ATP-sensitive K ϩ (K ATP ) channels are present on the sarcolemma (sarcK ATP channels) and mitochondria (mitoK ATP channels) of cardiac myocytes. Amiodarone, a class III antiarrhythmic drug, reduces sudden cardiac death in patients with organic heart disease. The objective of the present study was to investigate the effects of amiodarone on sarcK ATP and mitoK ATP channels. Single sarcK ATP channel current and flavoprotein fluorescence were measured in guinea pig ventricular myocytes to assay sarcK ATP and mitoK ATP channel activity, respectively. Amiodarone inhibited the sarcK ATP channel currents in a concentration-dependent manner without affecting its unitary amplitude. The IC 50 values were 0.35 M in the inside-out patch exposed to an ATP-free solution and 2.8 M in the cell-attached patch under metabolic inhibition, respectively. Amiodarone (10 M) alone did not oxidize the flavoprotein. In addition, the oxidative effect of the mitoK ATP channel opener diazoxide (100 M) was unaffected by amiodarone. Exposure to ouabain (1 mM) for 30 min produced mitochondrial Ca 2ϩ overload, and the intensity of rhod-2 fluorescence increased to 246 Ϯ 16% of baseline (n ϭ 9). Amiodarone did not alter the ouabain-induced mitochondrial Ca 2ϩ overload (236 Ϯ 10% of baseline, n ϭ 7). Treatment with diazoxide significantly reduced the ouabain-induced mitochondrial Ca 2ϩ overload (158 Ϯ 15% of baseline, n ϭ 8, p Ͻ 0.05 versus ouabain); this effect was not abolished by amiodarone (154 Ϯ 10% of baseline, n ϭ 8, p Ͻ 0.05 versus ouabain). These results suggest that amiodarone inhibits sarcK ATP but not mitoK ATP channels in cardiac myocytes. Such an action of amiodarone may effectively prevent ischemic arrhythmias without causing ischemic damage.
To clarify the pathophysiological significance of endothelin (ET) in the ischemic myocardium, we examined the effect of endothelin-1 (ET-1) on the ATP-sensitive K+ current (IK.ATP) and compared it with that of ET-3 in guinea pig ventricular cells using conventional microelectrode and patch clamp techniques. In isolated guinea pig papillary muscles, ET-1 (30 nM) markedly increased developed tension (DT), with little influence on action potential duration (APD), whereas ET-3 at the same concentration failed to affect DT or APD. Both nicorandil (1 mM) and cromakalim (30 microM) markedly shortened APD and decreased DT in papillary muscles. ET-1, but not ET-3, partially reversed the nicorandil-induced decreases in APD and DT in a concentration-dependent manner. ET-1 also attenuated the cromakalim-induced decreases in APD and DT. In single ventricular myocytes, both nicorandil and cromakalim increased a steady-state outward current, which was sensitive to 1 microM glibenclamide, suggesting that these drugs activate IK.ATP. ET-1 (30 nM) significantly inhibited the IK.ATP, whereas ET-3 failed to affect it. The ET-1 induced inhibition of IK.ATP was abolished by BQ-485 (100 nM), an ETA receptor-selective antagonist. Neither the protein kinase C (PKC) inhibitor staurosporine (20 nM) nor the calmodulin antagonist W-7 (50 microM) affected the inhibitory action of ET-1 on the nicorandil-induced IK.ATP. In pertussis toxin (PTX)-treated cells, the inhibitory action of ET-1 on IK.ATP was augmented rather than attenuated. These results suggest that ET-1 partially inhibits the IK.ATP through the activation of ETA receptors, although the precise intracellular mechanism remains to be clarified. Because activation of the ATP-sensitive K+ channels is considered to protect the ischemic myocardium, the partial inhibition of IK.ATP by ET-1 may lead to the aggravation of myocardial injury, potentially due to an increase in transmembrane Ca2+ influx.
Abstract. Some class I antiarrhythmic drugs induce a sporadic hypoglycemia by producing insulin secretion via inhibition of ATP-sensitive K + (K ATP ) channels of pancreatic β-cells. It remains undetermined whether amiodarone produces insulin secretion by inhibiting K ATP channels. In this study, effects of amiodarone on K ATP channels, L-type Ca 2+ channel, membrane potential, and insulin secretion were examined and compared with those of quinidine in a β-cell line (MIN6). Amiodarone as well as quinidine inhibited the openings of the K ATP channel in a concentration-dependent manner without affecting its unitary amplitude in inside-out membrane patches of single MIN6 cells, and the IC 50 values were 0.24 and 4.9 μM, respectively. The L-type Ca 2+ current was also inhibited by amiodarone as well as quinidine in a concentration-dependent manner. Although glibenclamide (0.1 μM) or quinidine (10 μM) significantly potentiated the insulin secretion from MIN6 cells, amiodarone (1 -30 μM) failed to increase insulin secretion. Amiodarone (30 μM) and nifedipine (10 μM) significantly inhibited the increase in insulin secretion produced by 0.1 μM glibenclamide. Amiodarone (30 μM) produced a gradual decrease of the membrane potential, but did not produce repetitive electrical activity in MIN6 cells. Glibenclamide (1 μM) produced a slow depolarization, followed by spiking activity which was inhibited by 30 μM amiodarone. Thus, amiodarone is unlikely to produce hypoglycemia in spite of potent inhibitory action on K ATP channels in insulin-secreting cells, possibly due to its Ca 2+ channel-blocking action.
Effects of alpha 1-adrenoceptor stimulation on the action potential shortening produced by K+ channel openers (KCOs) or hypoxia and on the ATP-sensitive K+ current (IK.ATP) activated by KCOs were examined in guinea-pig ventricular cells by using conventional microelectrode and patch-clamp techniques. In papillary muscles, nicorandil (1 mM) or cromakalim (30 microM) markedly shortened the action potential duration (APD) (to 51 +/- 2% and 40 +/- 5% of each control value). Addition of 100 microM methoxamine, an alpha 1-adrenoceptor agonist, partially but significantly reversed the KCOs-induced APD shortening (to 69 +/- 3% and 50 +/- 4% of each control value). The APD-prolonging effect of methoxamine was antagonized by 1 microM prazosin (alpha 1-antagonist) and 100 nM WB4101 (alpha 1A-antagonist) but not by 10 microM chloroethylclonidine (alpha 1B-antagonist). In papillary muscles exposed to a hypoxic, glucose-free solution, APD declined gradually. In the presence of 100 microM methoxamine or 10 microM glibenclamide, the hypoxia-induced action potential shortening was significantly inhibited. In single ventricular myocytes, the KCOs increased a steady-state outward current that was abolished by glibenclamide (1 microM), thereby suggesting that these KCOs activate IK.ATP. Methoxamine (100 microM) significantly inhibited the nicorandil-induced IK.ATP by 18 +/- 5% and the cromakalim-induced IK.ATP by 16 +/- 2%. 4 beta-Phorbol 12-myristate 13-acetate (100 nM), a protein kinase C activator, failed to mimic the alpha 1-adrenoceptor-mediated inhibition of the nicorandil-induced outward current. Staurosporine (30 nM), a protein kinase C inhibitor, also failed to affect the partial inhibition of IK.ATP by methoxamine. Neither intracellular loading of heparin (100 micrograms/ml), an inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ release inhibitor, nor IP3 (20 microM) plus inositol 1,3,4,5-tetrakisphosphate (IP4 5 microM) could affect the inhibitory action of methoxamine. In conclusion, alpha 1A-adrenergic stimulation partially inhibits IK.ATP in cardiac cells. Neither protein kinase C activation nor IP3 formation appears to be involved in the partial inhibition of IK.ATP. The alpha 1A-adrenoceptor-mediated inhibition of IK.ATP may be deleterious for ischemic myocardium and partly offset the cardioprotective effect of KCOs because attenuation of action potential shortening may potentially increase Ca2+ influx in ischemic cells.
To investigate the means by which doxapram affects the control of ventilation, ventilatory function and P0.1 have been related to serum doxapram concentration during a 45-min infusion of doxapram hydrochloride in 7 healthy, conscious subjects under normoxic conditions. Serum doxapram concentrations increased during the infusion: 1.88, 2.48, 3.42, and 3.97 micrograms/ml after 5, 10, 30 and 45 min, respectively. The majority of significant changes in the measurements from the baseline were observed at 30 and 45 min: VE, VT, P0.1, P0.1/end-tidal CO2 tension, VT/Ti and blood pressure were increased, and end-tidal CO2 tension was decreased. No significant changes in Pdimax, Ti/Ttot, VE/P0.1, and P0.1/(VT/Ti) were observed. A correlation was observed between the % increases in P0.1 and VE and doxapram concentration, and between VE and P0.1. The doxapram-induced increase in VE appears to be caused by increased neural drive. It is related to the serum drug concentration in the conscious subject.
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