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Biomedical subjects

M A Weber

Publications and source records attributed to M A Weber.

At least 73 records · Page 4Linked to original sources
PubMed1998

Paracrine interaction in testicular somatic cells.

Initiation of spermatogenesis is regulated by signals derived from intratubular Sertoli cells as well as extratubular Leydig cells, both being systemic targets of hypophyseal gonadotropins. In addition to Leydig and Sertoli cells, a number of other cell types are present in the testis viz. peritubular cells, macrophages and vascular components. The specific paracrine functions of these cells are only partially understood. The peritubular and Sertoli cells form the structural scaffold of the germinal epithelium and are responsible for intratubular pressure, release and transport of spermatozoa and the formation of the blood-testis barrier. We have performed ex vivo and in vitro studies on the ultrastructure of peritubular and Sertoli cells and the distribution of steroid hormone receptors, cytoskeletal and extracellular matrix proteins using rat testes from different stages of postnatal development. Morphological observations were related to in vitro findings of gene expression on the respective hormones and structural proteins. In the developing rat testis, the peritubular cells showed a strong and consistent expression of fibronectin, entactin, laminin as well as the glucocorticoid, androgen, estrogen and partially also the progesterone receptor, while the Sertoli cells were devoid of glucocorticoid receptor and entactin. The glucocorticoid receptor was present in around 20% of the intratubular germ cells (in the 2nd postnatal week) and in 50% of the peritubular cells. In Leydig cells also, the expression reached its climax in the 3rd weak and declined thereafter. This is perhaps pointing to a differentiation-inhibiting role of glucocorticoids in gonocyte differentiation. In the 3rd developmental week, the androgen receptor was present in about 15% of all gonocytes and later in 50% of peritubular cells and about 40% of interstitial cells. The estrogen receptor was absent in peritubular cells of the adult testis. The progesterone receptor was present in about 30% of the peritubular and 25% of the Leydig cells. Taking into account the significant increase in seminiferous tubules following postnatal developmental day 18, the peritubular cells seem to exert an androgen dependent growth stimulus to the seminiferous cords perhaps via the Sertoli cells. In vitro studies of peritubular and Sertoli cells cultured either alone or in co-culture showed by RT-PCR the expression of the androgen and the glucocorticoid receptors in both cell types, as well as fibronectin. Secretion of fibronectin occurred in a clear-cut time-dependent increase in monocultures of peritubular cells (on day 3 of culture). In co-cultures of Sertoli and peritubular cells, fibronectin bio- synthesis was down-regulated. The paracrine interplay between extracellular matrix and hormonal signals joining peritubular and Sertoli cells is essential in the differentiation of the seminiferous tubules.

Animals↗
PubMed1997

Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study.

BACKGROUND: We attempted to characterize age-related changes in blood pressure in both normotensive and untreated hypertensive subjects in a population-based cohort from the original Framingham Heart Study and to infer underlying hemodynamic mechanisms. METHODS AND RESULTS: A total of 2036 participants were divided into four groups according to their systolic blood pressure (SBP) at biennial examination 10, 11, or 12. After excluding subjects receiving antihypertensive drug therapy, up to 30 years of data on normotensive and untreated hypertensive subjects from biennial examinations 2 through 16 were used. Regressions of blood pressure versus age within individual subjects produced slope and curvature estimates that were compared with the use of ANOVA among the four SBP groups. There was a linear rise in SBP from age 30 through 84 years and concurrent increases in diastolic blood pressure (DBP) and mean arterial pressure (MAP); after age 50 to 60 years, DBP declined, pulse pressure (PP) rose steeply, and MAP reached an asymptote. Neither the fall in DBP nor the rise in PP was influenced significantly by removal of subsequent deaths and subjects with nonfatal myocardial infarction or heart failure. Age-related linear increases in SBP, PP, and MAP, as well as the early rise and late fall in DBP, were greatest for subjects with the highest baseline SBP; this represents a divergent rather than parallel tracking pattern. CONCLUSIONS: The late fall in DBP after age 60 years, associated with a continual rise in SBP, cannot be explained by "burned out" diastolic hypertension or by "selective survivorship" but is consistent with increased large artery stiffness. Higher SBP, left untreated, may accelerate large artery stiffness and thus perpetuate a vicious cycle.

Adult↗
PubMed1997

Comparison of type 1 angiotensin II receptor blockers and angiotensin converting enzyme inhibitors in the treatment of hypertension.

UNLABELLED: RENIN-ANGIOTENSIN SYSTEM AND HYPERTENSION: The renin-angiotensin system is integral to the mechanisms that sustain hypertension. Hypertensive patients with inappropriately high renin levels have an increased risk of cardiovascular events, and thus there is continuing interest in treating hypertension with drugs that not only reduce blood pressure but also have an inhibitory effect on the renin-angiotensin system. INHIBITORS OF THE RENIN-ANGIOTENSIN SYSTEM: Angiotensin converting enzyme (ACE) inhibitors decrease blood pressure and ameliorate the symptoms of congestive heart failure. Drugs that selectively block the AT1 angiotensin II receptor are now entering clinical practice for the treatment of hypertension and, very likely, congestive heart failure. PHARMACOLOGIC DIFFERENCES: There are some important theoretical differences between ACE inhibitors and AT1 blockers in their actions on the renin-angiotensin system. ACE inhibitors ostensibly prevent the formation of angiotensin II. However, this action is far from complete, as measurable plasma concentrations of ACE remain during chronic therapy with these agents. AT1 receptor blockers work selectively at the AT1 receptor, leaving the AT2 receptor unaffected. The importance of this selectivity has not yet been established, but AT2 receptors are thought to mediate inhibitory effects on growth. It has been postulated that the selective blockade by this new class of drugs will directly decrease the growth-promoting actions of angiotensin II at the AT1 receptor, while leaving the growth-inhibitory effects of the AT2 receptor unaffected. The clinical relevance of these differing pharmacologic properties of ACE inhibitors and AT1 blockers have not yet been established. BLOOD PRESSURE, METABOLIC AND RENAL EFFECTS: AT1 receptor blockers appear to have relatively high trough:peak efficacy ratios compared with ACE inhibitors. However, in patients with essential hypertension compared with normal volunteers, the M value, a measure of glucose clearance and insulin sensitivity, is reduced. Both the ACE inhibitor delapril and the AT1 blocker candesartan have shown a beneficial effect on insulin sensitivity, and candesartan appears to restore the M value to normal. While ACE inhibitors have been shown to have strongly beneficial actions in the kidneys, comparable data are not yet available for AT1 blockers. SIDE EFFECTS: The relatively common problem of cough observed with ACE inhibitors does not occur with AT1 blockers. FUTURE WORK: Future studies must address metabolic and cardiovascular questions that have not yet been answered. It will also be of interest to determine whether the combination of AT1 blockers and ACE inhibitors, especially in more resistant forms of congestive heart failure or hypertension, might confer additive benefits.

Angiotensin Receptor Antagonists↗
PubMed1997

The importance of pulsatile components of hypertension in predicting carotid stenosis in older adults.

OBJECTIVE: To evaluate pulsatile components of the blood pressure as risk markers for carotid stenosis in isolated systolic hypertension. DESIGN: Duplex scans with Doppler measures of the blood flow velocity were used to diagnose carotid stenosis in 187 participants in the Systolic Hypertension in the Elderly Program and in 187 normotensive and mildly hypertensive control subjects. METHODS: The systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure, and mean arterial pressure (MAP) were selected as independent variables. A logistic regression model for carotid stenosis was used to adjust for potentially confounding risk factors. Serial models, each containing single or double blood pressure variables, were run to compare risk markers for carotid stenosis. Receiver operating characteristic curves were compared to assess the predictive value of each model. RESULTS: In the multivariate analysis, both the SBP (P = 0.005) and the pulse pressure (P < 0.001) were predictive of carotid stenosis, but the DBP and MAP were not. However, when either the SBP or the pulse pressure was included in the model, the DBP was associated negatively with carotid stenosis (P < 0.001 and P = 0.023, respectively). An increased pulse pressure and a decreased DBP were independent risk markers for carotid stenosis. Comparison of receiver operating characteristic curves indicated that the pulse pressure had superior predictive value to the SBP (P = 0.034). CONCLUSIONS: The pulse pressure is the single best predictor of carotid stenosis. There is a negative correlation between the DBP and carotid stenosis for subjects with isolated systolic hypertension, but this can be demonstrated only after one has stratified for the SBP or for the pulse pressure. Thus, the pulsatile components of the blood pressure, increased pulse pressure and decreased DBP, are the most sensitive risk markers for the diagnoses of carotid stenosis.

Adult↗
PubMed1996

Combination therapy with diuretics: an evolution of understanding.

One of the current recommendations for the treatment of hypertension is a stepped-care approach in which a second drug is added to a first-line agent when adequate blood pressure control has not been achieved. It has been well demonstrated in multiple studies that the response rate to any single class of antihypertensive agent, given as monotherapy, is approximately 45-55%. Thus, in approximately half of the hypertensive population, a second drug will be required. This is not surprising, since it is now well recognized that hypertension is a multifaceted disease process. The use of combination therapy with low-dose diuretics (< 25mg hydrochlorothiazide [HCTZ] or its equivalent) has become a very attractive alternative choice to first-line therapy. The data from clinical trials clearly demonstrate that 6.25 mg or 12.5 mg HCTZ has an additive or synergistic effect on blood-pressure reduction when used in combination with most drugs. At low doses, the side-effect profile with diuretics is similar to placebo. Furthermore, metabolic side effects are significantly reduced when diuretics are used in low doses. The use of low-dose diuretics in combination with other first-line agents significantly enhances blood-pressure control and reduces the likelihood of adverse events and alteration in carbohydrate, lipid, and electrolyte metabolism. Thus, combination therapy with low-dose diuretics provides an attractive alternative approach to first-line treatment of essential hypertension.

Blood Pressure↗
PubMed1996

Angiotensin II receptor inhibition. A new therapeutic principle.

Angiotensin II receptor antagonists represent a new class of drugs that provide a site-specific blockade of the effects of angiotensin II. Losartan potassium, the first compound of this drug class, has recently become available in the United States. The clinical experience with angiotensin II receptor antagonists has demonstrated that these drugs are safe and efficacious for the treatment of hypertension and, possibly, congestive heart failure. Unlike with angiotensin-converting enzyme inhibitors, the incidence of cough observed with angiotensin receptor antagonists is similar to that with placebo. Although several angiotensin receptors have been characterized, the effects of losartan and other angiotensin receptor antagonists under development are selective for the angiotensin II type 1 receptor. Unlike angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists do not inhibit bradykinin metabolism or enhance prostaglandin synthesis. The antihypertensive efficacy of the angiotensin receptor antagonists has been documented to be similar to that of angiotensin-converting enzyme inhibitors. If the findings of clinical studies corroborate the initial reports on efficacy and safety, it seems likely that the angiotensin receptor antagonists will be added to the list of drugs that have been deemed suitable for first-line therapy in the treatment of hypertension and congestive heart failure.

Angiotensin II↗
PubMed1996

Novel delivery system for verapamil designed to achieve maximal blood pressure control during the early morning.

Because the risk of cardiovascular events appears to be greatest in the early morning, this period is a time during which adequate blood pressure (BP) control appears to be most desirable. In this study, a controlled-onset extended-release system (COER-24) that delivers verapamil in a manner designed to achieve maximal levels of drug during the early morning surge in BP was compared with placebo. Ninety-five patients with mild to moderate hypertension were studied. Of this group, 49 patients (mean age 57.6 +/- 1.4 years; 35 men and 14 women) were randomized to take verapamil COER-24 240 mg at 10 PM, and 46 subjects (mean age 55.8 +/- 1.5 years; 29 men and 17 women) were randomized to take placebo. Ambulatory BP monitoring was performed after a 4-week initial placebo period and was repeated after 4 weeks of treatment with verapamil or placebo. Verapamil COER-24 resulted in significant (p < 0.001) decreases in mean whole-day systolic and diastolic BP (-8.2/-6.3 mm Hg; baseline 152/93.0 mm Hg) when compared with placebo (+0.3/-0.9 mm Hg; baseline 150.3/93.2 mm Hg). From 6 AM to noon, verapamil COER-24 resulted in a change in systolic and diastolic BP of -11.6/-9.0 mm Hg, which was significantly (p < 0.001) greater than the change that occurred with placebo (-0.5/-1.0 mm Hg) during the same period. In the last 4 hours of the dosing interval (6 PM to 10 PM), verapamil COER-24 caused significantly greater (p < 0.001) decreases in BP (-7.4/-4.8 mm Hg) than did placebo (+2.7/+1.0 mm Hg). These data demonstrate that the COER-24 system, when administered in the late evening, achieves maximal BP reduction during the early morning hours. Moreover, BP reductions were sustained throughout the 24-hour period.

Blood Pressure↗
PubMed1996

Measurement of short-term, intermediate, and long-term outcomes of treating hypertension.

Hypertension is widely treated by primary care physicians as well as by cardiologists and other specialists. Clinical progress is often monitored by blood pressure measurements and other routine evaluations, but more sophisticated approaches may be required to learn whether treatment is effectively protecting the heart, kidneys, and other susceptible areas. Outcome measures therefore involve quantification of short-term, intermediate and long-term clinical observations; and, in addition, assessment of overall effectiveness must take into account economic factors and the levels of satisfaction perceived by patients, physicians, and health plans.

Adult↗
PubMed1996

Antihypertensive therapy and quality of life. Influence of blood pressure reduction, adverse events, and prior antihypertensive therapy.

Quality of life is an important attribute of antihypertensive therapy. Previous studies have not addressed the importance of a patient's prior pharmacotherapy on quality of life, which may serve as the basis of reference for a new therapy. Nor have previous studies compared commonly used quality of life instruments for consistency, or investigated whether improvement or worsening of quality of life correlates with adverse events or blood pressure reduction. Two hundred eighteen hypertensive patients with diastolic blood pressure (95 to 114 mm Hg) after a 4- to 5-week placebo washout period were enrolled in a randomized double-blind, parallel group dose-escalation trial to compare the effects of amlodipine (2.5 to 10 mg), bisoprolol (2.5 to 10 mg)/hydrochlorothiazide (HCTZ) 6.25, and enalapril (5 to 20 mg) on blood pressure, adverse events, and quality of life. Three quality of life instruments (General Well-Being Index, Vital Signs Quality of Life, Zung Self-Rating Depression Scale) were administered during original therapy, after placebo washout, and after 12 weeks of optimally titrated clinical trial pharmacotherapy. Our results demonstrated that removal from prior therapy had no detectable influence on subsequent evaluation of quality of life. The three quality of life instruments were consistent with the changes observed with the three therapies: a trend toward better quality of life with amlodipine and bisoprolol/HCTZ. Adverse events, but not systolic or diastolic blood pressure reduction correlated directly with changes in quality of life.

Adrenergic beta-Antagonists↗
PubMed1996

Role of hypertension in coronary artery disease.

Historically, stroke, heart failure and renal insufficiency were seen as the major complications of untreated hypertension. More recently, it has become evident that coronary heart disease is probably the most common outcome of this condition. Unlike the other complications of hypertension, coronary events have not been reduced in a meaningful fashion by traditional antihypertensive drug therapy. A partial explanation may lie in the fact that hypertension typically consists of a syndrome of inherited metabolic and cardiovascular abnormalities, and treatment that focuses primarily on blood pressure without taking into account the other factors that contribute to atherosclerotic disease can have only limited protective effects. The coronary hypothesis in hypertension extends this reasoning into 3 separate components. First is an intrinsic tendency to excessive proliferative and hypertrophic activity in vascular tissue, presumably reflecting growth-promoting activity stimulated by increased endocrine and local paracrine effects; second is the impact of the commonly encountered concomitant risk factors, including high blood pressure, that exaggerate and accelerate development of the underlying atherosclerotic lesions; third are hemodynamic factors, including increased variability and sustained elevations of blood pressure, that can destabilize vascular lesions and precipitate acute events. Treatment of these hemodynamic factors in elderly patients, whose underlying vascular changes are already well advanced, is likely to effectively reduce the incidence of vascular endpoints. In younger patients, ongoing vascular proliferative changes and the impact of concomitant risk factors are equally as important as hemodynamic forces in producing coronary disease, and effective treatment must take all these issues into account.

Antihypertensive Agents↗
PubMed1996

Once-daily monotherapy with trandolapril in the treatment of hypertension.

Once-daily antihypertensive drugs that control blood pressure (BP) for the full 24-h dosing period, enhance patient compliance and may reduce the cardiovascular complications of hypertension which occur with increased frequency in the early morning. Since some once-daily agents are more effective than others in maintaining antihypertensive effects toward the end of the 24-h dosing interval this study was designed to evaluate the duration of antihypertensive action of trandolapril using 48 h ambulatory blood pressure monitoring (ABPM) in 41 patients with mild-to-moderate essential hypertension. Twenty-four hour ABPM was performed on two consecutive days (48 h) after a 4 week single blind placebo run-in period and repeated after an 8 week double-blind period during which 20 patients were randomized to treatment with trandolapril (2-4 mg once-daily) and 21 patients to matching placebo. During the second 48 h monitoring period, placebo rather than active medication was taken by both of the groups at the beginning of the second 24 h segment. Trandolapril reduced ambulatory systolic and diastolic BP by 9.4 and 6.2 mm Hg respectively (P < or = 0.01) during the first 24 h of the post treatment monitoring period while placebo increased the systolic and diastolic BPs in the same period by 3.8 and 2.6 mm Hg (P < 0.05). During the second monitoring period (hours 25-48), trandolapril reduced systolic and diastolic BP by 5.6 and 3.9 mm Hg while placebo increased BP by 2.3 and 1.6 mm Hg (P < 0.03). When compared to placebo by 2 h time blocks, throughout the 2 days of monitoring, trandolapril produced clinically significant decreases in systolic and diastolic BP for 30 and 28 h following dosing. This indicates that trandolapril can be considered a true once-daily antihypertensive agent.

Adult↗
PubMed1995

Blood pressure effects of the angiotensin II receptor blocker, losartan.

BACKGROUND: Losartan potassium, the first nonpeptide selective blocker of angiotensin II at the AT1 receptor, has been shown to exhibit clinical antihypertensive effects. The aim of the present study was to characterize the efficacy and duration of action of losartan by ambulatory blood pressure monitoring. METHODS: The study was performed in nonblack hypertensive patients whose baseline untreated clinical diastolic blood pressures were 95 mm Hg or higher and whose average 24-hour ambulatory diastolic blood pressures were 85 mm Hg or higher. Patients were randomized, double-blind, into four treatment groups: placebo (n = 32) or losartan, 50 mg once daily (n = 29), 100 mg once daily (n = 30), or 50 mg twice daily (n = 31). Clinical and 24-hour ambulatory blood pressures were measured at baseline (off treatment for at least 4 weeks) and after 4 weeks of treatment. RESULTS: By clinical sphygmomanometer measurements at the end of the 24-hour or 12-hour dosing intervals (trough), all three losartan dosages were significantly more effective than placebo at decreasing systolic and diastolic blood pressures. By average 24-hour ambulatory systolic/diastolic blood pressure measurements, the decreases produced were 0.0/0.2 mm Hg for placebo and 9.2/6.9, 9.9/6.4, and 13.2/8.5 mm Hg, respectively, for losartan, 50 mg once daily, 100 mg once daily, and 50 mg twice daily. All drug effects were different from placebo (P < .01). The effects of losartan, 50 mg twice daily, were not significantly different from those of losartan, 100 mg once daily, but, as expected, the effects were greater than those of losartan, 50 mg once daily (P < .05). Addition of hydrochlorothiazide, 12.5 mg/d, during an additional 2-week treatment period in patients whose clinical diastolic blood pressure remained at 85 mm Hg or higher while receiving monotherapy produced additional and clinically meaningful blood pressure decrements that were similar in all four treatment groups. There was no clinically important difference in the incidence of adverse events among the losartan-treated and placebo groups [corrected]. CONCLUSION: Ambulatory blood pressure monitoring, which virtually eliminated antihypertensive placebo responses, demonstrated clear 24-hour efficacy for losartan, 50 mg once daily, as well as for higher doses of 100 mg once daily and 50 mg twice daily. This AT1 receptor blocker had antihypertensive effects that appeared additive when combined with low-dose diuretic therapy. Losartan was generally well tolerated.

Adult↗
PubMed1995

Low-dose drug combination therapy: an alternative first-line approach to hypertension treatment.

To investigate the concept that the initial treatment of hypertension with low doses of two antihypertensives that have different modes of action and additive effects may achieve control of blood pressure and minimize the dose-dependent adverse effects seen with conventional monotherapy, a randomized, double-blind parallel group dose-escalation study was conducted. After a 4 to 5 week placebo washout period, 218 men and women with diastolic blood pressure between 95 and 114 mm Hg were randomly allocated to take: amlodipine (2.5 to 10 mg), enalapril (5 to 20 mg), and the low-dose combination of bisoprolol (2.5 to 10 mg) with 6.25 mg of hydrochlorothiazide (HCTZ). All drugs were administered once daily, titrated to optimal response, and taken for a total of 12 weeks. Blood pressure was measured 24 hours after dose. The response rates (either a diastolic blood pressure < or = 90 mm Hg or a decrease of diastolic pressure > or = 10 mm Hg) were 71% for bisoprolol-6.25 mg HCTZ, 69% for amlodipine, and 45% for enalapril. The mean decreases in systolic/diastolic blood pressure from baseline were 13.4/10.7, 12.8/10.2, and 7.3/6.6 mm Hg for bisoprolol-6.25 mg HCTZ, amlodipine, and enalapril, respectively. The mean change with enalapril was less than the other drugs (p < 0.01), although the once-daily dosing of enalapril and the maximum dose of 20 mg might not have been optimal for this agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗