AM 92016 hydrochloride

AM 92016 hydrochloride is a specific inhibitor of delayed rectifier potassium current [1].

Potassium channel is an ion channel and acts to reset the resting potential and shapes the action potential. Delayed rectifier potassium channel (IK) is activated by the influx of Na+ and discharges K+, which repolarizes the membrane. IK restricts the duration of the nerve impulse.

AM 92016 hydrochloride is a specific iK inhibitor. In guinea-pig and rabbit ventricular cells, AM 92016 significantly increased action potential duration with 20% and 90% repolarization levels, respectively. Also, AM 92016 (1 μM) inhibited IK activated by step depolarizations in a time-dependent way [1]. In rabbit sino-atrial node cells, AM 92016 (50 nM) significantly inhibited IK with IC50 value of 40 nM in a concentration-dependent way [2]. In vascular smooth muscle cells (VSMC), AM92016 hydrochloride inhibited NO-induced ERK1/2 dephosphorylation [3].

In guinea-pigs, AM 92016 (1-5 mg/kg) significantly increased heart rate, left ventricular systolic pressure, systolic arterial blood pressure and the contractile index dp dtmax. AM 92016 exhibited proarrhythmic activity [4].

References:
[1].  Connors SP, Gill EW, Terrar DA. Actions and mechanisms of action of novel analogues of sotalol on guinea-pig and rabbit ventricular cells. Br J Pharmacol, 1992, 106(4): 958-965.
[2].  Lei M, Brown HF. Inhibition by Compound II, a sotalol analogue, of delayed rectifier current (iK) in rabbit isolated sino-atrial node cells. Naunyn Schmiedebergs Arch Pharmacol, 1998, 357(3): 260-267.
[3].  Palen DI, Belmadani S, Lucchesi PA, et al. Role of SHP-1, Kv.1.2, and cGMP in nitric oxide-induced ERK1/2 MAP kinase dephosphorylation in rat vascular smooth muscle cells. Cardiovasc Res, 2005, 68(2): 268-277.
[4].  Hagerty MJ, Wainwright CL, Kane KA. The in-vivo cardiovascular effects of a putative class III anti-arrhythmic drug, AM 92016. J Pharm Pharmacol, 1996, 48(4): 417-421.

Role of SHP-1, Kv.1.2, and cGMP in nitric oxide-induced ERK1/2 MAP kinase dephosphorylation in rat vascular smooth muscle cells.[Pubmed:15967421]

Cardiovasc Res. 2005 Nov 1;68(2):268-77.

OBJECTIVE: Nitric oxide (NO) elicits relaxation in vascular smooth muscle cells (VSMC) that is associated with guanylate cyclase (GC) and K(+) channel activation. In this study we determined the mechanisms that lead to ERK1/2 MAP kinase dephosphorylation in response to NO. METHODS: VSMC were treated with the NO donor SNAP or sodium nitroprusside (SNP), and ERK1/2, Src homology (SH) 1 domain-containing protein tyrosine phosphatase (SHP-1), and Kv.1.2 phosphorylation were assessed by immunoprecipitation and Western blot analysis. RESULTS: NO decreased basal ERK1/2 phosphorylation in a dose- and time-dependent manner. NO-induced ERK1/2 dephosphorylation was detected at 1 min and sustained for 30 min. Pre-treatment with the GC inhibitor ODQ or the protein tyrosine phosphatase inhibitor I prevented ERK1/2 dephosphorylation induced by SNAP. The inhibition of protein phosphatase 1A/2A had no effect on ERK1/2 dephosphorylation induced by SNAP. Treatment with cromakalim A, a nonspecific K(+) channel activator, also induced ERK1/2 dephosphorylation, while blockade of Kv.1.2 K(+) channels (AM92016 hydrochloride) prevented NO-induced ERK1/2 dephosphorylation. In addition, SNAP induced SHP-1 phosphorylation, and the Kv.1.2 dephosphorylation increase and SHP-1 phosphorylation was blocked by ODQ or AM92016. The basal interaction between ERK1/2 and SHP-1 was decreased in response to SNAP stimulation. SHP-1 also interacted with Kv.1.2 under basal conditions and participates in Kv.1.2 activation. Using the mouse mesenteric resistance artery, we found that ERK1/2 MAP kinase is involved in regulation of myogenic tone. CONCLUSION: Thus, our study provides the first evidence that NO controls basal ERK1/2 phosphorylation by a signaling cascade that involves a dynamic signaling complex between cGMP, Kv.1.2 and SHP-1.

Inhibition by Compound II, a sotalol analogue, of delayed rectifier current (iK) in rabbit isolated sino-atrial node cells.[Pubmed:9550297]

Naunyn Schmiedebergs Arch Pharmacol. 1998 Mar;357(3):260-7.

The effects of Compound II, a sotalol analogue, on spontaneous electrical activity and on three membrane currents (the delayed rectifier current, iK, the long-lasting inward calcium current, i(Ca,L) and hyperpolarization activated inward current, i(f)) were investigated in rabbit isolated sino-atrial node cells by whole cell clamp with amphotericin-permeabilised patches. A submaximal concentration of Compound II (50 nM) had a significant effect on the time and voltage dependent activation of iK and caused a positive shift of the iK activation curve. As well as blocking i(Kr), it caused some degree of block of i(Ks). Block of iK by Compound II was found to be concentration dependent with an IC50 of approximately 40 nM. 1 microM Compound II nearly completely blocked iK without significantly affecting the peak current or I/V relationships of i(Ca,L) or i(f). 50 nM Compound II caused a significant prolongation of APD100 and of cycle length. It also decreased diastolic depolarization rate without significantly affecting MDP and action potential amplitude. It is concluded that Compound II, a sotalol analogue, slows spontaneous activity of isolated rabbit SA node cells through a selective inhibition of iK.

The in-vivo cardiovascular effects of a putative class III anti-arrhythmic drug, AM 92016.[Pubmed:8794994]

J Pharm Pharmacol. 1996 Apr;48(4):417-21.

AM 92016 (1-(4-methanesulphonamidophenoxy)- 3-(N-methyl-3-4-dichlorophenethylamino)-2-propanol benzoic acid salt), an oxypropanolamine analogue of sotalol, has been shown to possess Class III anti-arrhythmic properties in-vitro at concentrations showing 1000 times more potency than sotalol. The aim of this study was to characterize the effects of AM 92016 in-vivo. When administered to anaesthetized guinea-pigs, AM 92016 (10 micrograms kg-1 -5 mg kg-1) significantly increased heart rate, systolic arterial blood pressure, left ventricular systolic pressure and the contractile index dp dtmax. AM 92016 also significantly decreased the QT interval of the electrocardiogram from 135 +/- 10 to 105 +/- 4 ms (5 mg kg-1). The time to onset of the first arrhythmia and ventricular fibrillation, induced by intravenous infusion of ouabain, was shortened in the presence of AM 92016. Ouabain-induced ventricular fibrillation occurred at 18 +/- 5 and 12 +/- 3 min (P < 0.05) in control and AM 92016-(1 mg kg-1) treated guinea-pigs, respectively. An infusion of AM 92016 (2.5 micrograms kg-1 min-1) to anaesthetized pigs significantly increased the total number of arrhythmias occurring following coronary artery occlusion from 266 +/- 26 in control pigs to 535 +/- 148 (P < 0.05) in those receiving AM 92016. The time to onset of ventricular fibrillation was also significantly reduced in anaesthetized pigs from 24 +/- 1 to 18 +/- 3 min in the presence of AM 92016. The drug did not change haemodynamics in the anaesthetized pig. We conclude that AM 92016 exhibited proarrhythmic rather than antiarrhythmic activity when administered in-vivo to either guinea-pigs or pigs.

Actions and mechanisms of action of novel analogues of sotalol on guinea-pig and rabbit ventricular cells.[Pubmed:1393293]

Br J Pharmacol. 1992 Aug;106(4):958-65.

1. The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2. In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3. Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 microM). Action potential prolongation by compound II was also unaffected in the presence of 10 microM tetrodotoxin. 4. Compound II (1 microM) did not influence IK1 assessed from the current during ramp changes in membrane potential (20 mV s-1) over the range -90 to -10 mV. 5. Compound II (1 microM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK.6. Submaximal concentrations of compound II were without effect on activation of IK with time at a membrane potential of + 40 mV, and no changes were detected in the time constants of the two components of IK decay over the range of potentials - 60 to 0 mV. Compound 11 (50 nM) appeared to cause a small shift in the activation of IK with membrane potential (an apparent shift of approximately 10mV in the depolarizing direction at the mid-point of the curve).7. Log dose-response curves for action potential prolongation and for blockade of IK by compound II were similar. The IC50 for compound II was approximately 30 nM.8. It is concluded that this novel series of compounds prolongs action potential duration, and that in the case of compound II the evidence supports a potent selective effect on the time-dependent potassium current IK, an effect which can account for this prolongation.

AM-92016 hydrochloride is a specific blocker of rectifier potassium current (IK). AM-92016 hydrochloride delays rectifier potassium channel (IK), repolarizes the membrane thereby restricting the duration of the nerve impulse thereby restricting the duration of the nerve impulse.

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