The influence of two beta-adrenoceptor antagonists, propranolol and pindolol, on the haemodynamic effects of papaverine, isoprenaline and noradrenaline was investigated in 9 male patients with first degree essential hypertension. Propranolol and pindolol were given according to a doubleblind, crossover scheme. Heart rate and blood pressure were measured before and after each treatment. Propranolol 670 microgram/kg i.v. reduced the supine and standing systolic blood pressures by 2.3% and 1.6%, respectively. Similarly, the intravenous administration of pindolol 35 microgram/kg reduced supine and standing systolic blood pressure by 5.5% and 8.3% respectively (clinically insignificant). Neither drug affected diastolic blood pressure. Following propranolol, there were moderate reduction in supine and standing heart rates, respectively by 24% and 20%(p < 0.001). Similarly, but to a lesser extent, pindolol reduced supine and standing heart rate by 12% and 17%(p < 0.001). The effects of papaverine, which, at 1.5 mg/kg i.v. reduced systolic blood pressure by 5-10% and increased heart rate by 8-15%, were not significantly influenced by the beta-blockers. The blood pressure and heart rate responses to isoprenaline, on the other hand, were attenuated or inhibited by both beta-blockers. While the beta-blockers inhibited the beta-adrenoceptor component of noradrenaline, the pressor component of noradrenaline, which is mediated through the alpha-adrenoceptors, was not influenced by propranolol, but was inhibited after pindolol. It is concluded that pindolol differs qualitatively from propranolol in that it inhibited both the alpha and beta-adrenoceptor effects of noradrenaline.

Combined administration of verapamil, a phenylalkylamine calcium-entry antagonist, with a pure beta-adrenoceptor blocker, propranolol, produces profound cardiovascular depression associated with decreased hepatic clearance of both drugs. We have therefore studied the combination of verapamil and pindolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity (ISA), to evaluate whether or not the property of ISA will confer protection from the usual toxic effects observed with verapamil and a beta-adrenoceptor blocking agent. In an anesthetized dog model, dosing regimens which produced stable plasma concentrations of either verapamil and/or pindolol resulted in drug effects which were closely related to the plasma levels of the individual agents. When pindolol was combined with verapamil, profound depression of cardiac pump function occurred, similar to that previously found with propranolol. Further, plasma concentrations of verapamil promptly increased into a toxic range during combined administration with pindolol. In summary, since the cardiovascular depression resulting from verapamil and pindolol in combination is similar to that which occurs with verapamil and propranolol, ISA does not appear to obviate the toxic effects of verapamil and a beta-adrenoceptor agent in combination.

The partial beta adrenoceptor agonist properties of cicloprolol, xamoterol and pindolol have been compared in vivo (anesthetized catecholamine-depleted or pithed rats) and in vitro (guinea pig or rat right atria and guinea pig tracheal muscle preparations) conditions. All three compounds increased heart rate in the former preparations, and their intrinsic activities relative to isoproterenol were 0.7, 0.65 and 0.45, respectively. The positive chronotropic effects of cicloprolol or xamoterol were competitively antagonized by betaxolol or propranolol; however, part of those induced by pindolol were resistant to these beta adrenoceptor antagonists. None of these compounds increased the spontaneous beating rate of isolated guinea pig atria; however, xamoterol only increased heart rate in isolated rat atria, and its intrinsic activity with respect to isoproterenol was 0.4. Pindolol, xamoterol and cicloprolol behaved as competitive beta-1 adrenoceptor antagonists against isoproterenol-induced tachycardia in a pithed rat model. In order to mimic the intrinsic effects of the partial agonist drugs, control dose-response curves for isoproterenol were determined in pithed rats in which the base-line heart rate was elevated by thoracic spinal cord stimulation. In this in vivo preparation, xamoterol and pindolol were more potent beta-1 adrenoceptor antagonists than cicloprolol; however, cicloprolol and xamoterol, in contrast to pindolol, were selective for beta-1 adrenoceptors. In isolated spontaneously beating guinea pig right atria, cicloprolol and xamoterol were equipotent beta-1 adrenoceptor antagonists but were about 50 times less potent than pindolol. In isolated rat atria, the beta-1 adrenoceptor antagonist potency of xamoterol was greater (pA2 = 8.7) than in guinea pig atria (pA2 = 7.8). The potencies of cicloprolol and pindolol did not vary between these species. In catecholamine-depleted rats, high i.v. doses of cicloprolol had vasodilator activity that was partly mediated by beta-2 adrenoceptors. In carbachol-contracted guinea pig trachea, cicloprolol and xamoterol, in contrast to pindolol, were relatively inactive against isoproterenol-induced relaxation. In conclusion, cicloprolol and xamoterol, similarly to pindolol, behave as agonists and antagonists of beta-1 adrenoceptors. However, only cicloprolol and xamoterol show an elevated degree of selectivity toward the beta-1 adrenoceptor subtype.

Beta adrenoceptor antagonists are effective in the symptomatic management of angina pectoris. This paper examines critically the possible influence of the ancillary properties of beta 1 selectivity, partial agonism and membrane-stabilizing action on the response in anginal patients. The response is categorized according to experimental, pharmacological and clinical endpoints, placing emphasis on the possible errors which may arise from extrapolation from the former to the latter. It is concluded: That selective beta adrenoceptor antagonism confers limited, but tangible advantages over non-selective antagonists in regard to patients with reversible airways obstruction, and also in the metabolic and haemodynamic response to acute hypoglycaemia. Cardioselectivity does not influence the central haemodynamic response to exercise, but lessens adrenaline-mediated hypertensive responses to smoking and hypoglycaemia. Non-selective partial agonists cause less reduction in resting ventricular function, but their effects on cardiac output during exercise are indistinguishable from full antagonists. Membrane stabilizing properties have a marked influence on the tolerability of these agents in terms of unwanted, nonspecific central nervous system symptoms. Unresolved questions relate to the influence of partial agonism on fatigue, metabolic responses, especially blood lipids and glucose, and the possibility of lesser efficacy in angina compared to full antagonists.

In intact cats, cumulative doses (0.1-10 mg/kg i.v.) of labetalol produced dose-dependent decreases in heart rate and arterial blood pressure and dose-dependently reduced i.v. phenylephrine induced pressor responses. In spinal cats devoid of resting sympathetic tone, labetalol (1 mg/kg i.v.) produced a sustained elevation of heart rate and a transient fall in arterial blood pressure. In reserpine-pretreated, adrenalectomized cats, labetalol produced quantitatively the same effects as in spinal cats, indicating that the cardiovascular effects observed in cats with no resting sympathetic tone are due to a direct action of labetalol rather than via catecholamine release. The elevated heart rate due to labetalol in spinal cats was reduced by subsequent administration of the beta-adrenergic receptor antagonist, propranolol. Further, pretreatment with propranolol prevented the tachycardic and depressor effects of labetalol in spinal cats. In a separate group of spinal cats, labetalol administered in cumulative doses of up to 1 mg/kg i.v., produced graded increases in heart rate and also dose dependently reduced i.v. isoproterenol-induced tachycardic responses. Pindolol, a beta-adrenergic receptor antagonist with partial beta-agonist activity, produced similar effects in spinal cats at cumulative doses of 1-30 micrograms/kg. These results indicate that the alpha- and beta-adrenergic receptor antagonist, labetalol possesses partial beta-adrenergic receptor agonist activity. This intrinsic sympathomimetic action of labetalol appears to be more sustained on cardiac than on vascular beta-adrenergic receptors.

A double-blind multicentre study of 349 hypertensive patients was performed to compare the side-effects of the two beta-blockers atenolol (selective beta 1-blocker) and pindolol (beta 1- and beta 2-blocker with Intrinsic sympathomimetic activity (ISA] in equipotential doses (100 mg atenolol vs. 15 mg pindolol). Male and female patients aged 20-65 years with essential hypertension WHO stages I and II were included. Patients were examined 1 and 6 months after the start of treatment, and side-effects were recorded. The antihypertensive effect was similar for the two drugs. After 1 month there was significantly less bradycardia (P less than 0.01), cold hands and feet (P less than 0.05) and tiredness (P less than 0.02) in the pindolol group, and less sleep disturbance (P less than 0.02) in the atenolol group. After 6 months there was no significant difference in sleep disturbance, but the differences in the other side-effects remained significant.

In clinical practice it is essential to bear stress-induced cardiomyopathy (SICMP) in mind as it is an insufficiently known cardiac pathology that mimics acute coronary syndromes (ACS), often with signs of cardiac failure. In the chronic phase, it poses differential diagnostic problems with regard to coronary artery pathology. Taxonomic confusion, due to the pathology also being called "takotsubo" or "ampulla cardiomyopathy", has resulted in inappropriate diagnoses and therapy. Available evidence strongly suggests that, in the presence of several cardiac risk factors, excessive sympathetic stimulation may induce this cardiomyopathy. The predilection of this cardiomyopathy for Mediterranean and Indo-Asian women, who represent 85% of cases, is probably explained by the fact that there is a significant correlation between female gender, a short (<158 cm) stature, a small (<1.9 m(2)) body surface area, and hypoplastic coronary arteries. Furthermore, 40% of SICMP patients have a hypoplastic branching of the coronary arteries in the apical region of the heart. This anomaly strongly favors the apical localization of the dyskinesia. The prognosis of SICMP is good as far as life expectancy is concerned. However, in most cases, the symptoms become chronic, medical treatment rarely improves dyspnea and chest pain, and the quality of life is, therefore, reduced. In this paper, we address diagnostic misunderstandings and we review the clinical and pathophysiological features of SICMP.

An episode of torsades de pointes, an unusual ventricular tachyarrhythmia, developed in a 59-year-old coronary patient who was treated with 100 mg. four times a day mexiletine orally. The PR, QRS, and QT intervals were normal. The ventricular arrhythmias resembled in part, the patient's previous ventricular premature complexes, but there were some relevant morphological differences. The plasma electrolytes were within normal limits. Mexiletine, which is chemically and electrophysiologically similar to lidocaine, probably caused this arrhythmia. Although mexiletine is a useful antiarrhythmic drug, it should be added to the list of drugs associated with atypical ventricular tachycardia.

The influence of two beta-adrenoceptor antagonists, propranolol and pindolol, on the haemodynamic effects of papaverine, isoprenaline and noradrenaline was investigated in 9 male patients with first degree essential hypertension. Propranolol and pindolol were given according to a doubleblind, crossover scheme. Heart rate and blood pressure were measured before and after each treatment. Propranolol 670 microgram/kg i.v. reduced the supine and standing systolic blood pressures by 2.3% and 1.6%, respectively. Similarly, the intravenous administration of pindolol 35 microgram/kg reduced supine and standing systolic blood pressure by 5.5% and 8.3% respectively (clinically insignificant). Neither drug affected diastolic blood pressure. Following propranolol, there were moderate reduction in supine and standing heart rates, respectively by 24% and 20%(p < 0.001). Similarly, but to a lesser extent, pindolol reduced supine and standing heart rate by 12% and 17%(p < 0.001). The effects of papaverine, which, at 1.5 mg/kg i.v. reduced systolic blood pressure by 5-10% and increased heart rate by 8-15%, were not significantly influenced by the beta-blockers. The blood pressure and heart rate responses to isoprenaline, on the other hand, were attenuated or inhibited by both beta-blockers. While the beta-blockers inhibited the beta-adrenoceptor component of noradrenaline, the pressor component of noradrenaline, which is mediated through the alpha-adrenoceptors, was not influenced by propranolol, but was inhibited after pindolol. It is concluded that pindolol differs qualitatively from propranolol in that it inhibited both the alpha and beta-adrenoceptor effects of noradrenaline.

Tiapamil (Ro 11-1781) is a new calcium antagonist. Several investigators have reported about its efficacy against cardiac arrhythmias and angina pectoris. However, there was no study that assessed a possible relationship between hemodynamic effects and plasma concentration. Our study was aimed to investigate any possible relationship between cardiovascular effects of tiapamil and its plasma concentration. We selected 8 coronary; patients (6 males and 2 females) with a mean age of 61.9 yr and a mean weight of 70.9 kg. Tiapamil was administered per os at the dose of 250 mg t.i.d. for 4 consecutive days. Hemodynamic data were obtained by means of echocardiography, ECG and sphygmomanometry. Plasma concentrations of Ro 11-1781 and its major metabolites were measured by means of high pressure liquid chromatography. With tiapamil, the morning systolic BP fell from 130.6 +/- 19.5 (mean +/- SD, pretreatment) to 114.4 +/- 18.2 mm Hg on day 4, the change being clinically and statistically significant (P less than 0.02 by paired t-tests). Diastolic BP and HR remained unchanged. LVEDD and LVESD were not affected to any relevant extent, but VCF was significantly (P less than 0.05) and persistently increased. Tiapamil was well absorbed, but large interindividual variations were observed. As a general rule, no direct relationship between plasma concentrations and hemodynamic effects could be demonstrated. However, the number of patients is too small to allow general conclusions. At the above dose, tiapamil did not elicit any clinically detectable negative inotropic or negative chronotropic effect, probably because of its lowering effect on systolic BP.

The effects of Ro 12-4713, a vasodilator, on blood pressure and heart rate, were tested in 13 ambulant patients with mild to severe hypertension. The patients received Ro 12-4713 in total oral doses ranging from 1.5 to 4 mg/kg over a 3-5 day period. Standard laboratory tests were done 24 h before and after the study. Standing and supine blood pressure and heart rate were determined before, and every hour for 6-8 h after drug administration. ECGs were recorded before, during and at the end of each study day. Ro 12-4713 reduced the pretreatment standing and supine-blood pressure from 213 +/- 34/126 +/- 21 mmHg and 218 +/- 31/130 +/- 20 mmHg to 156 +/- 33/85 +/- 9 mmHg and 158 +/- 25/88 +/- 11 mmHg at the end of Day 5. Heart rate was only transiently increased in patients with pretreatment values of less than 90 beats/min. Although abnormal ECGs tended towards normalization, there were 2 cases of T-wave inversion (the patients remained asymptomatic). Raised BUN levels tended to decrease towards normal. Side effects reported spontaneously by patients (headaches, palpitations, dizziness, nausea and one case of water retention) appeared to be transient in nature. Ro 12-4713 appeared to be a very potent and long lasting antihypertensive agent, whose inherent side effects were only transient in nature.

The potency and efficacy of a single dose of a new aldosterone antagonist, potassium 17 a-hydroxy-6 beta, 7 beta-methylene-3-oxo-D-homo-17a alpha-pregna-4,16-diene-21-carboxylate (Ro 12-2503), in reversing the renal effects of exogenous aldosterone were compared to those of spironolactone, and placebo. The study was performed according to double-blind and crossover procedure in six healthy male subjects. Both drugs, spironolactone and Ro 12-2503, did not completely antagonize the effects of aldosterone. The efficacy of Ro 12-2503 in terms of the urinary Na+/K+ ratio and the urinary Na+ concentration was less than that of spironolactone. Spironolactone produced a slightly greater natriuresis, but the difference was not significant. The method described, based on standard bioassay techniques permits a comparison of the two drugs, and may prove useful in the screening and evaluation of aldosterone antagonists.

26 patients who had undergone right heart catheterization were enrolled in the study. The average age was 51.7 +/- 15 years. Half the patients showed coronary artery disease at selective coronary angiography. His bundle recordings and atrial pacing were performed before and 10 min after 1 or 1.5 mg/kg i.v. tiapamil. In addition, arterial blood pressure was recorded. P-R interval increased from a mean value of 153 +/- 36 to 168 +/- 49 ms (p less than 0.05) due to an increase in the A-H time from 88 +/- 19 to 97 +/- 23 ms (p less than 0.05). Arterial blood pressure and heart rate decreased significantly. These changes were more pronounced in patients with coronary artery disease. In the groups with the higher dosage, the differences from the control values were greater than in the patient groups receiving 1.0 mg/kg. Sinus node recovery time tended to increase in all groups but the differences did not reach significance. Patients with the 'sick sinus syndrome' were not studied.