Depressor effects of captopril in DOCA-salt hypertensive rats: role of vasopressin

Oral administration of the angiotensin I-converting enzyme inhibitor captopril produced a substantial reduction of blood pressure in DOCA-salt hypertensive rats. After oral administration of captopril (30 mg/kg), mean blood pressure decreased from 172 +/- 11 to 148 +/- 9 mmHg (P less than 0.01) in one hour and its antihypertensive effects lasted for the next seven hours. Plasma vasopressin levels showed a marked elevation in DOCA-salt hypertensive rats compared with control values (22 +/- 5 versus 5 +/- 3 pg/ml). This increase in vasopressin was significantly reduced by captopril from 25 +/- 5 to 8 +/- 6 pg/ml. In addition, whole body vascular reactivity to norepinephrine was examined. Responsiveness was at first attenuated but returned to control value in spite of reduction of both plasma vasopressin and blood pressure. Thus, captopril reduces blood pressure in DOCA-salt hypertensive rats and the fall in blood pressure is accompanied by reduction of plasma vasopressin and attenuation of vascular reactivity.     

Blood Pressure Variations,Hemorheological Determinants,and Platelet Aggregation in Hypertensive Patients with Unstable Angina

Plasma viscosity, fibrinogen, haematocrit and ß-thromboglobulin were assessed on venous blood samples taken within 24 hours of admission from 20 consecutive male hypertensive patients with unstable angina and 20 male hypertensive patients with stable angina, matched for clinical variables.

Besides, all patients underwent automated indirect blood pressure monitoring for 24 hours, starting just after hospitalization.

Despite similar average 24-hour, day-time and night-time systolic and diastolic blood pressure, hypertensive patients with unstable angina showed an increased variability of 24-hour (p<0,01) and day-time (p<0,05) systolic and diastolic blood pressure, together with higher values of all haemorhelogical parameters (plasma viscosity, fibrinogen and haematocrit) (p<0,01) and ß-thrombogobulin (p<0,05), when compared with hypertensive patients with stable angina. Moreover, significant correlations between plasma viscosity and 24-hour systolic (r=0,42, p<0,01) and diastolic (r=0,39, p<0,05) blood pressure variability were shown in hypertensive patients with unstable angina.

Besides, in the same patients, the haematocrit was positively correlated with 24-hour systolic blood pressure variability (r=0,37, p<0,05).

Our data further support the relevance of rheological determinants, platelet activation and haemodynamic factors in the genesis of the high risk condition of unstable angina.     

EFFECT OF NICARDIPINE VERSUS ENALAPRIL ON PLASMA ENDOTHELIN-1 IN HYPERTENSIVE PATIENTS WITH TYPE 2 DIABETES MELLITUS

We compared the effects of dihydropyridine type Ca channel blocker slow-release nicardipine and angiotensin converting enzyme inhibitor enalapril on plasma endothelin-1 (ET-1) levels in hypertensive type 2 diabetic patients (n = 20). Nicardipine or enalapril was administered for 6 months by a crossover design. Nicardipine and enalapril comparably lowered blood pressure. Enalapril significantly reduced urinary albumin excretion in microalbuminuric patients, whereas nicardipine did not. Urinary β2-microglobulin excretion was significantly increased during nicardipine treatment. However, both drugs significantly reduced plasma ET-1 as compared with pretreatment levels, close to that in healthy control (2.9 ± 0.3 pg/ml in control, 4.8 ± 0.3 pg/ml before treatment, 3.2 ± 0.3 pg/ml during nicardipine vs before treatment p<0.05, 2.9 ± 0.4 pg/ml during enalapril vs before treatment p<0.01). The decrease in plasma ET-1 was significantly correlated with the increase in natriuresis in normoalbuminuric patients treated with enalapril (r=?0.82, p<0.01) but not in those treated with nicardipine. Although nicardipine and enalapril had different renal effects, both drugs equally suppressed plasma ET-1 levels in hypertensive patients with type 2 diabetes.     

Handgrip Increases Endothelin-1 Secretion in Normotensive Young Male Offspring of Hypertensive Parents

Objectives. We tested the hypothesis that an abnormal response of plasma endothelin-1 (ET-1) is elicited by handgrip exercise (HG) in young normotensive offspring of hypertensive parents.Background. It has been hypothesized that ET-1 is involved in blood pressure control and plays a pathophysiologic role in the development of clinical hypertension.Methods. Two groups of healthy male subjects, 11 with hypertensive parents (group A) and 10 without a family history of hypertension (group B), underwent 4 min of HG at 50% maximal capacity. Heart rate and blood pressure and plasma levels of ET-1, epinephrine and norepinephrine were measured at baseline, peak HG, and after 2 (R2) and 10 (R10) min of recovery.Results. Group A had higher norepinephrine levels than group B throughout the test (baseline 181 ± 32 [SEM] vs. 96 ± 12 pg/ml, p < 0.05; peak HG 467 ± 45 vs. 158 ± 12 pg/ml, p < 0.000001; R2 293 ± 46 vs. 134 ± 8 pg/ml, p < 0.01; R10 214 ± 27 vs. 129 ± 10 pg/ml, p < 0.0005); no significant difference in epinephrine levels was detected. Compared with group B subjects, group A had higher baseline ET-1 levels (1.07 ± 0.14 vs. 0.59 ± 0.11 pg/ml, p < 0.02), which increased to a greater extent at peak HG (1.88 ± 0.31 vs. 0.76 ± 0.09 pg/ml, p < 0.005) and R2 (2.46 ± 0.57 vs. 1.31 ± 0.23 pg/ml, p < 0.05) and remained elevated at R10 (3.16 ± 0.78 vs. 0.52 ± 0.09 pg/ml, p < 0.002). Multivariate analysis demonstrated that only a family history of hypertension (chi-square = 7.59, p = 0.0059) and ET-1 changes during HG (chi-square = 4.23, p = 0.0398) were predictive of blood pressure response to HG and that epinephrine and norepinephrine were not.Conclusions. The response to HG in offspring of hypertensive parents produced increased ET-1 plasma levels and resulted in a sustained ET-1 release into the bloodstream during recovery compared with offspring of normotensive parents. This may be an important marker for future clinical hypertension.     

Hemodynamic and endocrine changes associated with captopril in diuretic-resistant hypertensive patients

To evaluate the therapeutic efficacy of oral angiotensin-converting enzyme inhibition with low-dose (average 30 mg/day) captopril in diuretic-resistant hypertension, its long-term cardiocirculatory action was determined by dye-dilution method and venous-occlusion forearm plethysmography in 11 uncontrolled patients taking a thiazide diuretic. Significant declines in mean blood pressure (average 12.4 ± 1.4 percent) and systemic vascular resistance (28.7 ± 3.2 percent) accompanied an increase in cardiac output (24.8 ± 4.1 percent). Forearm vascular resistance (16.0 ± 2.7 percent) decreased considerably, but the decrease in limb vascular resistance did not parallel the fall in systemic vascular resistance in magnitude (p < 0.01), indicating that arteriolar dilatation occurred on a selective basis. Plasma renin activity increased after therapy as plasma aldosterone levels consistently fell, while plasma norepinephrine concentrations were not changed. There was a direct correlation between pretreatment plasma renin activity and the magnitude of the decline in systemic vascular resistance (p < 0.05).These findings suggest that the Inhibition of angiotensin-converting enzyme with captopril in diuretic-resistant hypertensive patients improves cardiocirculatory function through selective dilatation. The reordering of regional blood flow, which appears to result from release of angiotensin-mediated vasoconstriction as well as the suppression of aldosterone, may underlie the prolonged benefit observed in these patients. This oral vasodilator in very low dose appears to represent an effective adjunct for the treatment of hypertension refractory to diuretics.     

Atrial Natriuretic Factor Response to Acute Volume Expansion in Borderline Hypertension. Role of Ace-Inhibition and Changes in Peripheral Venous Tone

Abnormalities in the response of atrial natriuretic factor (ANF) to volume expansion have been reported in hypertensive-prone animals and men as well as in hypertensive patients undergoing ACE-inhibition. To investigate some of the mechanisms affecting ANF release in borderline hypertensive patients (BHT) we have studied 16 subjects by assessing their neuro-humoral and hemodynamic response to a two-hour isotonic i.v. NaCl infusion carried out during short-term administration of either placebo or captopril. ACE-inhibition increased baseline venous distensibility (VV₃₀:1.4 vs 1.6 ml/100 ml;p<.05) and reduced the prompt (45′) ANF response to saline loading (10.3±13 vs 42.7±15%;p<.05)) without affecting the overall ANF release (120′:92±25 vs 65.8±20%;NS)). A significant pressor increase in response to NaCl loading was observed exclusively after ACE-inhibition (SBP:5.2±2 vs 2.4±1%; p < .05 - DBP:7.1±3 vs 2±3%; p < .025) and occurred along with a peripheral arterial and venous constriction and with an increase in plasma levels of an endogeneous Na⁺/K⁺ ATPase inhibitor (8.8 ± 4 vs ?2±4%; p <.05). We conclude that the ANF response to saline infusion is delayed by ACE-inhibition in borderline hypertensives. The abnormalities observed in ANF response could follow the changes in peripheral venous distensibility and contribute to the pressor and neuro-humoral derangements described in borderline hypertensives during volume expansion.     

Effects of Quinapril Hydrochloride in Patients with Essential Hypertension and Impaired Renal Function

The short-term effects of administration of an angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride (quinapril) (5–10mg/day), for 12 weeks on blood pressure and renal function were evaluated in 8 patients (60.5±7.3 years old, mean±SD) with mild to moderate essential hypertension and mild impairment of renal function due to nephrosclerosis. Systolic blood pressure and diastolic blood pressure were significantly reduced from 163.0± 4.0 to 132.3± 17.6 mmHg (p<0.01) and from 98.3± 4.6 to 81.5± 6.4 mmHg (p<0.001), respectively, before to after treatment. Both renal plasma flow (RPF) and glomerular filtration rate (GFR) were significantly increased in all patients, from 203.9 ± 33.3 to 245.4 ± 36.7 ml/min/1.73m² (p<0.01), and from 43.4± 6.4 to 53.5± 4.6 ml/min/1.73m² (p<0.05), respectively.

Short-term quinapril administration was beneficial to renal function in patients with essential hypertension and impaired renal function.     

Sympathetic activity in idiopathic dilated cardiomyopathy. Influence of captopril and hydralazine

Summary To study the interrelationship between myocardial norepinephrine content, left ventricular (LV) and right ventricular (RV) function, morphological changes, and plasma catecholamine concentrations, 20 patients with idiopathic dilated cardiomyopathy underwent endomyocardial biopsy and ventricular angiography. The strongest correlation was found between LV ejection fraction (EF) and myocardial norepinephrine content (r=0.87; p<0.001). Myocardial norepinephrine content was much weaker correlated to RV EF (r=.55; p<0.005), and no correlation was found to morphological changes or plasma norepinephrine concentration. The hemodynamic and neurohumoral effects of hydralazine versus captopril after the first dose were compared in a crossover trial including 15 patients with idiopathic dilated cardiomyopathy. Hydralazine induced increases in heart rate and cardiac index (p<0.01) and decreases in mean arterial pressure and pulmonary wedge pressure (p<0.01 and p<0.005, respectively). These hemodynamic effects were associated with increased plasma norepinephrine concentrations during upright exercise (p<0.05) and increased plasma renin activity (p<0.01). After captopril, norepinephrine plasma concentrations showed a tendency to lower levels during upright exercise, although mean arterial pressure decreased significantly (p<0.01). These data suggest that, in patients with idiopathic dilated cardiomyopathy, myocardial norepinephrine depletion strongly reflects left ventricular dysfunction. The different patterns of neurohumoral response to hydralazine versus captopril may be important for their long-term effect and for the prognosis of patients with idiopathic dilated cardiomyopathy. It remains to be established whether the myocardial catecholamine content is differently influenced by either drug, and whether this effect is related to the drug response after long-term treatment.     

Neurogenic factors in low renin essential hypertension

The interrelationships between blood pressure, plasma catecholamines and plasma renin activity (PRA) were studied in 12 patients with low PRA, in 18 patients with essential hypertension and normal PRA and in 11 normal subjects, after being supine for 1 hour, standing 1 hour and after the oral administration of furosemide, 80 mg. Patients with low PRA were older and had higher (p < 0.05) mean blood pressure levels (113 ± 4.2 mg Hg) than patients with normal PRA (103 ± 1.9 mm Hg). Plasma norepinephrine levels were 145 ± 14 ng/liter in normal volunteer subjects, 202 ± 25 ng/liter in hypertensive subjects with normal PRA and 203 ± 26 ng/liter in hypertensive subjects with low PRA. The increase of plasma norepinephrine and epinephrine after standing 1 hour and after the administration of furosemide was similar in hypertensive subjects with low or normal PRA and in normal volunteer subjects. However, the increase in PRA after standing or after the administration of furosemide was significantly reduced in patients with low PRA. These data suggest that patients with low PRA have a normally responsive sympathetic nervous system and that the low PRA may be due to a defective renin response to the sympathetic nerve stimulation. Blood pressure was significantly correlated with plasma catecholamines in normal volunteer subjects (r = 0.71, p < 0.05) and in the hypertensive patients (r = 0.49, p < 0.05). An analysis of the regression lines for the two groups suggests that increased vascular reactivity to catecholamines may account for the increased blood pressure at each level of catecholamines in hypertensive subjects as compared to normal volunteer subjects. Basal plasma aldosterone levels were similar in patients with low and with normal PRA.Norepinephrine clearance was lower in hypertensive than in normotensive subjects.     

Poor Blood Pressure and Urinary Albumin Excretion Responses to Home Blood Pressure-Based Antihypertensive Therapy in Depressive Hypertensive Patients

J Clin Hypertens (Greenwich). There has been no report comparing the changes in home blood pressure (HBP) and target organ damage between depressive and nondepressive hypertensives receiving antihypertensive therapy based on HBP monitoring. This study was a multicenter prospective study conducted by 7 doctors at 2 institutions. The authors prospectively studied 42 hypertensive patients with home systolic blood pressure >135 mm Hg. Participants were divided into a depression group (Beck Depression Inventory score >10; n=21) and a nondepression group (Beck Depression Inventory score <9, matched for HBP level; n=21). The authors performed antihypertensive therapy to reduce home systolic blood pressure to below 135 mm Hg and, 6 months later, evaluated the urinary albumin/creatinine ratio (UACR). Although patients in the depression group tended to require the addition of a greater number of medications than those in the nondepression group (2.3±1.0 vs 1.7±1.0 drugs, P<.05), HBP was reduced similarly in both groups at 6 months (depression group: 150±17/78±11 mm Hg to 139±11/73±8 mm Hg, P<.001; nondepression group: 150±11/76±9 mm Hg to 135±9/70±8 mm Hg, P<.01). The reduction of UACR was smaller in the depression group than in the nondepression group (2.4 vs 10.1 mg/gCr, P<.05). Depressive hypertensive patients required a larger number of antihypertensive drugs to control HBP, and showed a smaller reduction in UACR than nondepressive hypertensives.     

Captopril in congestive heart failure resistant to other vasodilators

In an attempt to study the possible mechanism(s) by which captoprilcontrols resistant heart failure, sequential haemodynamic studies(radioisotope technique) and humoral measurements (plasma reninactivity, plasma aldosterone and plasma catecholamines) wereobtained in 11 such patients. The studies were made at the timepatients became unresponsive to other vasodilators (hydralazineorprazosin); the vasodilator drug was then discontinued andfive days later, the ‘no-vasodilator’ studies wereobtained. Captopril therapy was then started. Optimum dailymaintenance dose of captopril varied from 75 to 200 mg in differentpatients. Studies were again repeated aftera period of timeequal to the duration of the previous vasodilator therapy. Digitalisand diureticdoses were kept constant throughout.Captopril improvedeffort tolerance in ten patients. Haemodynamically, mean bloodpressure and peripheral resistance were lower than during vasodilatortherapy (85±3-l v. 92±3-3 mmHgand 47±4-4v. 59±4-4 U.M², respectively; p<0-05 for both). Cardiacindexwas higher during captopril treatment (l-95±0-15 v. l-63±0-10l/m¹,p<0-01) and pulmonary mean transit was normalized by captopril(14-6±l-7 v. 18-4±l-3s, p<0-05).Humoral indicesrevealed a significant (p<0-05) reduction in plasma aldosteroneduring captopril therapy (25-9±5-6 ng/dl during captopril,v. 62±22 ng/dl with novasodilators and 50-9±6-lng/dl with other vasodilators). Moreover, there was a decreasein circulating plasma catecholamines during captopril treatment,but differences between the three treatment periods were notstatistically significant.Data suggest that the effectivenessof captopril in controlling congestive heart failure that becameresistant to other forms of vasodilator therapy might be relatedto more than one factor including persistent haemodynamic unloading,decrease of plasma aldosterone, and possibly reduction of sympatheticactivity.     

Reversal of left ventricular hypertrophy with captopril: Heterogeneity of response among hypertensive patients

Reversal of left ventricular hypertrophy (LVH) has been reported not to occur with all antihypertensive agents. Moreover, a dissociation between blood pressure response to medical therapy and reversal of ventricular hypertrophy has been previously observed. To evaluate the effects of captopril we studied the electrocardiographic (ECG) changes in 26 severe hypertensive patients who received the drug for more than one year. In 14 patients with normal pretreatment ECG, captopril controlled blood pressure effectively [132±2.9 (SE) to 104±3.9 mmHg, p<0.001], but had no effect on ECG voltage. In 12 patients with pretreatment LVH, two different response patterns were observed despite similar blood pressure control (144±4.9 to 102±3.1 mmHg and 148±7.3 to 109±7.3 mmHg, p<0.001 for both): seven had complete normalization of ECG while five had residual LVH pattern. No significant difference was found between the latter two groups in regard to age, sex, weight, etiology of hypertension, pretreatment ECG voltage, blood pressure, plasma renin activity, duration of treatment and duration of maintained blood pressure control. The reversal of LVH pattern occurred early (between 12 to 16 months) with no overall correlation between lowering of blood pressure and ECG voltage changes. The heterogeneity of response observed in this study suggests that factors other than blood pressure control modify the reversal of cardiac hypertrophy by antihypertensive therapy.     

Enalapril & Nifedipine in Essential Hypertension: Synergism of the Hypotensive Effects in Combination

ABSTRACT

Twelve male hypertensive patients who had required enalapril and nifedipine to control their blood pressure were entered into a study of modified 2 × 2 factorial design (3 week study periods) to determine the effect of each drug separately and in combination. Factorial analysis indicated that enalapril alone (20 mg/d) lowered supine blood pressure by 10±2/8±1 mmHg, nifedipine alone (30 mg/d) lowered supine blood pressure by 11±2/8±1 mmHg and there was a positive interactive effect of 10±3/7±2 mmHg (P < 0.001) such that the combination lowered supine blood pressure by 32±3/24±2 mmHg. The effects of the individual drugs were both significant (P < 0.001) but did not differ from each other.

Enalapril and nifedipine are both effective antihypertensive drugs and in some hypertensive patients their effects appear to be synergistic.     

Exaggerated Response to Electrical Nerve Stimulation of Angiotensin II Release in Isolated Perfused Hind Legs of Spontaneously Hypertensive Rats

Previously we reported that a large amount of immunoreactive angiotensin II (Ang II) was released from isolated perfused rat hind legs at steady rates for several hours. In view of a recent intriguing hypothesis that the vascular renin-angiotensin system plays an important role in the maintenance of high blood pressure in certain forms of experimental hypertensive models, the release of immunoreactive Ang II from isolated hind legs of spontaneously hypertensive rats (SHR) was examined in comparison with normotensive rats of Wistar-Kyoto strain (WKY) by using a Sep-Pak C₁₈ cartridge directly connected to the perfusion system. We also examined effect of electrically-induced nerve stimulation on the release of immunoreactive Ang II in the two strains. High performance liquid chromatography demonstrated the presence of Ang II in the prefusate. The spontaneous release of immunoreactive Ang II was as high as about 300 to 500 pg/30 min, tended to be higher in SHR rats (435.0±68.2 pg/30 min) than in WKY rats (342.1±65.1 pg/30 min), and stable up to 3 hours of perfusion for both strains. Periarterial nerve stimulation elicited a significant increment in the release of immunoreactive Ang II in either SHR (p<0.02) or WKY rats (p<0.05); however, the amount of released immunoreactive Ang II evoked by nerve stimulation was significantly greater in SHR than in WKY rats (781.3±89.6 vs 498.8±54.6 pg/30 min, p<0.05). These results further provide evidence for local generation and release of Ang II in peripheral vascular tissues, and are consistent with the hypothesis that the vascular renin-angiotensin system is one of important factors responsible for the maintenance of blood pressure.     

Neuropeptide Abnormalities Suggest a Dopaminergic Basis for High Blood Pressure in the Spontaneously Hypertensive Rat

The spontaneously hypertensive rat (SHR) and the stroke-prone substrain (sp-SHR) have been reported to have several abnormalities in levels of peptides both in tissue and in plasma (β- endorphin, prolactin, thyroid stimulating hormone and vasopressin) when compared to the Wistar Kyoto (WKY) normotensive control rat. As the secretion of these peptides is under dopaminergic control and the abnormalities consistently suggest under-activity of the dopaminergic control system in the brain, injections of dopamine (0.4 mg/kg) were given i.c.v. to 10 SHR, 10 renal artery stenosis hypertensive rats (LRAS) and 10 genetically hypertensive rats of the New Zealand strain (GHR). Mean blood pressure fell from 205±6(SEM) mmHg to 128±8 mmHg in the SHR (p<0.001), from 184±7 mmHg to 176±7 mmHg in the LRAS (p>0.05) and from 157±5 mmHg to 138±6 mmHg in the GHR (p<0.02). These effects were unlikely to be due to leakage of dopamine out into the periphery as i.v. dopamine (0.4 mg/kg) increased blood pressure in these animals.     

Effect of Captopril on Blood Pressure and on the Renin-Angiotensin-Aldosterone System in Coarctation of the Aorta

To investigate the role of the renin-angiotensin-aldosterone system in hypertension due to coarctation of the aorta (COA), upright mean arterial pressure (MAP), plasma renin activity (PRA) and plasma aldosterone (Aldo) were determined before and 90 minutes after a single oral dose of captopril (25 mg) in eight patients with COA and in fourteen with essential hypertension (EH). There was no significant difference in MAP, PRA or Aldo values between the two groups in base-line conditions. After captopril administration, MAP and Aldo decreased significantly in both groups (p>0.01), whereas PRA showed a marked increase in patients with COA (p>0.001) and no significant changes in EH patients (from 1.5±2.2 to 49.7±9.8 and from 5.6±0.9 to 8±1.5 ng/m1/3h respectively). Conclusions: 1) MAP reduction and marked renin increase after captopril in COA patients support the view that systemic hypertension in COA is, at least in part, renin mediated and 2) the evaluation of PRA after captopril could be helpful in the decision to proceed with more invasive procedures in patients with suspicious clinical features of COA or with residual post-coarctectomy hypertension.     

Plasma renin activity and norepinephrine as predictors for antihypertensive effects of nifedipine and captopril

To examine predictors for the efficacy of antihypertensive agents, we investigated the effects of nifedipine and captopril on blood pressure (BP) and humoral factors in patients with essential hypertension. Eleven essential hypertensive patients (mean age: 54) were treated with long acting nifedipine at 20 to 40 mg/day for 8 weeks and 25 essential hypertensives (mean age: 51) were treated with captopril at 37.5 to 75 mg/day. Blood pressure was measured every 2 weeks. Plasma renin activity (PRA), and plasma concentrations of aldosterone, epinephrine and norepinephrine were determined before and at the end of treatment. Both nifedipine and captopril decreased BP (nifedipine: mean BP 119 +/- 3 to 101 +/- 2 mm Hg, captopril: 124 +/- 2 to 100 +/- 2, P less than .01 for each), whereas neither of them affected heart rate. The 8-week treatment of nifedipine showed no significant effect on humoral factors. Captopril increased PRA by 63% (P less than .05) and decreased plasma epinephrine by 42% (P less than .01) and norepinephrine by 35% (P less than .01). The change in mean BP was positively correlated with pretreatment PRA (r = 0.68, P less than .01) in nifedipine-treated patients and inversely with pretreatment norepinephrine (r = -0.53, P less than .01) in captopril treatment. The results suggest that both nifedipine and captopril were effective antihypertensive agents and that the long term treatment of nifedipine is more effective in essential hypertensives with lower PRA, while captopril is more effective in those with higher plasma norepinephrine concentration.     

Hemodynamic effects of captopril in patients with severe chronic heart failure

The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25 mg dose, the cardiac index increased from 1.82 ± 0.14 to 2.28 ± 0.30 liters/min/m² (p < 0.05) while pulmonary capillary wedge pressure decreased from 22.7 ± 2.0 to 14.7 ± 4.7 mm Hg (p < 0.05). Mean blood pressure and systemic vascular resistance decreased from 85.7 ± 6.7 to 71.2 ± 12.0 mm Hg (p < 0.001) and from 1,909 ± 246 to 1,362 ± 347 dynes-s-cm⁵ (p < 0.001), respectively. Heart rate did not change significantly. There was an inverse relation between maximal augmentation in cardiac index and maximal reduction in pulmonary capillary wedge pressure (r = ?0.82, p < 0.01). While most patients demonstrated a constant hemodynamic benefit after repeated administration of captopril, some exhibited a triphasic response with attenuation of effects after the second dose and restoration of effects after the third dose. These hemodynamic benefits were observed in patients with stable chronic heart failure whose plasma renin activity was within normal range (1.1 to 7.3 ng/ml/hour).     

Sympathetic responsiveness and plasma norepinephrine during therapy of chronic congestive heart failure with captopril

The interaction of cardiac function and sympathetic tone in severe chronic heart failure was evaluated in 24 patients by assessing the cardiac index/plasma norepinephrine relationship. Potential changes were assessed during first-dose and long-term captopril therapy including sympathetic responsiveness to the gravitational stress of head-up tilt. Baseline cardiac index and norepinephrine levels demonstrated a significant inverse correlation (r = ?0.640, p < 0.001). Norepinephrine decreased from 803 ± 116 to 635 ± 76 pg/ml following first-dose captopril therapy (p < 0.02), with overall hemodynamic improvement. However significant first-dose correlations were not observed. During long-term therapy, norepinephrine decreased from 694 ± 118 to 457 ± 106 pg/ml, associated with improvement of symptoms and exercise tolerance. The extent of cardiac index increase was matched by norepinephrine reduction, so that their correlation was maintained (r = ?0.540, p < 0.02). First-dose and long-term therapy were associated with improved responsiveness of sympathetic tone to the reduction of cardiac index induced by the gravitational stress of tilt. In summary, sympathetic tone was increased in severe heart failure, correlating inversely with cardiac function. Although there was improvement of cardiac function with first-dose captopril therapy, significant correlations of supine improvement with reduction of sympathetic tone were noted primarily with long-term therapy. Responsiveness of sympathetic tone to the stress of tilt however, was evident during first-dose and long-term therapy.     

Comparison of effects of combined ACE inhibitor and low-dose thiazide diuretic with ACE inhibitor alone on insulin action in patients with hypertension and Type 2 diabetes: a double-blind crossover study

Aims To establish the safety in terms of insulin sensitivity of a low dose thiazide/ACE inhibitor combination. Methods We examined the effects on insulin sensitivity of captopril either alone or in combination with low-dose bendroflumethiazide (1.25 mg) in 15 hypertensive Type 2 diabetic patients. Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomised, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendroflumethiazide (CB) (1.25 mg). Results Blood pressure was lower following CB compare to C (138/83 vs. 144/85 mmHg; P < 0.05) and both were lower than baseline (153/92 mmHg; P < 0.01). CB resulted in a significant increase in fasting plasma glucose compared to C (9.6 ± 2.6 vs. 8.5 ± 1.6 mmol/l; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (25.1 ± 13.3 vs. 34.2 ± 16.8 µmol/kg/min; P < 0.01) as were isotopically determined glucose utilisation rates (29.0 ± 12.4 vs. 36.6 ± 17.3 µmol/kg/min; P < 0.05). There was no significant difference in fasting endogenous glucose production between treatments (CB 9.3 ± 3.3 vs. C 8.6 ± 1.6 µmol/kg/min), nor between suppression following insulin (CB 4.0 ± 2.1 vs. C 4.3 ± 3.1 µmol/kg/min). Conclusions Combination of low-dose bendroflumethiazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone.