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PubMed1985

Mechanisms of supersensitivity to sympathomimetic amines in the chronically denervated heart of the conscious dog.

Mechanisms of denervation supersensitivity to sympathomimetic amines were studied in conscious animals. Norepinephrine, 0.1 micrograms/kg, increased left ventricular dP/dt significantly more (4208 +/- 828 mm Hg/sec) in dogs with cardiac denervation than in intact dogs (1029 +/- 280 mm Hg/sec), P less than 0.01, whereas responses to isoproterenol were similar in both groups. Denervation supersensitivity to isoproterenol could be demonstrated only after opposing reflex effects were blocked. After ganglionic blockade, norepinephrine still induced 2- to 3-fold greater increases in left ventricular dP/dt and 3- to 7-fold greater increases in heart rate in cardiac-denervated dogs, whereas isoproterenol and prenalterol, not taken up by presynaptic nerve endings, elicited only 40%-50% greater increases in left ventricular dP/dt and heart rate in dogs with cardiac denervation. The density of beta-adrenergic receptors [( 3H]dihydroalprenolol) was elevated (P less than 0.01) in denervated left ventricles (105 +/- 6.9 fmol/mg protein, n = 8) compared to normal left ventricles (70 +/- 6.3 fmol/mg protein, n = 12). This was accompanied by enhanced isoproterenol-mediated adenylate cyclase activity. However, muscarinic cholinergic receptor density, [( 3H]quinuclidinyl benzilate), decreased from control levels of 251 +/- 11 fmol/mg protein (n = 7) to 193 +/- 14 fmol/mg protein (n = 6). Thus, chronic cardiac denervation results in upregulation of the beta-adrenergic receptor and down-regulation of the muscarinic receptor. The increased beta-adrenergic receptor density and adenylate cyclase stimulation correlated well with the amount of denervation supersensitivity to isoproterenol and prenalterol, but accounted for only a minor fraction of denervation supersensitivity to norepinephrine. The major mechanism of denervation supersensitivity to norepinephrine appears to involve lack of the norepinephrine reuptake.

Adenylyl Cyclases↗

PubMed1982

Confusional paranoid psychosis after withdrawal from sympathomimetic amines: two case reports.

Paranoid psychosis may result from intoxication with, or withdrawal from amphetamines. The authors describe two cases of paranoid confusional psychosis commencing 1 week after the patients' withdrawal from sympathomimetic amines. The pathophysiology for this unusual disorder may be agonist-induced dopamine receptor hypersensitivity.

Adult↗

PubMed1989

Intrinsic sympathomimetic activity counteracts beta-blocker inhibition of renin activation.

Enzymatically inactive renin (IR) is the predominant circulating form of renin. Sympathetic activity may influence plasma renin activity (PRA) by regulation of the conversion of IR to active renin (AR, PRA). It has been demonstrated previously that beta blockade lowers PRA at least partly through inhibition of this conversion process. The authors hypothesized that beta blockade and intrinsic sympathomimetic activity (ISA) would have opposing effects on production of AR from its inactive precursor. Eighteen primary hypertensives (12 male, 6 female, mean age 57.7 +/- 2.7) were entered in a placebo-controlled, double-blind crossover study of the effects of equipotent doses of pindolol and propranolol on mean +/- SEM systolic BP, diastolic BP, heart rate, active renin (AR), total renin (TR), inactive renin (IR), and % AR/TR. Drug dose was titrated to achieve a goal DBP of 90 mmHg or less. Active renin was defined as the rate of generation of angiotensin I in 37 degrees C plasma at pH 5.7. Total renin was determined by preincubation of plasma aliquots with 1.5 mg/mL trypsin in the presence of 5 mM benzamadine for one hour at -4 degrees C prior to assay of renin activity. Inactive renin was calculated as TR minus AR. The BP responses achieve by dose titration of propranolol and pindolol were virtually identical at rest, indicating equivalent depressor effects of the two beta blockers. Heart rate and active renin were, however, lowered to a much greater extent with propranolol as compared with pindolol. The lack of significant pindolol-induced fall in % AR/TR suggests that this drug has little net effect on the formation of AR from IR.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1985

Intrinsic beta-sympathomimetic activity of dilevalol, R, R-isomer of labetalol.

The potency and selectivity of the intrinsic beta-sympathomimetic activity (ISA) of dilevalol were studied with isolated guinea-pig trachea and pithed rat. This drug relaxed the contracture of isolated guinea-pig tracheal preparation induced by histamine in a dose-dependent manner. The dose-response curves of dilevalol and labetalol were shifted to the right with propranolol pretreatment. The relaxing potency of dilevalol was approximately 4.7 times more potent than that of labetalol. Dilevalol markedly reduced the diastolic blood pressure with only a slight increase of heart rate in pithed rats, while isoproterenol and pindolol caused moderate to marked positive chronotropic effects in proportion to their hypotensive effects. These results suggest that dilevalol has more potent ISA than labetalol and shows more beta 2-adrenoceptor selectivity than pindolol.

Adrenergic beta-Agonists↗

PubMed1988

The utility of a long-acting sympathomimetic agent, procaterol, for nocturnal asthma.

Patients with nocturnal asthma have their lowest pulmonary function and lowest serum epinephrine level at 4 to 6 AM. We studied a new long-acting beta-adrenergic agonist, procaterol, in ten patients with nocturnal asthma. The patients received 0.1 mg of procaterol one night and a placebo the other night in random order. Pulmonary function tests were performed every two hours from 10 PM to 8 AM. Pulmonary sounds were recorded using a modified stethoscope and were subsequently analyzed to estimate the proportion of time occupied by wheezing (est Tw/Ttot). The forced expiratory volume in one second (FEV1) while receiving the placebo and procaterol were similar at 10 PM (placebo, 1.35 +/- 0.18 L [mean +/- SE]; procaterol, 1.48 +/- 0.20 L); however, by 4 AM, the FEV1 had dropped significantly lower on the night with the placebo (1.01 +/- 0.14 L) than the night with procaterol (1.30 +/- 0.19 L; p less than 0.05). The est Tw/Ttot was similar at 12 AM for both nights, but at 4 AM, there was a significant increase in the est Tw/Ttot for the group with placebo but not the group with procaterol. The use of a long-acting beta-adrenergic sympathomimetic agent reversed the obstruction of the airways seen with nocturnal asthma.

Asthma↗

PubMed1979

The effect of sympathomimetic drugs on contractility of the vas deferens in vitro and in vivo.

The sympathomimetic drugs noradrenaline, methoxamine, tyramine and norephedrine caused rhythmic contractions in isolated human vasa deferentia. Provided the drug was not washed out, these contractions lasted for the entire duration of the experiment (4-6 h). These contractions were mediated via alpha-adrenoreceptors. Intravenous administration of methoxamine or oxymetazolene to rats or guinea-pigs produced contractions of the vas deferens in vivo in some experiments but was accompanied by severe cardiovascular side effects. A local method of application was developed, using mixtures of tyramine with Silastic prepared as collars specially designed to fit round the vas deferens. Acute and chronic insertion of these slow-releasing devices around the vas deferens of rats produced rhythmic contractions of the vas deferens without any serious side effects.

Animals↗

PubMed1986

Relative potencies of various beta-adrenoceptor antagonists (BAA) at the level of the human myocardial beta-adrenoceptor-adenylate cyclase (AC) complex. Is intrinsic sympathomimetic activity (ISA) due to AC activation?

Nine different beta-adrenoceptor antagonists (BAA), five with intrinsic sympathomimetic activity (ISA), were examined for their ability to inhibit isoproterenol-stimulated adenylate cyclase (AC) activity and specific 125I-cyanopindolol (CYP) binding in crude membrane particles from human myocardium. The BAA's were: propranolol, pindolol, timolol, alprenolol, metoprolol, atenolol, prenalterol, ICI 141.292 'Visacor', and ICI 118.587 'Corwin'. Whether BAAs with strong ISA were able to stimulate AC activity by themselves were examined in separate experiments and compared to the AC stimulation by full agonists. All the BAAs caused a concentration dependent, and at high doses apparently complete, inhibition of both isoproterenol-stimulated AC activity and 125I-CYP binding. Both assays made possible a 'potency-ranking' of the different BAAs (pindolol greater than or equal to propranolol and timolol greater than ICI 142.292 and alprenolol greater than ICI 118.587, prenalterol and metoprolol greater than atenolol). Corrected IC50-values, derived from inhibition curves with both techniques, show that receptor binding and inhibition of receptor function follow each other closely. Prenalterol caused a very weak AC activation (5.4% of maximum), whereas the 'ISA-blockers', pindolol, ICI 141.292, and ICI 118.587 were unable to stimulate AC activity at concentrations which completely displaced 125I-CYP binding. In comparison, norepinephrine stimulated AC activity to the same level as isoproterenol (three to four times basal activity) and the beta 2-selective agonist terbutaline caused some 50% of maximal AC stimulation. This raises the question whether ISA is due to AC activation. The effect upon AC activation and 125I-CYP binding of drugs with beta-selectivity shows that both beta 1- and beta 2-receptors are coupled to the AC.

Adenylyl Cyclases↗

PubMed1979

Effects of beta2-sympathomimetic on histamine-stimulated gastric acid secretion in dogs.

The effect of a selective beta2-adrenoceptor agonist on histamine-stimulated gastric acid secretion was studied in conscious gastric-fistula dogs. A dose-dependent inhibition was found, most pronounced for the lowest doses of histamine. The inhibition was on the volume, whereas the acidity was unchanged. The pulse rate was increased by the beta2-agonist and by histamine. Propranolol prevented the inhibition of acid secretion as well as the increase in pulse rate. Practolol had no effect on the inhibition of acid secretion but reduced the increase in pulse rate. Dose-response experiments with six doses of histamine and two doses of the beta2-agonist showed unchanged calculated maximal response and an increase in D50. It is concluded that the beta2-agonist inhibits histamine-induced acid secretion in the dog, but to a lesser degree that pentagastrin-induced acid secretion, as found in earlier experiments. The inhibition follows competitive kinetics, and beta2-receptors are probably involved. The influence of beta2-sympathomimetics on the mechanism of gastric acid secretion is discussed.

Animals↗

PubMed1981

Value of combining B2 sympathomimetic metered aerosol and oral theophylline in children with asthma.

We report the results of a double blind controlled trial on 12 children with clinical asthma. Each child received three different treatment regimens; terbutaline sulphate 0.5 mg (Bricanyl) via a metered aerosol; orally administered theophylline 5 mg/kg (Somophyllin); or a combination of both. As expected, the metered aerosol therapy produced significantly greater early bronchodilatation than therapy with theophylline alone. In addition, the combined therapy produced a significantly greater bronchodilatation after three hours than the metered aerosol alone (P less than 0.05). This trend was also observed after one and two hours, but did not reach significance (0.1 greater than P greater than 0.05). We conclude that there is value in combining a B2 sympathomimetic metered aerosol and oral theophylline in children with asthma.

Administration, Oral↗

PubMed1999

In vitro and in vivo characterization of intrinsic sympathomimetic activity in normal and heart failure rats.

Clinical studies conducted with carvedilol suggest that beta-adrenoceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many beta-adrenoceptor antagonists are weak partial agonists and possess significant intrinsic sympathomimetic activity (ISA), which may be problematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes. At equieffective beta1-adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffective, and dose-related increase in heart rate in both pithed SD rats (ED50 = 5 and 40 microgram/kg, respectively) and SHHF rats (ED50 = 6 and 30 microgram/kg, respectively). The maximum effect of both compounds in SHHF rats was approximately 50% of that observed in SD rats. In contrast, carvedilol and bisoprolol had no significant effect on resting heart rate in the pithed SD or SHHF rat. The maximum increase in heart rate elicited by xamoterol and bucindolol was inhibited by treatment with propranolol, carvedilol, and betaxolol (beta1-adrenoceptor antagonist) but not by ICI 118551 (beta2-adrenoceptor antagonist) in neonatal rat. When the beta-adrenoceptor-mediated cAMP response was examined in cardiomyocytes, an identical partial agonist/antagonist response profile was observed for all compounds, demonstrating a strong correlation with the in vivo results. In contrast, GTP-sensitive ligand binding and tissue adenylate cyclase activity were not sensitive methods for detecting beta-adrenoceptor partial agonist activity in the heart. In summary, xamoterol and bucindolol, but not carvedilol and bisoprolol, exhibited direct beta1-adrenoceptor-mediated ISA in normal and heart failure rats.

Adrenergic beta-Agonists↗

PubMed1990

Improvement from pulmonary hyperinflation and bronchial obstruction following sympathomimetics systemically given in infants with broncho-pulmonary diseases.

Functional disorders and efficacy of treatment with a beta-2-agonist salbutamol (Ventolin), 0.225 mg/kg bodyweight, systemically given, were evaluated by infant whole-body plethysmography in 60 infants (64 data sets) with broncho-pulmonary disease belonging to three diagnostic groups: 24 survivors after respiratory distress syndrome, 21 patients with recurrent wheezing, and 15 infants with cystic fibrosis. The values of thoracic gas volume (IGV) and airway resistance (Raw) prior to the drug administration showed a scattered distribution, which was unrelated to the 3 diagnostic groups. Therefore, stratification into 4 functional groups was performed. In 25 tests (22 infants) normal lung function (TGV less than 130% pred., Raw less than 130% pred.); in 16 tests pulmonary hyperinflation (TGV greater than 130% pred., Raw less than 130% pred.); in 10 tests hyperinflation and bronchial obstruction (TGV and Raw greater than 130% pred.); and in 13 tests (12 patients) bronchial obstruction (TGV less than 130% pred; Raw greater than 130% pred.) were found. The response to beta-2-agonists was evaluated by vector analysis (circular statistics) revealing different response groups. With respect to the initial lung function abnormality and due to a stratification into different "response groups", beta adrenoreceptor agonists showed a volume-response (decrease in end-expiratory level) in 63% of infants with pulmonary hyperinflation, a flow response (improvement of airway resistance) in 54% of infants with predominantly bronchial obstruction and a mixed-response (decrease of TGV and Raw) in 70% of infants with mixed functional abnormalities, at least if the drug is given systemically. However, distinction into functional groups and its response to a sympathomimetic agent is only possible when both, changes in TGV and concomitant changes in Raw are accurately assessed.

Airway Resistance↗

PubMed1990

[High-dose inhaled beta-2 sympathomimetics in severe bronchial asthma].

We made the observations that in patients with severe bronchial asthma, the inhalative dose of beta-2 sympathomimetics that was required for optimal bronchial dilation revealed a large inter-individual scatter. In 21 patients, the inhalation of a maximum of 10 metered doses of salbutamol at intervals of five minutes each, led to a mean (SD) increase in the FEV 1.0 from 1.3 (0.6) 1 to 1.8 (0.7) 1. The maximum increase in the FEV 1.0 was achieved in 10 patients following the inhalation of 1 to 3 metered doses, and in 11 patients after 4 to 10 such doses. The individual requirement for inhaleable beta-2 agonists should therefore be taken into account when planning treatment.

Administration, Inhalation↗

PubMed1985

[Cardiac tolerance of a beta-2-sympathomimetic spray: fenoterol. Apropos of 37 patients followed using a Holter monitor during a brief treatment protocol].

37 subjects with stable asthma and a mean age of 50.3 undertook a protocol to study the cardiac tolerance to a spray B2SM. A Holter monitor was performed before and 48 hours after the institution of a Fenoterol spray in 4 daily doses of 600 micrograms at fixed times. Before starting treatment with a beta 2 sympathomimetic spray (B2SM) 11 subjects had abnormal traces with significant auricular extra-systoles in 4, ventricular extra-systoles in 5 and both in one subject: one patient had a run of ventricular tachycardia without symptoms. On Fenoterol, a worsening of pre-existing extra systoles was noted thrice, one was auricular the other two ventricular. Two patients had brief runs of ventricular tachycardia but the role of Fenoterol was uncertain; one of the patients was very elderly and hypoxaemic. In the second and elevated theophylline level of 20 micrograms/l was noted. The arrythmogenic power of a B2SM seems weak, but in certain situations such as hypoxaemia, metabolic acidosis and overdosage of theophylline, over consumption of B2SM in association with the above factors could contribute to serious arrhythmias. Also in this study in which there was a protocol limited in time, no premature conclusion should be made on the crucial problem of the cardiovascular risks of B2SM in the basic treatment of asthma but raises the problem of the arrythmogenic potential of the drug association of Theophylline + B2SM.

Adult↗

PubMed1978

Hypotensive and bradycardic effects of classical alpha-sympathomimetic drugs upon intravenous administration to pentobarbitone-anaesthetized rats.

The effects of the classical alpha-sympathomimetic drugs naphazoline, tramazoline, xylometazoline, tetryzoline and oxymetazoline on blood pressure and heart rate of pentobarbitone-anaesthetized (75 mg/kg; i.p.) normotensive rats were studied following intravenous injections. With the aid of this experimental animal model a dose dependent decrease in mean arterial pressure and heart rate could be established for these agents, oxymetazoline excepted, for which only the bradycardia could be quantified. It is suggested that central alpha-adrenoceptors are involved in the mechanism of this cardiovascular inhibition in view of the most specific alpha-adrenoceptor-stimulating properties of these ddrugs. Additionally, the results indicate that the use of pentobarbitone as the anaesthetic enhances the hypotensive action of these agents, so that their pronounced peripheral vasopressive response can be overcome.

Adrenergic alpha-Agonists↗

PubMed1989

The importance of inhalation of beta 2 sympathomimetic drugs in the home care treatment of asthma in children.

In order to improve the care of asthma attacks in children and to reduce hospitalization, 50 patients and their parents were taught a home program using beta 2 sympathomimetic drugs administered by aerosol inhaler. The parents obtained recordings of respiratory rate and pulmonary flow meter. A control group of 50 patients received only slow-release theophylline. Inhalation therapy improved the respiration recorded by reduced respiratory rate and pulmonary flow meter while visits to the emergency department and hospital admissions were reduced by 60%. Absence from school was also reduced by 60%. Benefits to the patient and to cost containment have been achieved by home care treatment.

Administration, Inhalation↗

PubMed1989

[Ventricular function in mitral valve prolapse: effects of beta adrenergic blockers with and without intrinsic sympathomimetic activity].

A corollary of the "cardiomyopathy therapy" implies that mitral valve prolapse may cause intrinsic myocardial depression. The impairment of ventricular function may not be detected in basal conditions, but could be unmasked by superimposing depressant factors. The use of beta-blockers constitutes the first choice treatment for the symptomatic management of patients with mitral valve prolapse. Therefore, we tested the hypothesis that myocardial depression could be shown during beta-blockade in the uncomplicated primary form of mitral valve prolapse. The results of echocardiographic and radionuclide angiographic evaluation of left ventricular function during basal conditions, as well as under beta-blockade with propranolol and pindolol, do not lend support to the cardiomyopathy hypothesis of the pathogenesis of primary mitral valve prolapse. However, significant decreases of heart rate, left ventricular ejection fraction and peak velocity of left ventricular systolic emptying were seen with propranolol, but not with pindolol. Beta-blockade with intrinsic sympathomimetic activity may be preferable therapeutic option for patients with mitral valve prolapse.

Adolescent↗

PubMed1989

[Effect of beta blockers with intrinsic sympathomimetic activity on blood pressure and blood lipids in patients with essential hypertension].

The aim of this study was to compare the effects of a beta-blocker (mepindolol) with intrinsic sympathomimetic activity (ISA) to a beta-blocker (metoprolol duriles) without ISA. Hypertensive patients with more than 50 years of age were selected and randomly allocated to receive either 5 mg/day mepindolol (Group A, 10 patients), or 200 mg/day metoprolol duriles (Group B, 9 patients), or placebo (Group C, 10 patients). They were submitted to clinical exam, stress testing and plasma lipids dosage before and after four weeks of treatment. At rest, there were a significant reduction of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) in all groups. The mean values for SBP, DBP and HR at rest after treatment were respectively: 154.0, 95.5, 73.7 (Group A); 148.8, 94.4, 70.1 (Group B); 153.0, 96.0, 77.8; (Group C). During stress testing, there were a significant reduction of SBP, HR and double product (DP). The DBP remained unchanged. The mean values for SBP, DBP, HR and DP during stress testing after treatment were respectively; 198.0, 115.5, 124.3, 246.9 (Group A); 198.8, 114.4, 144.6, 283.2 (Group B); 202.2, 119.0, 143.5, 283.4 (Group C). Total cholesterol, HDL-cholesterol, and LDL-cholesterol, have not changed with both beta-blockers. There were a significant increase in plasma triglycerides and VLDL-cholesterol levels after treatment with beta-blockers. In conclusion, both mepindolol and metoprolol were similarly effective in reducing arterial blood pressure of hypertensive patients. There were not significant differences between the beta-blocker with or without ISA in regard to their effects on plasma lipids.

Aging↗

PubMed1985

Beta blockers with intrinsic sympathomimetic activity.

A new class of beta-adrenergic blockers with the pharmacologic property of intrinsic sympathomimetic activity (ISA) is emerging for use in the treatment of hypertension. These agents decrease blood pressure and systemic vascular resistance, while the heart rate and cardiac output at rest are maintained. Beta blockers with ISA may be used in clinical situations where non-ISA beta blockers are relatively contraindicated, such as sinus bradycardia, sick sinus syndrome, Raynaud-like symptoms and chronic obstructive lung disease.

Adrenergic beta-Antagonists↗