMed1994

Sympathetic nervous system involvement in essential hypertension: increased platelet noradrenaline coincides with decreased beta-adrenoreceptor responsiveness.

Platelet catecholamine content may reflect integrated plasma catecholamine concentrations over time. The present study aimed at examining sympathetic nervous system (SNS) involvement in essential hypertension by assessing platelet noradrenaline (NA) and typically beta-adrenoreceptor mediated responses to adrenaline (A) infusion as indices of sympathetic tone. Healthy white men were recruited by public advertising and screening (mean +/- SD): Hypertensives (n = 13, sitting blood pressure [BP] 153 +/- 13/106 +/- 7 mmHg, age 34 +/- 5 years, weight 83 +/- 10 kg) were compared to normotensives (n = 13, sitting BP 114 +/- 9/75 +/- 9 mmHg, age 30 +/- 6 years [n.s.], weight 82 +/- 9 kg [n.s.]). Loss of platelet granular contents (including NA) prior to analysis was minimized by studying young subjects (age range 20-40 years, minimal atherosclerosis), using arterial blood sampling, and processing blood immediately. These procedures resulted in plasma beta-thromboglobulin and platelet factor 4 levels which were not significantly different between groups. Sympathetic activation resulting from stress was minimized by not labelling subjects as either hypertensive or normotensive. Mean arterial platelet NA content was significantly higher in hypertensives (64 +/- 31 pg/mg of platelet weight) compared to normotensives (43 +/- 20 pg/mg, p < 0.05) both at baseline and following 35% expansion of the circulating platelet pool by A infusion (p < 0.05) and correlated with arterial NA in the hypertensives (r = 0.79, p < 0.002) but not in the normotensives (r = 0.04, n.s.). Similar increases in platelet and plasma A during infusion in both groups suggest unchanged platelet uptake capacity and plasma clearance in the hypertensive group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Sodium metabolism, hypertension, and diabetes.

The hypertension that frequently accompanies diabetes mellitus is characterized by abnormalities of sodium (Na) metabolism at all physiologic levels: whole-body, renal, and cellular. The most consistently described abnormality is an expansion of exchangeable Na, which seems to be closely associated with increased proximal renal tubular Na reabsorption and suppression of membrane sodium-potassium ATPase activity in circulating cells. Although recent interest has focused almost exclusively on the role of hyperinsulinemia in promoting renal Na retention and causing expansion of total body Na and Na-dependent hypertension, there is evidence that other factors in addition to insulin excess are involved.

Animals↗
PubMed1994

The contribution of pleiotropy to blood pressure and body-mass index variation: the Gubbio Study.

Blood pressure (BP), body-mass index (BMI), and quantitative phenotypes thought to influence BP (e.g., lithium-sodium countertransport activity) were studied in 2,184 households comprising 5,376 people in Gubbio, Italy. Variance-components models were used to partition the variation of these phenotypes into components characterizing the effects of age-related, measured environmental, additive genetic, pleiotropic, unmeasured shared-household, and individual-specific (or random) factors. The goal of the investigation was to estimate the contribution of pleiotropy to variation in BP and BMI in population-based samples. Although our results suggest that numerous significant bivariate genetic correlations exist between BP and some of the traits investigated, they ultimately lead us to reject a prominent role for any individual bivariate pleiotropic system influencing the natural variation of BP. However, because we found evidence that many traits enter into small-impact pleiotropic relationships with BP, we cannot rule out the possibility that pleiotropic genes, when considered collectively, may contribute to BP variation at the population level. Similar results were obtained when BMI was taken as the primary variable of interest. We argue that the small but significant portion of BP variation explained by individual genes displaying bivariate pleiotropic effects is intuitive, in light of the relatively low heritabilities associated with quantitative cardiovascular phenotypes and the low phenotypic correlations between BP, BMI, and many other physiologically linked measures of cardiovascular function. Our results not only bear directly on both the nature of the multifactorial determinants of BP and the maintenance of BP variation in the population at large, but also emphasize the utility of variance-components models in epidemiologic and population genetics research. We discuss the implications of our results for genetic epidemiologists and medical researchers studying hypertension, as well as the limitations of our study and areas for future research.

Blood Pressure↗
PubMed1993

Contrasting effects of epinephrine on forearm hemodynamics and arterial plasma norepinephrine.

Circulating catecholamines are widely considered to cause vasoconstriction. However, in the present study an intravenous infusion of 0.01 micrograms/kg/min epinephrine for 10 min in healthy men (n = 40, 20 to 40 years of age), which raised arterial plasma epinephrine from 100 +/- 13 to 231 +/- 22 pg/mL (mean +/- SE), increased forearm blood flow (FBF) from 2.79 +/- 0.17 to 3.45 +/- 0.25 mL/100 forearm tissue/min (P < .001), and decreased forearm vascular resistance (FVR) from 37.0 +/- 2.4 to 31.1 +/- 2.1 (arbitrary units). Further stepwise increase in epinephrine infusion rate progressively raised FBF (to a maximum 6.91 +/- 0.46) and decreased FVR (to minimum 16.7 +/- 2.0), and increased arterial plasma norepinephrine by more than 60% (P < .001). Thus, circulating epinephrine in concentrations that can be produced by mental stress has, despite its ability to increase sympathetic drive, a regional vasodilating effect in the human forearm.

Adult↗
PubMed1993

Nephropathy in NIDDM is associated with cellular markers for hypertension.

OBJECTIVE: To determine if nephropathy in NIDDM is associated with cellular markers for hypertension. RESEARCH DESIGN AND METHODS: We compared 11 patients with clinical diabetic nephropathy with 15 control subjects with no diabetic nephropathy. The patients were white and had had NIDDM for > or = 9 yr and serum creatinine levels < or = 177 M (2.0 mg/dl). RESULTS: Patients with nephropathy were more obese and had higher blood pressures and triglyceride levels, and lower high-density lipoprotein cholesterol levels than control subjects. Erythrocyte sodium lithium countertransport activity, erythrocyte sodium content, and platelet sodium-proton exchange were higher in patients with nephropathy than in control subjects. CONCLUSIONS: The results of this small study suggest that in white patients with long-standing NIDDM, diabetic nephropathy is associated with cellular markers for hypertension. Measurement of cellular markers for hypertension may be useful to identify patients who are at risk for developing nephropathy.

Antiporters↗
PubMed1993

Evaluation of self-measured home vs. clinic intra-arterial blood pressure.

Home blood pressure (BP) monitoring is useful in the clinical management of patients with hypertension and the identification of those with "white-coat" hypertension; i.e. high readings in the clinic but normal BP at home. In the process of evaluating this technique, we compared self-measured home BP with intra-arterial BP. Healthy white men (n = 40) of 20-40 years of age and body weight below 95 kg were recruited by advertising in the local newspaper. Following a standardized procedure, performed within 2-4 weeks of a response to the advertisement, BP was measured by a physician at a clinic screening, by the subject at home (14 readings in 7 days) and finally in the clinic concomitantly intra-arterially and oscillometrically. The correlation coefficient for mean (M) home BP (r = 0.73) and oscillometric BP (r = 0.74) against intra-arterial BP were slightly higher than for screening BP (r = 0.65). However, in plots of the differences for individual MBP between the methods against the average of the methods, it appears that at levels of average MBP above 100 mmHg, screening BP overestimates the BP level, while this was not the case for home BP or oscillometric BP. Thus, by using intra-arterial measurement as standard of comparison, subject self-measured home BP is a reliable method of estimating blood pressure level in young men. Home BP measured shortly after screening and recruitment provides useful information of resting BP in subjects who potentially may have initial anxiety about BP measurement.

Adult↗
PubMed1992

Does blood pressure reduction necessarily compromise cardiac function or renal hemodynamics? Effects of the angiotensin-converting enzyme inhibitor quinapril.

Clinical studies indicate that the angiotensin-converting enzyme inhibitor quinapril is an effective antihypertensive agent when administered once daily. At the end of a 4-week, double-blind crossover trial comparing quinapril and placebo, patients were admitted for a hemodynamic profile study 12 hours after taking the previous dose. A final 20 mg dose of quinapril had no additional effect on blood pressure. This is interesting inasmuch as the plasma half-life of the active metabolite quinaprilat is approximately 2 hours and the effective accumulation half-life is approximately 3 hours. The blood pressure reduction in patients with mild hypertension receiving long-term quinapril therapy may be more closely related to prolonged angiotensin-converting enzyme inhibition or to an effect on tissue angiotensin II concentration than to the plasma half-life. This may be the case particularly for cardiac output and renal circulation, because quinapril lowers total vascular resistance without increasing cardiac output or disturbing autoregulation of renal blood flow. Reduced ventricular wall stress, improved diastolic function, and lower renal perfusion pressure may spare cardiac function and glomeruli from hypertensive vascular damage.

Adult↗
PubMed1991

Cation transport markers as predictors of hypertension.

Of the abnormalities of cation transport described in human essential hypertension, an increased maximal activity for red blood cell lithium-sodium (RBC Li(+)-Na+) countertransport is the most appealing candidate for a genetically mediated marker for risk of future hypertension. Population studies have demonstrated that the distribution of values for countertransport can be modelled statistically as a mixture of two overlapping subpopulations. These two modes could result from the action of a single principal determinant, and pedigree-based studies of the genetic transmission of RBC Li(+)-Na+ intertransport activity have suggested that factor may represent the effect of a major monogenic influence segregating in a Mendelian recessive fashion. Although the molecular nature of the proposed genetic lesion underlying high RBC Li(+)-Na+ countertransport is not yet known, a recent linkage study suggests it may be localized to chromosome 4. A preliminary report of a prospective analysis of the predictive value of high RBC Li(+)-Na+ countertransport for future hypertension supports its utility as a premorbid marker for genetic risk of future hypertension. Allelic differences at a genetic locus controlling RBC Li(+)-Na+ countertransport activity may contribute directly to interdividual blood pressure differences or may be linked to other genes that do.

Biological Transport↗
PubMed1991

Neurohumoral and metabolic effects of short-term dietary NaCl restriction in men. Relationship to salt-sensitivity status.

Published observations suggest that not everyone benefits from severe dietary NaCl restriction, since blood pressure responses appear heterogeneous and adverse metabolic effects may occur. We studied the cardiovascular, neurohumoral, and metabolic effects of 7 day periods of 20 v 200 mEq/day NaCl diets in 27 men. Twelve subjects were salt sensitive (SS), defined as mean intraarterial pressure (MAP, mm Hg) during high NaCl greater than or equal to 5% above MAP on low NaCl. Eleven subjects were salt resistant (SR), defined as MAP during the low NaCl phase greater than or equal to MAP during the high NaCl phase. The SR subset had a tendency to greater neurohumoral activity, assessed by changes in mean values for plasma norepinephrine (NE, P = .12) and plasma renin activity (PRA, P less than .001) on the low v high NaCl diet. In SR subjects the low v high NaCl diet also raised mean values for creatinine (P = .03), uric acid (P = .001), and low density cholesterol (LDL-C, P = .03), but not fasting insulin (P = .15). In SS subjects, the low v high NaCl diet did not raise NE (P = .35), although the PRA was greater (P = .002). Among SS subjects, mean values for uric acid (P = .005) and insulin (P = .02) were greater during the low v high NaCl phase, while creatinine (P = .15) and LDL-C (P = .67) were not different. The data suggest that severe, short-term NaCl restriction can be undesirable, especially in SR subjects, since potentially adverse neurohumoral and metabolic changes are not counterbalanced by the benefits of a lower MAP.

Adult↗
PubMed1991

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↗
PubMed1991

Effects of lovastatin treatment on red blood cell and platelet cation transport.

Hypercholesterolemia frequently accompanies hypertension, and it has been suggested that by affecting membrane lipid composition, hypercholesterolemia may cause or accentuate abnormalities in several red blood cell transports associated with hypertension. Such an effect might obfuscate the relation of membrane markers to hypertension and decrease their usefulness in genetic studies of the heritable basis of hypertension. To determine if changing plasma lipids affects membrane transport, we studied the effects of the cholesterol-lowering agent lovastatin on red blood cell lithium-sodium countertransport and sodium-potassium-chloride cotransport, red blood cell sodium and water content, and platelet amiloride-sensitive volume responsiveness to cytoplasmic acidification, an indirect measure of sodium-proton exchange that has been proposed as a new membrane marker for hypertension. In a 24-week, placebo-controlled, double-blinded, randomized trial, lovastatin significantly lowered total and low density lipoprotein cholesterol and raised high density lipoprotein cholesterol. Red blood cell lithium-sodium countertransport and sodium-potassium-chloride cotransport were not significantly altered. Red blood cell sodium content decreased significantly in the lovastatin-treated group, probably as a result of an increase in red blood cell sodium-potassium pump activity. Platelet amiloride-sensitive responses to cytoplasmic acidification were significantly depressed by lovastatin treatment, suggesting that lowering plasma cholesterol may suppress platelet sodium-proton exchange. It has been hypothesized that the hyperlipidemias frequently observed in essential hypertensive patients may alter membrane lipid composition and affect membrane cation transport activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

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↗
PubMed1991

Salt loads raise plasma fatty acids and lower insulin.

Some fatty acids are potent inhibitors of angiotensin binding and aldosterone production in adrenal glomerulosa cells and thereby may be involved in regulating salt and water balance. To study the possible regulation of fatty acids by salt, we measured the levels of unesterified fatty acids in plasma from patients subjected to extremes of dietary salt intake and saline infusion. Insulin and catecholamines, two known regulators of plasma fatty acids, also were measured. Infusion of 2 l saline over 4 hours caused the levels of most unesterified fatty acids to rise. Total unesterified fatty acids rose 60-100%. A high salt diet caused a smaller rise in total unesterified fatty acids (approximately 33%). In both instances, oleic and palmitoleic acids showed the greatest proportionate increases, whereas stearic acid was relatively unaffected. When salt loads were administered by either intravenous or dietary routes, plasma insulin levels fell by approximately 50%. Plasma norepinephrine increased after saline infusion but not during a high salt diet. Postsaline levels of fatty acids correlated inversely with postsaline levels of aldosterone, supporting a possible role for fatty acids as physiological regulators of the adrenal glomerulosa. A rise in plasma fatty acids and fall in insulin in response to salt loads could act in concert to increase sodium excretion, constituting a physiological mechanism contributing to salt and water balance.

Chromatography, High Pressure Liquid↗
PubMed1991

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↗
PubMed1991

Potential deleterious impact of dietary salt restriction on cardiovascular risk factors.

Excessive intake of dietary salt is thought to promote hypertension in Western societies, and some have recommended salt restriction for the general population. While such restriction is thought to be innocuous, few studies have examined the impact of dietary salt on cardiovascular risk factors other than blood pressure. In a randomized, placebo-controlled, doubly blinded comparison of one week periods of 20 vs. 208 mEq/d NaCl intake in 27 hypertensives and normotensives, we found that salt restriction had no significant effect on blood pressure (p = 0.45) and a generally adverse impact on risk factors for cardiovascular disease. Stringent, short-term dietary salt restriction caused increases in total and low-density lipoprotein cholesterol that were of borderline significance (p = 0.07). These lipid effects probably resulted from plasma volume contraction, as they were coincident with significant rises in hemoglobin (p = 0.01), hematocrit (p less than 0.001), total protein (p less than 0.01) and albumin (p = 0.01); such changes may act together to increase whole-blood viscosity. In addition, plasma norepinephrine (p = 0.02), fasting plasma insulin (p = 0.02) and glucose-to-insulin ratio (p = 0.01) increased during salt restriction. The potentially adverse impact of dietary salt restriction on the risk factor profile for cardiovascular disease suggests that further studies are necessary before a reduction in dietary salt intake can be prescribed for the general population.

Adult↗
PubMed1991

The renally compromised older hypertensive: therapeutic considerations.

Although the slow progression of renal insufficiency caused by aging does not usually reach the clinical disease level, nephron loss may be accelerated by the concomitant presence of hypertension and renal artery atherosclerosis. Treatment of hypertension and correction of other risk factors promoting atherosclerosis is appropriate in the elderly. Consideration should be given to a search for reversible causes of renal functional deterioration in elderly patients, particularly in those with increasingly refractory hypertension. In the uncomplicated elderly hypertensive, renal function appears to be adequately preserved if blood pressure is well controlled, although there may be a subset in whom factors other than blood pressure itself, such as glomerular hemodynamic disturbances, promote progressive renal dysfunction.

Aged↗