Antiadrenergic Effects Research Articles

ELECTROPHYSIOLOGICAL (EP) EFFECTS OF D-SOTALOL ON HYPOXIG MYOCARDIUM

The EP effects of acute hypoxia (H) are probably responsible for many clinical arrhythmias (A) in children. Sotalol is a potent anti-A agent with classll (β-blocking) and ClassIII (Amiodarone-like) actions. Its D isomer (DS) should be devoid of β-blockade & be a pure ClassIII agent. We evaluated the cellular EP effects of DS on acutely hypoxic myocardium using rabbit atrial muscle and standard microelectrode techniques. Following control action potential (AP) recordings, tissues were exposed to 10−4M DS, acute H, or DS+H for 20 min. Continuous AP recordings showed no changes in maximum diastolic potential or Vmax from any intervention. The effects on AP amplitude (APA), AP duration (APD) at 50 and 90% repolarization and atrial effective refractory period (AERP) are shown (*p<0.05; +p<0.01): By prolonging AERP and APD proportionally, DS showed typical ClassIII activity. Its acute onset and lack of antiadrenergic effects provide significant advantages over Amiodarone. DS does not, however, alter the EP effects of acute H and may be of little benefit in treating A induced or exacerbated by H.

Dependence on Benzodiazepines

Bupropion, a specific dopamine reuptake inhibitor, was compared to amitriptyline in two multicenter studies involving 183 depressed outpatients and inpatients. Initial results from these ongoing studies provide additional evidence of the antidepressant activity of bupropion. At the end of the treatment periods (6 weeks for inpatients and 13 weeks for outpatients), bupropion appeared to be at least as effective as amitriptyline. However, bupropion exerted a slightly but nonsignificantly smaller overall therapeutic effect than amitriptyline during the first 4 weeks of drug treatment. Slight weight loss and dopaminergic side effects, such as insomnia, nausea/vomiting, and anorexia, were somewhat more common among bupropion-treated patients. Compared to bupropion, amitriptyline induced more weight gain and had more anticholinergic, antihistaminic, and antiadrenergic side effects. In view of its numerous sites of action, amitriptyline does not appear to be the ideal antidepressant. It remains to be demonstrated whether bupropion has any advantage over secondary amine tricyclic antidepressants, such as nortriptyline and desipramine.

The pathophysiology of sexual dysfunction associated with antipsychotic drug therapy in males: A review

Sexual dysfunction is commonly encountered in men receiving antipsychotic drug therapy. Ejaculatory dysfunction has been most commonly reported, but erectile dysfunction, decreased libido, priapism, and a change in the sensation of orgasm have also been noted. The anticholinergic and antiadrenergic effects of antipsychotics may cause problems with erection and ejaculation. Antipsychotics block dopamine synapses in the central nervous system and may suppress sexual interest because of this. The hyperprolactinemia seen with these compounds may also have adverse consequences on sexual functioning. The effects of antipsychotics on gonadotropins and testosterone are not clear. A variable which confounds much of the research in this area is the possibility of an underlying neuroendocrine abnormality in patients with schizophrenia.

On the ionic mechanism underlying adrenergic-cholinergic antagonism in ventricular muscle.

In atrial muscle, acetylcholine (ACh) decreases the slow inward current (Isi) and increases the time-independent outward K+ current. However, in ventricular muscle, ACh produces a marked negative inotropic effect only in the presence of positive inotropic agents that elevate cyclic adenosine monophosphate (AMP). A two-microelectrode voltage-clamp method was used on cultured reaggregates of cells from 16--20-d-old embryonic chick ventricles to determine the effects of ACh on Isi and outward current during beta-adrenergic stimulation. Only double penetrations displaying low-resistance coupling were voltage-clamped. Cultured reaggregates are advantageous because their small size (50--250 microns) permits better control of membrane potential and adequate space clamp. Tetrodotoxin (10(-6) M) and a holding potential of --50 to --40 mV were used to eliminate the fast Na+ current. Depolarizing voltage steps above --40 mV caused a slow inward current to flow that was sensitive to changes in [Ca]o and was depressed by verapamil (10(-6) M). Maximal Isi was obtained at --10 mV and the reversal potential was about +25 mV. Isoproterenol (10(-6) M) increased Isi at all clamp potentials. Subsequent addition of ACh (10(-6) M) rapidly reduced Isi to control values (before isoproterenol) without a significant effect on the net outward current measured at 300 ms. The effects of ACh were reversed by muscarinic blockade with atropine (5 X 10(-6) M). We conclude that the anti-adrenergic effects of ACh in ventricular muscle are mediated by a reduction in Ca2+ influx during excitation.

Effects of digitalis on the human sick sinus node after pharmacologic autonomic blockade

To study the effects of digitalis on the sinus node and the mechanisms involved, 16 patients with the sick sinus syndrome had electrophysiologic assessment of sinus nodal function during (1) control study, (2) after pharmacologic autonomic blockade with propranolol (0.2 mg/kg body weight and atropine sulfate 0.04 mg/kg intravenously), and (3) 10 minutes after 0.01 mg/kg of intravenous ouabain. The study was completed within 30 minutes of pharmacologic autonomic blockade. During the control study 50 percent of patients had an abnormal corrected sinus nodal recovery time or abnormal sinoatrial conduction time, or both. The effects of ouabain on sinus nodal function were compared with those after pharmacologic autonomic blockade. Ouabain significantly increased both intrinsic sinus cycle length (ouabain 975 ± 194 ms [mean ± standard deviation]; autonomic blockade 1,025 ± 218 ms, probability [p] < 0.001) and corrected sinus nodal recovery time (ouabain 615 ± 503 ms; autonomic blockade 575 ± 536 ms, p < 0.05). In contrast there was no significant change in sinoatrial conduction time after ouabain (ouabain 141 ± 56 ms; autonomic blockade 132 ± 45 ms; difference not significant). The effects of ouabain were similar in patients with both normal and abnormal sinus nodal function. These findings suggest that (1) digitalis in therapeutic doses has a depressant effect on intrinsic sinus nodal automaticity in patients with normal as well as abnormal sinus nodal function; (2) digitalis has no significant effects on sinoatrial conduction; and (3) the effects of digitalis on sinus nodal automaticity are primary and independent of its vagal and antiadrenergic effects.

Retarded ejaculation: a review.

Retarded ejaculation is the persistent difficulty or inability to ejaculate despite the presence of adequate sexual desire, erection, and stimulation. The causes of this dysfunction may be organic, i.e., medical illness or drug ingestion (particularly medications with antiadrenergic effects), the result of surgical interventions, or secondary to inhibiting psychological factors. With regard to psychological determinants, fear, guilt, resentment, and passively have all been implicated, although objective studies are rare. The sexual object choice of men with retarded ejaculation has ben reported by several clinicians and investigators to be other than adult members of the opposite sex, while the marital relationship of these males has been considered etiological in other instances. Outcome assessment to date consists mostly of individual case reports or reports on small groups of patients treated without controls. To some extent, routine reliance on long-term traditional therapy has yielded to shorter, symptomatic learning-based treatments. While improved outcomes have been reported, many patients do not respond well. It is not yet possible to objectively predict succes or failure. Since it is our impression that this sexual dysfunction is more common than previously assumed (or is increasing in frequency), our present lack of data should soon be remedied.

Effects of catecholamines, histamine, and nitroglycerin on flow, oxygen utilization, and adenosine production in the perfused guinea pig heart.

Effects of catecholamines, histamine, and nitroglycerin on flow, oxygen utilization, and adenosine production in the perfused guinea pig heart.

Reduction in plasma norepinephrine during fenfluramine treatment

Plasma norepinephrine levels were reduced to 30% of placebo levels during the administration of fenfluramine, 120 mg/day, for 10 or more days. There was also a significant reduction in plasma dopamine beta-hydroxylase activity during fenfluramine treatment, suggesting that chronic administration may induce antiadrenergic effects which may be useful in the treatment of disorders affected by circulating catecholamines.

The effects of acetylstrophanthidin on the response of the AV junction to adrenergic stimulation studied in dogs

The response of the AV junction to adrenergic stimulation was studied in 35 anesthetized open-chest dogs before and after the injection of acetylstrophanthidin (5mug) directly into the AV node artery. An AV junctional rhythm was obtained under control conditions by injecting norepinephrine (n = 9) or isoproterenol (n = 8) into the AV node artery and by stimulation of the left stellate ganglion (n = 11) after selectively injecting propranolol into the sinus node artery. Acetylstrophanthidin brought about various degrees of conduction block from simple PR interval prolongation to complete heart block, and decreased the chronotropic response of the AV junction to adrenergic stimulation. In seven animals the appearance of a spontaneous second degree AV block did not reduce the AV junctional response to adrenergic stimulation. Acetylstrophanthidin also reduced the ventricular acceleration produced by adrenergic stimulation during atrial fibrillation. These results suggest that the anti-adrenergic effect of cardiac glycosides may not only be involved in the mechanism of AV conduction disturbances during digitalis intoxication, but may also play a role in slowing the ventricular rate during atrial fibrillation.

Monoiodotyrosine: effects on tissue amines and cold survival.

The effects of monoiodotyrosine (MIT) on cold survival and levels of tissue amines in rats were studied. MIT was found to impair cold suvival and to lower levels of norepinephrine (NE). These experiments confirm previous pharmacologic evidence that MIT has an anti-adrenergic effect. Cold stress lowered brain NE levels but failed to lower brain dopamine levels, a finding consistent with current views of the role of brain mechanisms in temperature regulation.

Interaction between cyclic adenosine monophosphate and cyclic gunaosine monophosphate in guinea pig ventricular myocardium.

The purpose of this study was to examine the mechanisms underlying adrenergic-cholinergic antagonism in ventricular myocardium. Myocardial contractility, cyclic adenosine monophosphate (AMP) levels, and cyclic guanosine monophosphate (GMP) levels were measure in isolated guinea pig ventricles after treatment with various inotropic agents given alone and simultaneously with acetylcholine. Acetylcholine alone markedly elevated cyclic GMP levels but did not substantially change myocardial contractility. However, the same concentration of acetylcholine significantly attenuated the inotropic effect of isoproterenol and histamine, two drugs that may act by increasing myocardial levels of cyclic AMP. The decrease in the inotropic response to isoproterenol did not appear to be due to a decrease in the generation of cyclic AMP, because cyclic AMP levels were similar in hearts receiving isoproterenol alone and those receiving isoproterenol with acetylcholine. Dibutyryl cyclic GMP also antagonized the intropic action of isoproterenol. Acetylcholine did not alter the inotropic effects of ouabain, an agent that increases myocardial contractility without changing cyclic AMP levels. These results suggest that cyclic GMP mediates the antiadrenergic effects of acetylcholine by specifically antagonizing the inotropic actions of cyclic AMP.

Brain monoamines participation in the control of growth hormone secretion in different animal species

Publisher Summary This chapter describes the brain monoamines participation in the control of growth hormone (GH) secretion in different animal species. A large body of evidence has been accumulated for the involvement of brain monoamines in the control of growth hormone secretion. The neuro-pharmacological studies performed in the rat showed that drugs endowed with anti-adrenergic effects were capable of blocking the release of GH induced by insulin hypoglycemia. Administration of NE and DA into the lateral ventricles of normal, and hypophysectomized rats to circumvent the blood brain barrier to catecholamines was followed by decreased GH levels in the anterior pituitary, and by depletion of hypothalamic GRF. Studies conducted in conscious fasted baboons showed that β-adrenergic blockade, resulting from intravenous infusion of phentolamine, significantly depressed GH secretion, while β-adrenergic blockade with propranolol and ganglionic blockade with trimetaphan were associated with a significant prompt rise in GH. The observed GH changes seemed not to be associated with alterations in plasma glucose, or NEFA levels, although, lowered plasma NEFA, and glucose levels were present following propranolol administration.

Effects of Ouabain, Atropine, and Ouabain and Atropine, on A-V Nodal Conduction in Man

The prolongation of A-V transmission time that occurs with increasing rates of right atrial pacing has been used to study the effect of ouabain and of ouabain plus atropine on A-V nodal conduction in 14 patients with normal A-V nodes. Drugs were injected into the superior vena cava or pulmonary artery over a 1- to 2-min period. Atropine in a dose of 0.02 mg/kg shortened A-V conduction time by an average of 0.112 sec; ouabain alone in a dose of 0.01 mg/kg lengthened A-V conduction time by 0.053 sec. Ouabain given after large doses of atropine did not prolong A-V conduction at any paced rate. Thus, in these resting patients with normal A-V nodal function, usual digitalizing dosages of ouabain did not have an extravagal or antiadrenergic effect on A-V nodal conduction.

The effects of psychotropic drugs on the cholinergic and adrenergic system

Summary The changes of LD 50 of phenmetrazine as an adrenergic drug and physostigmine as a cholinergic drug, induced by previous administration of psychotropic drugs were investigated. Chlorpromazine and levomepromazine as neuroleptics had a strong antiadrenergic, but no anticholinergic effect whereas the thymoleptics, imipramine, amitriptyline, prothiadene and propazepine had only a considerable anticholinergic effect, which was in correlation to the degree of their clinical antidepressive activity. Chlorprothixene which shows clinically both antidepressive and neuroleptic effects in the clinic had both anticholinergic and antiadrenergic effects. The described test is proposed as convenient screening test for distinguishing neuroleptic and thymoleptic drugs. The mode of action of thymoleptics is discussed from the point of view of these findings.

Studies of the antiadrenergic effects of nitroglycerin on the dog heart.

Using anesthetized dogs, the possible antiadrenergic effects of nitroglycerin upon the myocardium were studied. Observations were made upon changes in heart rate, myocardial oxygen consumption, systolic vigor, and the electrocardiograms. Data are presented showing the effects of nitroglycerin and adrenergic agents when given separately and in combination. Results indicate that in dogs, nitroglycerin produces no antiadrenergic effects on the myocardium. The suggestion is made that the T wave changes seen after adrenergic stimulation in dogs may not be due to anoxia.

Anti-Adrenergic Effects of Nitroglycerin on the Heart

The therapeutic effect of nitroglycerin is generally attributed to its coronary dilator effect alone. In contrast, it could be shown that nitroglycerin also counteracts the chronotropic as well as the electrocardiographic T-wave depressing effects of epinephrine, arterenol and cardiac sympathin upon the heart. Accordingly, its therapeutic action in angina pectoris is suspected as being largely due to a chemical protection of the heart muscle against the chemically anoxia-producing effects of sympathomimetic amines.