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Publications (3)8.74 Total impact

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    ABSTRACT: We tested the hypothesis, that ATP-sensitive potassium (K(ATP)) channels limit cardiac energy demand by a feedback control of mean power output at increased cardiac rates. We analysed the interrelationships between rising energy demand of adult rat and guinea pig left ventricular papillary muscle and down-regulatory electromechanical effects mediated by K(ATP) channels. Using the K(ATP)-opener pinacidil the stimulation frequency was increased stepwise and the mechanical parameters and action potentials were recorded. Power output was derived from force-length area or force-time integral calculations, respectively. Simultaneously oxygen availability in the preparations was estimated by flavoprotein fluorescence measurements. ADP/ATP ratios were determined by HPLC. We found highly linear relationships between isotonic power output and the effects of pinacidil on isotonic shortening in both rat (r(2)=0.993) and guinea pig muscles (r(2)=0.997). These effects were solely observed for the descending limb of shortening-frequency relationships. In addition, a highly linear correlation between total force-time integral-derived power and pinacidil effects on action potential duration (APD(50), r(2)=0.92) was revealed. Power output became constant and frequency-independent in the presence of pinacidil at higher frequencies. In contrast, the K(ATP)-blocker glibenclamide produced a lengthening of APD(50) and increased force transiently at higher power levels. Pinacidil prevented core hypoxia and a change in ADP/ATP ratio during high frequency stimulation. We conclude, that pinacidil-primed cardiac K(ATP) channels homeostatically control power output during periods of high energy demand. This effect is associated with a reduced development of hypoxic areas inside the heart muscle by adapting cardiac function to a limited energy supply.
    European journal of pharmacology 11/2009; 628(1-3):116-27. · 2.59 Impact Factor
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    ABSTRACT: Blood stasis is one of the key risk factors in deep vein thrombosis. Localized blood oxygen and glucose depletion are main characteristics observed during stasis. However, the causal chain leading to clot formation is still obscure. According to our hypothesis, energy depletion causes opening of K(ATP) channels present on monocytes, facilitating influx of calcium and triggering tissue factor-(TF)-dependent procoagulatory activity and eventually clot formation. Using Reverse-Transcript-PCR (RT-PCR) in magnetically enriched human monocytes, mRNA transcription of the K(ATP)-channel subunits Kir6.1 and Kir6.2 could be confirmed. Membrane potential and cytosolic calcium were recorded by time-resolved flow cytometry. The specific K(ATP)-channel opener pinacidil caused a glibenclamide-sensitive hyperpolarization of monocytes and a prolongation of cytosolic calcium transients triggered by purinergic stimulation. TF-initiated whole blood clotting time (TiFaCT) was accelerated comparing 2 and 8 h of simulated in vitro blood stasis using blood of male healthy volunteers. Both with and without activation of the monocytes with 100 ng/ml LPS, the K(ATP)-channel blocker glibenclamide resulted in a significantly (p<0.001) prolonged clotting time after 8 h of stasis compared to vehicle control and LPS, respectively. In the course of stasis, flow cytometry showed an increase in monocytes expressing TF (0.1% and 1.3% after 2 and 8 h, respectively). LPS (100 ng/ml) increased the amount of TF expression significantly to 36%, whereas 30 microM glibenclamide partly reversed this increase down to 24%. Phosphatidylserine-exposure (PSE) on monocytes increased strongly during stasis by 11.2 times, a process which glibenclamide attenuated by 23%. LPS increased PSE further by 65%, which glibenclamide reduced by 50%. In conclusion, presence of integral subunits of K(ATP)-channels is demonstrated in human monocytes. These channels are able to enhance Ca(2+)-dependent intracellular signalling and can increase TF-activity and phosphatidylserine exposure thereby accelerating clot formation during stasis by monocytes.
    Life Sciences 03/2007; 80(11):989-98. · 2.30 Impact Factor
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    ABSTRACT: In this study, we tested a series of 12 previously identified, highly effective propafenone-type multidrug resistance (MDR) modulators for their possible undesirable effects on cardiac tissue. We used rat papillary muscle preparations and quantitatively determined the potency of these substances to block action potential (AP) upstroke velocity (Vmax) and to prolong APD50. Simultaneously, the effects on isometric twitch parameters were evaluated. Concentration-response curves were obtained for all parameters. Within a subset of the compounds, we found a significant rank correlation (r' = 0.87; p < 0.05) between potencies to block Vmax (kiVmax) and to inhibit daunomycin efflux in MDR cells (IC50). Surprisingly, the most lipophilic compounds with additional aromatic side chains completely lacked effects on AP and mechanical twitch parameters, although they are the most effective MDR modulators. Additional structural modifications such as fluoride substitution of the aromatic ring, introduction of arylpiperazine or piperidine side chains, as well as modifying the hydrogen bond acceptor strength of the carbonyl group did not reestablish cardiac side effects. In contrast, when these substances were truncated at the phenylpropiophenone moiety of the propafenone core structure, cardiac effects reoccurred. We conclude that aromatic substituents in the vicinity of the nitrogen atom prevent interaction with ion channels, likely due to steric hindrance, and are thus a prerequisite for eliminating unwanted cardiac effects.
    Journal of Pharmacology and Experimental Therapeutics 12/2003; 307(2):589-96. · 3.86 Impact Factor