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PubMed2000

Disopyramide block of K(ATP) channels is mediated by the pore-forming subunit.

The class Ia antiarrhythmic agent disopyramide blocks native ATP-sensitive K+ (K(ATP)) channels at micromolar concentrations. The K(ATP) channel is a complex of a pore-forming inwardly rectifying K+ channel (Kir6.2) and a sulfonylurea receptor (SUR). The aim of the present study was to further localize the site of action of disopyramide. We have used a C-terminal truncated form of Kir6.2 (Kir6.2delta26), which--in contrast to Kir6.2--expresses independently of SUR. Kir6.2delta26 channels were expressed in African green monkey kidney COS-7 cells, and enhanced green fluorescent protein (EGFP) cDNA was used as a reporter gene. EGFP fluorescence was visualized by a laser scanning confocal microscope. Disopyramide applied to the cytoplasmic membrane surface of inside-out patches inhibited Kir6.2delta26 channels half-maximally at 7.1 microM (at pH 7.15). Lowering the intracellular pH to 6.5 potentiated the inhibition of Kir6.2delta26 channels by disopyramide. These observations suggest that disopyramide directly blocks the pore-forming Kir6.2 subunit, in particular at reduced intracellular pH values that occur under cardiac ischaemia.

Animals↗
PubMed1984

Determination of (R)- and (S)-disopyramide in human plasma using a chiral alpha 1-acid glycoprotein column.

The direct resolution and quantitation of (R)- and (S)-disopyramide, isolated from human plasma, was accomplished using a chiral alpha 1-acid glycoprotein column. A LiChrosorb RP-2 column (50 X 3.0 mm I.D.) was used as a precolumn. Phosphate buffer, pH 6.20, containing 2-propanol and N,N-dimethyloctylamine was used as mobile phase. The precision of the determination of (R)- and (S)-disopyramide in human plasma, expressed as the relative standard deviation, was 1.8% and 3.3% for (R)- and (S)-disopyramide, respectively, at a drug level of 0.5 micrograms/ml. In two subjects who received a single capsule of racemic disopyramide (150 mg), the plasma levels of the (R) isomer were about half those of the (S) isomer. The half-lives of (R)- and (S)-disopyramide were similar.

Chromatography, High Pressure Liquid↗
PubMed2001

Disopyramide and its metabolite enhance insulin release from clonal pancreatic beta-cells by blocking K(ATP) channels.

In an insulin-secreting pancreatic beta-cell line (MIN6), insulin release was caused by disopyramide, an antiarrhythmic drug with Na-channel blocking action, and its main metabolite mono-isopropyl disopyramide (MIP). Insulin secretion, measured as immunoreactive insulin (IRI), was accelerated to 265.7% of the control by disopyramide and to 184.4% by MIP, with half-effective concentrations (EC50) of 30.9 +/- 1.5 microM and 92.4 +/- 2.2 microM. We tested the possibility that these drugs induce insulin release by inhibiting ATP-sensitive K+ (K(ATP)) channels of MIN6 cells. In the cell-attached or ATP-free inside-out mode with patch membranes on MIN6 cells, K-selective channels were recorded with unitary conductance of 70.5 +/- 3.5 pS (150 mM external K+ ions at room temperature). The channels were concluded to be MIN6-K(ATP) channels because they were closed by extracellular high glucose (11.0 mM) or glibenclamide (200 nM) and were reversibly activated by diazoxide (50 microM). In the inside-out patch mode, they were inhibited by micromolar ATP. In both cell-attached and insideout mode, disopyramide and MIP inhibited single MIN6-K(ATP) channels. In the inside-out mode, they produced a dose-dependent inhibition of channel activity: the half-blocking concentrations (IC50) were 4.8 +/- 0.2 microM for disopyramide and 40.4 +/- 3.1 microM for MIP. It was therefore concluded that both agents exert insulinotrphic effect through the inhibition of membrane K(ATP) channels in MIN6 cells.

ATP-Binding Cassette Transporters↗
PubMed1987

Effects of intravenous disopyramide and quinidine on normal myocardium and on the characteristics of arrhythmias: intraindividual comparison in patients with sustained ventricular tachycardia.

Intraindividual comparison of the acute response to intravenous quinidine and to intravenous disopyramide was performed in 27 patients with sustained ventricular tachycardia (VT) who underwent serial electrophysiological studies. In each patient, sustained VT could be reproducibly initiated by programmed ventricular stimulation during control studies. Quinidine and disopyramide prevented inducibility of sustained VT in 7 and 8 of the 27 patients, respectively. Six patients were concordant responders to both drugs and 18 patients were concordant non-responders resulting in a total of 24 patients (89%) who had a concordant result (P less than 0.01). In the 18 non-responders with inducible sustained VT after both drugs, quinidine and disopyramide caused qualitatively and quantitatively similar changes in the characteristics of the VT: prolongation of the interval between the initiating extrastimulus and the first beat of VT by 36 and 39%, and an increase in VT cycle length by 21 and 29%, respectively. The QRS morphology of VT was concordantly altered in 13 of these 18 patients (72%). In all 27 patients, quinidine and disopyramide caused a quantitatively similar prolongation of ventricular refractoriness by 12 and 14%, of the QRS duration by 14 and 13% and of the QTc interval by 13 and 13%, respectively. The clinical data obtained at comparable plasma concentrations confirm the experimental presumption that quinidine and disopyramide have qualitatively and quantitatively similar electrophysiological effects not only on normal myocardium but also on the characteristics of VT, resulting in a significant concordance of antiarrhythmic responses.

Adult↗
PubMed1988

Disopyramide in the maintenance of sinus rhythm after electroconversion of atrial fibrillation. A placebo-controlled one-year follow-up study.

In this multicentre study, 90 patients who left hospital in sinus rhythm after electroconversion of atrial fibrillation were randomized to double-blind treatment with either disopyramide (n = 44) or placebo (n = 46). The groups were comparable regarding age and sex distribution, duration of atrial fibrillation, heart volume and NYHA-classification. Life-table analysis was used to estimate the percentage of patients still in sinus rhythm and tolerating treatment at control visits after 1, 3, 6, 9 and 12 months. After 1 month there was already a significant difference (P less than 0.01) between the two groups (disopyramide 70%, placebo 39%), a difference that was still remaining after 12 months (disopyramide 54%, placebo 30%). Twenty-four patients, all relapsing to atrial fibrillation before six months on placebo, were converted to sinus rhythm once again. They were then treated with disopyramide in an open manner and after 12 months 37% were still in sinus rhythm. From the results of this study, disopyramide seems to be a useful drug in maintaining sinus rhythm after electroconversion of atrial fibrillation.

Adult↗
PubMedDate not supplied

Resting and rate-dependent depression of maximum rate of depolarisation (Vmax) in guinea pig ventricular action potentials by mexiletine, disopyramide, and encainide.

The influence of stimulation rate on the ability of mexiletine, disopyramide, and encainide to depress the maximum rate of depolarisation (Vmax) of intracellular action potentials has been studied in guinea pig ventricular myocardium, using standard microelectrode techniques. Mexiletine and disopyramide produced modest depression of Vmax even in the absence of stimulation (resting block), while encainide did not. All three drugs produced progressive depression of Vmax as stimulation rate was increased over a wide range of interstimulus intervals (rate-dependent block). This relationship between interstimulus interval (ISI) and depression of Vmax was steepest for mexiletine, least marked for disopyramide, and intermediate for encainide. Mexiletine also exhibited the fastest response to a sudden change of frequency. During a train of stimuli at ISI of 300 ms after a rest period, Vmax fell rapidly, reaching 61% of its final value by the second beat. In response to a similar train of stimuli, disopyramide and encainide produced exponential falls of Vmax with rate constants of -0.113 AP (AP = action potential) and -0.025 AP, respectively. Similar trends were seen in the recovery of cells from this rate-dependent block at the end of a train of stimuli. Time constants for this process for mexiletine, disopyramide, and encainide were 471.2 ms, 12.2 s, and 20.3 s, respectively. It is concluded that the rapid onset of and recovery from rate-dependent block seen with mexiletine may explain its lack of effect on conduction of sinus beats at concentrations that suppress extrasystoles and tachycardias.

Action Potentials↗
PubMedDate not supplied

Evaluation of combined administration of verapamil and disopyramide in dogs.

The electrophysiologic and hemodynamic effects of concurrent administration of verapamil and disopyramide were studied in morphine-chloralose-anesthetized dogs. Twenty-one dogs were studied; seven received verapamil alone, seven received disopyramide alone, and seven received the two drugs in combination. Both drugs were administered by intravenous infusion, resulting in sustained plasma levels within the therapeutic range. Effects were measured every 30 min and compared with baseline (pretreatment) values. In all three groups heart rate and cardiac output decreased slightly; however, the effect produced by the combination was not significantly different from that produced by either drug alone. Most of the electrophysiologic changes observed in the combined-treatment dogs could be attributed to the individual effects of either verapamil or disopyramide and were not suggestive of any interaction between these two drugs. In the combined-treatment dogs the atrial and ventricular refractoriness increased in the same way as with disopyramide alone, and the spontaneous discharge rate of the sinus node and the conduction through the atrioventricular node were slowed as with verapamil alone. However, a significant prolongation of the sinus node recovery time occurred in the combined-treatment dogs. Five of the seven dogs experienced at least one episode of sinus arrest following pacing. The profile of effects observed may be dependent, in part, on the model we utilized. However, our data suggest that the combination of verapamil and disopyramide may produce severe sinus node depression.

Animals↗
PubMed1993

Action potential prolongation exhibits simple dose-dependence for sotalol, but reverse dose-dependence for quinidine and disopyramide: implications for proarrhythmia due to triggered activity.

Plasma drug concentrations in patients who develop torsade de pointes while receiving quinidine or disopyramide treatment have been reported to be usually in or below the therapeutic range, whereas patients developing the same complication during sotalol treatment usually have drug concentrations well above the therapeutic range. We wished to provide a cellular electrophysiologic rationale for this observation. Standard intracellular microelectrode techniques were used to record action potentials (APs) from canine Purkinje fibers at interstimulus intervals (ISI) of 1,000-6,000 ms, with and without three varying concentrations of quinidine, disopyramide, and sotalol. Cesium chloride 0.5 mM was added to reduce spontaneous diastolic depolarization. We observed a biphasic response in action potential duration (APD) to quinidine and disopyramide. Low concentrations tended to prolong APD, particularly at slower drive rates, whereas this effect tended to reverse as the concentration was increased. In contrast, sotalol produced a consistent, monophasic dose-dependent increase in APD across the therapeutic concentration range and well beyond it. We also observed an apparent increased likelihood of early afterdepolarizations (EADs), with or without triggered activity, at low concentrations of quinidine and disopyramide, with a trend toward reversal as the concentration was increased. We conclude that the biphasic dose response observed for APD with quinidine and disopyramide is due to the opposing effects of these agents on outward potassium and inward sodium currents and may cast some light on the clinical observation noted above. Sotalol on the other hand appears to produce EADs and triggered activity only at high concentrations.

Action Potentials↗
PubMed1998

Disopyramide, imipramine, and amitriptyline bind to a common site on the transient outward K+ channel.

Previous work demonstrated that several antiarrhythmic agents and antidepressive drugs block transient outward K+ current (I(to)) in rat ventricular myocytes. The antiarrhythmic drug, disopyramide, and the tricyclic antidepressants, imipramine and amitriptyline, block the I(to) channel mainly when it is in the open state. The rate of recovery from block induced by disopyramide is so slow that the drug produces a use-dependent block at 1 Hz, whereas the rate of recovery from block in the presence of imipramine and amitriptyline is fast enough so as not to induce any use-dependent block at this frequency. We studied the effects of the combinations of disopyramide-imipramine and disopyramide-amitriptyline on I(to) to detect possible interactions between the drugs on I(to) blockade. The effects of imipramine and amitriptyline on the use-dependent effect induced by disopyramide and on the rate of recovery of the channels blocked by this drug allow us to conclude that there is only one common receptor site in the channel molecule for the three drug molecules.

Amitriptyline↗
PubMed1981

Acute intervention studies in patients with myocardial infarction using atenolol, propranolol, oxprenolol and disopyramide phosphate.

The value of beta-blockade and of disopyramide phosphate in the immediate treatment of patients with suspected acute myocardial infarction was assessed in two placebo controlled trials. In the first study 388 patients with suspected acute myocardial infarction were randomly allocated to treatment with propranolol, atenolol, or placebo, and when analysed on an initial intention to treat basis there was no significant difference between the three groups in respect of the mortality at one year. In addition, there was no evidence to suggest that either atenolol, or propranolol reduced the incidence of 'serious' ventricular arrhythmias in the coronary care unit. In the second study 473 patients with suspected acute myocardial infarction were randomly allocated to treatment with oxprenolol, disopyramide phosphate, or placebo. Again no significant differences were seen with respect to the mortality at six weeks. There was, however, a significantly increased incidence of heart failure in the group which received disopyramide phosphate. Patients who received this drug also showed a reduced number of dysrhythmic episodes on 24-hour ECG recordings, but this trend did not achieve statistical significance. These results suggest that none of the three beta-blockers tested nor disopyramide phosphate is likely to reduce the mortality from acute myocardial infarction when given prophylactically, although disopyramide phosphate does reduce the incidence of 'serious' ventriicular arrhythmias.

Adrenergic beta-Antagonists↗
PubMed1980

Enhanced metabolism and diminished efficacy of disopyramide by enzyme induction?

1 Monitoring plasma levels of mono-N-dealkyldisopyramide (MND), the most important metabolite of disopyramide, has been considered unnecessary. 2 We measured plasma levels of both disopyramide and MND in 64 consecutive patients receiving long term oral therapy with disopyramide. 3 Six patients were found with high plasma levels of MND, and simultaneously low levels of disopyramide. 4 Three of these patients were taking simultaneously phenytoin. The other three had a relatively high dose of disopyramide with regard to their renal function. One patient had terminal uremia, three had less severe renal dysfunction. 5 The underlying mechanism and clinical significance of the findings are discussed.

Aged↗
PubMed1983

Sustained release disopyramide compared to plain capsules after change-over from intravenous infusion.

The plasma concentration profile of disopyramide was examined in 13 patients with arrhythmias following acute myocardial infarction. Intravenous loading doses of 1.5 mg/kg followed by 0.7 mg/kg and then infusion of 0.3 mg kg-1h-1 resulted in final concentrations between 2.4 and 4.9 mg l. Change-over to oral therapy with disopyramide sustained release (SR) tablets was smooth, and therapeutic plasma concentrations were maintained throughout. Comparison of the plasma concentrations in a subsequent cross-over study with disopyramide plain capsules 150 mg every 6 h and SR tablets 250 mg every 12 h, each being administered for 3 days to attain a steady state, showed that the bioavailability and the variation of the plasma concentration were similar with both regimens. In patients with body weight between 62 and 92 kg disopyramide SR tablets 250 mg every 12 h matched the preceding infusion rate of 0.3 mg kg-1h-1 resulting in plasma concentrations close to steady state already on the first day of oral therapy. The absorption of disopyramide SR tablets is only moderately delayed, and the preparation can be used twice daily in direct succession of intravenous infusion.

Adult↗
PubMed1987

Disopyramide protein binding in plasma from patients with nephrotic syndrome during the exacerbation and remission phases.

1 Plasma protein binding of disopyramide was determined twice in plasma from seven patients with severe nephrotic syndrome when the disease activity was markedly different for each patient (mean +/- s.d. of serum albumin 21 +/- 4 vs 29 +/- 3 g l-1 (P less than 0.05), proteinuria 13.6 +/- 9.6 vs 2.2 +/- 1.7 g day-1 (P less than 0.01), and alpha 1-acid glycoprotein 0.34 +/- 0.12 vs 0.95 +/- 0.28 g l-1 (P less than 0.01) during the exacerbation vs remission phases, respectively). 2 Plasma samples containing disopyramide at the concentrations of 0.2-12.0 micrograms ml-1 were analysed by ultrafiltration. The free fractions at the proposed therapeutic concentration range (2.0-6.0 micrograms ml-1) were significantly (P less than 0.01) greater during the exacerbation phase than during the remission phase. 3 Multiple linear regression analysis revealed that the free fraction of disopyramide at 3.0 micrograms ml-1 correlated much better with alpha 1-acid glycoprotein (partial correlation coefficient = 0.85, P less than 0.01) than with albumin (partial correlation coefficient = 0.25, P less than 0.05). 4 The binding data of disopyramide analysed by a model assuming one specific binding site and nonspecific binding(s) demonstrated that the capacity constant correlated significantly (r = 0.97, P less than 0.001) with plasma alpha 1-acid glycoprotein. 5 The results suggest that a total concentration of disopyramide within the therapeutic range may not be a reliable guide for a safe dosing scheme in patients with severe nephrotic syndrome, particularly during the exacerbation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Disopyramide pharmacokinetics and metabolism: effect of inducers.

1. The disposition of orally administered disopyramide was studied in a population of smokers (n = 6) and non-smokers (n = 8) before and during phenobarbitone treatment (100 mg daily for 21 days; Cp 21st day = 13.9 +/- 2.0 micrograms ml-1). The comparative inducibility of these populations by phenobarbitone was assessed as was the inductive effect of cigarette smoking, per se. Furthermore, the determinants of the intensity of the inductive effect were examined, as well as the effect of the barbiturate on the binding of disopyramide to alpha 1-acid glycoprotein (AGP). 2. Smokers and non-smokers exhibited similar half-lives (6.48 +/- 1.49 vs 6.66 +/- 1.02 h), apparent total body clearances (0.100 +/- 0.020 vs 0.117 +/- 0.034 l h-1 kg-1), mean renal clearances (0.043 +/- 0.0093 vs 0.057 +/- 0.013 l h-1 kg-1) and apparent intrinsic metabolic clearances (0.057 +/- 0.015 vs 0.060 +/- 0.024 l h-1 kg-1) before phenobarbitone treatment. 3. Both populations responded comparably to barbiturate exposure in that apparent intrinsic metabolic clearance more than doubled. Interestingly, the magnitude of this increase was highly dependent on the observed baseline apparent intrinsic metabolic clearance, (r' = 0.81; P less than 0.001). 4. Phenobarbitone treatment of non-smokers resulted in an increase in the AUC of the active metabolite N-despropyl disopyramide (MND), but not significantly (3.8 +/- 1.6 vs 4.1 +/- 2.3 micrograms ml-1 h). Similar results were observed in smokers (3.5 +/- 1.4 vs 3.9 +/- 2.0 micrograms ml-1 h, respectively). 5. The percent of administered dose recovered in urine as disopyramide in non-smokers was significantly decreased upon phenobarbitone treatment (43 +/- 6% vs 25 +/- 5%), whereas the percent of dose recovered as MND increased significantly in this group (25 +/- 6% vs 31 +/- 5%). The population of smokers responded similarly. 6. At doses typically used to achieve hepatic microsomal enzyme induction in man, phenobarbitone treatment caused no significant change or trend towards a change in serum AGP concentrations as measured using the radial immunodiffusion method in nonsmokers (67.4 +/- 19.9 mg dl-1 vs 68.0 +/- 40.7 mg dl-1) or smokers (64.5 +/- 15.7 vs 67.9 +/- 14.9). Similarly, when AGP concentration was estimated in serum from non-smokers using a nephelometric method no effect attributable to phenobarbitone was observed (47.9 +/- 1.3 vs 47.9 +/- 16.8 mg dl-1). Consistent with this observation, disopyramide free fraction was not affected by barbiturate treatment.

Adult↗
PubMed2005

Population pharmacokinetic investigation of disopyramide by mixed effect modelling using routine clinical pharmacokinetic data in Japanese patients.

OBJECTIVE: To estimate the population pharmacokinetic parameters of disopyramide using non-linear mixed effects modelling. METHOD: A total of 148 serum levels from 109 patients (61 males and 48 females) receiving disopyramide were collected. RESULTS: The final pharmacokinetic model was Cl (L/h)=3.75.TBW0.567.AGE-0.374.Conc(-0.719).1.48(DOSE>or=5), Vd (L/kg)=4.13 and k(a) (h-1)=0.363, where Cl is total body clearance, Vd is apparent volume of distribution, k(a) is absorption rate constant, TBW is total bodyweight (kg), AGE is age (years), Conc is the concentration of disopyramide (microg/mL), and DOSE>or=5=1 for patient received 5 mg/kg/day of disopyramide dosage or over and 0 otherwise. CONCLUSION: Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target disopyramide concentrations and the desired therapeutic effect.

Absorption↗
PubMed1984

Effects of disopyramide on the electrocardiogram and ventricular function in the unanesthetized dog.

The antiarrhythmic compound disopyramide has been shown to possess negative inotropic effects. The present study was conducted to establish the effects of graded doses of disopyramide on ventricular function and electrocardiograms from healthy, awake dogs. Electrocardiograms and echocardiograms were obtained during a control period, and during an experimental period in which the six dogs on test received 7.5, 15 or 30 mg disopyramide per kg body weight orally three times per day. Six other dogs served as vehicle controls. No changes of statistical significance occurred in heart rate. The PQ interval was prolonged at all doses, the QRS complex was prolonged only at the highest dose, and the QT interval was prolonged at the intermediate and high doses. Left ventricular pre-ejection period (PEP) was prolonged in a dose-dependent relationship, and the left ventricular ejection time (ET) was shortened only at the highest dose. The percent shortening fraction of the left ventricle (% delta D) decreased significantly at intermediate and high doses, while the ratio of pre-ejection period to ejection time increased in a dose-dependent relationship. Conclusions are that even in therapeutic levels disopyramide produces significant reduction in left ventricular function, and that ratio of PEP/ET correlates better with the dose of disopyramide than did % delta D. This study demonstrates the feasibility of evaluating cardiac effects of compounds by non-invasive means.

Animals↗
PubMed1985

Atrial tachyarrhythmias after cardiac surgery: results of disopyramide therapy.

Of 1,247 consecutive patients who underwent cardiac surgery, 297 (24%) developed a post-operative atrial tachyarrhythmia. Of these patients, 201 were suitable for treatment according to the study protocol. All patients were initially given digoxin 0.75 mg intravenously (i.v.). After two hours, those 156 patients whose atrial arrhythmias persisted were given a 2 mg/kg loading dose of disopyramide (i.v.), followed by a constant i.v. infusion (0.4 mg kg-1 h-1) or oral therapy (600 mg daily). Within a further 12 hours, 75 patients (48%) reverted to sinus rhythm, 24 within one hour. Thus 120/201 patients (60%) reverted to sinus rhythm within 14 hours of commencing therapy. Reversion rates of those patients with both atrial fibrillation and flutter (AF/AFL) were significantly lower than those with AF (p less than 0.001) or AFL (p less than 0.02) alone. A further 70 patients reverted to sinus rhythm in one to 13 (mean four) days on continued drug therapy. Elective cardioversion restored sinus rhythm in six subjects. Atrial arrhythmias persisted in five patients (2.5%) at hospital discharge. Side-effects of disopyramide were noted in 19% of patients. Urinary retention was common (11.5%). Four patients with atrial flutter developed 1:1 atrioventricular conduction with the disopyramide loading dose. One patient with atrial fibrillation developed ventricular tachycardia during injection of the loading dose of disopyramide, but was successfully cardioverted to sinus rhythm. Two further patients developed significant hypotension (less than 90 mmHg systolic). Disopyramide is effective in the treatment of post-operative atrial tachyarrhythmias, but its routine use in this situation may be associated with an unacceptably high incidence of side-effects.

Atrial Fibrillation↗
PubMed1987

A kinetic analysis of the endplate ion channel blocking action of disopyramide and its optical isomers.

The effects of the antiarrhythmic agent disopyramide was studied on responses from voltage-clamped endplates at the neuromuscular junction of the garter snake. Disopyramide reduced endplate current amplitude and decay time constant in a concentration- and voltage-dependent manner. Endplate current decays remained monophasic in the presence of the drug. These results were interpreted in terms of the drug blocking the open form of the acetylcholine receptor-ion channel complex. Disopyramide produced a greater reduction of the amplitude of endplate currents than of miniature endplate currents. The reduction in miniature endplate current amplitude was not voltage-dependent. Analysis of endplate current driving functions showed that this was due to the rapid occurrence of channel block during the rising phase of the endplate current. The residual reduction, apart from that produced by channel block, is most probably due to receptor block. Disopyramide had a voltage-dependent blocking rate constant of about 10(7) M-1 S-1 at -90 mV. The unblocking rate constant was estimated from the results of experiments using paired ionophoretically applied pulses of acetylcholine. This value was again voltage-dependent and approximately 1 s-1. The actions of the (+)- and (-)-stereoisomers of disopyramide on endplate current decay were identical, indicating that the channel binding site at the neuromuscular junction is not stereoselective.

Acetylcholine↗