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It has been argued that activation of KATP channels in the sarcolemmal membrane of heart muscle cells during ischemia provides an endogenous cardioprotective mechanism. In order to test whether the novel cardioselective KATP channel blocker HMR 1098 affects cardiac function during ischemia, experiments were performed in rat hearts during ischemia and reperfusion. Isolated perfused working rat hearts were subjected to 30 min of low-flow ischemia in which the coronary flow was reduced to 10% of its control value, followed by 30-min reperfusion. In the first set of experiments the hearts were electrically paced at 5 Hz throughout the entire protocol. At the end of the 30-min ischemic period the aortic flow had fallen to 44±2% (n=8) of its nonischemic value in vehicle-treated hearts, whereas in the presence of 0.3 µmol/l and 3 µmol/l HMR 1098 it had fallen to 29±7% (n=5, not significant) and 8±2% (n=12, P<0.05), respectively. Glibenclamide (3 µmol/l) reduced the aortic flow to 9.5±7% (n=4, P<0.05). In control hearts the QT interval in the electrocardiogram shortened from 63±6 ms to 36±4 ms (n=10, P<0.05) within 4–6 min of low-flow ischemia. This shortening was completely prevented by 3 µmol/l HMR 1098 (60±5 ms before ischemia, 67±6 ms during ischemia, n=9, not significant). When rat hearts were not paced, the heart rate fell spontaneously during ischemia, and HMR 1098 (3 µmol/l) caused only a slight, statistically non-significant reduction in aortic flow during the ischemic period. In order to investigate whether HMR 1098 shows cardiodepressant effects in a more pathophysiological model, the left descending coronary artery was occluded for 30 min followed by reperfusion for 60 min in anesthetized rats. Treatment with HMR 1098 (10 mg/kg i.v.) had no statistically significant effects on mean arterial blood pressure and heart rate during the control, ischemia and reperfusion periods. At the end of the reperfusion period, aortic blood flow was slightly reduced by HMR 1098, without reaching statistical significance (two-way analysis of ANOVA, P=0.15). Myocardial infarct size as a percentage of area at risk was not affected by HMR 1098 (vehicle: 75±3%, HMR 1098: 72±2%, n=7 in each group). In conclusion, cardiodepressant effects of HMR 1098 were observed only in isolated perfused working rat hearts which were continuously paced during global low-flow ischemia. In the model of anesthetized rats subjected to regional ischemia, HMR 1098 had no significant effect on cardiac function or infarct size. [ABSTRACT FROM AUTHOR]

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 µmol/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 µmol/l, whereas 10 µmol/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 µmol/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 µmol/l) caused a prolongation of the action potential duration at 90% repolarization (APD90) by 19%–27%. In the presence of isoproterenol (10 µmol/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 µmol/l and 1 µmol/l, prolonged the MAPD90 by 3% and 10%, respectively, with no further prolongation at 10 µmol/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 µmol/l HMR 1556, but it decreased by 15% at 10 µmol/l. Other parameters, like the heart rate and coronary flow, were only slightly decreased at 1 µmol/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. [ABSTRACT FROM AUTHOR]

Objective: The aim was to characterise the new compound HOE642 as a selective and cardioprotective Na+/H+ exchange inhibitor in various models. Methods: The effect of HOE642 was tested in the osmotically activated Na+/H+ exchange of rabbit erythrocytes and in propionate induced swelling of human thrombocytes. Recovery of pH after an NH4Cl prepulse and effects on other ion transport systems by patch clamp technique were investigated in rat cardiomyocytes, NHE subtype specifity of the compound was determined by 22Na+ uptake inhibition in a fibroblast cell line separately expressing subtype isoforms 1–3. Protective effects of HOE642 in cardiac ischaemia and reperfusion by ligation of coronary artery were investigated in isolated working rat hearts and in anaesthetised rats. Results: HOE642 concentration dependently inhibited the amiloride sensitive sodium influx in rabbit erythrocytes, reduced the swelling of human platelets induced by intracellular acidification, and delayed pH recovery in rat cardiomyocytes. In the isolated working rat heart subjected to ischaemia and reperfusion HOE642 dose dependently reduced the the incidence and the duration of reperfusion arrhythmias. It also reduced the the release of lactate dehydrogenase and creatine kinase, and preserved the tissue content of glycogen, ATP, and creatine phosphate. In anaesthetised rats undergoing coronary artery ligation intravenous and oral pretreatment with HOE642 caused a dose dependent reduction or a complete prevention of ventricular premature beats, ventricular tachycardia, and ventricular fibrillation. The compound was well tolerated and neutral to circulatory variables. Other cardiovascular agents tested in this model were not, or were only partly, effective at doses showing marked cardiodepressive effects. Conclusions: HOE642 is a very selective NHE subtype 1 inhibitor showing cardioprotective and antiarrhythmic effects in ischaemic and reperfused hearts. Further development of well tolerated compounds like HOE642 could lead to a new therapeutic approach in clinical indications related to cardiac ischaemia and reperfusion. [ABSTRACT FROM PUBLISHER]

Current noise power spectra of the voltage-channel (V = 0) Necturus gallbladder, exposed to NaCl-Ringer's on both sides contained a relaxation noise component, which overlapped with a 1/f alpha noise component, with alpha being about 2. Substitution of all Na+ by K+ on either the serosal or mucosal side increased the relaxation as well as the 1/f alpha noise component considerably. In Necturus gallbladder both noise components are reduced by addition of 10 mM, 2,4,6-triaminopyrimidine (TAP) or 5 mM BA2+ to the mucosal side, as well as by acidification of the mucosal solution to pH 5 and lower. Five mM of tetraethylammonium (TEA+) added to the mucosal solution, abolished K+ relaxation noise and decreased the 1/f alpha noise component. Applying a Cs+ concentration gradient across the epithelium did not yield relaxation noise. However, if Rb+ was substituted for all Na+ on one side, a Lorentzian noise component appeared in the spectrum. Its plateau was smaller than with KCl-Ringer's on the respective side. These data confirm the existence of fluctuating K+ channels in the apical membrane of the Necturus gallbladder. Furthermore it can be concluded that these channels have the permeability sequence K+ greater than Rb+ greater than Cs+. The inhibition of the fluctuations by mucosal acidification indicates the existence of acidic sites in the channel. The single-channel conductance was estimated to be between 6.5 and 40 pS. [ABSTRACT FROM AUTHOR]

Transepithelial current fluctuations were recorded in Necturus gallbladder, clamped at negative as well as positive potentials up to 64 mV. With NaCl-Ringer's (+10 mm TAP) on both sides a mucosa-negative potential enhanced the relaxation noise component, present at zero potential, and produced peaking in the power spectrum at potentials above −36mV. Concomitantly at these potentials an inductive as well as a capacitive low-frequency feature appeared in the impedance locus. Clamping at positive potentials of 18 mV suppressed the relaxation noise component. At potentials above 51mV the spectral values increased predominantly at low frequencies. In this case the power spectrum showed only a 1/ f noise component. The experiments confirm the previous finding that a K efflux through fluctuating apical K channels exists under normal conditions. With serosal KCl-Ringer's the initial Lorentzian component was enhanced at negative but suppressed at positive potentials. The increase at negative potentials was less pronounced than in experiments with NaCl-Ringer's on both sides, indicating saturation of the fluctuating K current component. With mucosal KCl-Ringer's a negative potential depressed the initial relaxation noise component, whereas it was enhanced at +18 mV clamp potential. In the latter case an additional Lorentzian component became apparent at higher frequencies. At potentials of 36 mV and above the low-frequency Lorentzian disappeared whereas the corner frequency of the high-frequency component increased. The latter experiments demonstrate that the relaxation noise component in Necturus gallbladder consists of two superimposed Lorentzians. As the relaxation times of these two components behave differently under an electrical field, there may exist two different types of K channels. It is demonstrated that peaking in the plateau of power spectra can be explained by frequency-dependent attenuation effects, caused by a polarization impedance. [ABSTRACT FROM AUTHOR]

The present study examines the influences of pH and Ca and several putative inhibitors on the basolateral K channel of the rectal gland of Squalus acanthias. Excised membrane patches were examined using the patch clamp technique. It is shown that reduction of the calcium activity on the cytosolic side to less than 10 mol/l has no detectable inhibitory effect on this channel. Conversely, increase in calcium activity to some 10 mol/l reduced the activity of this channel. Variations in cytosolic pH had only a moderate effect on the current amplitude: alkalosis by one pH unit increased and acidosis reduced the single current amplitude by some 15%. Several inhibitors were tested in excised patches when added to the cytosolic side. Ba (≈5·10 mol/l), quinine (≈10 mol/l), quinidine (≈10 mol/l), lidocaine (≈1 mmol/l), tetraethylammonium (≈10 mmol/l), Cs (≈10 mmol/l), and Rb (≈20 mmol/l) all blocked this K channel reversibly. We conclude that the basolateral K channel of the rectal gland is distinct from other epithelial K channels inasmuch as it is not stimulated by Ca directly, but that it is qualitatively similar to many other known K channels with respect to its sensitivity towards blockers. [ABSTRACT FROM AUTHOR]