Intravenous antazoline, a first-generation antihistaminic drug with antiarrhythmic properties, is a suitable agent for pharmacological cardioversion of atrial fibrillation induced during pulmonary vein isolation due to the lack of influence on atrio-venous conduction and high clinical effectiveness (AntaEP Study).

AIMS: Antazoline is a first-generation antihistaminic drug used primarily in eye drop formulations. When administered intravenously, antazoline displays antiarrhythmic properties resulting in a rapid conversion of recent-onset atrial fibrillation (AF) to sinus rhythm (SR). The aim of the study was to assess the influence of antazoline on atrio-venous conduction and other electrophysiological parameters in patients undergoing AF ablation. METHODS: An experimental prospective study. Patients scheduled for the first-time AF ablation, in SR and not on amiodarone were enrolled. Atrio-venous conduction assessment and invasive electrophysiological study (EPS) were performed before and after intravenous administration of 250 mg of antazoline. In case of AF induction during EPS, antazoline was administered until conversion to SR or a cumulative dose of 300 mg. RESULTS: We enrolled 14 patients: 13 (93%) men, mean age 63.4 (59.9-66.8) years, mean CHA2 DS2 -VASc score 1.6 (1.0-2.2). Antazoline was administered in a mean dose 257.1 (246.7-267.6) mg. Pulmonary vein potentials and atrial capture during pulmonary vein stimulation were present before and after the administration of antazoline. Wenckebach point and atrial conduction times did not change significantly, but atrio-ventricular node effective refractory period improved-324.7 (275.9-373.5) ms vs 284.3 (256.2-312.4) ms, P = 0.02. Antazoline was effective in all 5 (100%) cases of AF induction during EPS. There were no serious adverse events. CONCLUSION: Due to the lack of influence on atrio-venous conduction and high clinical effectiveness, antazoline may be suitable for pharmacological cardioversion of AF occurring during AF ablation.

Antiarrhythmic effect of antazoline in experimental models of acquired short- and long-QT-syndromes.

Aims: Antazoline is a first-generation antihistamine with antiarrhythmic properties. This study examines potential electrophysiological effects of antazoline in short-QT-syndrome (SQTS) and long-QT-syndrome (LQTS). Methods and results: Sixty-five rabbit hearts were Langendorff-perfused. Action potential duration at 90% of repolarization (APD90), QT-interval, spatial dispersion (DISP), and effective refractory period (ERP) were measured. The IK, ATP-opener pinacidil (1 µM, n = 14) reduced APD90 (-14 ms, P < 0.01), QT-interval (-14 ms, P < 0.01), and ERP (-11 ms, P < 0.01), thus simulating acquired SQTS. Additional infusion of 20 µM antazoline prolonged repolarization. Under baseline conditions, ventricular fibrillation (VF) was inducible in 5 of 14 hearts (10 episodes) and in 5 of 14 pinacidil-treated hearts (21 episodes, P = ns). Antazoline significantly reduced induction of VF (0 episodes, P < 0.05 each). Further 17 hearts were perfused with 100 µM sotalol and 17 hearts with 300 µM erythromycin to induce acquired LQTS2. In both groups, prolongation of APD90, QT-interval, and ERP was observed. Spatial dispersion was increased (sotalol: +26 ms, P < 0.01; erythromycin: +31 ms, P < 0.01). Additional infusion of antazoline reduced DISP (sotalol: -22 ms, P < 0.01; erythromycin: -26 ms, P < 0.01). Torsade de pointes (TdP) occurred in 6 of 17 sotalol-treated (22 episodes, P < 0.05 each) and in 8 of 17 erythromycin-treated hearts (96 episodes P < 0.05 each). Additional infusion of antazoline completely suppressed TdP in both groups (P < 0.05 each). Acquired LQTS3 was induced by veratridine (0.5 µM, n = 17) and similar results were obtained (APD90: +24 ms, P < 0.01, QT-interval: +58 ms, P < 0.01, DISP: +38 ms, P < 0.01). Torsade de pointes occurred in 10 of 17 hearts (41 episodes, P < 0.05 each). Antazoline significantly reduced TdP (2 of 17 hearts, 4 episodes, P < 0.05 each). Conclusion: Antazoline significantly reduced induction of VF in an experimental model of acquired SQTS. In three experimental models of acquired LQTS, antazoline effectively suppressed TdP.

Novel naphthyloxy derivatives - Potent histamine H3 receptor ligands. Synthesis and pharmacological evaluation.

A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H3 receptor affinity. Most compounds showed high affinities with Ki values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H3 receptor with a Ki value of 21.9 nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC50 = 312 nM) and in vivo in the rat dipsogenia model (ED50 = 3.68 nM). Moreover, compound 11 showed positive effects on scopolamine induced-memory deficits in mice (at doses of 10 and 15 mg/kg) and an analgesic effect in the formalin test in mice with ED50 = 30.6 mg/kg (early phase) and ED50 = 20.8 mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; H3R Ki = 53.9 nM), was accepted for Anticonvulsant Screening Program at the National Institute of Neurological Disorders and Stroke/National Institute of Health (Rockville, USA). The screening was performed in the maximal electroshock seizure (MES), the subcutaneous pentylenetetrazole (scPTZ) and the 6-Hz psychomotor animal models of epilepsy. Neurologic deficit was evaluated by the rotarod test. Compound 13 inhibited convulsions induced by the MES with ED50 of 19.2 mg/kg (mice, i.p.), 17.8 (rats, i.p.), and 78.1 (rats, p.o.). Moreover, 13 displayed protection against the 6-Hz psychomotor seizures (32 mA) in mice (i.p.) with ED50 of 33.1 mg/kg and (44 mA) ED50 of 57.2 mg/kg. Furthermore, compounds 11 and 13 showed in vitro weak influence on viability of tested cell lines (normal HEK293, neuroblastoma IMR-32, hepatoma HEPG2), weak inhibition of CYP3A4 activity, and no mutagenicity. Thus, these compounds may be used as leads in a further search for histamine H3 receptor ligands with promising in vitro and in vivo activity.

Antazoline-insights into drug-induced electrocardiographic and hemodynamic effects: Results of the ELEPHANT II substudy.

BACKGROUND: Antazoline is an old antihistaminic and new antiarrhythmic agent with unknown mechanisms of action which recently has been shown to effectively terminate atrial fibrillation. The aim of study was to examine the effects of antazoline on hemodynamic and ECG parameters. METHODS: Antazoline was given intravenously in three 100 mg boluses to 10 healthy volunteers (four males, mean age 40 + 11 years). Hemodynamic and ECG parameters were measured using impedance cardiography [systolic (sBP), diastolic (dBP), mean (mBP) blood pressure, stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and heart rate (HR), P wave, PR interval, QRS complex, QT and corrected QT (QTcF) interval]. Plasma concentration of antazoline was also measured. RESULTS: Antazoline caused significant prolongation of P wave, QRS as well as QT and QTcF (101 ± 10 vs 110 ± 16 ms, p < .05, and 101 ± 12 vs 107 ± 12 ms, p < .05, 399 ± 27 vs 444 ± 23 ms, p < .05, and 403 ± 21 vs 448 ± 27 ms, p < .05, respectively). Also, a significant decrease in SV was noted (94.9 ± 21.8 vs 82.4 ± 19.6 ml, p < .05). A significant correlation between changes in plasma drug concentration and changes in CO, HR, and dBP was found. CONCLUSIONS: Antazoline impairs slightly hemodynamics, significantly reducing SV. Significant prolongation of P wave and QRS duration corresponds to drug-induced prolongation of conduction, whereas QT prolongation represents drug-induced prolongation of repolarization.

Antiarrhythmic drugs for pharmacological cardioversion of atrial fibrillation and sex differences: Insights from the CANT II Study.

BACKGROUND: Data on sex differences in terms of action of antiarrhythmic agents (AADs) are limited. This study aimed to evaluate the clinical profile of patients with atrial fibrillation (AF), and efficacy and safety of AADs used for pharmacological cardioversion (PCV) of AF. METHODS: This research was a sub-analysis of the retrospective multicenter Cardioversion with ANTazoline II (CANT) registry, which comprised 1365 patients with short-duration AF referred for urgent PCV with the use of AAD. Patients were categorized according to and compared in terms of clinical parameters and PCV outcomes. The primary endpoint was return of sinus rhythm within 12 hours after drug infusion, and the composite safety endpoint involved bradycardia <45 bpm, hypotension, syncope, or death. RESULTS: The sex distribution of patients qualified for PCV was even (men, n = 725; 53.1%). Females were older and more symptomatic and had higher CHA2DS2-VASc scores, higher prevalence of tachyarrhythmia, and higher use of chronic anticoagulation. The overall efficacy (71.4% vs. 70.1%; P = 0.59) and safety (5.2% vs. 4.6%; P = 0.60) of PCV was comparable in men and women. Amiodarone (68.3% vs. 65.9%; P = 0.66) and antazoline (77.1% vs. 80.0%; P = 0.19) had similar efficacy in men and women, but propafenone had a lower rate of rhythm conversion in men (64.7% vs. 79.3%; P = 0.046). None of the assessed AADs differed in terms of safety profile in both sexes. CONCLUSION: Female patients with AF have different clinical profiles but similar efficacy and safety of AADs as compared to male participants. Propafenone has significantly lower efficacy in men, which requires further investigation.

Repurposing of Antazoline Hydrochloride as an Inhibitor of Hepatitis B Virus DNA Secretion.

Hepatitis B virus (HBV) belongs to Hepadnaviridae family and mainly infects hepatocytes, which can cause acute or chronic hepatitis. Currently, two types of antiviral drugs are approved for chronic infection clinically: interferons and nucleos(t)ide analogues. However, the clinical cure for chronic infection is still rare, and it is a huge challenge for all researchers to develop high-efficiency, safe, non-tolerant, and low-toxicity anti-HBV drugs. Antazoline hydrochloride is a first-generation antihistamine with anticholinergic properties, and it is commonly used to relieve nasal congestion and in eye drops. Recently, an in vitro high-throughput evaluation system was constructed to screen nearly 800 compounds from the Food and Drug Administration (FDA)-approved Drug Library. We found that arbidol hydrochloride and antazoline hydrochloride can effectively reduce HBV DNA in the extracellular supernatant in a dose-dependent manner, with EC50 of 4.321 µmol/L and 2.910 µmol/L in HepAD38 cells, respectively. Moreover, the antiviral effects and potential mechanism of action of antazoline hydrochloride were studied in different HBV replication systems. The results indicate that antazoline hydrochloride also has a significant inhibitory effect on HBV DNA in the extracellular supernatant of Huh7 cells, with an EC50 of 2.349 µmol/L. These findings provide new ideas for screening and research related to HBV agents.

Evidence for imidazoline receptors involvement in the agmatine antidepressant-like effect in the forced swimming test.

This study investigated the involvement of the imidazoline receptors in the antidepressant-like effect of agmatine in the forced swimming test. The antidepressant-like effects of agmatine (10 mg/kg, i.p.) in the forced swimming test was blocked by pretreatment of mice with efaroxan (1 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I2/alpha2-adrenoceptor antagonist) and antazoline (5 mg/kg, i.p., a ligand with high affinity for the I2 receptor). A subeffective dose of agmatine (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with clonidine (0.06 mg/kg, i.p, an imidazoline I1/alpha2-adrenoceptor agonist), moxonidine (0.5 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor agonist), antazoline (1 mg/kg, i.p.) and MK-801 (0.001 mg/kg, i.p., a non-competitive NMDA receptor antagonist), but not with efaroxan (1 mg/kg, i.p.) and idazoxan (0.06 mg/kg, i.p.). Pretreatment of mice with yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist) blocked the synergistic antidepressant-like effect of agmatine (0.001 mg/kg, i.p.) with clonidine (0.06 mg/kg, i.p). A subeffective dose of MK-801 (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with antazoline (5 mg/kg, i.p.), but not with efaroxan (1 mg/kg, i.p.) or idazoxan (0.06 mg/kg, i.p.). In conclusion, this study suggests that the anti-immobility effect of agmatine in the forced swimming test is dependent on its interaction with imidazoline I1 and I2 receptors.

Effective suppression of atrial fibrillation by the antihistaminic agent antazoline: First experimental insights into a novel antiarrhythmic agent.

INTRODUCTION: The antihistaminic antazoline (ANT) was reported to be highly effective and safe for rapid conversion of atrial fibrillation (AF). We therefore analyzed underlying mechanisms in an experimental whole-heart model. METHODS AND RESULTS: Isolated and retrogradely perfused rabbit hearts underwent a standardized protocol employing atrial burst pacing-induced AF in five of 20 hearts under baseline conditions (seven episodes). Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Two monophasic action potential recordings on the left- and two on the right atrial epicardium showed a decrease in atrial action potential duration (aAPD, -25 msec, P<.05) and atrial effective refractory period (aERP; -52 msec, P<.01) after infusion of acetylcholine (1 µmol/L) and isoproterenol (1 µmol/L). This led to induction of AF in 14 of 20 hearts (145 episodes). Simultaneous infusion of ANT (20 µmol/L) led to a complete suppression of AF in all inducible hearts. Treatment with ANT also led to a significant increase in aAPD (+41 msec, P<.01) and aERP (+74 msec, P<.05), leading to a marked increase in atrial postrepolarization refractoriness (aPRR, +33 msec, P<.01). Results were compared to 13 rabbits treated with flecainide. Flecainide induced a significant increase in aPRR and resulted in induction of AF in seven of 13 hearts (51 episodes) while 11 of 13 hearts were inducible with acetylcholine and isoproterenol (93 episodes). CONCLUSION: Administration of ANT was highly effective in suppressing AF. The antiarrhythmic effect could be explained by a significant increase in postrepolarization refractoriness as a result of a more marked increase in aERP as compared with aAPD.

Emesis induced by 4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343): evidence for a predominant central muscarinic M1 mediation.

The emetic action of 4-(m-chlorophenylcarbamoyloxy)-2- butynyltrimethylammonium chloride (McN-A-343) was investigated in the unanaesthetized cat, after it was injected into the cerebral ventricles, through chronically-implanted cannulae. Intracerebroventricular injection of McN-A-343 produced dose-dependent and shortlasting emesis, which was not completely abolished after ablation of the area postrema. The predominantly selective muscarinic M1 antagonist, pirenzepine as well as the mixed muscarinic M1 and M2 antagonist, atropine, injected into the cerebral ventricles, attenuated or abolished the emesis evoked by intracerebroventricular McN-A-343. Both atropine and pirenzepine produced dose-dependent inhibition of the emesis evoked by McN-A-343. However, the ID50 value for atropine was approximately five times greater than that for pirenzepine. Abolition of McN-A-343-induced emesis only occurred with the largest dose of atropine (1 mg). On the other hand, selected ganglionic blocking agents, an alpha- and beta-adrenoceptor blocking agent, a dopamine antagonist, a 5-hydroxytryptamine antagonist and an antihistamine, all injected into the cerebral ventricles, had no significant effect on emesis evoked by McN-A-343, similarly injected. The emetic response to intracerebroventricular injection of McN-A-343 was attenuated or abolished in cats pretreated with hemicholinium-3, triethylcholine, reserpine and 6-hydroxydopamine, intracerebroventricularly. On the contrary, the emetic response to intracerebroventricular injection of McN-A-343 was not altered in cats pretreated with intracerebroventricular injections of bretylium, alpha-methyl-p-tyrosine and 5,6-dihydroxytryptamine. It is postulated that the emesis produced by McN-A-343, injected into the cerebral ventricles, is mediated through muscarinic M1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of imidazoline drugs on human blood platelet aggregation.

The effect of seven commonly used in therapy imidazoline derivatives on human blood platelet aggregation was studied. Three of the agents, i.e. clonidine, antazoline and tetryzoline were classified as partial agonists of the receptor responsible for aggregation. Two other drugs, i.e. phentolamine and tolazoline act as competitive antagonists of relatively high receptor affinity. The remaining imidazolines: xylometazoline and naphazoline effectively inhibit the platelet receptor in a non-competitive manner. The last two compounds seem to be selective alpha 2-adrenoceptor antagonists.

The kinetics of competitive antagonists on guinea-pig ileum.

1 The kinetics of action of some competitive muscarinic and histamine antagonists were examined on guinea-pig isolated ileum and their behaviour compared with the predictions of the interaction-limited model described by Paton (1961). 2 The kinetics of antagonism were not consistent with the predictions of this model: (1) The apparent dissociation rate constant calculated from the decrease in occupancy on washout was not independent of the concentration of antagonist. (2) The dissociation rate constant of a 'slow' antagonist calculated from the change in occupancy when a 'fast' antagonist was superimposed varied with the concentration of fast antagonist. (3) If the concentration of slow antagonist was increased when the fast antagonist was superimposed so that the equilibrium occupancy of the 'slow' was the same as before, a transitional phase was observed. 3 The kinetics of antagonism were observed in longitudinal muscle strips and intact pieces of ileum, bathed in Tyrode or Krebs solution, and with isometric and isotonic recording. No evidence was found that the discrepancies between the interaction-limited model and the observed kinetics could be accounted for by the experimental method used. 4 It is therefore concluded that either access is rate-limiting in these circumstances or, if interaction is rate-limiting, some alternative interaction-limited model is required to describe the kinetics of antagonism. In either case it would seem unwise at this time to calculate antagonist-receptor rate constants from the observed kinetics of antagonism.

An analysis of the purinergic component of active muscle vasodilatation obtained by electrical stimulation of the hypothalamus in rabbits.

In anaesthetized rabbits, electrical stimulation of the hypothalamus in areas analogous to the defence area in cats produces the 'defence reaction.' This response includes signs of arousal and a large increase in blood flow to skeletal muscle in the hind limb caused by a vasodilatation in the skeletal muscle vasculature. The vasodilatation is a sympathetic response, and it is not dependent upon muscle activity in the hind limb. The muscle vasodilatation is insensitive to alpha-adrenoceptor, beta-adrenoceptor, cholinoceptor and histamine receptor antagonists. Intra-arterial injections of the purinoceptor agonists, adenosine triphosphate (ATP) and adenosine, mimic the vasodilatation produced by electrical stimulation. The P1-purinoceptor blocker, aminophylline, attenuates adenosine-induced vasodilatation, but it does not affect the vasodilatation produced by ATP or hypothalamic stimulation. The P2-purinoceptor blocker, antazoline, attenuates the vasodilatation produced by both ATP and hypothalamic stimulation. Our results suggest that the muscle vasodilatation produced by hypothalamic stimulation is mediated by purinergic nerves which release ATP and act on P2-purinoceptors.

Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor.

This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate-induced necrosis and on apoptosis induced by low extracellular K+ in cultured cerebellar granule cells. Exposure (30 min) of energy deprived cells to L-glutamate (1-100 microM) caused a concentration-dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC50=5 microM) was blocked by the specific NMDA receptor antagonist MK-801 (dizocilpine). Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 microM (EC100) L-glutamate with the rank order (EC50 in microM): antazoline (13)>cirazoline (44)>LSL 61122 [2-styryl-2-imidazoline] (54)>LSL 60101 [2-(2-benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2-(1,4-benzodioxan-6-yl)-4,5-dihydroimidazole](101)>RX82 1002 (2-methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K+) which does not involve stimulation of NMDA receptors. Imidazol(ine) drugs and agmatine fully inhibited [3H]-(+)-MK-801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting against L-glutamate neurotoxicity correlated well (r=0.90) with the potency of the same compounds competing against [3H]-(+)-MK-801 binding. In HEK-293 cells transfected to express the NR1-1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage- and concentration-dependent block of glutamate-induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC50 of 10-12 microM at 0 mV. It is concluded that imidazol(ine) drugs and agmatine are neuroprotective against glutamate-induced necrotic neuronal cell death in vitro and that this effect is mediated through NMDA receptor blockade by interacting with a site located within the NMDA channel pore.

Antagonism of levcromakalim by imidazoline- and guanidine-derivatives in rat portal vein: involvement of the delayed rectifier.

1. In rat whole portal veins, guanabenz (100 nM to 10 microM) and antazoline (100 nM to 100 microM) each increased the amplitude, frequency and duration of spontaneous contractions. In addition, guanabenz (30 microM) and antazoline (30 microM) each antagonized the ability of levcromakalim (3 nM to 10 microM) to inhibit the spontaneous contractions of this tissue. 2. Whole-cell voltage-clamp recordings were made from freshly-isolated rat portal vein cells dispersed by a collagenase/pronase enzyme treatment. The ability of several agents (antazoline, cirazoline, clonidine, guanabenz and phentolamine, each containing an imidazoline or guanidine moiety), to modulate potassium (K) currents and to inhibit the actions of levcromakalim was investigated. 3. Antazoline, cirazoline, clonidine, guanabenz and phentolamine (each at a concentration of 30 microM) had little effect on control non-inactivating currents but inhibited the delayed-rectifier current, IK(V). 4. Levcromakalim (1 microM) induced a non-inactivating current, IK(ATP), and also inhibited the delayed rectifier current, IK(V). 5. Glibenclamide (1 microM) had no effect on control delayed rectifier or non-inactivating currents, but it inhibited the simultaneous induction of IK(ATP) and reduction of IK(V) produced by levcromakalim (1 microM). 6. Antazoline, cirazoline, clonidine and guanabenz (each at a concentration of 30 microM) prevented the induction of IK(ATP) by levcromakalim (1 microM). Phentolamine (30 microM) and clonidine (30 microM) each inhibited the IK(ATP) generated by levcromakalim (1 microM). 7. It is concluded that a variety of agents which possess either an imidazoline (antazoline, cirazoline, clonidine and phentolamine) or a guanidine (guanabenz) moiety within their structure inhibit the delayed rectifier current, IK(V). This action may thus be mediated via a so-called non-adrenoceptor imidazoline binding site. Furthermore, the ability of these ligands to inhibit IK(V) and to antagonize both the induction of IK(ATP) and the vasorelaxation produced by levcromakalim is consistent with the view that the channel (KATP) which underlies IK(ATP) is a voltage-insensitive state of the delayed rectifier K-channel (Kv).

Imidazoline antagonists of alpha 2-adrenoceptors increase insulin release in vitro by inhibiting ATP-sensitive K+ channels in pancreatic beta-cells.

1. Islets from normal mice were used to study the mechanisms by which imidazoline antagonists of alpha 2-adrenoceptors increase insulin release in vitro. 2. Alinidine, antazoline, phentolamine and tolazoline inhibited 86Rb efflux from islets perifused with a medium containing 3 mM glucose, i.e. under conditions where many adenosine 5'-triphosphate (ATP)-sensitive K+ channels are open in the beta-cell membrane. They also reduced the acceleration of 86Rb efflux caused by diazoxide, an opener of ATP-sensitive K+ channels. 3. ATP-sensitive and voltage-sensitive K+ currents were measured in single beta-cells by the whole-cell mode of the patch-clamp technique. Antazoline more markedly inhibited the ATP-sensitive than the voltage-sensitive current, an effect previously observed with phentolamine. Alinidine and tolazoline partially decreased the ATP-sensitive K+ current. 4. The four imidazolines reversed the inhibition of insulin release caused by diazoxide (through opening of ATP-sensitive K+ channels) or by clonidine (through activation of alpha 2-adrenoceptors) in a concentration-dependent manner. Only the former effect correlated with the ability of each drug to increase control insulin release stimulated by 15 mM glucose alone. 5. It is concluded that the ability of imidazoline antagonists of alpha 2-adrenoceptors to increase insulin release in vitro can be ascribed to their blockade of ATP-sensitive K+ channels in beta-cells rather than to their interaction with the adrenoceptor.

H2-receptors in the human ocular surface.

Ten normal human volunteers participated in a two-part study of H2-receptor activity in the ocular surface. Dimethylaminopropylisothiourea (trivial name, dimaprit dihydrochloride), a highly selective H2-receptor agonist, produced vasodilation without itch. Pretreatment with the H2-receptor antagonist, cimetidine, significantly blocked the vasodilatory effect of dimethylaminopropylisothiourea, whereas pretreatment with the H1-receptor antagonist, antazoline phosphate, did not. We conclude that H2-receptors are present in the human ocular surface.

Inhibition of voltage-gated Ca2+ channels by antazoline.

We showed recently that imidazolines exert neuroprotection against hypoxia and NMDA toxicity in cerebellar and striatal neuronal cultures, through a voltage-dependent blockade of glutamatergic NMDA receptors. Here, we report that in striatal neuronal cultures from mouse embryos the imidazoline compound, antazoline, inhibits voltage-gated Ca2+ channels by acting at a phencyclidine-like site. This effect was fast, fully reversible, voltage-dependent and predominant on P/Q- and N-type Ca2+ channels. Taken together, these results suggest that imidazolines may elicit neuroprotective effects also by decreasing the release of glutamate through inhibition of presynaptic Ca2+ channels.

Antazoline increases insulin secretion and improves glucose tolerance in rats and dogs.

In vivo effects of an imidazoline devoid of alpha2-adrenoceptor antagonistic properties, antazoline, on insulin secretion and glycemia were investigated both in fasted rats and dogs. In both species, antazoline (1.5 mg/kg i.v.) transiently increased insulinemia without affecting basal plasma glucose levels. In contrast, during an i.v. glucose tolerance test, antazoline markedly potentiated insulin release and thus increased the glucose disappearance rate. In rats, during an oral glucose tolerance test, the intragastric administration of antazoline (1.5 mg/kg) clearly enhanced insulin secretion and reduced hyperglycemia. In dogs provided with a venous pancreatico-duodenal bypass, antazoline (0.5 mg/kg i.v.) induced an immediate and transient increase in insulin and somatostatin but not in glucagon pancreatico-duodenal outputs. In conclusion, intravenously and orally administered, the imidazoline antazoline is able to stimulate insulin secretion in vivo and improve glucose tolerance. The imidazoline compounds could therefore have a potential therapeutic relevance as new antihyperglycemic insulinotropic agents.

Effects of imidazolines and derivatives on insulin secretion and vascular resistance in perfused rat pancreas.

The effects of imidazolines and derivatives were studied on insulin secretion and vascular resistance in the isolated perfused rat pancreas. On insulin secretion, two imidazoline alpha 2-adrenoceptor antagonists, efaroxan (1-100 microM) and RX821002 (10 microM), had a stimulating response; however, idazoxan, like the non-imidazoline alpha 2-adrenoceptor antagonist yohimbine, was ineffective at 10 microM. The oxazoline rilmenidine with alpha 2-adrenergic activity at 10 microM), an imidazoline devoid of alpha 2-adrenergic activity, also had an insulin-releasing effect. On pancreatic vessels, all imidazolines tested (efaroxan, RX821002, antazoline and idazoxan), in contrast to yohimbine, induced vasoconstriction. Rilmenidine did not have a vasoconstrictor effect after blockade of alpha 2-adrenoceptors. Furthermore, the efaroxan-induced insulin release or vasoconstriction was not affected by the blockade of alpha 2- and alpha 1-adrenoceptors. This study shows that imidazolines and derivatives are able to stimulate insulin release and induce vasoconstriction in the rat pancreas. These effects cannot be ascribed to an interaction with alpha-adrenoceptors but may involve different types of imidazoline sites.

Evidence for two different imidazoline sites on pancreatic B cells and vascular bed in rat.

The relative potencies of imidazoline compounds to induce insulin secretion and vascular resistance were compared in the isolated perfused rat pancreas. On insulin secretion, only the two imidazolines, antazoline and efaroxan, induced a concentration-dependent response, antazoline being 10 times more potent than efaroxan. In contrast, idazoxan, a blocker of imidazoline I1 sites, at concentrations up to 30 microM, antagonized the insulin response to 10 microM efaroxan (IC50 approximately equal to 14 +/- 2 microM) without affecting that to 3 microM tolbutamide. On pancreatic vessels, not only antazoline and efaroxan but also idazoxan induced a concentration-dependent vasoconstriction; the rank order of agonist potency was antazoline > efaroxan > idazoxan. In addition, cimetidine, an imidazole known to bind imidazoline I1 sites, ineffective per se, partially reversed the insulin stimulatory effect of efaroxan without affecting its vasoconstrictor effect. This study demonstrates that the insulin secretory and vasoconstrictor actions of imidazolines involve different imidazoline sites in rat pancreas. The results provide evidence for an I1 type mediating insulin secretion on B cells and an I2 type mediating vasoconstriction in vessels.