Effect of intravenous digoxin on the heart at rest and during isometric exercise: a noninvasive study in normal and autonomically blocked volunteers

Nine healthy volunteers were studied with echocardiography and systolic time intervals before and after administration of 1 mg digoxin intravenously at supine rest and during 3-min isometric handgrip exercise. Eight of them were also studied following autonomic blockade, atropine (0.04 mg/kg), and propranolol (0.2 mg/kg) administered intravenously, otherwise the study program was the same. At rest, intravenous digoxin decreased the heart rate from 61 +/- 3 to 50 +/- 2 beats/min (p less than 0.001). Blood pressure, preload [defined as left ventricular end-diastolic diameter (LVEDD)] or afterload [estimated as left ventricular midsystolic circumferential wall stress (WS)], did not change. Fractional shortening increased from 29 +/- 2 to 33 +/- 2% (p less than 0.05), and the electromechanic systole time index (QS2i) decreased from 522 +/- 7 to 500 +/- 5 ms (p less than 0.01). The results indicate improved contractility due to digoxin. During handgrip, the heart rate decreased from 73 +/- 5 to 65 +/- 5 beats/min (p less than 0.01) as a result of digoxin. The LVEDD, WS or ejection phase indices, and systolic time intervals, did not change, suggesting that digoxin does not affect inotropy during isometric exercise. There was no changes in heart rate, preload or afterload, as a result of intravenous digoxin during autonomic blockade. Fractional shortening rose from 25 +/- 1 to 29 +/- 2 (p less than 0.05) and QS2i fell from 561 +/- 3 to 533 +/- 4 ms (p less than 0.001). The results indicate increased inotropy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacodynamic without pharmacokinetic interaction between cicloprolol, a partial beta 1-adrenoceptor agonist, and digoxin in healthy subjects.

1. Cicloprolol is a partial beta 1-adrenoceptor agonist considered for the treatment of patients with coronary artery disease and impaired left ventricular function. In such patients, digoxin remains in widespread use. 2. We assessed the pharmacokinetic and pharmacodynamic interaction between oral cicloprolol 50 mg day-1 and oral digoxin 0.25 mg day-1 in 10 healthy male volunteers, using a double-blind, randomised protocol, during three 8 day periods. Digoxin was given alone during the first period to reach steady state; then digoxin was given with cicloprolol or placebo during the second and third periods, according to a cross-over design. 3. No significant adverse effects were observed. 4. The pharmacokinetics of digoxin were not different significantly at the end of the placebo-digoxin and cicloprolol-digoxin periods. 5. A significant increase in minimum heart rate and mean nocturnal heart rate, assessed by 24 h Holter recordings, was observed at the end of the cicloprolol-digoxin period as compared with the placebo-digoxin period (means +/- s.e. mean, 57.1 +/- 3.2 beats min-1 vs 52.2 +/- 3.1 beats min-1, P less than 0.01; and 65.6 +/- 3.8 beats min-1 vs 59.9 +/- 3.9 beats min-1, P less than 0.01, respectively). 6. A significant increase in left ventricular ejection fraction and shortening fraction, assessed by echocardiography, was noted at the end of the cicloprolol-digoxin period as compared with the placebo-digoxin period (means +/- s.e. mean, 66.4 +/- 1.4% vs 61.3 +/- 1.2%, P less than 0.05; and 37.0 +/- 1.1% vs 33.3 +/- 0.9%, P less than 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension.

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double-blind, placebo-controlled, cross-over study. 2. After a 4 week placebo run-in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/- 15/7 mmHg) received rilmenidine 1-2 mg day-1, and atenolol 50-100 mg day-1, each for 4 weeks, with a 4 week placebo wash-out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min-1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min-1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.     

Effect of the combination of alinidine and other anti-anginal drugs on heart rate and blood pressure in healthy volunteers.

1. Heart rate and blood pressure changes following the administration of alinidine 30 mg alone and in combination with atenolol 25 mg, nifedipine retard 20 mg and glyceryl trinitrate 500 micrograms were investigated in three groups of six healthy male volunteers. 2. Concomitant administration of alinidine and atenolol reduced (P less than 0.05) supine, standing and exercise heart rate when compared with alinidine alone. The maximum reduction in exercise heart rate was 116 +/- 2.4 beats min-1 for the combination vs 129.0 +/- 3.1 beats min-1 for alinidine alone. 3. Supine (3, 4, 8 h) and standing (2 h) systolic BP were also reduced (P less than 0.05) with the alinidine and atenolol combination compared with alinidine alone. Little change occurred in diastolic blood pressure. 4. Alinidine and nifedipine in combination reduced (P less than 0.05) the nifedipine induced increase in heart rate in the supine (2, 4 h) and standing (4 h) position and following exercise (2, 4 h). No further decreases in systolic and diastolic blood pressure occurred with the combination. 5. Alinidine administered 2 h before a glyceryl trinitrate challenge reduced (P less than 0.05) the glyceryl trinitrate induced increase in standing heart rate at all time intervals (1 to 6 min); the maximum reduction occurred at 3 min (105.0 +/- 4.3 (glyceryl trinitrate) vs 86.8 +/- 6.7 beats min-1 (combination]. Systolic blood pressure was further reduced at all time intervals with glyceryl trinitrate taken in the presence of alinidine.(ABSTRACT TRUNCATED AT 250 WORDS)     

A dose-ranging study to evaluate the beta-adrenoceptor selectivity of single doses of betaxolol.

1. Six normal subjects were given single oral doses of betaxolol 10 mg (B10), 20 mg (B20), 40 mg (B40), 80 mg (B80), propranolol 40 mg (P40), or placebo (PL) in a single-blind randomised cross-over design. 2. beta 1-adrenoceptor blockade was assessed by reductions in exercise heart rate. Betaxolol produced dose-related reductions in exercise heart rate (beats min-1) up to a ceiling at B40, after which B80 showed a lesser effect: (158 +/- 8 PL, 128 +/- 3 B10, 123 +/- 2 B20, 116 +/- 4 B40, 136 +/- 10 B80, 135 +/- 4 P40). All doses of betaxolol (except B80) produced greater reductions compared with P40: (B10 P less than 0.001, B20 P less than 0.005, B40 P less than 0.001). 3. beta 2-adrenoceptor blockade was assessed by attenuation of finger tremor and cardiovascular responses to graded infusions of i.v. isoprenaline. Dose-response curves were constructed and the doses required to increase heart rate by 25 beats min-1, finger tremor by 200%, calf blood flow by 0.5 ml dl-1 min-1, and decrease diastolic blood pressure by 10 mm Hg, after each treatment were calculated. These were then compared with placebo responses and expressed as dose-ratios. 4. Dose-ratios for finger tremor showed significant attenuation by all doses of betaxolol (compared with PL): B10 1.5 +/- 0.18 (P less than 0.05), B20 2.62 +/- 0.45 (P less than 0.005), B40 2.55 +/- 0.33 (P less than 0.001), B80 2.48 +/- 0.48 (P less than 0.01); and by P40 6.49 +/- 1.12 (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of intra-arterial and indirect blood pressures at rest and during isometric exercise in hypertensive patients before and after metoprolol.

1. Blood pressure was measured both directly and indirectly in seven hypertensive patients before and after a single oral dose of 100 mg metoprolol, at rest and during sustained handgrip. 2. Intra-arterially measured systolic and diastolic blood pressure increased linearly with time during sustained handgrip at 50% of maximal voluntary contraction. This linearity persisted for 60 s or more in most cases. Heart rate increased linearly for the first 30 s. 3. Indirectly measured blood pressure using an observer bias minimizing Auto-Manometer, under-read systolic and over-read diastolic pressure both at rest and during handgrip. 4. By exact timing of recorded values during handgrip and linear extrapolation (or interpolation) from base-line readings, mean values at 30 and 60 s of handgrip were calculated. The relationship between direct and indirect values remained the same at base-line and 30 s of handgrip. At 60 s of handgrip, this was true only for diastolic pressure. For systolic pressure, indirect and direct values almost coincided. 5. After metoprolol, directly recorded pressure fell slightly (7--12 mm Hg, 0.02 less than P less than 0.10), both at rest and during handgrip, and heart rate fell by 15--18 beats/min (P less than 0.01). The systolic blood pressure and heart rate effect of metoprolol at 1 min handgrip correlated with peak plasma drug levels. Indirectly measured blood pressure did not change significantly. 6. The rate of rise in heart rate and blood pressure from base-line to 60 s handgrip was not significantly influenced by metoprolol.     

Increases in plasma beta-endorphin concentrations during exercise do not contribute to increases in heart rate following autonomic blockade in man.

1. Intrinsic heart rate (IHR: heart rate following autonomic blockade with atropine and propranolol) increases with exercise. The opioid antagonist naloxone has been shown to decrease IHR at rest, raising the possibility that increases in IHR with exercise are beta-endorphin related, since beta-endorphin concentrations have also been shown to rise during exercise. 2. We examined the effects of naloxone (10 mg) on IHR and plasma beta-endorphin levels during aerobic exercise in eight healthy, male subjects in a single blind, crossover study. 3. IHR increased with 25 min bicycling from 97.1 +/- 1.4 to 129.7 +/- 1.2 beats min-1 (mean +/- s.e. mean). This rise was not affected by administration of naloxone. 4. Plasma beta-endorphin concentration rose from 31.1 +/- 3.8 to 94.9 +/- 23.9 pg ml-1 after 25 min exercise. This exercise-induced rise in beta-endorphin concentration was further increased (P less than 0.05) in the presence of naloxone. 5. Our results confirm a rise in IHR and beta-endorphin concentrations with acute exercise but indicate that the changes in IHR are not endorphin-related.     

Responses to mental stress and physical provocations before and during long term treatment of hypertensive patients with beta-adrenoceptor blockers or hydrochlorothiazide.

1 Cardiovascular and sympatho-adrenal responsiveness to mental stress (CWT; a colour word test), orthostatic testing (ORT) and a cold pressor test (CPT) were examined in three groups of hypertensive patients (n = 14-16) before and after 6 months treatment with metoprolol (243 +/- 26 mg daily), propranolol (149 +/- 16 mg daily) or hydrochlorothiazide (50 +/- 8 mg daily) in an open trial design. 2 Treatment reduced outpatient blood pressures in the three groups similarly (from approximately 155/102 to 135/90 mm Hg). During treatment resting blood pressures in the laboratory were clearly reduced by beta-adrenoceptor blockade but not by thiazide treatment. Metoprolol and propranolol caused similar reductions of basal heart rates and plasma glycerol levels, whereas only propranolol reduced cyclic AMP concentrations in plasma. 3 Before treatment CWT and CPT increased systolic and diastolic blood pressures by about 30%. Heart rate increased by about 30 beats min-1 during CWT and 10-15 beats min-1 during CPT and ORT. Small venous plasma adrenaline responses were evoked by all tests, whereas noradrenaline was elevated mainly by CPT and ORT. Dopamine levels did not change. 4 Heart rate responses to all stressors were markedly and similarly reduced, whereas blood pressure responses were essentially unchanged during metoprolol or propranolol treatment. In the thiazide group circulatory responses to CWT were slightly attenuated, whereas responses to ORT and CPT were unchanged. 5 The systolic blood pressure levels were reduced throughout the test session in all three groups, although less so in the hydrochlorothiazide group. Both beta-adrenoceptor antagonists clearly reduced diastolic blood pressure and heart rate levels at rest and during stress, whereas thiazide treatment caused no significant changes in these respects. 6 The rate pressure product, which increased by 80-100% in response to CWT before treatment, was more markedly reduced by beta-adrenoceptor blockade than by thiazide treatment both at rest and during stress. 7 Self ratings (visual analogue scales) of stress and irritation were increased by CWT in a similar fashion before and during treatment in all groups. beta-adrenoceptor blockade was associated with higher subjective ratings of tiredness at rest, but not after CWT. Performance in the CWT increased slightly more in the thiazide group. The physiological responses to CWT were not correlated to the subjective responses.(ABSTRACT TRUNCATED AT 400 WORDS)     

The cardiovascular effects of xamoterol, a beta 1-adrenoceptor partial agonist, in healthy volunteers at rest.

The cardiovascular effects of three single intravenous doses of a beta 1-adrenoceptor partial agonist, xamoterol (0.025, 0.05 and 0.1 mg kg-1) and placebo were studied in six healthy volunteers at rest using a single-blind design. In addition to heart rate and blood pressure measurements, cardiac contractility was measured by means of M-mode echocardiography and systolic time intervals. Ambulatory 24 h Holter-monitoring of the electrocardiogram was performed. Plasma concentrations of xamoterol were measured. Compared to baseline, xamoterol (0.025 mg kg-1) increased heart rate (61 +/- 3-68 +/- 3 beats min-1, means and SEM) and systolic blood pressure (119 +/- 3-138 +/- 5 mm Hg) but decreased pre-ejection period (100 +/- 4-76 +/- 5 msec). Stroke volume (88 +/- 6-104 +/- 10 ml), cardiac output (4.8 +/- 0.4-6.6 +/- 0.61 min-1), velocity of circumferential fibre shortening (1.15 +/- 0.06-1.50 +/- 0.06 circ s-1) were increased by xamoterol. No significant changes were produced by placebo. No dose-dependent effects were seen and maximum effects were produced by 0.025 mg kg-1 xamoterol. Significant effects were observed for 2 h. The areas under the plasma concentration curves (AUC0-12) showed a linear dose response. No adverse effects attributable to xamoterol were seen in haematological, biochemical, urinalysis or electrocardiographic tests. Four volunteers were aware of a more forceful heart beat after xamoterol, but this was mild and transient. It is concluded that xamoterol has a positive inotropic action.     

Reserpine induces vascular alpha 2-adrenergic supersensitivity and platelet alpha 2-adrenoceptor up-regulation in dog.

1. The aim of the present study was to investigate the influence of catecholamine levels on the regulation of alpha 2-adrenoceptor sensitivity in dogs. 2. Blood pressure and heart rate values at rest, plasma catecholamine levels, platelet and adipocyte alpha 2-adrenoceptors as well as the alpha 2-mediated cardiovascular responses to clonidine (10 micrograms kg-1 i.v., after alpha 1-, beta-adrenoceptor plus muscarinic blockade) or noradrenaline (0.5, 1, 2 and 4 micrograms kg-1 i.v. after alpha 1- and beta-adrenoceptor blockade) were measured before and after reserpine treatment (0.1 mg kg-1 day-1 s.c. over 15 days). 3. Reserpine induced a significant decrease in resting systolic and diastolic blood pressures (213 +/- 2/87 +/- 6 mmHg before vs 158 +/- 5/59 +/- 3 mmHg after treatment) as well as in heart rate (91 +/- 2 beats min-1 before vs 76 +/- 3 beats min-1 after treatment). 4. A 5 min tilt test performed under chloralose anesthesia, failed to modify blood pressure before treatment whereas it induced a significant fall in the same animals after the 15 day treatment. Plasma levels of noradrenaline significantly decreased (262 +/- 58 vs 66 +/- 31 pg ml-1) whereas plasma adrenaline levels were unchanged. 5. The alpha 2-mediated pressor responses to noradrenaline were significantly increased after reserpine. Clonidine induced a marked pressor effect (+72 and +45% in systolic and diastolic blood pressures respectively) after reserpine treatment. This effect was suppressed by administration of RX-821002, a new specific alpha 2-adrenoceptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contrasting effects of verapamil and amlodipine on cardiovascular stress responses in hypertension

AIMS: To compare the effects of two long-acting calcium antagonists of different types on cardiovascular stress responses in hypertension. METHODS: One-hundred and forty-five patients with mild to moderate hypertension and a mean (+/- s.e.mean) age of 51 +/- 0.9 years received for 8 weeks the phenylalkylamine verapamil sustained release (240 mg) and the dihydropyridine amlodipine (5 mg) in a double-blind cross-over design, both after 4 weeks of placebo. Blood pressure, heart rate and plasma noradrenaline were monitored during 3 min of sustained isometric handgrip and 2 min of cold pressor. RESULTS: Blood pressure was equally reduced by both drugs. After 3 min handgrip, systolic blood pressure, heart rate and rate-pressure product were lower with verapamil compared with amlodipine. Verapamil attenuated the increases in systolic blood pressure (25 +/- 2 vs 30 +/- 2 mmHg, difference 4.6, 95% CI (1.0, 8.1), P < 0.01) and rate-pressure product (3.1 +/- 0.2 vs 3.6 +/- 0.3 x 10(3) mmHg x beats min(-1), difference 0.5, 95% CI (0.1, 0.9), P < 0.01) during handgrip compared with amlodipine. Similar results were observed during cold pressor. Plasma noradrenaline levels were lower with verapamil compared with amlodipine at rest and after both tests, but the increases in plasma noradrenaline were not significantly different. CONCLUSIONS: Verapamil is more effective in reducing blood pressure and rate-pressure product responses to stress compared with amlodipine. Although plasma noradrenaline is lower with verapamil at rest and after stress, the increase during stress is not different.     

Selectivity profile of the novel muscarinic antagonist UH-AH 37 determined by the use of cloned receptors and isolated tissue preparations.

1. We investigated the presence of dopamine D1 receptors in the myocardium of anesthetized pigs using intravenous infusions of dopamine, alone and after alpha- and beta-adrenoceptor blockade and intracoronary infusions of the selective D1 receptor agonist, fenoldopam. 2. Intravenous infusion of dopamine (2.5, 5 and 10 micrograms kg-1 min-1 for 10 min, n = 6) caused dose-dependent changes in heart rate (from 94 +/- 6 to 132 +/- 10 beats min-1, P less than 0.05), the maximal rate of rise of left ventricular pressure (LVdP/dtmax; from 2280 +/- 170 to 4800 +/- 410 mmHgs-1, P less than 0.05), mean arterial blood pressure (from 87 +/- 5 to 62 +/- 3 mmHg) and systemic vascular resistance (from 40 +/- 4 to 28 +/- 2 mmHgl-1 min, P less than 0.05). The increases in heart rate and LVdP/dtmax were abolished when dopamine was infused after alpha- and beta-adrenoceptor blockade. The vasodilator response was, however, only minimally affected. 3. Intravenous infusions of dopamine decreased coronary vascular resistance from 0.90 +/- 0.06 to 0.53 +/- 0.07 mmHg ml-1 min 100 g (P less than 0.05). This action of dopamine was not observed when dopamine was infused after blockade of the alpha- and beta-adrenoceptors. 4. Pretreatment with alpha- and beta-adrenoceptor blockade had no effect or only slightly attenuated the dopamine-induced decrease in vascular resistance of the brain, kidneys, adrenals and small intestine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of temazepam on blood pressure regulation in healthy elderly subjects.

1. Blood pressure regulation was studied in 12 healthy elderly subjects after double-blind randomised administration of placebo, 15 mg and 30 mg temazepam at 10.00 h and 22.00 h. 2. Supine and standing heart rate and blood pressure were measured after daytime administration and supine measurements were obtained during sleep. 3. Temazepam caused a fall in systolic blood pressure and an increase in heart rate after morning administration. These changes were greater in the standing position and were dose-dependent; for standing blood pressure and heart rate 1 h after administration there was a 7 mm Hg fall and 6 beats min-1 increase after 15 mg temazepam and a 10 mm Hg fall and 8 beats min-1 increase after 30 mg temazepam. Temazepam magnified the fall in systolic blood pressure and increase in heart rate that occurred with standing. Temazepam enhanced the fall in systolic blood pressure that occurred during sleep (mean +/- s.d.; placebo: -23 +/- 10 mm Hg, 15 mg temazepam: -31 +/- 13 mm Hg, 30 mg temazepam: -36 +/- 14 mm Hg). 4. These changes in blood pressure regulation caused by temazepam may have clinical importance in some elderly individuals.     

Effects of atropine on left ventricular volumes and ejection and filling rates at rest and during exercise.

1. The influence of the parasympathetic nervous system on left ventricular function including ejection and filling rates was studied by radionuclide cardiography in eight healthy young men at rest and during upright exercise. 2. After parasympathetic blockade induced by atropine, the mean heart rate (HR) at upright rest increased from 67 to 114 beats min-1, cardiac output (CO) from 4.05 to 5.17 1 min-1 (both P less than 0.001), and the diastolic blood pressure by 13 mm Hg (P less than 0.01). 3. Stroke volume (SV), left ventricular end diastolic and end systolic volume all decreased significantly after atropine. The relative ejection time increased from 0.33 to 0.51 of the cardiac cycle length (P less than 0.001), and the appropriate ejection and filling rates increased by 13% (P less than 0.05) and 147% (P less than 0.001), respectively. Haemodynamic changes in the supine position were virtually the same. 4. During exercise atropine increased HR from 115 to 146 beats min-1 (P less than 0.001) and CO by 12% (P less than 0.05), whereas SV decreased by 12% (P less than 0.05) and the systolic blood pressure by 16 mm Hg (P less than 0.001). Changes in ejection and filling rate of the left ventricle were of the same nature as those found at rest. 5. Thus apart from its HR limiting properties, secondary effects of parasympathetic nervous tone are dilatation of the left ventricle and enhancement of ejection, effects that are counteracted by atropine.     

Acute effects of ketanserin on left ventricular function, metabolism and coronary blood flow

An acute intravenous bolus of 10 mg ketanserin (a specific 5-HT antagonist) caused an abrupt fall in left ventricular systolic pressure of 17 +/- 9.2 mm Hg (P less than 0.025) in ten patients undergoing cardiac catheterisation for chest pains. A fall in pulmonary artery diastolic pressure of 2.1 +/- 0.74 mm Hg (P less than 0.02) was also observed. No changes in resting heart rate occurred and the response to pacing was largely unmodified by ketanserin, except for a reduction in pulmonary vascular resistance (3.70 +/- 1.27 units to 2.97 +/- 1.44 units, P less than 0.05), at the fastest rate (136 +/- 3 beats/min). At the highest pacing rate coronary sinus blood flow fell (83 +/- 12 ml 100 g-1 min-1 to 68 +/- 8 ml 100 g-1 min-1, P less than 0.05), as did myocardial oxygen consumption (18 +/- 2 ml-1 min to 14 +/- 1 ml min-1, P less than 0.05) after the drug. No changes in the parameters of left ventricular contractile function could be attributed to ketanserin, save for a modest increase in the ejection fraction (48 +/- 6% to 57 +/- 6%, P less than 0.05) in seven patients. There were no alterations in myocardial metabolism of lactate, pyruvate, hydroxybutyrate, glycerol nor free fatty acids after ketanserin. The findings are consistent with a peripheral site of action of this drug and its blood pressure lowering effect in the subjects suggest a non-specific hypotensive action rather than an anti-hypertensive effect.     

Effects of a long-term treatment with alacepril on left ventricular hypertrophy and function in patients with essential hypertension.

The authors examined the effects of a long-term treatment with the angiotensin-converting enzyme inhibitor, alacepril, with respect to the reversal of left ventricular hypertrophy and the improvement of left ventricular function. Ten uncomplicated essential hypertensive patients with left ventricular hypertrophy, aged 53 +/- 8 years, were treated with alacepril alone for 12 months. All patients underwent echocardiography to to assess left ventricular dimensions and function before and after the treatment. After the treatment, blood pressure was decreased significantly from 163 +/- 14.1/98 +/- 4.2 to 142 +/- 20.3/86 +/- 11.0 mm Hg (each, P less than .01), whereas heart rate did not change (66 +/- 6 versus 69 +/- 8 beats/min). The left ventricular mass index was decreased significantly from 146 +/- 27 to 119 +/- 29 g/m2 (P less than .01). Ejection fraction, fractional shortening, peak shortening rate, and peak lengthening rate all improved significantly after the treatment. There was a significant inverse relationship between fractional shortening and end-systolic wall stress before the treatment (r = .63, P less than .05), and this relationship did not change after the treatment. It is concluded that alacepril improved both left ventricular systolic and diastolic function without causing any consistent augmentation of left ventricular contractility.     

Acute electrophysiologic effects of intravenous amiodarone are independent of a sympatholytic action in humans

Previous experiments in animals demonstrated a novel sympatholytic action of acute intravascular amiodarone (AM). It is not known if this action also occurs in humans. Twelve male volunteers performed handgrip for 10 min before and after 300 mg intravenous (IV) AM over 60 min. The effect of handgrip was determined from changes in blood pressure (BP), heart rate (HR), and cardiac noradrenaline (NA) spillover. Changes in cardiac spillover of dihydroxyphenylglycol (DHPG), the metabolite of NA, were measured during AM infusion. The electrophysiological effects of AM were determined from changes to the A-H intervals during right atrial stimulation (100 beats/min). Handgrip increased HR (63 +/- 2 to 84 +/- 5 beats/min and 65 +/- 3 to 84 +/- 4 beats/min), systolic BP (141 +/- 4 to 179 +/- 6 mm Hg and 140 +/- 4 to 179 +/- 7 mm Hg), and cardiac NA spillover (11.9 +/- 4 to 44.3 +/- 13 ng/min and 17.3 +/- 4 to 55.5 +/- 11 ng/min) before and after AM, respectively (P < 0.02 in all groups). There was good correlation between increases in cardiac NA spillover and HR (r2 = 0.86) and systolic BP (r2 = 0.87). AM increased the A-H interval (95.5 +/- 18 to 107.8 +/- 20 ms, P < 0.02). There was no difference in hemodynamic or NA response to handgrip before or after the AM infusion. There was also no change in DHPG cardiac spillover during AM infusion. Acute IV AM did not exert a sympatholytic action in humans, with no attenuation in hemodynamic or NA response to handgrip or increase in DHPG production, despite producing an electrophysiologic response.     

The effect of propranolol, verapamil and dantrolene treatment on cardiac hypertrophy, enhanced myocardial contractility and tachycardia in the hyperthyroid rat

Experimentally induced hyperthyroidism is associated with cardiac hypertrophy, tachycardia and elevated myocardial contractility. To investigate the possibility of ameliorating the cardiac changes pharmacologically, hyperthyroid rats were treated with propranolol, verapamil or dantrolene. Cardiac hypertrophy was assessed from the heart mass: body mass ratio and cardiac function was measured in vitro. Both verapamil and propranolol reversed the cardiac hypertrophy of the hyperthyroid animals from 0.92 +/- 0.02 mg.g-1 to 0.70 +/- 0.01 mg.g-1 (P less than 0.001) and 0.72 +/- 0.02 mg.g-1 (P less than 0.001) respectively. Verapamil was effective in reducing the spontaneous heart rate from 331 +/- 8 beats.min-1 to 273 +/- 7 beats.min-1 (P less than 0.001) while propranolol reduced the dP/dtmax of the hyperthyroid hearts from 4089 +/- 87 mmHg.s-1 to 3497 +/- 97 mmHg.s-1 (P less than 0.001). Dantrolene had no effect on any parameter. We conclude from our results that cardiac hypertrophy of the hyperthyroid heart can be reversed by treatment with propranolol and verapamil probably via their inotropic and chronotropic properties.     

Pharmacokinetics of digoxin: relationship between response intensity and predicted compartmental drug levels in man.

A study designed to investigate the relationship between the pharmacokinetics of digoxin and a measure of its pharmacological effect has been conducted. Serum digoxin concentrations and systolic time intervals were measured concurrently in 12 normal male volunteers following a 1.0 mg i.v. bolus injection. The averaged serum digoxin concentration--time and response--time data were analyzed pharmacokinetically using a three-compartment open model and nonlinear least-squares fitting. When only the serum level--time data were analyzed, a close relationship was found between calculated digoxin levels in the slowly distributing (deep) peripheral compartment and response of the heart to digoxin, as measured by changes in the QS2 index (delta QS2I). Although it was not possible to distinguish clearly a linear from a nonlinear relationship between digoxin levels in the deep compartment and delta QS2I, the nonlinear relationship gave the best overall fit when both serum digoxin and delta QS2I data were fitted simultaneously. The simultaneous fit yielded a total body clearance of digoxin of 3.6 ml/min/kg and a terminal t1/2 of 42 hr.     

Hemodynamic effects during rest and exercise of bucindolol in hypertensive men

Bucindolol is an investigational beta-adrenergic blocking agent with intrinsic sympathomimetic and vasodilatory activity in animals. In a double-blind, six-way, crossover study of six mild-to-moderate hypertensive men, the effects of bucindolol 100, 200, and 300 mg/d on resting blood pressure, heart rate, forearm blood flow, and vascular resistance measured by pneumoplethysmography, and blood pressure and heart rate after cycle and handgrip exercise were compared with those of propranolol 160 and 320 mg/d and placebo after q12h administration for five doses. Both bucindolol and propranolol significantly suppressed heart rate after cycle exercise in comparison with placebo (-33 to -48 beats/min), demonstrating beta blockade. Suppression of resting heart rate by propranolol (-20 beats/min) was significantly (P less than .05) greater than bucindolol (-7 to -8 beats/min); a similar treatment difference in heart rate was noted after handgrip exercise (-18 to -19 vs -1 to -8 beats/min, respectively). Bucindolol and propranolol decreased resting blood pressure to the same extent (in comparison with placebo; P less than .05 at peak activity, 2 hr postdose). Bucindolol tended to increase forearm blood flow and decrease forearm vascular resistance (P less than .05 at 4 hr postdose) in comparison with placebo. The effect of propranolol on forearm blood flow and forearm vascular resistance was not significant compared with placebo. These data are consistent with intrinsic sympathomimetic and vasodilatory activity of bucindolol in hypertensive men.