Paroxysmal atrial fibrillation. A common but neglected entity.

Paroxysmal atrial fibrillation is an extremely common form of atrial fibrillation seen by most physicians. Despite making up more than 40% of the cases of atrial fibrillation, its management continues to be neglected in the medical literature. Many of the recent large-scale prospective trials have excluded these patients. Limited data suggest that paroxysmal atrial fibrillation should be treated in a similar fashion as chronic atrial fibrillation.

Celiprolol, a compound which attenuates myocardial acidosis and improves regional segmental function following ischemia in dogs: a comparison with propranolol.

Celiprolol, propranolol or saline were administered to separate groups (n = 5-6) of anesthetized dogs in which a critical stenosis was applied to the circumflex coronary artery for 90 min and then reperfused for 30 min. Test drugs were administered at 30 min poststenosis and the effects on pH, regional function and endocardiogram were monitored. A reduction in coronary flow of 54 +/- 2% (n = 27) yielded marked increases in hydrogen ion concentration (H+) of 17 +/- 2 X 10(-8) and ischemic endocardial ST segment of 6 +/- 1 mV while ischemic segmental shortening decreased 75 +/- 9%. Heart rate, arterial pressure and normal regional function were not altered. Celiprolol 0.1 and 1 mg/kg, i.v., reversed the alterations in H+ and ischemic ST segment to prestenosis values while improving ischemic segmental shortening 20 and 38%, respectively, and not affecting heart rate. Propranolol 0.1 and 1 mg/kg, i.v., reversed the alterations in H+ and ischemic ST segment to prestenosis values while further decreasing ischemic segmental shortening 66 and 30%, respectively. Upon reperfusion, ischemic segmental shortening returned to prestenosis values in the group treated with celiprolol 1 mg/kg, i.v., while the propranolol- and saline-treated groups further decreased. It is concluded that celiprolol is efficacious in normalizing myocardial function and ischemia-induced electrophysiological changes following coronary artery stenosis.

Evaluation of alpha-adrenergic cardiac stimulation in anesthetized dogs: can this play a role in propranolol insensitive cardiostimulatory effects of celiprolol.

The role of alpha-adrenergic systems in modulating contractility and rate in the canine heart is not completely understood. This was evaluated by examining alpha-agonists and antagonists in ganglionic- and beta-blocked, anesthetized dogs. Also, partial agonist effects of the beta-blocker celiprolol in the ganglionic blocked dog are insensitive to propranolol and may be mediated via alpha-2 antagonism. Prazosin (0.3 mg/kg), yohimbine (0.3 mg/kg), celiprolol (3 mg/kg) and vehicle were administered to ganglionic-(mecamylamine 2 mg/kg) and beta-adrenergic-(propranolol 1 mg/kg + 0.3 mg/kg/hr) blocked dogs. Clonidine (0.3 and 3.0 micrograms/kg), phenylephrine (3 micrograms/kg) and norepinephrine (0.3 microgram/kg) produced significant increases in arterial pressure with minimal chronotropic or inotropic effects. Celiprolol produced sustained increases in heart rate and contractile force of 15 +/- 3 beats/min and 33 +/- 7 percent (X +/- SEM) without significant vascular alpha antagonism. Yohimbine, prazosin and vehicle were without significant chronotropic or inotropic effects. However, yohimbine and prazosin selectively reduced pressor responses to clonidine and phenylephrine, respectively. In further studies adding prazosin or phentolamine before treatment with celiprolol did not attenuate its effects on heart rate and contractility. These results do not support significant inotropic or chronotropic effects of alpha-adrenergic receptor modulation in anesthetized dogs. The cardiac stimulatory effects of celiprolol do not appear to be mediated via cardiac alpha receptors.

Celiprolol, a compound possessing weak alpha 2-adrenergic antagonist properties in the dog.

Studies were conducted to evaluate the effects of celiprolol on alpha-adrenergic stimulation of dog saphenous vein rings (postsynaptic effect) and on catecholamine outflow from the dog coronary circulation during sympathetic nerve stimulation in vivo (presynaptic effect). In venous rings, celiprolol, 10(-6) to 10(-4) M, shifted the concentration-response curve to BHT 920 in a concentration-related manner, but had no effect on the response to methoxamine at concentrations less than 10(-4) M. During continuous stimulation of the right stellate ganglion, celiprolol, 1-10 mg/kg i.v., increased the catecholamine concentration in the coronary sinus, while decreasing heart rate. In contrast, propranolol did not affect catecholamine concentration but decreased heart rate, rauwolscine increased both catecholamine concentration and heart rate, and clonidine decreased both catecholamine concentration and heart rate. These results are consistent with the hypothesis that celiprolol possesses weak alpha 2-antagonist properties in addition to its beta 1-blocking activity.

Measurement of oxygen tension in the ischemic myocardium using encased polargraphic oxygen electrodes.

The ability to continuously monitor the delicate balance between blood flow and oxygen consumption would be a great asset in the study of myocardial ischemia. The present study was performed, in anesthetized dogs, to validate the use of encased polargraphic oxygen electrodes in the study of myocardial ischemia. Polargraphic oxygen electrodes were placed in the area to be rendered ischemic at fixed tissue depths of 3 mm (epicardium) and 9 mm (endocardium). Endocardial and epicardial oxygen tensions as well as the ratio of endocardial to epicardial oxygen tension and left circumflex coronary flow were monitored. Ischemia was induced by decreasing left circumflex coronary flow by 50%. Upon completion of a 20-min poststenotic period, endocardial pO2, endocardial/epicardial ratio, and coronary flow were significantly decreased (59 +/- 7, 52 +/- 7, and 55 +/- 4%, respectively) whereas epicardial pO2 was slightly decreased. Nitroglycerin (10 micrograms/kg, i.v.) markedly increased endocardial pO2 and endocardial/epicardial ratio above poststenotic control (13 +/- 5 mmHg and 64 +/- 10%, respectively) whereas epicardial pO2 was not significantly decreased. The increases in endocardial pO2 occurred at a point where coronary flow and mean arterial pressure were not significantly changed. Conversely, dipyridamole (125 micrograms/kg, i.v.) significantly increased coronary flow (26 +/- 2 ml/min/100 g) although it did not appreciably alter endocardial or epicardial pO2. It is concluded that encased polargraphic oxygen electrodes provide a quantitative method for determination of oxygen tension in the ischemic myocardium.

The antagonist and partial beta agonist properties of celiprolol in isolated rat cardiac tissue.

Celiprolol was evaluated for its antagonist and partial beta agonist effects in rat spontaneously beating right atria and in electrically stimulated left ventricular strips. Celiprolol, like propranolol, produced a parallel concentration-related rightward shift of the isoproterenol (ISO) (beta agonist) concentration-response curve without decreasing the maximum response in rat right atria. The pA2 values for celiprolol and propranolol were 7.02 +/- 0.30 and 8.45 +/- 0.29, respectively. Unlike propranolol, however, celiprolol increased the resting spontaneous rate at concentrations 3 X 10(-7) to 10(-4)M. ISO alone produced a concentration-related increase in heart rate of rat right atria (maximum 149 +/- 15 bpm at 3 X 10(-7)M). Whereas, celiprolol increased atrial rate a maximum of 49 +/- 5 bpm at 10(-6)M. ISO produced a concentration-related increase in the developed tension of rat right ventricular strips (maximum 79 +/- 4% at 10(-6)M. Celiprolol, by contrast, had no effect on developed tension in concentrations up to 10(-3)M. In separate experiments, celiprolol alone increased right atrial rate a maximum of 40 +/- 6 bpm at 10(-5)M. Pretreatment with propranolol (10(-6)M) completely blocked the increase in rate. It is concluded that celiprolol is a potent and competitive beta antagonist and a partial agonist with approximately 33% of the efficacy (comparing maximum stimulating concentrations) and 0.01 the potency of ISO in rat right atria (at ED50 concentrations). Celiprolol, however, unlike ISO, has no inotropic effect in rat ventricular strips suggesting possible differences in their agonist properties.

Celiprolol: a new beta adrenoceptor antagonist with novel ancillary properties.

Celiprolol HC1 is a new cardioselective beta-blocker with properties which may make it the next advance in the evolution of this class of compounds. Its cardioselectivity has been demonstrated both in vitro and in vivo, with an intravenous potency equivalent to atenolol. The compound is devoid of a membrane stabilizing effect which is reflected in anesthetized dogs by a lack of myocardial electrophysiological effects. The compound induces a vasodilator effect in anesthetized dogs which is partially attenuated by propranolol, suggesting a weak beta 2-agonist activity. This beta 2-agonist property is also manifested in other peripheral tissues and undergoes down-regulation with repeat exposure. In contrast to other beta-blockers, celiprolol produces a bronchodilation in anesthetized cats which is propranolol-resistant. Isolated tissue studies suggest that a weak alpha 2-blocking effect contributes to this bronchodilation, although another unknown mechanism participates as well. Celiprolol induces a cardiac stimulation in anesthetized dogs which is inhibited by propranolol. The mechanism for this effect appears to be due to adrenergic interaction. These unique properties of celiprolol convey salutary effects in the clinical use of celiprolol.

Effects of celiprolol in anesthetized dogs with reduced myocardial function.

Celiprolol HCl is a new cardioselective beta adrenoceptor antagonist with both mild propranolol-sensitive partial agonist activity and propranolol-insensitive cardiostimulatory properties. The purpose of the present investigation was to assess the significance of this unique pharmacological profile in a study of the effects of celiprolol in anesthetized dogs with depressed myocardial function. Dogs were acutely instrumented to directly monitor myocardial contractile force (CF), arterial pressure (AP), heart rate (HR), and ECG limb lead II. Mecamylamine 1 mg/kg i.v., and verapamil, 0.5 mg/kg i.v., reduced CF (80 +/- 6 g), HR (76 +/- 4 beats/min), and AP (59 +/- 8 mm Hg). Celiprolol (3 mg/kg i.v.) did not produce any further decrement in myocardial function. There were no appreciable ECG changes. These data suggest that celiprolol may be the drug of choice in patients receiving verapamil, since it should not further compromise myocardial function.

Effects of nitroglycerin, dipyridamole, nifedipine, verapamil and diltiazem on canine coronary arterial rings contracted with 5-hydroxytryptamine and anoxia.

Anoxia has been shown to potentiate the constrictor effects of 5-hydroxytryptamine (5HT) in isolated vascular tissue. In the present study, canine coronary arterial rings were incubated with various treatments and exposed to 5HT (4 X 10(-7) M) and anoxia (95% N2 and 5% CO2). Developed tension was increased by 250 +/- 40 mg by 5HT alone and 2,000 +/- 90 mg by 5HT and anoxia. Calcium (5 mM) potentiated, while inorganic (lanthanum, 10(-2) M) and organic calcium antagonists (nifedipine, verapamil and diltiazem; IC50 = 7 X 10(-9), 7.3 X 10(-8) and 2.4 X 10(-7) M, respectively) blocked the anoxic potentiation. Anoxia alone decreased resting tension (RT). Methysergide 3 X 10(-5) M inhibited both the 5HT- and anoxia-potentiated responses. Nitroglycerin decreased RT and inhibited the anoxic response (IC50 = 7.6 X 10(-6) M), while dipyridamole decreased RT and did not affect the anoxic response. These data suggest that the potentiation of 5HT contraction by anoxia is dependent upon extracellular calcium influx and is linked to a 5HT receptor. In addition, inhibition of the anoxic response can be achieved at other sites and is not a property common to all coronary vasodilators.

Celiprolol, a potent cardioselective beta 1-adrenoceptor antagonist with mild alpha 2-adrenoceptor antagonist properties.

Celiprolol is a cardioselective beta-adrenoceptor antagonist, with interesting propranolol-insensitive cardiostimulatory, vasodilatory and bronchodilatory effects. Recent reports suggest that mild alpha 2-adrenoceptor antagonism may contribute to these effects. The present investigation further explored the alpha 2 effects of celiprolol. In isolated electrically-stimulated rat atria celiprolol (1.0 and 10 mumol/l) significantly increased the release of [3H]-norepinephrine, consistent with the blockade of pre-junctional alpha 2-adrenoceptors. Evidence for post-synaptic alpha 2-adrenoceptor antagonist activity was obtained in studies of the effects of celiprolol on the pressor response to clonidine and either phenylephrine or methoxamine in perfused hind-limbs of dogs (pretreated with mecamylamine and propranolol) and pithed rats. In the dog, celiprolol (10 mg/kg) significantly inhibited the vasoconstrictor response of clonidine while in the rat higher doses were required (> or = 12.5 mg/kg). Celiprolol did not affect the pressor response induced by alpha 1-agonists. We conclude that celiprolol possesses a mild alpha 2-adrenoceptor blocking action which may contribute to its unconventional profile.

In vivo anti-allergic and bronchopulmonary pharmacology of REV 3164 in rats and guinea-pigs.

REV 3164 has been evaluated in a variety of intact rodent models to reveal potential utility in the prophylactic treatment of asthma. REV 3164 was found a potent, orally active inhibitor of rat (IgE) passive cutaneous anaphylaxis (PCA, ED50 = 0.9 mg/kg). By contrast, at 50-200 mg/kg p.o., it did not affect guinea-pig (IgG1) PCA. In PCA rats, both REV 3164, 1-36 mg/kg i.p., and the known inhibitor of mast cell mediator release, disodium cromoglycate (DSCG), 2-54 mg/kg i.p., blocked cutaneous wheals caused by i.v. antigen challenge but not by intradermal serotonin or histamine. Neither REV 3164 (0.1-10 mg/kg i.p.) nor DSCG (2-54 mg/kg i.p.) affected Compound 48/80-induced wheals. REV 3164 (0.01-1 mg/kg i.v. or 10 mg/kg i.p.) abolished rat (IgE) passive lung anaphylaxis (PLA, ED50 = 0.05 mg/kg i.v. for inhibition of elevated airway resistance). At 10 mg/kg i.p., REV 3164 did not affect active lung anaphylaxis in guinea-pigs pharmacologically manipulated to enhance the production and action of slow reacting substance of anaphylaxis (SRS-A), nor did it exhibit anticholinergic activity in the rat. REV 3164 (100 mg/kg i.p.) did not protect conscious guinea-pigs from histamine aerosol-induced collapse. It is concluded that REV 3164 is an oral inhibitor of IgE-dependent immediate hypersensitivity in the rat with biological activities in rats and guinea-pigs similar to DSCG.

Angiotensin-converting enzyme inhibitory and antihypertensive activities of pivalopril (RHC 3659-(S)).

Pivalopril (RHC 3659-(S); (S)-N-cyclopentyl-N-(2-methyl-3-pivaloylthiopropionyl) glycine) is a new compound with a hindered sulfur group that has been compared to captopril for oral angiotensin-converting enzyme (ACE) inhibition in rats and dogs and antihypertensive activity in rats. In separate groups of conscious normotensive rats, pivalopril (0.03-1.0 mg/kg, orally [p.o.]) produced a dose-related antagonism of angiotensin I (AngI)-induced pressor effects. The ED50 for pivalopril and captopril was 0.1 mg/kg. In conscious normotensive dogs, pivalopril (incremental doses of 0.01-1.0 mg/kg, p.o.) produced a dose-related antagonism of AngI pressor effects. The ED50 was 0.17 mg/kg for pivalopril and 0.06 mg/kg for captopril. At equieffective doses the two compounds had similar durations of action. In sodium-deficient, conscious spontaneously hypertensive rats (SHR), pivalopril (1-100 mg/kg, p.o.) produced a dose-related reduction in mean arterial pressure. The potency and duration were similar to those of captopril. In the sodium-replete SHR, 5 days of oral dosing with pivalopril, 100 mg/(kg . day), decreased mean arterial pressure more effectively than captopril, 100 mg/(kg . day). No tolerance developed to the antihypertensive effect of either drug. It is concluded that pivalopril is a potent, orally effective ACE inhibitor and antihypertensive agent.

Preclinical studies of indapamide, a new 2-methylindoline antihypertensive diuretic.

Indapamide is a new indoline antihypertensive diuretic agent whose chemical structure differs substantially from those of the thiazides. The hydrophobic indoline moiety of indapamide confers a lipid solubility to the molecule that is 5 to 80 times greater than that of the thiazide diuretics. Thus indapamide accumulates in vascular smooth muscle at a concentration 10 times higher than that of protein-free perfusate. The affinity of indapamide for vascular smooth muscle manifests itself in vitro and in vivo as a decrease in reactivity following various pharmacologic interventions. Moreover, in vitro studies have demonstrated that indapamide decreases the inward calcium current and the transmembrane influx of calcium. The diuretic effect of indapamide is predominantly due to inhibition of sodium reabsorption at the cortical diluting segment of the distal convoluted tubule. In animal studies, intravenous indapamide has no effect on glomerular filtration rate or renal blood flow. Indapamide is well absorbed and extensively metabolized in animals and humans, with biliary excretion being the predominant route of elimination in animals. Most important, repeat administration of indapamide to dogs with both kidneys removed produces no accumulation of intact indapamide or its metabolites. Extensive drug safety studies in animals indicate that indapamide produces no overt toxicity and exhibits a good margin of safety.

Effect of indapamide on volume-dependent hypertension, renal haemodynamics, solute excretion and proximal nephron fractional reabsorption in the dog.

Indapamide, a newly developed antihypertensive agent with modest diuretic properties, reduced mean arterial pressure toward normal in dogs made hypertensive with salt and DOCA, while low-dose furosemide (0.1 mg per day) and hydrochlorothiazide (1 and 50 mg per day) did not result in similar degrees of blood pressure control. Indapamide, low-dose furosemide and hydrochlorothiazide treatment all resulted in similar decreases in body weight suggesting that the antihypertensive effect of indapamide occurs through a mechanism independent of contraction of extracellular fluid volume. Intravenous indapamide at doses of 0.3, 1.0 and 3.0 mg/kg caused progressive increases in sodium, potassium and chloride excretion when urine losses were replaced by isotonic saline to prevent extracellular fluid volume contraction. Only at 3.0 mg/kg did plasma potassium decrease significantly (2.92 +/- 0.03 to 2.69 +/- 0.05 mmol/l; p less than 0.05). Neither glomerular filtration rate (GFR) nor renal blood flow (flowmeter) decreased in a dose-related manner; however, effective renal plasma flow assessed by para-aminohippurate clearance did decrease about 15% at the highest dose (p less than 0.05). Proximal re-collection micropuncture studies demonstrated decreased proximal reabsorption. Cortical diluting segment reabsorption was decreased, but CNa + CH2O/GFR increased from 7% to 11% (p less than 0.05). These results indicate that, at doses up to 3.0 mg/kg, indapamide causes a natriuresis which is modest and similar to that seen with thiazides. No decrease in GFR or renal blood flow was observed. This drug apparently exerts a natriuretic effect through an inhibition of solute reabsorption in both the proximal nephron and the cortical diluting segment.

Arrhythmias in chronic pulmonary disease.

Arrhythmias often complicate the course of patients with severe respiratory disease; the frequency of arrhythmias in patients with this condition approaches that seen with acute myocardial infarction. No one rhythm disturbance predominates, but rapid atrial and ventricular rhythms are characteristic. In the setting of acute respiratory failure, several conditions may predispose to arrhythmias. Hypoxemia, a serum pH that is too high or too low, and a low serum potassium may produce arrhythmias by disturbing the myocardial cellular milieu. Drugs such as digitalis, epinephrine, and theophylline may also act as myocardial irritants. The first step in therapy is to careful examination, it is helpful to note the specific effect of the arrhythmia on the patient. Some rhythm disturbances are well tolerated, while others are associated with serious problems in ventilation and perfusion. In many cases the control of respiration, correction of pH and electrolyte imbalance, and provision of bronchial hygiene will restore a normal sinus rhythm. Such measures are essential even when antiarrhythmic drugs or cardioversion are needed.

Spontaneous rupture of a coronary artery with false aneurysm formation. Successful surgical repair.

A patient with diffuse atherosclerotic coronary arterial disease was demonstrated to have a spontaneous rupture of the proximal right coronary artery, with formation of a false aneurysm. This was recognized at angiographic study, and the patient subsequently underwent a revascularization operation with suture ligation of the aneurysm.