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ABSTRACT: The myocardial Na(+)/H(+) exchanger isoform 1 (NHE-1) represents a major H(+) extrusion mechanism for intracellular pH (pH(i)) regulation especially during ischaemia and early reperfusion. Paradoxically, however, its activation contributes to induction of cell injury because Na(+)/H(+) exchange is coupled closely to elevations in intracellular [Ca(2+)] through the Na(+)/Ca(2+) exchanger. NHE-1 is exquisitely sensitive to intracellular acidosis but other factors may have also stimulatory effects via phosphorylation-dependent processes, like autocrine and paracrine agents as well as hormonal factors such as endothelin-1, angiotensin II and alpha-1-adrenoceptor agonists. In addition, phosphorylation-independent NHE-1 activation mechanisms are known, e.g. cell shrinkage. To date at least 8 NHE isoforms have been identified and designated as NHE-1-8. All, except NHE-6 and NHE-7, which are located intracellularly, are restricted to the sarcolemmal membrane. The NHE-1 subtype is the predominant isoform in the heart, but NHE-6 is also expressed in the heart. Newly developed, selective NHE-1 inhibitors possess potent cardioprotective properties. The efficacy of NHE-1 inhibitors in experimental studies with ischaemia/reperfusion has led to clinical trials for the evaluation of these agents in high-risk patients with coronary artery disease (GUARDIAN Trial) and acute myocardial infarction (ESCAMI Trial). The GUARDIAN trial demonstrated only for the coronary artery by-pass graft (CABG) patient population a reduction in the primary cardiovascular endpoint (death and reoccurring myocardial infarction). However, recent evidence also suggests that NHE-1 inhibition may be conducive to attenuation of remodelling processes after myocardial infarction, independently of infarct size reduction and blood pressure. In addition, in separate preclinical studies, the NHE-1 inhibitor cariporide also prevented and/or caused regression of age-related and hypertension-induced myocardial fibrosis and hypertrophy. NHE-1 inhibitors thus offer substantial promise for clinical development for attenuation of both a) acute responses to myocardial injury, b) chronic post-infarct and hypertension- and age-related responses resulting in the development of heart failure.
Archiv für Experimentelle Pathologie und Pharmakologie 11/2003; 368(4):239-46. · 2.65 Impact Factor
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ABSTRACT: The inhibitory effects of the anesthetic barbiturate pentobarbital on the slow ( I(Ks)) and fast component ( I(Kr)) of cardiac delayed rectifier potassium currents ( I(K)) and on the inward rectifier potassium currents ( I(K1)) were examined in Xenopus oocytes expressing the human minK, human ether-á-go-go related gene (HERG) and guinea pig Kir2.2, respectively. Block of native I(K) ( I(Ks) and I(Kr)) and inward rectifier potassium current ( I(K1)) by pentobarbital was examined in guinea pig ventricular myocytes. In oocytes using the two electrode voltage clamp technique potassium currents of hminK-, HERG- and Kir2.2-expressing oocytes were inhibited by pentobarbital with IC50 values of 0.20, 1.58 and 0.54 mM, respectively. I(Ks) block was time- and voltage-independent and had no influence on activation at positive voltages although it shifted voltage-dependent activation to more positive voltages. Pentobarbital-induced HERG inhibition was not dependent on voltage but influenced the deactivation kinetics and shifted half-maximal activation to more negative voltages. In guinea pig cardiomyocytes, using the patch clamp technique, I(Ks) and I(Kr) were inhibited by pentobarbital with IC50 values of 0.18 mM and 2.75 mM, respectively. I(Kr) deactivation and I(Ks) activation kinetics were only slightly influenced by pentobarbital, if at all. Block of I(K1) was weakly voltage-dependent with IC(50) values of 0.26 mM (-40 mV) and 0.91 mM (-120 mV). The data show that pentobarbital suppresses both cloned ( I(K), I(Kir2.2)) and native ( I(K), I(K1)) cardiac potassium currents with the highest affinity for I(Ks).
Archiv für Experimentelle Pathologie und Pharmakologie 02/2002; 365(1):29-37. · 2.65 Impact Factor
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ABSTRACT: The inhibitory effects of the novel Kv1.5 channel blocker, S9947 (2'-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide), on cloned human Kv1.5 (hKv1.5), expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells, and on native cardiac ultrarapid delayed rectifier potassium currents (IKur) in rat (ventricle myocytes) and human (atrial myocytes) were investigated. The influence of S9947 on the action potential was examined in rat ventricular myocytes. Using the two-electrode voltage-clamp technique in Xenopus oocytes and the patch-clamp technique (whole cell configuration) in CHO cells, hKv1.5 was inhibited by S9947 with IC50 values of 0.65 M and 0.42 M, respectively. In addition, inhibition of human Kv4.3 (hKv4.3) and HERG by 10 M S9947 was low (~20%) and absent, respectively. Using the patch-clamp technique in the whole cell configuration, IKur currents in rat ventricular (rIKur) cardiomyocytes and human atrial (hIKur) cardiomyocytes were inhibited by S9947 with IC50 values of 0.96 M and 0.07 M, respectively. In contrast, rat cardiac inward rectifier current (rIK1) and rat (rIto) and human (hIto) cardiac transient outward currents were only inhibited by ~20% with 10 M S9947. In rat cardiomyocytes, using the patch-clamp technique, action potential duration was increased by S9947 in a concentration-dependent (0.3-10 M) and rate-independent manner. The data show that S9947 suppresses both cloned (Kv1.5) and native (IKur) cardiac potassium currents. Furthermore, S9947 prolongs rat action potential in a rate-independent manner.
Archiv für Experimentelle Pathologie und Pharmakologie 10/2001; 364(5):472-478. · 2.65 Impact Factor
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ABSTRACT: Chromanol HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methylmethanesulfonamide], a novel inhibitor of the slow component of the delayed outward current in heart muscle cells (IKs), has been characterized in several in-vitro systems. mRNA encoding for the human protein minK was injected into Xenopus oocytes, leading to the expression of IKs channels. HMR 1556 inhibited this current half-maximally at a concentration of 120 nmol/l (IC50). Expression of the K+ channels Herg, Kv1.5, Kv1.3 and Kir2.1, and also the cationic current HCN2, were blocked little or not at all by 10 mol/l HMR 1556. In isolated ventricular myocytes from the guinea pig the whole-cell patch-clamp method revealed inhibition of the IKs current with an IC50 of 34 nmol/l. Other current components, like IKr and IK1, were only slightly blocked at an HMR 1556 concentration of 10 mol/l, whereas 10 mol/l HMR 1556 inhibited the transient outward current Ito and the sustained outward current Isus in rat ventricular myocytes by 25% and 36%, respectively. The L-type Ca2+ channel in guinea pig cardiomyocytes was blocked by 10 mol/l HMR 1556 by 31%. Guinea pig right papillary muscles were investigated by the micropuncture technique at various pacing rates. In the frequency range of 0.5-7 Hz HMR 1556 (1 mol/l) caused a prolongation of the action potential duration at 90% repolarization (APD90) by 19%-27%. In the presence of isoproterenol (10 mol/l) the prolongation of the APD90 was more pronounced at low pacing rates (47% at 0.5 Hz and 35% at 1 Hz, compared with 25% at 7 Hz). The monophasic action potential was recorded in Langendorff-perfused guinea pig hearts. In spontaneously beating preparations, HMR 1556, at 0.1 mol/l and 1 mol/l, prolonged the MAPD90 by 3% and 10%, respectively, with no further prolongation at 10 mol/l. The prolongation was much greater at low pacing rates [25% at 100 beats per min (bpm) and 13% at 150 bpm] than at fast pacing rates (9% at 350 bpm). The left ventricular pressure LVPmax was not affected at 1 mol/l HMR 1556, but it decreased by 15% at 10 mol/l. Other parameters, like the heart rate and coronary flow, were only slightly decreased at 1 mol/l HMR 1556. In conclusion, HMR 1556 is a potent and selective inhibitor of the IKs current in guinea pig ventricular myocytes. The prolongation of the action potential duration is maintained at fast pacing rates.
Archiv für Experimentelle Pathologie und Pharmakologie 10/2000; 362(6):480-488. · 2.65 Impact Factor
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ABSTRACT: The ISK (also called minK) protein, although it is structurally unrelated to any other ion channel subunit, induces slowly activating, voltage-dependent K+ channels (IminK) in Xenopus oocytes or HEK293 cells. The quaternary structure of the IminK channel complex has long remained a mystery but recent studies suggest an interaction of the ISK protein with a traditional K+ channel subunit, identified in man as KVLQT1. It is unclear at this point what the mechanism of this interaction is, or whether the ISK protein may also interact with other ion channel subunits. However, there is an abundance of information regarding the role and regulation of the ISK protein in the IminK channel complex, discussed in this review by Andreas Busch and Hartmut Suessbrich. The ISK protein is expressed in different tissues, where IminK activation may have distinct net effects on cell function. This fact makes IminK an excellent target for pharmacological agents.
Trends in Pharmacological Sciences.
