A single dose of three different ophthalmic beta-blockers antagonizes the chronotropic effect of isoproterenol in healthy volunteers

The systemic effect of three beta-blocking eyedrops was compared in a placebo-controlled, double-blind trial in 12 healthy male volunteers. Each subject received successively each treatment in random order at weekly intervals. The eyedrops administered were as follows: 0.5% timolol, 2% carteolol, 0.6% metipranolol, and placebo. We evaluated the intraocular pressure and systemic beta-blockade 3 hours after a single administration of one eyedrop in each eye. The systemic beta-blocking effect was evaluated by the isoproterenol sensitivity test, that is the dose of isoproterenol required to increase resting heart rate by 25 bpm (I25). Each beta-blocking eyedrop antagonized the chronotropic effect of isoproterenol. I25 for placebo was 3.1 +/- 0.5 micrograms, for metipranolol 5.2 +/- 0.9 micrograms (P less than 0.005), for timolol 10.9 +/- 1.9 micrograms (P less than 0.001), and for carteolol 39.6 +/- 5.4 micrograms (P less than 0.0005). Each treatment significantly decreased the intraocular pressure: metipranolol 3.6 +/- 0.4 mm Hg (P less than 0.001), timolol 2.44 +/- 0.4 mm Hg (P less than 0.01), and carteolol 2.38 +/- 0.48 mm Hg (P less than 0.01) compared with placebo. The resting heart rate and blood pressure were not influenced by the treatments. Even though the results might be different in the case of an earlier or a later time of evaluation or chronic administration, we believe that the isoproterenol sensitivity test may be used to evaluate the systemic effect of beta-blocking eyedrops.     

Beta blockade by oral propranolol and labetalol

beta-Adrenergic blockade after single, oral doses of labetalol or propranolol was evaluated in a double-blind, placebo-controlled study by an isoproterenol sensitivity test and handgrip exercise in 10 healthy men. The tests were performed with subjects resting in a supine position. At the doses used, there was no effect on heart rate and blood pressure in either the resting position or in the isometric exercise phase. It is possible that exercise-induced changes in blood pressure and heart rate were reduced by higher vagal tone in this young group tested in the supine position. Isoproterenol increased heart rate and reduced diastolic blood pressure in a dose-dependent manner. The dose of isoproterenol at which heart rate increased 25 bpm above the resting rate (CD25; 1.36 +/- 0.18 microgram) was of the order of that at which diastolic blood pressure fell 25 mm Hg from baseline (HD25; 1.07 +/- 0.07 microgram). There was a significant positive correlation between CD25 and HD25 in the 10 subjects. Propranolol and labetalol induced a dose-dependent, parallel shift to the right in the dose-response curves of isoproterenol effects on heart rate and diastolic blood pressure, indicating that both drugs are nonselective, competitive antagonists of beta-adrenergic receptors. On the average, propranolol was 17 and 19 times more potent than labetalol in antagonizing the chronotropic and hypotensive actions of isoproterenol, respectively.     

Conditions for augmentation of renin release by theophylline

Isoproterenol, dopamine, glucagon and dibutyryl cyclic AMP (DB-cAMP) increase renin release at low but not at control blood pressure. These findings suggest that autoregulated afferent arteriolar dilation is a prerequisite of renin release mediated by intracellular generation of cyclic AMP. To examine this hypothesis further the effects on renin release of theophylline, which would maintain high intracellular concentration of cAMP by inhibiting phosphodiesterase, were studied in anesthetized dogs. After inhibiting beta-adrenergic stimulation with propranolol, theophylline increased renin release significantly from 0.7 +/- 0.2 to 1.8 +/- 0.7 micrograms/min at control blood pressure and from 23 +/- 4 to 41 +/- 5 micrograms/min at a renal perfusion pressure of about 50 mmHg. The greater effect at low blood pressure occurred despite adjustment of the infusion rate of theophylline to keep arterial plasma concentration of theophylline unaltered. Isoproterenol infusion at low blood pressure raised renin release from 41 +/- 11 to 76 +/- 19 micrograms/min before and 54 +/- 13 to 108 +/- 31 micrograms/min during continuous infusion of theophylline. The renin release response to infusion of theophylline at low blood pressure was not enhanced by DB-cAMP infusion. We conclude that arteriolar dilation provides a condition for stimulation of renin release during the theophylline infusion. Theophylline infusion may augment the effect of isoproterenol on renin release by delaying the intracellular degradation of cAMP.     

Comparison of the autonomic effects of procainamide and N-acetylprocainamide in the dog

The autonomic effects of procainamide (PA) and N-acetylprocainamide (NAPA) were studied in anesthetized dogs. High plasma concentrations of PA (31 +/- 1.3--64 +/- 3.4 micrograms/ml) and NAPA (64 +/- 3.4--127 +/- 8.3 micrograms/ml)) reduced base-line mean arterial pressure and heart rate and attenuated the pressor and positive chronotropic responses to bilateral carotid occlusion and the negative chronotropic response to vagal stimulation. Neither drug reduced the pressor or positive chronotropic responses to catecholamines (epinephrine, phenylphrine, isoproterenol), however. In fact, at some doses PA and NAPA accentuated the pressor and positive chronotropic effects of epinephrine. Similarly, the depressor response to acetylcholine was not reduced by these drugs; it was significantly increased at some doses. In the isolated hindlimb (constant flow) PA and NAPA reduced the pressor response to preganglionic (sympathetic chain) stimulation but not to postganglionic (femoral and sciatic nerves) stimulation. We conclude that NAPA, like PA, at high plasma levels is vagolytic and attenuates baroreceptor-mediated reflexes associated with reduced arterial pressure. These effects appear to be due to ganglionic blockade.     

Cardiovascular effects of verapamil in essential hypertension

Calcium antagonists may affect the regulation of body sodium and adrenergic-dependent mechanisms. Exchangeable sodium, blood volume, plasma norepinephrine, renin, aldosterone, pressor responsiveness to norepinephrine, heart rate responses to isoproterenol, and lipid metabolism were studied in 15 patients with essential hypertension after 8 weeks of treatment with verapamil (348 +/- 68 (SD) mg/day). Supine blood pressure decreased from 153/103 +/- 19/12 mm Hg to 140/95 +/- 14/12 mm Hg (P less than 0.01). Exchangeable sodium, blood volume, plasma norepinephrine, renin and aldosterone, serum total cholesterol, the lipoprotein fractions, and apoprotein levels were unchanged. The norepinephrine pressor and the isoproterenol chronotropic doses tended to increase, whereas the dose-response curve of blood pressure related to plasma norepinephrine was significantly displaced to the right (F = 5.34; P less than 0.05). The antihypertensive effect of verapamil is associated with a decreased cardiovascular pressor responsiveness to norepinephrine without changes in endogenous noradrenergic activity. Moreover, verapamil does not modify the sodium/fluid volume state, the activity of the renin-angiotensin aldosterone axis, or lipid metabolism.     

Interaction between autonomic tone and the negative chronotropic effect of adenosine in humans

Prior studies have demonstrated that sympathetic tone may influence the effects of adenosine on His-Purkinje automaticity, and that enhanced vagal tone may influence its effects on the sinus node. However, the interaction between autonomic tone and the effects of adenosine on the sinus node in humans remains unknown. Therefore, this study was designed to investigate the interaction between different states of autonomic tone and the bradycardiac response of the sinus node to adenosine. In 11 patients without structural heart disease who underwent a clinically indicated electrophysiology procedure, the sinus cycle length was measured before and after a 12-mg bolus of adenosine in the baseline state, during an infusion of 2 mcg/min of isoproterenol, after the administration of 0.2 mg/kg of propranolol, and again after the administration of 0.04 mg/kg of atropine. Adenosine significantly lengthened the sinus cycle length in the baseline state (760 +/- 165 vs 909 +/- 188 ms, P < 0.05), during isoproterenol infusion (516 +/- 67 vs 766 +/- 146 ms, P < 0.05), after propranolol (850 +/- 153 vs 914 +/- 143 ms, P < 0.05) and after the combination of propranolol and atropine (662 +/- 76 vs 801 +/- 121 ms, P < 0.05). The degree of lengthening in sinus cycle length was significantly greater (P < 0.05) during isoproterenol infusion (253 +/- 157 ms, or 51% +/- 40%) than in the baseline state (149 +/- 85 ms, or 20% +/- 12%), after propranolol (68 +/- 53 ms, or 8% +/- 8%), and after propranolol and atropine (140 +/- 110 ms, or 21% +/- 18%). The negative chronotropic effect of adenosine is influenced by autonomic tone. The effect of adenosine on the sinus node is accentuated by beta-adrenergic stimulation and unaffected by beta-adrenergic blockade or combined beta-adrenergic and cholinergic blockade.     

Effect of nifedipine and theophylline in asthma

The effect of nifedipine, 10 mg po q.i.d. for 2 weeks, was studied in a randomized, double-blind, crossover trial in nine patients with asthma receiving theophylline. Nifedipine did not significantly affect the mean (+/- SD) morning peak expiratory flow rate (PEFR; 336 +/- 130 L/min for drug vs. 349 +/- 92 L/min for placebo), evening PEFR (393 +/- 69 L/min for drug vs. 367 +/- 66 L/min for placebo), symptom score (27.4% +/- 22.9% for drug vs. 33.8% +/- 26.4% for placebo), or the number of albuterol inhalations per day (5.8 +/- 3.5 for drug vs. 6.2 +/- 4.1 for placebo). Furthermore, there was no change in PEFR 30, 60, or 120 minutes after nifedipine dosing. Nifedipine did not significantly affect the steady-state serum theophylline trough levels (9.1 +/- 2.2 mg/ml for drug vs. 10.2 +/- 1.9 micrograms/ml for placebo) or the theophylline pharmacokinetic parameters, such as the elimination t1/2, peak serum concentration, time to peak, and AUC(0-24). We conclude that nifedipine has little, if any, effect on the clinical status, PEFR, or theophylline serum levels in patients with asthma who receive theophylline.     

Mexiletine effects on theophylline disposition

The effect of mexiletine administration on steady-state plasma theophylline concentrations was studied in eight normal healthy men in a prospective open label nonrandomized two-way crossover trial. Repeated doses of 300 mg of sustained-release theophylline were given every 12 hours for 9 days. Mexiletine hydrochloride, 200 mg every 8 hours, was given for five consecutive doses starting on the morning of day 6. Mexiletine increased theophylline levels in all subjects. Mean predose (trough) levels rose from 8.1 +/- 0.1 microgram.ml-1 to 13.4 +/- 0.6 micrograms.ml-1 and AUC(0-12) from 96.8 +/- 9.1 to 160.2 +/- 3.7 micrograms.ml-1.hr. Plasma clearance was reduced by mexiletine from 44.7 +/- 5.1 to 25.4 +/- 1.2 ml.hr-1. Both N-demethylated metabolites of theophylline were decreased by 60% by mexiletine, whose levels remained within its therapeutic range. Theophylline levels returned to pre-mexiletine values when this drug was discontinued. Mexiletine reduces theophylline clearance and increases its plasma concentration by inhibiting N-demethylation of theophylline. Plasma theophylline levels should be monitored when mexiletine is added.     

Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men

The effect of age on the induction of theophylline metabolism by phenytoin was examined in healthy young and old male cigarette smokers (greater than or equal to 20 cigarettes/day) and nonsmokers. Two single dose studies of theophylline pharmacokinetics were performed, one as a base-line control and another after a 2-week course of phenytoin. Phenytoin was administered as an i.v. loading dose followed by oral ingestion. The dose was adjusted to achieve total phenytoin plasma concentrations within a low therapeutic range (10-13 micrograms/ml). Free phenytoin concentrations in plasma were slightly higher in old (nonsmokers 0.84 +/- 0.13 micrograms/ml; smokers 0.89 +/- 0.12 micrograms/ml) than in young (nonsmokers 0.75 +/- 0.10 micrograms/ml; smokers 0.72 +/- 0.10 micrograms/ml) subjects, but the differences were not significant. Base-line plasma theophylline clearance was 30% lower in old compared with young nonsmokers (34.0 +/- 2.5 vs. 48.8 +/- 2.6 ml/hr/kg, P less than .001), whereas the small age difference between old and young smokers (86.0 +/- 8.4 vs. 72.4 +/- 8.0 ml/hr/kg) was not significant. Smokers had higher values of theophylline clearance than nonsmokers regardless of age. Half-life was prolonged in old nonsmokers in proportion to decreased clearance, despite a slight decrease in volume of distribution. Phenytoin induced theophylline metabolism to an equal degree in both age groups and in both smokers (young 42.6 +/- 6.5%; old 47.3 +/- 3.6%) and nonsmokers (young 56.3 +/- 8.8%; old 45.4 +/- 6.4%). The magnitude of its induction in smokers was additive to that of cigarette smoking. Old age was associated with a modest selective reduction in N-demethylated metabolic pathways to 3-methylxanthine and 1-methyluric acid, whereas smoking preferentially induced the formation of these products. Phenytoin increased the production of all theophylline primary metabolites to an equal degree in both old and young subjects. The urinary excretion of 6 beta-hydroxycortisol was not influenced significantly by age or smoking and increased 2- to 3-fold in all subject groups with phenytoin. These results confirm earlier observations of a reduction in basal oxidative capacity in elderly nonsmoking males. They also demonstrate that the ability to induce the metabolism of theophylline by smoking or phenytoin and the ability to induce the metabolism of cortisol by phenytoin are maintained in old age.     

Insurmountable beta receptor blockade by ICI 147,798 in rabbits

In rabbits, the characteristics of cardiac beta-1 receptor blockade produced by ICI 147,798, a novel beta receptor blocking agent with diuretic properties, were evaluated and compared with those of propranolol. In conscious rabbits, i.v. injections of 0.31, 1.0 and 3.1 mg/kg of ICI 147,798 and 1.0 mg/kg of propranolol caused significant bradycardia. ICI 147,798 produced a dose-dependent shift to the right of the dose-response (chronotropic) curve of isoproterenol with suppression of the maximal tachycardia, an effect characteristic of insurmountable beta receptor blockade. Propranolol also produced a shift to the right of the dose-response curve of isoproterenol without affecting the maximal tachycardia. ICI 147,798-induced antagonism was specific for beta adrenoceptors as it failed to modify the effects of acetylcholine, angiotensin II, phenylephrine, adenosine, histamine and prostaglandin E2 on mean arterial pressure and heart rate. In rabbits with prior autonomic blockade, ICI 147,798, like propranolol, failed to inhibit the positive chronotropic effects of theophylline which are mediated by postreceptor mechanisms. In reserpinized rabbits, ICI 147,798 was found to have no intrinsic sympathomimetic activity. Unlike the effects of propranolol, which were attenuated by first-pass through the hepatic vascular bed, the effects of ICI 147,798 were unaffected suggesting an absence of first-pass metabolism. The effects of propranolol (1.0 mg/kg i.v.) were not detectable at 24 hr after injection, whereas significant beta receptor blocking activity was still present at 24 hr after ICI 147,798 (1.0 mg/kg i.v.). The results suggest that ICI 147,798 is a specific, long-acting, insurmountable beta-1 receptor blocking agent without intrinsic sympathomimetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of amiodarone upon the canine sinus node and atrioventricular junctional region

Amiodarone was selectively perfused into the sinus node artery and atrioventricular node artery of 51 dogs. Amiodarone had an immediate negative chronotropic and dromotropic effect. Threshold concentration was 2.5 micrograms/ml. 25 and 50 micrograms/ml of amiodarone injected into the sinus node artery slowed the heart by 25.6 +/- 3.1 and 33.7 +/- 2.6 beats/min (mean +/- 1 SEM), respectively. Amiodarone 25 and 50 micrograms/ml injected into the AV node artery during AV junctional rhythm slowed the AV junctional pacemaker by 12.2 +/- 1.8 and 17.4 +/- 1.7 beats/min, respectively. Injections of amiodarone into the AV node artery during sinus rhythm regularly increased AV conduction time sometimes causing 2 degrees AV block at the highest concentration used. Impaired conduction was exclusively measured at the level of the A-H interval in the His electrogram. Neither atropine nor propranolol prevented the negative chronotropic effects of amiodarone. Amiodarone had no significant effect on sinus node response to either stellate stimulation or intranodal administration of norepinephrine. The negative chronotropic action of amiodarone was significantly enhanced when amiodarone was administered in a perfusate containing low (0.6 mM) instead of normal calcium. Taken collectively these observations indicate that amiodarone has immediate depressant electrophysiologic effects on both the sinus node and the AV junction and that these early effects might involve the blockade of the slow channel.     

Caffeine and theophylline as adenosine receptor antagonists in humans

Substantial in vitro and animal data suggest that methylxanthines, such as caffeine and theophylline, act as adenosine receptor antagonists. To test this hypothesis in humans, we first determined if theophylline would antagonize the effects of adenosine. Intravenous administration of adenosine, 80 micrograms/kg/min, increased heart rate 28 +/- 6 bpm, systolic blood pressure 19 +/- 5 mm Hg and minute ventilation 6.1 +/- 2.2 liters/min. All these changes were significantly attenuated during theophylline administration (17 +/- 3 bpm and 1 +/- 2 mm Hg and 1.6 +/- 0.6 liters/min, respectively, P less than .05), at a dose (10 mg/kg over 1 hr, followed by 1.8 micrograms/kg/min i.v.) that produced plasma theophylline levels of 17 +/- 2 micrograms/ml (94 microM). We then determined if chronic caffeine consumption resulted in upregulation of platelet adenosine receptors in eight normal volunteers. After 7 days of caffeine abstinence, the adenosine analog 5'-N-ethylcarboxamidoadenosine produced a dose-dependent inhibition of thrombin-induced aggregation (EC50 = 69 nM). Subjects then were given caffeine, 250 mg p.o. 3 times a day for 7 days. Actual caffeine withdrawal, that is, virtual disappearance of caffeine in plasma, was apparent 60 hr after the last dose of caffeine. Caffeine withdrawal produced a significant shift to the left of 5'-N-ethylcarboxamidoadenosine inhibition of aggregation (EC50 = 49 nM, P less than .01), implying sensitization and/or upregulation of adenosine receptors as seen after chronic exposure to an antagonist. These results suggest that methylxanthines act as adenosine receptor antagonists in humans.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduction of serum theophylline levels by terbutaline in children with asthma

We studied the effect of oral terbutaline on serum theophylline levels in 12 children with asthma. Sustained-release theophylline (10 mg/kg twice a day) was given with placebo or terbutaline (0.075 mg/kg three times a day) in a chronic, randomized, double-blind, crossover design. The trough serum theophylline concentration fell from 13.8 +/- 4.0 to 10.8 +/- 3.6 micrograms/ml and the peak expiratory flow rate increased from 285 +/- 30 to 310 +/- 29 L/min after terbutaline. Further investigation is needed to clarify the mechanism of action by which terbutaline decreases serum theophylline levels.     

Reflex vagal withdrawal and the hemodynamic response to intravenous isoproterenol in the presence of beta-antagonists

To investigate the contribution of reflex vagal tone to the hemodynamic response after intravenous isoproterenol, 12 healthy subjects received isoproterenol by both bolus injection and continuous infusion before and after atropine, and during intravenous infusion of the beta 1-selective antagonist atenolol and the nonselective beta-antagonist, propranolol. With bolus injections, atropine displaced the heart rate dose-response curve for atenolol to the right, implying reflex withdrawal of cardiac vagal tone, but did not alter the heart rate dose-response curve for propranolol. With continuous infusions of isoproterenol, atropine displaced the heart rate dose-response curves for both atenolol and propranolol to the left, implying the presence of a reflex increase rather than withdrawal in cardiac vagal tone. These reflex changes in cardiac vagal tone can be partly understood by changes in mean arterial pressure and pulse pressure. As the two methods of isoproterenol administration are associated with contrasting contributions from reflex vagal tone, dose ratios obtained for the displacement of the heart rate dose-response curve by beta-antagonists may differ.     

Evidence for cardiac beta 2-adrenoceptors in man

We compared the effects of single doses of 50 mg atenolol (cardioselective), 40 mg propranolol (nonselective), and placebo on both exercise- and isoproterenol-induced tachycardia in two experiments involving nine normal subjects. Maximal exercise heart rate was reduced from 187 +/- 4(SEM) after placebo to 146 +/- 7 bpm after atenolol and 138 +/- 6 bpm after propranolol, but there were no differences between the drugs. The effects on isoproterenol tachycardia were determined before and after atropine (0.04 mg/kg IV). Isoproterenol sensitivity was determined as the intravenous dose that increased heart rate by 25 bpm (CD25) and this was increased from 1.8 +/- 0.3 micrograms after placebo to 38.9 +/- 8.3 micrograms after propranolol and 8.3 +/- 1.7 micrograms after atenolol. The difference in the effects of the two was significant. After atropine the CD25 was unchanged after placebo (2.3 +/- 0.3 micrograms) and atenolol (7.7 +/- 1.3 micrograms); it was reduced after propranolol (24.8 +/- 5.0 micrograms), but remained different from atenolol. This change with propranolol sensitivity was calculated as the apparent Ka, this was unchanged by atropine (11.7 +/- 2.1 and 10.1 +/- 2.5 ml/ng). These data are consistent with the hypothesis that exercise-induced tachycardia results largely from beta 1-receptor activation that is blocked by both cardioselective and nonselective drugs, whereas isoproterenol activates both beta 1- and beta 2-receptors so that after cardioselective blockade there remains a beta 2-component that can be blocked with a nonselective drug. While there appear to be beta 2-receptors in the human heart, their physiologic or pathologic roles remain to be defined.     

Effect of intranasal histamine on nasal mucosal blood flow and the antidiuretic activity of desmopressin.

The effects of exogenous histamine on nasal mucosal blood flow and the systemic activity of intranasally administered desmopressin, a vasopressin analogue, were studied in normal volunteers. Ten subjects received either saline or histamine (1, 20, 100, and 500 micrograms) by intranasal spray. Maximal nasal mucosal blood flow response, determined by laser doppler velocimetry, demonstrated a significant (P less than 0.05) linear relationship to histamine dose. Eight additional subjects received each of the following intranasal treatments: 20 micrograms histamine followed by 10 micrograms desmopressin; normal saline followed by 10 micrograms desmopressin; 20 micrograms histamine followed by vehicle; or normal saline and vehicle. Nasal blood flow was determined before and after each treatment. Desmopressin activity was assessed by measuring urine osmolality, flow rate, electrolyte, and creatinine concentration for 24 h after each treatment. The effect of histamine and desmopressin was greater than desmopressin alone, with respect to nasal blood flow response (103 +/- 24 vs. 4 +/- 17%, mean +/- SEM, P less than 0.02), initial urine osmolality (520 +/- 123 vs. 333 +/- 75 mosM, P less than 0.03), urine electrolyte (potassium, 45 +/- 11 vs. 28 +/- 7 meq/liter; sodium, 68 +/- 21 vs. 36 +/- 8 meq/liter, P less than 0.03) and creatinine concentrations (95 +/- 23 vs. 60 +/- 13 mg/dl, P less than 0.03), and the duration of decrease in urine flow rate compared with saline and vehicle. These results suggest that the systemic activity of intranasal desmopressin is enhanced by increasing local nasal blood flow and are consistent with increased transnasal absorption of the peptide.     

Selective effects of clonidine on the canine sinus node

The direct and indirect chronotropic effects of clonidine (0.001--10 micrograms/ml) were studied by selective perfusion of the sinus node artery of 20 pentobarbital anesthetized dogs. Concentrations of 0.1, 1.0 and 10 migrograms/ml produced dose-related reductions in sinus rate of 3.7 +/- 0.9 (P less than .005), 6.9 +/- 1.8 (P less than .005) and 15.8 +/- 2.3 (P less than .0001) beats/min, respectivel. Sinus acceleration after right stellate ganglion stimulation at 16 and 32 Hz was significantly (P less than .05) inhibited by intranodal clonidine (0.1 microgram/ml). The positive chronotropic effect of norepinephrine (0.1 microgram/ml, sinus node artery) was not significantly affected by prior administration of clonidine. Atropine (1 mg/kg i.v. or 10 micrograms/ml, selectively perfused into the sinus node artery) had no effect on the sinus slowing produced by clonidine. Clonidine had an inconsistent effect on the response to vagal stimulation. Clonidine had an inconsistent effect on the response to vagal stimulation. Clonidine inhibits the heart rate increase after sympathetic nerve stimulation without affecting the heart rate response to norepinephrine infusion. The findings are consistent with previous observations that clonidine can inhibit norephinephrine release and demonstrate that this mechanism of action may occur within the sinus node.     

M2 muscarinic receptors inhibit isoproterenol-induced relaxation of canine airway smooth muscle.

Classification of muscarinic receptors in the central airways has revealed the coexistence of M2 and M3 muscarinic receptors in this tissue, with the M2 subtype being predominant. Although M3 muscarinic receptors have been linked to airway smooth muscle contraction, a functional role for the M2 subtype in this tissue has been unclear. In nonairway smooth muscle, stimulation of the M2 muscarinic receptor has been shown to be associated with inhibition of adenylyl cyclase. In the present study, characterization of muscarinic receptors in canine tracheal smooth muscle confirmed that the majority of these muscarinic receptors were of the M2 subtype (89 +/- 3%), with a minor population of M3 receptors (11 +/- 3%). In functional studies, both isoproterenol and forskolin cause a dose-dependent relaxation of precontracted airway smooth muscle. In tissues precontracted with methacholine, 11-([[2-(diethylamino)methyl]-1-piperidinyl]acetyl)5,11- dihydro-6H-pyrido[2,3-6][1,4]benzodiazepine-6-one (AF-DX 116), a selective M2 antagonist, shifted dose-response curves to both isoproterenol and forskolin significantly to the left. In contrast, AF-DX 116 did not alter relaxation induced by the K+ channel opener BRL 38227. Furthermore, the ability of AF-DX 116 to enhance isoproterenol-induced relaxation appears to be limited to smooth muscle precontracted with muscarinic agonists because AF-DX 116 had no effect on isoproterenol dose-response curves in muscle strips precontracted with histamine. Hexahydrosiladifenidol (HHSiD), a selective antagonist for M3 receptors, did not shift the isoproterenol dose-response curve in muscle precontracted with methacholine. This study demonstrates that stimulation of M2 muscarinic receptors in canine airway smooth muscle plays an important role in functional antagonism by reducing the relaxation caused by agents such as isoproterenol and forskolin.     

Electrophysiological effects of high-dose propranolol in dogs: evidence in vivo for effects not mediated by the beta adrenoceptor

Closed-chest dogs anesthetized with morphine and chloralose were studied to determine if direct or nonspecific cardiac electro-physiological effects of propranolol occur at clinically relevant plasma concentrations and to differentiate the nonspecific effects from those due to beta adrenoceptor blockade. In 19 dogs, ventricular monophasic action potential durations (MAP), ventricular effective refractory periods (VERP) and His bundle electrograms (A-H and H-V intervals) were measured at base line and during sequential infusions of isoproterenol, dl-propranolol and dl-propranolol plus an isoproterenol infusion designed to overcome beta blockade. A mean plasma propranolol level of 979 +/- 344 ng/ml produced a significant (P less than .05) prolongation of A-H (95 +/- 20-115 +/- 13 msec), MAP (179 +/- 26-194 +/- 14 msec) and VERP (159 +/- 12-177 +/- 13 msec). Infusion of the beta agonist, isoproterenol, returned A-H and MAP to values not significantly different from base line, whereas VERP remained prolonged at 174 +/- 11 msec (P less than .05). No significant changes occurred in a control group of 14 dogs infused with saline. In eight additional dogs, infusions of d- and dl-propranolol, given on separate days, were used to produce equal beta blockade determined by individual isoproterenol sensitivity tests. A-H, H-V, MAP and ventricular strength-interval curves (VRP) and diastolic thresholds (DT) were measured and treatment vs. base-line changes (delta) with d- and dl-propranolol were compared.(ABSTRACT TRUNCATED AT 250 WORDS)     

Racial differences in drug response: isoproterenol effects on heart rate following intravenous metoprolol

Healthy young black men and white men received single intravenous doses of metoprolol (0.07 mg/kg) or participated in an isoproterenol sensitivity study before and after metoprolol (0.07 mg/kg followed by 50 micrograms/min) in a randomized, crossed-over fashion. Noncompartmental pharmacokinetic parameters were calculated. The dose of isoproterenol versus change in heart rate response curves were constructed, and comparisons of dose ratio, ED50, Emax, and Ka, with the apparent association constant for metoprolol binding to beta 1-receptors, were made. There were no pharmacokinetic differences observed between the groups. The predicted Emax for the black group was 52.7 +/- 8.7 beats/min at a metoprolol concentration of 29.8 +/- 6.1 ng/ml, which was higher (p less than 0.05) than that in the white group, i.e., 43.7 +/- 7.3 beats/min at a concentration of 27.6 +/- 9.1 ng/ml. There were no differences in dose ratio, ED50, or Ka. The racial differences in beta 1-receptor responses to exogenous isoproterenol following metoprolol can simply be explained by an increase in beta 1-receptor activity in the black subjects, assuming homogeneity in cardiac beta 2-receptor responses.