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In hypertension, changes of cardiac anatomy and function are not just a simple consequence of the increased pressure load. The sympathetic nervous system activity is one of the factors which may influence the cardiac performance, and possibly also the cardiac anatomy of hypertensive patients. Several clinical studies have provided evidence of a subset of patients, usually with mild or borderline hypertension, with an increased cardiac performance, higher plasma catecholamine concentrations and/or greater response to beta-adrenergic stimulation. Animal studies have strongly suggested a possible role of adrenergic factors in the development of left ventricular hypertrophy (LVH). In man, plasma catecholamines are usually higher in hypertensive patients with LVH, and a correlation between left ventricular mass and plasma noradrenaline has also been observed. An impaired response to beta-adrenergic stimulation has been reported in hypertensive animals and in patients with LVH. Several studies have also suggested that reversal of LVH may be more easily induced by those antihypertensive drugs that reduce, or at least do not stimulate, the sympathetic activity, although exceptions to this statement may be observed.

Intra-arterial 24 hour blood pressure (BP) recording (OXFORD MEDILOG) was carried out in 10 patients with essential hypertension, 6 males and 4 females, aged between 41 and 58 years, 3 at WHO stage 1 and 7 at stage 2, in basal conditions and after 6 weeks of treatment with a fixed combination of 160 mg of slow-release oxprenolol and 20 mg of chlorthalidone per tablet (tb). The fixed combination was given once daily, in the morning, at the dosage of 1 tb, which was increased to 2 tbs o.d. after the first 2 weeks in 6 patients. Computer calculated mean BP and heart rate (HR) values from each consecutive hour of the day were obtained in all patients. Hourly trend of BP and HR were plotted and circadian variations were thus determined. Treatment with fixed combination o.d. significantly reduced systolic and diastolic BP, compared to pretreatment values, throughout of the 24 hours (p less than 0.01; p less than 0.001), without altering the circadian rhythm. Before and after 6 weeks of treatment, a bicycle exercise test was performed in 8 patients, who reached 85% of the maximal predicted HR. Pretreatment resting mean BP (+/- SD) was 190 +/- 31/108 +/- 10 mmHg (HR: 68 +/- 9 b/min) and those during the last minute of exercise 242 +/- 29/125 +/- 5 mmHg (HR: 147 +/- 13 b/min); posttreatment resting BP was 161 +/- 20/88 +/- 7 mmHg (HR: 58 +/- 7 b/min) and at peak exercise, 212 +/- 16/106 +/- 7 mmHg (p less than 0.025 for the systolic pressure; p less than 0.001 for the diastolic pressure).(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to examine the interrelationships between age, plasma catecholamines, plasma renin activity (PRA) and blood pressure in essential hypertensive (EH) patients. PRA, plasma noradrenaline (NA) and adrenaline (A) were measured in 76 consecutive EH patients (WHO stages 1-2, aged 24-66 years) and in 28 normotensive subjects (aged 25-64 years) studied at rest in supine position after 5 days of normal fixed sodium and potassium intake. Both plasma NA and A were slightly but significantly higher in EH patients (p less than 0.05). While no relationship was found between the various parameters in normotensive subjects, in EH patients, particularly those at WHO stage 2, plasma NA was directly related to mean blood pressure (MBP) (p less than 0.001) and PRA (p less than 0.01). Plasma A was weakly related to MBP (p less than 0.05); PRA was inversely related to age (p less than 0.01) but no relationship was found between NA or A and age. Partial correlation analysis confirmed all these relationships. In fact, NA was related to MBP also considering constant PRA (p less than 0.001) or age (p less than 0.001), and NA was related to PRA also considering constant MBP (p less than 0.01) or age (p less than 0.001). Acute pharmacological alpha- and beta-blockade, with labetalol 100 mg i.v., induced a reduction of MBP which was directly related to basal plasma NA (p less than 0.001). These results support the view that in EH the sympathetic nervous system might be in part responsible for PRA levels and for the severity of hypertension.

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)

Aortic rigidity, plasma noradrenaline and adrenaline, and hemodynamic parameters were measured in 48 essential hypertensive patients, 25 younger than 45 (Group I) and 23 of 45 years and over (Group II). Aortic rigidity was determined by the ratio of pulse pressure over stroke volume. Aortic rigidity and hemodynamic parameters were also determined after combined alpha-beta receptor blockade induced by Labetalol (mg 100 IV) or by Propranolol (mg 10 IV) plus Phentolamine (mg 10 IV). The aortic rigidity index was significantly higher in Group II, systolic arterial pressure being significantly higher. All other data, including plasma noradrenaline and adrenaline, were not significantly different in the two groups. In Group II a significant correlation (r = 0.62) was noted between aortic rigidity indexes and plasma noradrenaline values. The alpha-beta receptor blockade induced a decrease of aortic rigidity particularly in Group II, owing to a more marked decrease of systolic arterial pressure. A highly significant correlation was noted in Group II between the changes in aortic rigidity index and the basal plasma noradrenaline levels (r = 0.81). Therefore, the aortic rigidity in essential hypertensive patients older than 45 is influenced by the sympathetic nervous system activity, as judged by plasma noradrenaline levels. This influence seems related to an increase with age of aortic responsiveness to sympathetic stimulation.

Plasma catecholamines were simultaneously measured in duplicate plasma samples by the fluorimetric method of Renzini et al. (1970) Clin. Chim. Acta 39, 587-594) and by the radioenzymatic method of Da Prada & Zurcher ((1976) Life Sci. 19, 1161-1174). The correlation of noradrenaline and adrenaline plasma concentrations determined by the two methods were, respectively, r = 0.95 (p less than 0.001) and r = 0.75 (p less than 0.01). The fluorimetric method was less sensitive, but more economical and less time-consuming than the radioenzymatic method. The fluorimetric method is still of value for measuring plasma catecholamines in man.

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.

Thirty-two patients with moderate to severe essential hypertension whose supine diastolic blood pressure (SDBP) was greater than or equal to 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 less than 95 mm Hg), the dose of captopril was doubled for a further 6 weeks. 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 greater than 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.

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.

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.

Captopril was given to 15 unselected patients with essential hypertension (WHO II) at a dose range of 300 to 600 mg/day. Hemodynamic indexes (thermodilution) as well as levels of plasma norepinephrine, epinephrine, renin activity and aldosterone were determined simultaneously at the end of 2 weeks of placebo and after 8 weeks of captopril treatment. Systolic and diastolic arterial pressures were reduced significantly by treatment both supine (p less than 0.0025) and standing (p less than 0.0025). The diastolic arterial pressure was normalized (less than 95 mm Hg) in five patients and significantly reduced in four, whereas six patients were considered poor responders (mean arterial pressure decrease 10 mm Hg or less). The decrease in arterial pressure correlated significantly with the reduction in total peripheral resistance (r = 0.71), whereas cardiac index did not change and stroke index increased because of a slight decrease of heart rate. Plasma and urinary norepinephrine and epinephrine did not change during treatment. Moreover, the response of both heart rate and plasma catecholamines to upright posture was not altered by captopril treatment. Plasma renin activity increased and plasma aldosterone concentration decreased during treatment. These results suggest that inhibition of converting enzyme activity by captopril induces a reduction in arterial pressure through a reduction in total peripheral resistance. There was no evidence of an appreciable reduction in sympathetic nervous system activity during therapy.

Two hundred and one patients with essential hypertension, whose supine diastolic blood pressure (SDBP) was greater than or equal to 95 mmHg following 2 weeks of treatment with the optimal dose of a beta blocker-diuretic combination (Phase 1), were randomly assigned to the addition of either 25 or 50 mg captopril BID for 6 weeks (Phase 2). At the end of Phase 2, the dose of captopril was doubled in the patients not normalized (SDBP greater than or equal to 95 mmHg) and maintained in the others (SDBP less than 95) for an additional 4 weeks (Phase 3). At the end of Phase 3, the beta blocker was withdrawn in the normalized (SDBP less than 95 mmHg) patients, and captopril plus diuretic was given for 4 weeks (Phase 4). The addition of captopril at either dose level led to a significant fall (p less than 0.01) in standing and supine diastolic and systolic blood pressure after the first 2 weeks of treatment. There was no significant difference in response between the two dose levels of captopril. At the end of Phase 2, 59.4% and 55.8% of patients, respectively, assigned to 25 and 50 mg captopril BID, were normalized. Doubling the dose of captopril (Phase 3) led to approximately an additional 30% of patients being normalized. At the end of Phase 4 (captopril plus diuretic) the SDBP was still less than 95 mmHg in 63% of patients, whereas it was increased in the others. Side effects were noted in 10 patients (5%). The incidence was similar in each treatment group, and a total of four patients (2%) were withdrawn due to side effects.

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 authors studied 302 hospitalized patients, 164 males and 138 females aged 15-88 years (average 66 years), with severe infections. Cefotetan was administered to 278 of them at the dose of 1 or 2 g, b.i.d. or a single daily dose i.m. Other patients [24] were treated with a continuous intravenous infusion of cefotetan (3 g daily in 5% dextrose). Of these patients 121 were treated for urinary tract infections (UTI); 114 for respiratory tract infections (RTI); 41 for liver biliary duct infections (BDI); 17 for skin or skin structure infections (SKI); 6 for fever of unknown origin and 3 for sepsis. The following Gram-positive organisms [156] were isolated: Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus group D; and the following Gram-negative organisms [122]: Escherichia coli, Proteus vulgaris, Proteus mirabilis, Serratia spp., Klebsiella spp., Haemophilus influenzae and Pseudomonas aeruginosa. The overall eradication rate for Gram-positive organisms was 74% and for Gram-negative organisms it was 88%. The clinical response was satisfactory in 87.7% of patients (specifically, cefotetan was effective in 90% of UTI, 84.2% of RTI, 97.5% of BDI and 82.3% of SKI). The drug was well tolerated and side-effects (such as skin rash, diarrhoea, purpura and pain at the site of injection) occurred in only 4% of patients treated with cefotetan. In conclusion, cefotetan appears to be safe and highly effective for the treatment of severe infections in hospitalized patients.