Tumor necrosis factor alpha induces apoptosis in mammary adenocarcinoma cells by an increase in intranuclear free Ca2+ concentration and DNA fragmentation.

The incubation of human mammary adenocarcinoma cells (BT-20) with tumor necrosis factor alpha in the absence or presence of cycloheximide resulted in progressive DNA fragmentation. This was preceded by a sustained increase in intracellular free Ca2+ concentration and was not detected in cells pretreated with intracellular Ca2+ chelators, calmodulin antagonists, or activators of protein kinase C. Image analysis of fura-2-loaded BT-20 cells treated with tumor necrosis factor alpha revealed that, in many cells, the initial increase in Ca2+ level occurred in a cellular region that corresponded to the localization of the nucleus. Our findings suggest that tumor necrosis factor alpha can promote an increase in intranuclear free Ca2+ which, in turn, may stimulate Ca(2+)-dependent endonuclease activity, resulting in DNA fragmentation and apoptosis.

Autoantibodies against oxidatively modified low-density lipoproteins in NIDDM.

Diabetes is an independent risk factor in the development of atherosclerosis, although the pathophysiological processes underlying this association are poorly understood. The oxidation of low-density lipoprotein (LDL) is considered a key event in the development and progression of atherosclerosis because it generates molecular epitopes that are more atherogenic than parent LDL. A total of 138 patients suffering from non-insulin-dependent diabetes mellitus (NIDDM) and 80 matched control subjects were investigated. LDL oxidation was evaluated as the presence of autoantibodies against oxidatively modified LDL, since they mirror the in vivo occurrence of oxidative processes. NIDDM patients had an antibody ratio (calculated as the ratio of antibodies against modified versus native LDL) significantly higher than control subjects for Cu(2+)-oxidized LDL (1.88 +/- 0.6 vs. 1.05 +/- 0.3, P < 0.01, for IgG), malondialdehyde-modified LDL (2.54 +/- 0.73 vs. 2.04 +/- 0.11, P < 0.01, for IgG and 3.96 +/- 1.51 vs. 2.90 +/- 0.15, P < 0.01, for IgM), and malondialdehyde-modified human serum albumin (1.79 +/- 0.54 vs. 1.46 +/- 0.1, P < 0.05 for IgG). The possible role played by glycation in sensitizing LDL to oxidation was investigated by measuring autoantibodies against both glycated LDL (glycLDL) and glycoxydated LDL (glycoxLDL). NIDDM patients had an antibody ratio significantly higher than control subjects for anti-glycLDL and anti-glycoxLDL IgG (1.79 +/- 0.38 vs. 1.12 +/- 0.23, P < 0.01 and 2.55 +/- 1.03 vs. 1.39 +/- 0.44, P < 0.01, respectively) but not anti-glycLDL and anti-glycox-LDL IgM.(ABSTRACT TRUNCATED AT 250 WORDS)

Cross correlation of heart rate and respiration versus deep breathing. Assessment of new test of cardiac autonomic function in diabetes.

Cross correlation is a mathematical function whereby spectral analysis is used to describe the relationship between heart-rate fluctuations (256 R-R intervals) and respiration (simultaneously obtained by pneumotacograph). To assess its usefulness for testing autonomic integrity, cross correlation and deep breathing were compared in 141 diabetic subjects (aged 39 +/- 14 yr) and in 77 control subjects (aged 33 +/- 13 yr). To characterize patients, Valsalva maneuver, 30:15 ratio, tilt, and handgrip tests were performed in 96 of these patients; 23 had two or more abnormal tests (group A), 28 had one (group B), and 45 had none (group C). Sensitivity to parasympathetic withdrawal was compared in 9 control subjects (aged 26 +/- 4 yr) by four sequential 0.01-mg/kg i.v. atropine administrations. Reproducibility was compared in 11 control subjects (aged 25 +/- 2 yr) by repeating the tests four times for 2 consecutive days. Considering all 141 patients, cross correlation and deep breathing were less than 2SD of the mean of control subjects in 64 and 36 subjects, respectively. Considering patients who also performed other tests of autonomic function, cross correlation and deep breathing were less than 2SD of the mean of controls in 42 and 30 subjects, respectively (group A, 20 and 15; group B, 12 and 9; group C, 10 and 6). Cross correlation had better reproducibility than deep breathing (C.V. 10.3 vs. 30.6% at 6 breaths/min) and greater sensitivity to atropine (after the 1st injection, cross correlation and deep breathing decreased to 34.6 and 48.2% of baseline values, respectively; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Association between apolipoprotein(a) phenotypes and coronary heart disease at a young age.

OBJECTIVES: The purpose of this study was to investigate lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] phenotypes in relation to age of onset of coronary heart disease (CHD). BACKGROUND: Although Lp(a) levels have been extensively analyzed in relation to age of CHD, apo(a) phenotypes have not. METHODS: Three hundred and thirty-five consecutive CHD patients were enrolled and grouped according to their age of CHD onset (<45 years; 45 to 54 years; > or = 55 years). RESULTS: In each patient group Lp(a) levels were higher than in an age-matched control group, but among the patient groups no differences in Lp(a) levels were observed. Apolipoprotein(a) phenotype distributions showed significant differences between patients and age-matched control subjects. Among the patient groups the difference in percentage of subjects with two apo(a) isoforms of low molecular weight (MW) was highly significant (p < 0.001). Multivariate analysis showed that apo(a) phenotypes were the best predictors of early CHD (p < 0.000001). The age-specific odds ratios (ORs) of the presence of at least one apo(a) isoform of low MW for CHD declined with age; in particular apo(a) phenotypes had their highest predictive value in younger persons (OR: 14.62). The OR for the presence of two isoforms of low MW/presence of only isoforms of high MW was 40.88 in the younger age group, 27.17 in age group of 45 to 54 years and 15.83 in the older age group. CONCLUSIONS: The present article reports the first evidence of a strong independent association of apo(a) phenotypes with the age of onset of CHD. Thus, if our data are confirmed by larger studies, apo(a) phenotypes might be used together with Lp(a) levels as powerful genetic markers in assessing the actual risk of developing CHD at a young age.

Load dependence of isovolumic relaxation in intact heart: facts or artifacts?

In order to study the dependence of left ventricular isovolumic relaxation on preload, afterload, and contractility the effects of infusions of dextran, phenylephrine, and dobutamine were assessed in 10 closed chest anaesthetised dogs. Left ventricular and aortic pressures and left ventricular transverse diameters were measured by micromanometers and a tracking sonomicrometer. Isovolumic relaxation time constant was computed by two different single exponential models: the first (time constant Tw) assumed the horizontal asymptote as equal to zero, whereas the second (time constant Tl) assumed a variable asymptote (Pb). To compare the two models, deviations between observed and predicted left ventricular pressures during isovolumic relaxation were computed for both (average squared difference ARSSQw and ARSSQl respectively). Dextran infusion, although increasing preload indexes, did not affect Tl (from 35.1(2.6) to 38.5(2.2) ms, NS) (mean(SEM], but increased Tw (from 28.4(1.4) to 43.8(2.1) ms, p less than 0.001); Pb was significantly shifted upwards (from -7.9(2.4) to +8.2(2.8) mmHg, p less than 0.01). Pb correlated with left ventricular end diastolic pressure (r = 0.71, p less than 0.001). Phenylephrine infusion did not change the isovolumic relaxation time course (Tl from 36.4(3.5) to 46.2(6.1) ms, NS; Tw from 26.8(2.3) to 30.5(2.9) ms, NS) nor Pb (from -9.5(2.3) to -18.7(2.3) mmHg, NS). Dobutamine infusion reduced Tl significantly (from 35.2(3.7) to 25.3(2) ms, p less than 0.02), but did not change Tw (from 27.5(2.4) to 23.3(3.3) ms, NS) nor Pb (from -7.3(1.8) to -8.8(2.3) mmHg, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular autonomic modulation in essential hypertension. Effect of tilting.

To better understand the role played by the autonomic nervous system in essential hypertension, we used autoregressive power spectrum analysis to study the noncasual oscillations in RR interval, blood pressure, and skin blood flow in 40 subjects with mild to moderate hypertension and in 25 age-matched control subjects at low frequency (index of sympathetic activity to the heart and the peripheral circulation) and high frequency, respiratory related (index of vagal tone to the heart). RR interval, respiration, noninvasive systolic blood pressure, and skin arteriolar blood flow were simultaneously and continuously recorded with subjects in the supine position and immediately after tilting. The low-frequency component was not significantly different in the two groups either at the cardiac level (control versus hypertensive subjects: 39.1 +/- 4.3 versus 39.9 +/- 3.7 normalized units [NU]) or at the vascular level (1.52 +/- 0.17 versus 1.69 +/- 0.13 ln mm Hg2). After head-up tilting, the RR interval fluctuations were less in hypertensive subjects (low-frequency components from 39.9 +/- 3.7 to 48.4 +/- 4.1 NU, P < .05; high-frequency components from 53.9 +/- 3.7 to 44 +/- 4 NU, P < .05) than in control subjects (low-frequency components from 39.1 +/- 4.3 to 64.4 +/- 4.9 NU, P < .001; high-frequency components from 56.0 +/- 4.5 to 31.2 +/- 4.6 NU, P < .001); the low-frequency components in systolic blood pressure increased similarly in hypertensive subjects (to 2.43 +/- 0.17 ln mm Hg2, P < .0001) and in control subjects (to 2.44 +/- 0.21 ln mm Hg2, P < .01), but the low-frequency components in skin blood flow increased only in control subjects (from 5.34 +/- 0.45 to 6.55 +/- 0.53 mm Hg2, P < .01), not in hypertensive subjects (from 5.55 +/- 0.34 to 5.60 +/- 0.35 ln mm Hg2). In hypertensive subjects with left ventricular hypertrophy, the low-frequency components in systolic blood pressure did not increase after tilting (from 1.75 +/- 0.33 to 2.05 +/- 0.41 ln mm Hg2). Baroreflex sensitivity, as assessed by spectrum analysis, was significantly lower in hypertensive than in control subjects (5.17 +/- 0.49 versus 13.18 +/- 2.44 ms/mm Hg, P < .001. Power spectrum analysis did not reveal an increased sympathetic activity or reactivity either at the cardiac or at the vascular level. The decreased baroreceptor sensitivity in hypertensive subjects could explain the reduced change in sympathovagal balance in the tilt position at the cardiac level. In hypertensive subjects without left ventricular hypertrophy, cardiopulmonary reflex deactivation induced by tilting and/or amplification of sympathetic nervous tone by arteriolar structural change could have preserved the sympathetic activation at the vascular level.

Perindopril versus captopril: efficacy and acceptability in an Italian multicenter trial.

The aim of this 3-month, double-blind, double-dummy, parallel group study was to compare the antihypertensive efficacy and acceptability of perindopril (4-8 mg/day) in 54 patients (30 males, 24 females, 25-68 years of age) and captopril (50-100 mg/day) in 54 patients (39 males, 15 females, 29-66 years of age) in the treatment of essential hypertension. In a subgroup of 38 patients a complete echocardiographic study was performed. The two groups had similar (ANOVA) blood pressure (BP), heart rate (HR), body mass index, and duration of hypertension. Supine and standing BP was significantly reduced by both drugs, without differences between them. Owing to poor control of BP, hydrochlorothiazide (25 mg/day) was added to 27% of patients on perindopril and to 41% of patients on captopril (p less than 0.05). Normalization of supine diastolic BP (less than or equal to 90 mm Hg) was obtained in 67% of patients on perindopril and in 47% of patients on captopril (p less than 0.01). No change in HR was detected. Only mild untoward effects were recorded. Left ventricular mass was significantly reduced by either drug, with no change in systolic function. In conclusion, perindopril and captopril, at these doses, were both well tolerated and on average reduced BP to a similar extent; however, treatment with perindopril showed that fewer patients needed the addition of a thiazide and BP became normal in a larger number of patients.

Presence of autoantibodies against oxidatively modified low-density lipoprotein in essential hypertension: a biochemical signature of an enhanced in vivo low-density lipoprotein oxidation.

OBJECTIVE: We have previously reported that low-density lipoproteins (LDL) isolated from patients with essential hypertension are more susceptible to in vitro oxidation than lipoproteins isolated from normotensive control subjects. In the present study we investigated the occurrence of in vivo LDL oxidation in hypertensive patients. DESIGN: The presence of antioxidatively modified LDL autoantibodies was taken as a suitable index of in vivo LDL oxidation because, after oxidative modifications, LDL express antigenic epitopes that elicit an immune response. The antibody titres were measured in plasma from untreated patients with newly diagnosed essential hypertension. METHODS: An enzyme-linked immunosorbent assay method was employed, using native LDL, Cu(2+)-oxidized LDL and malondialdehyde-derivatized LDL (MDA-LDL) as antigens. Human serum albumin and MDA human serum albumin were also used to monitor cross-reactivity with other oxidized molecules. The antibody titre was expressed as the ratio between anti-modified and anti-native antigen absolute values. RESULTS: The patients with essential hypertension had an antibody ratio significantly higher than control subjects with respect to anti-Cu(2+)-oxidized LDL immunoglobulins G and M, and with respect to anti-MDA-LDL immunoglobulins G and M. A significant positive correlation was found between anti-MDA-LDL and anti-Cu(2+)-oxidized LDL antibody titres. The anti-MDA human serum albumin antibody titre was not different in the two groups of patients. An inverse correlation was detected between the anti-MDA-LDL immunoglobulin M titre and the age of the patients. CONCLUSIONS: The results obtained are consistent with the view that, during the early phases of hypertension development, LDL undergo in vivo oxidation that is mirrored by the generation of autoantibodies against epitopes of oxidized LDL. The oxidation process appears specific for LDL and might be relevant both for the progression of hypertension and for the development of the atherosclerosis that often complicates hypertension itself.

Low-density lipoprotein oxidation in essential hypertension.

OBJECTIVES: To investigate the occurrence of enhanced low-density lipoprotein (LDL) oxidation as an additional factor promoting atherosclerosis progression in hypertensive patients. DESIGN: The oxidation of plasma LDL was investigated in a group of untreated patients with mild-to-moderate essential hypertension without clinically evident target organ damage and in a group of control subjects. METHODS: LDL oxidation was evaluated as both the susceptibility to oxidation in vitro and the presence of plasma anti-oxidized LDL antibodies (as an index for oxidation in vivo). RESULTS: LDL from hypertensive subjects exhibited enhanced susceptibility to oxidation in vitro as revealed by early and accelerated generation of conjugated dienes after exposure to CuSO4. Vitamin E concentration in LDL from hypertensive subjects was slightly but significantly decreased and its efficiency in protecting LDL from oxidation was impaired. Furthermore, a higher plasma anti-oxidized LDL titre was found in hypertensive patients. Subclass analysis revealed that the contemporary presence of hypercholesterolaemia did not significantly modify either the increased susceptibility of LDL to oxidation or the presence of plasma anti-oxidized LDL antibodies detected in hypertensive patients. Moreover, no correlation was found between LDL oxidation parameters and blood pressure values. CONCLUSIONS: LDL from hypertensive patients is more susceptible to oxidation in vitro and is more promptly oxidized in vivo. These findings suggest a possible participation of LDL oxidation in promoting and accelerating the atherosclerosis that often develops in hypertensive patients.

Association of lipoprotein(a) levels and apolipoprotein(a) phenotypes with coronary heart disease in patients with essential hypertension.

BACKGROUND: Besides hypertension, several cardiovascular risk factors can play a role in the development of coronary heart disease (CHD) in hypertensive patients. Lipoprotein(a) [Lp(a)] is an important and independent cardiovascular risk factor, but its role in the development of CHD in hypertensives has not been studied. OBJECTIVE: To investigate whether or not Lp(a) levels and isoforms of apolipoprotein(a) [apo(a)] are predictors of CHD in patients with essential hypertension. METHODS: Lp(a) levels and apo(a) polymorphism were evaluated in 249 patients with essential hypertension, in 142 non-hypertensive patients with CHD and in 264 healthy controls. RESULTS: Hypertensives with CHD (n = 61) had Lp(a) levels [19 (range 0.5-73.5) versus 7 mg/dl (range 0-83.5), P < 0.001] and a percentage of apo(a) isoforms of low (< 655 kDa) relative molecular mass (RMM, 59.2 versus 25.9%, P < 0.001) higher than did those without CHD (n = 188). Moreover, there were more subjects with at least one apo(a) isoform of low RMM in the subgroup of patients with CHD than there were in that of those without CHD (80.3 versus 30.8%, P< 0.001). Lp(a) levels and apo(a) polymorphism did not differ significantly between hypertensive and non-hypertensive patients with CHD. Stepwise regression analysis indicated that high Lp(a) levels (P= 0.002073) and particularly the presence of at least one apo(a) isoform of low RMM (P < 0.000001) are strong predictors of CHD in hypertensive patients. CONCLUSIONS: Our data show that high Lp(a) levels and the presence of at least one apo(a) isoform of low RMM are strong and independent genetic risk factors for CHD in hypertensive patients. These findings suggest that Lp(a) and apo(a) isoforms should be assessed together with other cardiovascular risk factors to establish the overall CHD risk status of each hypertensive patient

Effect of enalapril on left ventricular mass and performance in essential hypertension.

The effect of enalapril on left ventricular (LV) morphology and function was studied in 12 hypertensive patients. The subjects were evaluated after 2 weeks of placebo and after 4 months of treatment with enalapril (20 or 40 mg once daily), using M-mode digitized echocardiograms. The drug reduced arterial blood pressure in all patients. Systemic vascular resistance decreased significantly without changes in cardiac output and heart rate. No patient had significant side effects. After treatment LV mass decreased significantly (233 +/- 46 to 204 +/- 37 g, p less than 0.01); the reduction was due to a decrease in septal and posterior wall thickness, without changes in LV diameter. LV systolic function remained unchanged, whereas peak lengthening rate of LV dimension, an index of LV diastolic function, increased significantly (4.05 +/- 1.8 to 5.11 +/- 1.8 s-1, p less than 0.01). After treatment the basal inverse correlation between peak shortening rate and wall stress did not change, the inverse correlation between peak lengthening rate and wall stress became closer and the basal inverse correlation between peak lengthening rate and LV mass disappeared. In conclusion, antihypertensive treatment with enalapril led to a significant regression of LV hypertrophy associated with improvement in LV diastolic performance and no deterioration of LV systolic function.

Left ventricular function after reversal of myocardial hypertrophy in systemic hypertension, and response to acute increase of afterload by cold pressor test.

Using digitized M-mode echocardiography, the left ventricular (LV) response to acute increase in blood pressure after regression of myocardial hypertrophy due to an effective antihypertensive treatment was evaluated. Fifteen hypertensive patients with basal LV hypertrophy (LV mass greater than 230 g, and normal LV diastolic diameter) and normal LV mass after 3 to 4 months of treatment with angiotensin-converting enzyme inhibitors were selected for study. Subjects performed a cold pressor test before and after therapy. LV systolic function was normal in all subjects. LV diastolic function (impaired at basal evaluation in 13 subjects) improved after therapy in all subjects, with normalization in 10. Before treatment, the cold pressor test induced significant increases in blood pressure and heart rate without changes in LV parameters. After regression of hypertrophy, the cold pressor test induced increases in hemodynamic parameters comparable to those of the basal test, and LV parameters remained unchanged. Our results indicate that regression of myocardial hypertrophy induced by angiotensin-converting enzyme inhibitors does not impair the ability of the left ventricle to face acute increases in afterload. The improvement in LV diastolic function (found at rest after reversal of hypertrophy) persists during the cold pressor test, which confirms that it is primarily due to LV mass reduction and is not simply a consequence of decrease in afterload induced by treatment.

Left ventricular anatomy and function in normotensive young adults with hypertensive parents. Study at rest and during handgrip.

Using digitized M-mode echocardiograms, we evaluated left ventricular (LV) anatomy and function at rest and during handgrip in 24 normotensive young adults with both parents hypertensive (HP+), each matched for age, sex, body weight, and body surface area with one normotensive adult with both parents normotensive (HP-). LV parameters were within the normal range in all HP+ and HP-. At rest, HP+ as compared to HP- had higher systolic and diastolic blood pressure (BP), septal and posterior wall thickness, and LV mass; LV diastolic diameter and end-systolic wall stress were similar in the two groups. Modified midwall fractional shortening, peak shortening rate of LV diameter and peak thickening rate of LV posterior wall, indices of LV systolic function, and peak lengthening rate of LV diameter and peak thinning rate of LV posterior wall, indices of ventricular relaxation, were significantly higher in HP+. Handgrip induced significant (P < .001) and percent-comparable increases of systolic and diastolic BP, heart rate, and cardiac output in HP+ and HP-; peak shortening and lengthening rates of LV diameter and peak thickening and thinning rates of LV posterior wall increased significantly in HP-, whereas in HP+ the value of the four parameters, higher at rest as compared to HP-, did not show any further increase. In conclusion, normotensive young adults with high genetic risk for hypertension have higher BP and thicker and overactive LV as compared to subjects with normotensive parents. Handgrip stimulates LV function in offspring of normotensives, but not the already hyperkinetic LV of hypertensive offspring.

Determinants of left ventricular function before and after regression of myocardial hypertrophy in hypertension.

Using digitized M-mode echocardiograms, we evaluated the determinants of left ventricular (LV) systolic and diastolic function in 30 hypertensives with LV hypertrophy (LV mass > 230 g and normal LV diastolic diameter), before (LV mass 319 +/- 26 g) and after normalization of LV mass (196 +/- 21 g) by antihypertensive treatment with angiotensin converting enzyme inhibitors. As a control group we selected 50 normal subjects. Using multiple regression analysis we studied the relative role of preload (LV end-diastolic diameter), afterload (end-systolic wall stress), inotropic state (systolic pressure/end-systolic LV diameter ratio), and LV mass on LV systolic (peak shortening rate of LV diameter) and diastolic function (peak lengthening rate of LV diameter). The major determinant of systolic function was the end-systolic stress in hypertensives before treatment and the systolic pressure/end-systolic LV diameter ratio in normals and in hypertensives after treatment. The major determinant of diastolic function was LV mass in hypertensives before treatment and end-systolic stress in normals and in hypertensives after normalization of LV mass by treatment. Preload seems not to influence LV function in normals and in hypertensives with normal LV diameter. The inotropic state is the major determinant of systolic function in normals and in hypertensives after treatment, whereas this role is played by afterload in hypertensives before treatment. The diastolic function is primarily influenced by after-load in normals and in hypertensives after regression of myocardial hypertrophy, whereas in hypertensives with myocardial hypertrophy LV mass is the major determinant of diastolic function.

Double-blind comparison of perindopril and captopril in hypertension. Effects on left ventricular morphology and function.

Using digitized M-mode echocardiograms, we compared, in a double-blind study, the effects of 4 to 8 mg perindopril given once daily and 25 to 50 mg captopril given twice daily on the left ventricle (LV) in 20 hypertensive patients. Both treatments significantly (P less than .001) lowered blood pressure, reducing systemic vascular resistances. After 3 months both drugs induced a comparable percentage of reduction in LV mass, with an increase in the peak rate of LV relaxation and no changes in the peak rate of LV contraction. Our results demonstrate that perindopril once daily is an effective antihypertensive agent; it is also able, like captopril, to induce regression of LV hypertrophy, with improvement in diastolic performance and no deterioration in ventricular systolic function.

Continuous monitoring of right ventricular volume changes using a conductance catheter in the rabbit.

To assess the reliability of conductance (G) catheter for evaluating right ventricular (RV) volume changes, a miniature (3.5F) six-electrode catheter was developed and tested in 11 New Zealand rabbit hearts. In five animals the heart was excised; in six it was left in the thorax. RV conductance was recorded while the RV was filled with blood in 0.25-ml steps at different left ventricular (LV) volumes. Linear correlation of measured conductance vs. reference volumes was computed. RV conductance was highly correlated with reference volume [correlation coefficient (r) ranging from 0.991 to 0.999]. Slope of regression lines was not significantly affected by LV volume variations in 1-ml steps or by acute conductance changes of structures surrounding the heart, whereas the intercept was affected only by the 0- to 1-ml LV volume change. In four rabbits, RV conductance changes during a cardiac cycle [stroke volume- (SV) G] were compared in vivo with electromagnetic flow probe-derived estimates of SV (SVem) as stroke volume was varied by graded inferior vena caval occlusion. SV-G correlated well with SVem (r ranging from 0.92 to 0.96). This correlation persisted after the thorax was filled with saline; however, significant differences were found in individual slopes (P < 0.001). These results show that the conductance catheter has a potential to reliably monitor in vivo relative RV volume changes in small-animal hearts.

Metabolic effects of the combination of captopril and hydrochlorothiazide in hypertensive subjects.

The medium-term (16 weeks) effects of the combination of captopril and hydrochlorothiazide (HCTZ) on some metabolic indexes, particularly on plasma lipoproteins, were evaluated in 20 mild to moderate hypertensive outpatients. After a 4-week wash-out period, the subjects were given one tablet of a new commercially available fixed combination once/daily (i.e., captopril 50 mg + HCTZ 25 mg). The dose could be titrated to a maximum of one tablet twice daily according to individual blood pressure responses. Both systolic and diastolic blood pressure significantly decreased at week 4 and showed a further decrease thereafter; the rate of responders (diastolic blood pressure at or below 90 mm Hg at the end of the study) was very high (90%). The only metabolic change was a small though significant increase in HDL cholesterol (P less than .05), almost entirely due to an increase in the denser HDL3 subfraction. The atherogenic fractions, namely total cholesterol, LDL cholesterol, and apoprotein B, showed no significant changes. Plasma triglycerides underwent a transient increase at week 8 (P less than .05) but thereafter fell. Plasma glucose, creatinine, uric acid, and potassium were unchanged. The fixed combination of captopril and HCTZ seems highly effective in lowering blood pressure and seems devoid of untoward metabolic effects. Its overall impact on the coronary risk profile in hypertensive subjects seems therefore to be favorable.

Improved left ventricular function after short-term treatment with fructose-1,6-diphosphate: echocardiographic study in chronic ischemic heart disease and idiopathic dilated cardiomyopathy.

The effect of fructose-1,6-diphosphate (FDP) on left ventricular function was assessed in seven patients with chronic ischemic heart disease and eight patients with idiopathic dilated cardiomyopathy. In a crossover study design each patient received 10 gm of FDP or saline placebo intravenously for three days. An M-mode echocardiographic assessment of left ventricular (LV) function was made before and after each treatment period. After FDP treatment, LV end-diastolic and systolic dimensions showed a 6% reduction (P less than 0.01), while peak lengthening rate of LV dimension in diastole and peak shortening rate of LV dimension in systole increased 17% and 10%, respectively (P less than 0.05). There was evidence that FDP was more effective in the patients with ischemic heart disease than in the patients with cardiomyopathy.

Computerized echocardiographic study of left ventricular function and cardiodynamic investigation with a new antihypertensive agent (indenolol).

Indenolol hydrochloride is a recently introduced antihypertensive substance. Although it has beta-adrenoceptor blocking activity, its action is due to total peripheral resistance reduction. We investigated the effects of indenolol therapy on left ventricular performance in 15 patients with essential hypertension. Assessments were made using systolic time intervals and computerized echocardiography. The echocardiographic and mechanocardiographic tracings were recorded three times: at the beginning of the trial, after seven days of placebo, and after three weeks of indenolol treatment. The indenolol therapy significantly decreased (P less than 0.001) systolic and diastolic blood pressures and heart rate in all patients, both in supine and standing positions. After three weeks of treatment, systolic time intervals and echocardiographic determinants of left ventricular function were substantially unchanged in comparison with the basal and placebo evaluations. We conclude that indenolol exerted a marked effect on chronotropism but no demonstrable negative effect on inotropism in patients with essential hypertension. No clinical signs of heart failure were recorded. Side effects were absent, and patient compliance was good in all cases.

Increase in plasma HDL-cholesterol in hypertensive patients treated with enalapril.

The effects of enalapril on plasma lipoproteins were evaluated in an open study of 12 normolipidemic outpatients with mild-to-moderate essential hypertension (World Health Organization stages I and II). After a two-week washout period, during which placebo was given, the patients received 20 to 40 mg/day of enalapril for 16 weeks. Treatment with enalapril was associated with significant increases in levels of HDL cholesterol (mean, 23%; P less than 0.001) and apoprotein A (mean, 11%; P less than 0.01), largely because of the increase in the subfraction HDL2 (mean, 43%; P less than 0.001), although the subfraction HDL3 also rose (mean, 14%; P less than 0.005). Total cholesterol and LDL cholesterol levels did not change, whereas triglycerides decreased significantly (mean, 26%; P less than 0.001). Apoprotein B was unchanged. Unlike diuretics and most beta-blockers, enalapril favorably affects plasma lipoprotein levels, thus improving the overall cardiovascular risk in hypertensive patients.