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Intraarterial blood pressure (BP) monitoring during free ambulation (Oxford technique) was carried out in 12 essential mild-to-moderate hypertensive patients undergoing 4 weeks treatment with felodipine, 10 mg given once daily in an extended release formulation. Compared to placebo, felodipine significantly reduced systolic and diastolic blood pressure throughout 24 h. The greatest reduction was observed at 10 AM, 3 h after drug administration (-32 +/- 6/-24 +/- 5 mm Hg for systolic and diastolic BP, respectively, P less than .001). Hourly BP values remained significantly lower up to and including the 24th hour during felodipine extended release treatment (-18 +/- 5/-11 +/- 3 mm Hg, P less than .001). Felodipine extended release also reduced 24 h blood pressure variability, evaluated on the standard deviation of each hourly mean (from 16.3 +/- 0.9/12.6 +/- 0.6 to 13.4 +/- 0.6/10.4 +/- 0.6 mm Hg, P less than .01). Furthermore, absolute BP values dropped significantly at the peaks of dynamic exercise (bicycle ergometer: from 248 +/- 13/123 +/- 11 to 204 +/- 24/102 +/- 13 mm Hg, P less than .001), isometric exercise (hand grip: from 232 +/- 18/133 +/- 16 to 180 +/- 20/101 +/- 16 mm Hg, P less than .001), and cold pressor test (from 229 +/- 20/127 +/- 14 to 178 +/- 22/99 +/- 15 mm Hg, P less than .001). In conclusion, felodipine extended release exerts a good antihypertensive effect which is maintained for 24 h and reduces the level of blood pressure peaks reached under different physical stresses.

To evaluate the effect of converting enzyme inhibition induced by enalapril on parasympathetic activity, we studied ten essential hypertensive patients, age range 38-58 years, WHO I-II. Parasympathetic evaluation was obtained by measuring the variation of heart period (VHP) during at least 1 minute of steady-state, regular respiration. VHP was derived from the difference between the mean of all maximum and the mean of all minimum heart periods. The higher the VHP, the higher the parasympathetic control of heart rate and vice versa. VHP was measured supine and with tilting (30 degrees, 60 degrees, 85 degrees). Blood pressure was reduced after 1 month of enalapril treatment, while the heart rate did not change. VHP increased at the end of enalapril treatment compared with placebo: in the supine position it increased from 36 +/- 3.2 ms to 44 +/- 3.5 ms, p less than 0.01. VHP was also increased by enalapril at 30 degrees (p less than 0.05) and 60 degrees (p less than 0.05), while no difference was observed at 85 degrees between placebo and enalapril. A positive correlation was found between supine enalapril changes of VHP and those of systolic and diastolic BP. In conclusion, enalapril seems to increase parasympathetic cardiovascular control in essential hypertensive patients. This result might explain the lack of increase in heart rate that would be expected as a result of the vasodilating effect of enalapril.

The possible involvement of peripheral dopaminergic mechanisms in the action of atrial natriuretic peptides was investigated in 10 subjects by administering 200 micrograms h-ANP 99-126 intravenously for 30 min during treatment with 50 mg carbidopa, a peripheral inhibitor of dopamine synthesis, every 8 h, or during placebo. Atrial natriuretic peptide (ANP) infusion during placebo was associated with a significant increase of diuresis, natriuresis, kaliuresis, urinary noradrenaline, and dopamine excretion. Plasma aldosterone significantly decreased. Blood pressure was slightly reduced. The administration of carbidopa significantly reduced urinary dopamine excretion but did not modify natriuresis, diuresis, indexes of adrenergic and renin-aldosterone system activity, blood pressure, or heart rate, both in basal conditions and in response to ANP infusion. We conclude that the effects of exogenous ANP administration are independent from dopaminergic mechanisms that involve the synthesis of dopamine outside the central nervous system, particularly in the kidney.

HPLC with electrochemical detection is useful in the assay of catecholamines in biological samples. Two types of chromatographic column are currently employed by most investigators: reverse phase C-18 (RPC-18) or strong cation-exchange (SCX) columns. Our aim was to evaluate the specificity, sensitivity and reproducibility of plasma and urinary catecholamine assay by these two columns. Our study indicates that both columns give very good performance for clinical purposes but sensitivity, precision at low concentration and specificity seem to be better with ion-exchange columns which are therefore preferred at the present time.

Morbidity and mortality are higher in hypertensive patients who have already developed cardiovascular complications. Several prospective epidemiological and clinical studies have indicated that regression of cardiovascular alterations, preferably when still at an initial stage, is a desirable goal in the treatment of hypertension. Clinical assessment of cardiac hypertrophy may be precisely obtained with echocardiography. Structural vascular changes may be evaluated indirectly in man by measuring minimal vascular resistance from maximal blood flow and arterial pressure. The results of a large number of studies have indicated that in hypertensive patients a significant regression of cardiovascular structural changes may be obtained with several antihypertensive drugs, but they have not yet established whether a complete "normalization" may be really obtained. Further studies are needed to identify factors that modulate regression of cardiac and vascular smooth muscle hypertrophy. Most important, it still remains to be clarified whether regression of cardiovascular structural changes in hypertensives significantly improves prognosis per se independently from blood pressure reduction.

In this study we measured plasma renin activity (PRA), plasma norepinephrine (NE) and epinephrine (E), heart rate (HR) and blood pressure (BP) in 89 supine (sup) essential hypertensive patients (pts), WHO I-II, after 3-5 days of fixed normal sodium and potassium intake; the same measurements were repeated after 30' of active standing (stand) in 44/89 pts. In the whole population NE was directly related to PRA, both in sup and in stand position (p less than 0.01). NE was above the upper limits of normotensive controls in 2/34 (6%) pts with low PRA, in 6/40 (17%) pts with normal PRA and in 6/15 (40%) pts with high PRA. In respect to normal PRA pts, HR was significantly lower in low PRA pts and higher in high PRA pts, both in sup and in stand position (p less than 0.05). Sup and stand NE and E were similar in low and normal PRA pts, while they were significantly higher in high PRA pts (p less than 0.05). These results suggest an increased adrenergic tone at least in some high PRA pts, and blunted responsiveness of renal and cardiac beta adrenergic receptors to adrenergic stimuli in low PRA pts.

The temporal relationship between the "crossing" of equisensitive atrial and ventricular pressure tracings and the initial components of the first heart sound of the homolateral intracardiac phonocardiogram was analyzed in 35 dog experiments. These studies showed that the first component of the first heart sound followed the atrioventricular valve closure (AV crossing) in all instances by an average time interval of 23 msec and that, at the time of its occurrence, there was a ventricular-atrial pressure gradient of 5 mm Hg in the right side and of 14 mm Hg in the left side of the heart. It is concluded that valvular closure, per se, does not cause the first component of the first heart sound. Actually the first heart sound occurs later during the period of isometric ventricular contraction, suggesting that the rise of ventricular pressure is responsible for its vibrations. Comparative analyses of right and left intracardiac and external phonocardiograms showed that the right side component of the first heart sound follows the left in about three-fourths of the cases and is coincident with it in the remainder and that these events are reflected in the same order in the external phonocardiogram.

The short- and long-term effects of two calcium channel blocking drugs, verapamil and nifedipine, on blood pressure, heart rate, plasma catecholamines, plasma renin activity, plasma volume and cardiac performance (echocardiography) were studied in essential hypertensive patients and in normal subjects. Verapamil, 160 mg orally, reduced blood pressure within 60 minutes in 22 hypertensive patients, but not in 12 normotensive subjects. Nifedipine, 10 mg sublingually, reduced blood pressure within 15 minutes in 19 hypertensive patients, but not in 7 normotensive subjects. Plasma noradrenaline was significantly increased both in normal subjects and in hypertensive patients only after nifedipine was administered. Verapamil (80 mg three times a day) first, and nifedipine (10 mg three times a day) thereafter, or vice versa, were given to 12 hospitalized hypertensive patients on a fixed sodium and potassium intake; the drugs produced similar blood pressure reductions, but heart rate and plasma catecholamines were increased only after nifedipine (p less than 0.05). Neither drug affected plasma volume, aldosterone or plasma renin activity. Long-term ambulatory treatment with verapamil (80 or 160 mg three times a day for 2 to 4 months) or nifedipine (10 mg three times a day for 2 months) produced changes in all variables that were similar to those observed in the hospital (controlled) study. Shortening fraction was significantly increased after nifedipine (p less than 0.05) but no change was observed after verapamil. In conclusion, blood pressure is effectively reduced by both verapamil and nifedipine; an appreciable adrenergic stimulation may be caused by nifedipine, but usually not by verapamil, and fluid retention, renin release or myocardial depression is not observed during verapamil or nifedipine treatment.

We evaluated the left ventricular mass index (LVMI) and the functional response to cold pressor and handgrip tests in 74 untreated essential hypertensive patients and 26 age and sex-matched normals. The same measurements were repeated in 22 essential hypertensives after 6 and 12 months of treatment (captopril or nitrendipine, plus diuretic or beta-blocker in a few cases) and in 21 essential hypertensives after withdrawal of treatment, a reduction in the LVMI and a further increase in blood pressure. Left ventricular systolic function was evaluated by the relationship between left ventricular end-systolic stress and fractional shortening. Highly significant negative correlations, with similar slopes and intercepts, were found between end-systolic stress and fractional shortening under basal conditions, after regression of left ventricular hypertrophy and after withdrawal of treatment, both at rest and at the peak of stress tests. An examination of each point of the relation between end-systolic stress and fractional shortening showed that very few points were beyond the 95% prediction limits of the correlation obtained in normal volunteers. These results indicate that left ventricular systolic function is normal in most untreated essential hypertensives, and is usually well maintained after regression of left ventricular hypertrophy during long-term treatment as well as after withdrawal of treatment, both at rest and during an acutely induced afterload increase.

In patients with hypertension, structural changes develop in the heart and in the systemic arteries that have a significant role in the maintenance and gradual worsening of the hypertensive disease. Blood pressure, basal and post-ischemic "maximal" forearm blood flow (strain-gauge venous occlusive plethysmography), and echocardiographic left ventricular mass index were measured in 28 hypertensive patients (WHO class I or II, 23 men and five women, aged 26 to 59 years). Minimal vascular resistance (mean arterial pressure/peak blood flow) was taken as an index of vascular structural changes. The same measurements were made in a group of 14 patients before and after long-term antihypertensive treatment: in eight patients after six and 12 months of treatment with captopril (50 mg twice a day, plus 25 mg of hydrochlorothiazide per day if necessary) and in six patients after six months of treatment with nitrendipine (20 mg per day, plus 50 mg of atenolol per day if necessary). A significant but weak direct correlation was found between the degree of left ventricular hypertrophy and mean arterial pressure (r = 0.41) or minimal vascular resistance (r = 0.31). Thus, patients were categorized according to whether they had left ventricular hypertrophy or impaired blood flow; the results suggested that left ventricular hypertrophy may be detected earlier than increased minimal vascular resistance. After six months of treatment, both captopril and nitrendipine significantly reduced left ventricular mass index and minimal vascular resistance. Left ventricular mass index was normalized in 50 percent of the patients, whereas minimal vascular resistance was normalized in one patient only. After 12 months of treatment, left ventricular mass index was normalized in all patients; minimal vascular resistance was on the average further reduced but normalized in only one additional patient. Thus, regression of cardiovascular structure also seems to occur earlier in the heart.

Physical exercise can induce micro-albuminuria, a urinary albumin excretion rate of 20-200 micrograms/min, in diabetics without micro-albuminuria at rest (stage II of diabetic nephropathy). The aim of the present study was to evaluate the acute effects of captopril, an angiotensin converting enzyme (ACE) inhibitor, and nifedipine, a calcium channel blocker, on exercise-induced micro-albuminuria in hypertensive diabetics with stage II nephropathy. Eleven hypertensive World Health Organisation (WHO) stages I-II non-obese diabetics (five insulin-dependent diabetics, six non-insulin dependent diabetics) underwent five submaximal cycloergometric tests, the first two in basal conditions, the other three after 24-h administration of captopril (25 mg twice a day), placebo (1 tablet twice a day) or nifedipine AR (20 mg twice a day) according to a randomized double-blind design. Our results demonstrate that despite a lower reduction in exercise blood pressure, captopril is more effective than nifedipine in blunting diabetic exercise-induced micro-albuminuria.

Vasodilator drugs lead to secondary baroreflex mediated chronotropic effects. The aim of the present study was to evaluate long term therapy with nicardipine, a calcium antagonist, on exercise performance and autonomic nervous system activity. Nicardipine was administered to 10 untreated mild-moderate essential hypertensive patients. Isometric (hand grip) and dynamic (bicycle ergometer) exercise, and parasympathetic activity evaluated on the basis of Variation of Heart Period (VHP) during regular breathing were determined. Blood pressure was significantly lowered by nicardipine both supine and standing (p less than 0.001). Heart rate did not change. The increase of blood pressure during isometric and dynamic exercise was similar both before and during nicardipine. The increase of heart rate during dynamic exercise was lowered by nicardipine. The lack of basal supine and standing chronotropic activation and the smaller increase of heart rate during bicycle ergometer could be explained by the observed increase in parasympathetic activity, as indicated by the rise of VHP.

This study evaluated by echocardiography (M-mode tracings, two-dimensional-guided) the effects of captopril administration for one year (25 to 50 mg twice a day, alone or in combination with hydrochlorothiazide when necessary) on left ventricular mass index, on systolic function at rest and during stress (hand grip for three minutes and cold pressor test for three minutes), and on diastolic function in 15 patients with essential hypertension (13 men and two women, aged 30 to 67 years) with left ventricular hypertrophy. In addition, supine and standing plasma catecholamine concentrations, plasma renin activity, and plasma aldosterone levels were measured. Examinations were performed during a placebo period and after three, six, and 12 months of captopril treatment. Blood pressure was significantly reduced (p less than 0.001), but heart rate did not change. Left ventricular hypertrophy was progressively reduced during treatment, mainly through reduction of left ventricular wall thickness. After one year, all patients had a normal left ventricular mass index (less than 120 g/m2). Before and during treatment, left ventricular systolic function, at rest and on maximal hand grip and cold pressor testing, evaluated on the basis of fractional shortening as related to end-systolic stress, was within the 95 percent confidence limits (calculated in a group of 25 normal subjects) in all 15 patients with essential hypertension. The percent increase in left ventricular dimensions during the diastolic rapid filling phase was significantly increased by treatment (p less than 0.05), indicating improvement of left ventricular relaxation. As expected, plasma renin activity was increased, plasma aldosterone levels were decreased, and plasma catecholamine concentrations did not change. These results indicate that long-term treatment with captopril has beneficial effects on left ventricular anatomy and function in patients with essential hypertension.

Vasodilator drugs reduce peripheral vascular resistance but lead to a secondary baroreflex-mediated chronotropic effect. After angiotensin-converting enzyme inhibition, blood pressure falls without associated tachycardia. In a previous study it was observed that enalapril increased vagal tone in essential hypertensive patients. In order to evaluate the effect of enalapril on sympathetic stimulation 10 mild to moderate hypertensive patients were studied during static (hand grip) and dynamic exercise (bicycle ergometer), after 2 weeks of placebo and after 1 month of treatment with 20–40 mg enalapril once daily. Enalapril significantly reduced blood pressure and the rate–pressure product at rest and at peak dynamic exercise. There was no effect on supine and maximal heart rate. Enalapril also significantly reduced blood pressure during hand grip, but did not interfere with the rate of the increase. Thus, enalapril does not seem to interfere with sympathetic adaptation to stress.

Pinacidil, a new cyanoguanidine derivative, is an antihypertensive agent with arteriolar vasodilating properties, which acts on precapillary resistance vessels. A trial was carried out in 30 patients with essential hypertension WHO I-II. The treatment period was divided into three phases. Hydrochlorothiazide (HCTZ) and amiloride were administered for 4 weeks in Phase 1 and supine and standing blood pressure decreased significantly. During Phase 2 pinacidil was added to HCTZ/amiloride for the following 3 months. A further significant reduction in blood pressure was obtained. In the next period of treatment (Phase 3) patients were divided into two groups. For 1 month Group A (15 patients) received pinacidil alone and Group B (15 patients) received HCTZ/amiloride. Conventional laboratory blood tests in all patients remained unchanged during treatment. Reported side effects during Phase 2 were headache (2 patients), dizziness (3 patients), palpitations (2 patients) and ankle oedema (2 patients). Plasma renin activity was slightly increased at the end both of Phases 1 and 2. Plasma catecholamines were increased but not significantly at the end of Phase 2 as compared to Phase 1. The results indicate that pinacidil is effective in lowering blood pressure in mild to moderate essential hypertension.

The effects on cardiac function of captopril (CPT) and digoxin (D) were compared in a study of 16 patients with chronic heart failure due to ischemic heart disease (15) and to congestive cardiomyopathy (1) (New York Heart Association class II n.13 and class III n.3). All patients were normotensive and in sinus rhythm. CPT 25 mg every 8 hours (t.i.d.) or D 0.25 mg once daily was given in a single-blind crossover design: A placebo (PLC) t.i.d. was given for 5 to 10 days, then CPT or D, according to a random sequence, replaced three or one of the PLC tablets; after one month, CPT and D were switched to PLC for 5 to 10 days; subsequently, the PLC tablets were replaced by CPT in the patients who previously received D and vice versa, and both treatments were again continued for one month. PLC, CPT, and D tablets were all identical. Diuretics once daily were given throughout the study. Plasma renin activity (PRA), plasma aldosterone (ALDO), plasma noradrenaline (NA), and adrenaline (A) were determined at the end of the two PLC periods and the two active treatments. A hand grip and a bicycle exercise were performed at the end of the two PLC periods and the two active treatments. No difference was noted between the PLC periods. PRA increased with CPT and did not change with D. ALDO was decreased by both CPT and D. NA and A were similarly decreased by both drugs, both supine and standing.(ABSTRACT TRUNCATED AT 250 WORDS)

In 14 essential hypertensive patients, aged 26-59 years, blood pressure, left ventricular mass index (LVMI), systolic function (M-mode echo, two-dimensionally guided), post-ischaemic 'maximal' forearm blood flow (strain gauge venous occlusion plethysmography), plasma renin activity, plasma catecholamines and aldosterone were measured before and after 6 and 12 months of treatment (eight patients were given captopril, 100 mg/day, + hydrochlorothiazide 25 mg/day in five patients, and six patients were given nitrendipine, 20 mg/day, + atenolol 50 mg/day in four patients). Minimal vascular resistance (mean blood pressure/peak forearm blood flow) was taken as an index of arterial structural changes. After 6 months of treatment significant reductions in blood pressure (P less than 0.001), LVMI (P less than 0.001) and minimal vascular resistance were observed. After 12 months of treatment blood pressure, LVMI and minimal vascular resistance were further reduced. The LVMI was normalized in nine cases and the minimal vascular resistance in two cases only. Aldosterone and plasma catecholamines did not change, whereas plasma renin activity was increased during captopril only. Before and during treatment the left-ventricular shortening fraction in relation to end-systolic stress in each patient at rest, and at peak of handgrip and cold pressor tests, fell within the 95% confidence limits of correlation obtained in normals. Thus, in essential hypertensives long-term treatment can induce normalization of LVMI before complete regression of arterial structural changes in the forearm. Left ventricular systolic function is preserved after normalization of LVMI, both at rest and during stress.

The aim of this study was to investigate and compare the effects of two calcium antagonist drugs, verapamil (VER) and nifedipine (NIF), on blood pressure (BP), heart rate (HR), plasma catecholamines (pCA), renin (PRA), plasma aldosterone (pALD), and plasma volume (PV) in a group of patients with mild to moderate essential hypertension. In 12 hypertensive patients on a fixed normal sodium and potassium intake, VER (80 mg t.i.d., per os) first and then NIF (10 mg, t.i.d. per os), or vice versa according to a random sequence, were each given for 8 days, with an interval of 5 days between the two treatments. Both NIF and VER significantly reduced BP (p less than 0.001); this reduction was quantitatively similar in both treatment schedules. Supine and standing PRA, pALD, and PV were not significantly affected by VER or NIF. HR and pCA were unchanged after VER, whereas they were significantly increased (p less than 0.05, at least) mainly in standing position after NIF treatment. The antihypertensive and metabolic effects of VER (80 mg t.i.d.) and NIF (10 mg t.i.d.) were maintained after chronic treatment (4 months with VER in 10 patients and 2 months with NIF in 12 patients). After 2 months of treatment with VER (160 mg t.i.d.) in 18 patients, BP was further reduced, while pCA were slightly increased. In conclusion, VER and NIF are effective and equipotent antihypertensive agents that do not induce significant renin stimulation or fluid retention; adrenergic stimulation seems to be greater with NIF, which should be taken into account in the clinical use of these drugs.

The effects of 2 calcium antagonist drugs, verapamil and nifedipine, on blood pressure, heart rate (HR), plasma catecholamines, plasma renin activity and some echocardiographic indexes of left ventricular anatomy and function were studied in 67 patients with essential hypertension. The short- and long-term antihypertensive effect of verapamil was not associated with significant changes in HR, plasma catecholamines or plasma renin activity; the decrease in blood pressure after nifedipine was associated with a significant increase in HR and plasma catecholamines (mainly noradrenaline) (p less than or equal to 0.05). These findings were confirmed in a crossover comparison in 12 hospitalized patients treated with verapamil and nifedipine for 8 days each. The dose of isoproterenol that increased HR by 25 beats/min was significantly increased during verapamil treatment (p less than 0.05) and decreased during nifedipine treatment (p less than 0.01). Stroke volume and shortening fraction increased slightly but significantly (p less than 0.05) with 3 months of nifedipine treatment, while no change was detected with verapamil treatment. Left ventricular mass was significantly decreased after effective antihypertensive treatment for 3 months with verapamil or nifedipine (p less than or equal to 0.05).

The aim of this study was to assess the effects of chronic antihypertensive treatment with verapamil and nifendipine on left ventricular (LV) anatomy and function, also in relation to adrenergic activity and beta-adrenergic sensitivity. In fact, it is known that, during antihypertensive treatment, changes of LV mass and function may be affected also by the level of adrenosympathetic tone. Blood pressure (BP), heart rate (HR), plasma catecholamines (pCA), beta-adrenergic responsiveness to isoproterenol (dose that increased HR by 25 beats/min = CD25), LV mass as well as systolic function (2D-guided M-mode echo), at rest and during stress (handgrip test [HG], 30% max, for 3 min), were measured on placebo, after 1 and 6 months of monotherapy with verapamil (VER, 240 mg/day, 9 patients) or nifedipine (NIF, 40 mg/day, 10 patients). Both treatments significantly reduced BP (p less than 0.05 at least). HR, pCA, and cardiac output did not change during treatment with VER, whereas they were slightly but significantly increased during treatment with NIF (p less than 0.05 at least). CD25 was significantly increased during treatment with VER (p less than 0.05) but not during treatment with NIF. Both treatments induced a significant reduction of LV mass after 6 months (p less than 0.01 with VER and p less than 0.05 with NIF).(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of advancing age on cardiovascular function has been the subject of many studies in the last few years. The increase of average life span and proportion of old people in the general population stimulated a number of studies in order to obtain a deeper knowledge of the normal physiology of aged individuals. Cross-sectional and longitudinal studies are used to examine the effects of aging. Both type of studies have some drawbacks. The cross-sectional study is planned to analyze at one time a group of individuals of different ages. In such study, it is difficult to eliminate genetic or environmental differences among groups. Furthermore, the older groups may represent a selected long-lived subset of the younger population. A longitudinal study examines the same individuals as their age advances and, therefore, a very prolonged time is required for studying humans. In such a study among many other obvious obstacles, an important one is the possible changes in methodology, not always easy to differentiate from age changes. In any case, the extent to which these studies may analyze the normal aging process is determined by the level of certainty regarding the absence of disease. This requirement can be difficult to be met, owing to the prevalence of atherosclerosis or occult coronary disease in the old age [1].

Thirty-two patients with moderate to severe essential hypertension whose supine diastolic blood pressure (SDBP) was ⩾95 mm Hg following 2 weeks' treatment with the optimal dosage of beta blocker-diuretic combination were randomly assigned to the addition of either Captopril 25 mg or 50 mg b.i.d. After 6 weeks' treatment, if patients were not normalized (SDBP The addition of Captopril led to a significant fall in standing and supine diastolic and systolic blood pressure at the end of the sixth and twelfth week of treatment. There was no difference in the change in blood pressure between the two groups. At the end of the study SDBP was normalized in 66% of patients and a further 12·5% had their SDBP reduced by >10%. Captopril 25 or 50 mg administered twice daily proved to be a very effective antihypertensive agent when added to a beta blocker-diuretic combination in patients resistant to optimal doses of these drugs.

A total of 1337 patients with mild to moderate essential hypertension were included in an open, multicentre trial to assess the response rate to the diuretic etozolin (200 mg once a day) and to verify whether the addition of the calcium antagonist verapamil (120 mg twice a day) in non-responders may have a favourable effect. Etozolin lowered diastolic blood pressure to below 95 mmHg in 67.8% of patients after 4 weeks of treatment and in 62.4% of patients after 12 weeks. The patients who failed to respond to etozolin were given verapamil (120 mg twice a day), and 72.8% of these patients showed a good response to the combined treatment. Normalization of blood pressure was achieved in 83.6% of the total patients. The incidence of side effects was 14.3%; withdrawal due to side effects was reported in 2.5% of patients. Abnormalities on the ECG were recorded in 5.5% of patients. No consistent metabolic or electrolyte change was observed. In conclusion, etozolin given at a dose of 200 mg once a day seems to be an effective and safe antihypertensive agent. Its antihypertensive effect remains unaltered for 12 weeks at least. The combination with verapamil may be effective in those who do not respond to etozolin alone.

The main hemodynamic characteristic of established essential hypertension is a raised peripheral resistance, while cardiac output is usually within normal limits [1]. Precapillary resistance vessels give the major contribution to the total peripheral resistance in the systemic circulation. Although the high peripheral resistance in essential hypertension can be related to an elevated vasoconstrictor tone, it has been demonstrated that an increased wall thickness in relation to the lumen in the precapillary vessels is of great importance for the maintenance and probably also for the progressive worsening of the hypertensive disease [2, 3]. In fact, many years ago Folkow and coworkers showed that as a consequence of the increased wall-to-lumen ratio, there must always be a greater change in resistance for any given degree of smooth muscle shortening in blood vessels [4].

A method for estimating cardiac output (CO) from the intra-arterial blood pressure profile ("contour method") was tested in 8 patients: 6 with essential hypertension, 1 with a pheochromocytoma and 1 with orthostatic hypotension. CO (1/min) was derived by the following formula: PSA (1+St/Dt) X HR 10(-3), where PSA is the area under the systolic portion of the pressure curve, St is the systolic and Dt the diastolic time, X is a correction factor, HR is the heart rate and 10(-3) is a conversion factor from ml/min to 1/min. The "contour method" was compared to the thermodilution CO method. The correlation between the 2 methods was highly significant: the r value in all patients during different conditions (supine, tilt, dynamic and static exercise) ranged from 0.91 to 0.97 with an intercept close to 0 and a slope close to 1. These results indicate that CO is properly measured from the intra-arterial blood pressure profile by the "contour method". A continuous hemodynamic monitoring can be derived applying the "contour method" to the intra-arterial blood pressure profile obtained with the Oxford technique.

Ibopamine, a dopamine derivative suitable for oral administration, is reported to improve cardiac function in patients with chronic heart failure. In order to evaluate the inotropic effect of ibopamine and to compare it with that of digoxin, we studied 10 patients with chronic heart failure (NYHA II-III). All patients were in sinus rhythm. After a washout period of 5 days, when the patients received a constant diuretic dosage and a placebo, ibopamine 100 mg t.i.d. or digoxin 0.25 mg o.d. was randomly given double-blind. The active treatment was continued for a 10-day period, and was followed by a second washout period of 5 days. Subsequently, the patients received digoxin if previously on ibopamine or ibopamine if previously on digoxin for 10 days. Diuretic was continued at the same dosage throughout the study. At the end of the two washout periods, all patients performed a static (hand grip) and a dynamic exercise (bicycle ergometer). Both ibopamine and digoxin improved cardiac response to both types of exercise compared to the washout periods. In particular, PEP/LVET decreased (p less than 0.001 for both drugs) and O2 consumption improved (from 586 +/- 48 to 716 +/- 35 ml/min for ibopamine and from 585 +/- 38 to 713 +/- 52 ml/min for digoxin). No difference was noted between the two drugs in the improvement of exercise tolerance. No side effects were noted with the two drugs. These data indicate that ibopamine could be a valid alternative to digoxin in heart failure patients in sinus rhythm when given for 10 days. More data are needed to evaluate the long-term efficacy of ibopamine.

An opposite modulatory influence of renal noradrenergic and dopaminergic activities on sodium excretion has been suggested. In this study urinary noradrenaline (UNA) and dopamine (UDA) excretion were evaluated in patients with borderline essential hypertension (BH; n = 9) and in patients with established essential hypertension (EH; n = 11) as well as in normal subjects (NT, n = 8), during normal sodium and potassium intake. Measurements were performed on fractionated urine collections on two separate days: on the first day under basal conditions and on the second day after saline infusion (SAL), 2L/2h, i.v. In BH, basal UNA and UDA were higher with respect to NT and EH. The difference was significant (p less than 0.05) in urine collected between 8 and 14 h. In all three groups, SAL induced a significant decrease in UNA and a significant increase in UDA; the decrease in UNA after SAL was significantly lower in EH in respect to BH and NT. In conclusion, the increased UDA in BH may represent a compensatory mechanism to a defect in sodium excretion, possibly due to elevated renal and/or systemic noradrenergic activity; the normal response to volume and salt loading suggests that the physiological modulation of sympathetic tone is still preserved in BH.

The effects of slow intravenous infusion of three different respiratory stimulants (dimefline, nikethamide and prethcamide) on minute and alveolar ventilation, blood gases and pH were studied in 18 patients with chronic pulmonary emphysema and chronic respiratory failure. For a more accurate assessment of the results of the double blind controlled trial, a factorial design in a Youden square scheme was employed. Respiratory rate, tidal volume, minute ventilation, arterial Po 2 , pH and heart rate failed to show significant changes after the intravenous infusion of the drugs. The other parameters studied (dead space, alveolar ventilation, CO 2 output, Paco 2 ) showed some differences but these were temporally similar for the three drugs. As improvement in respiratory and blood gases data was transient and slight and undesirable side-effects constant, it is concluded that the use of respiratory stimulants in management of chronic respiratory failure cannot be recommended.

The effect of atrial natriuretic peptide (ANP), before and after converting enzyme (CE) inhibition, was investigated in six primary hypertensive patients taking a constant diet. In this placebo-controlled, single-blind, randomized study, the patients received, on three different days, i.v. infusions of (a) placebo, or (b) alpha-human ANP, 150 micrograms over 30 min, or (c) alpha-human ANP after acute CE inhibition by enalapril (EN) 20 mg P.O., 4 h before ANP infusion. ANP infusion increased urinary sodium (p less than 0.001) and volume excretion. Blood pressure (BP), heart rate, stroke volume and shortening fraction (echocardiography), plasma renin activity (PRA), and plasma aldosterone did not change significantly. Urinary norepinephrine and dopamine were significantly increased (p less than 0.05) after ANP infusion. BP was significantly reduced after EN in every patient (p less than 0.05). ANP infusion during CE inhibition induced a more sustained increase of sodium excretion and diuresis with respect to ANP infusion alone (p less than 0.05). PRA was significantly reduced while no further reduction of BP was observed. These data suggest that CE inhibition may increase the natriuretic and diuretic effect of ANP in hypertensive patients.