showing 17 related works from this author
Failure of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) to inhibit soluble guanylyl cyclase in rat ventricular cardiomyocytes
1999
The effects of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase (sGC), were investigated in aortic rings and ventricular cardiomyocytes from rats. The production of cyclic GMP was stimulated by NO•-donors or carbachol. Additionally, the effects of ODQ were studied in cytosolic extracts from both tissues in which the cyclic GMP production was stimulated by S-nitroso-N-acetylpenicillamine (SNAP). In endothelium-intact aortic rings, SNAP (100 μM), 2,2′-(hydroxynitrosohydrazino)bis-ethanamine (DETA NONOate; 100 μM), or carbachol (10 μM) increased cyclic GMP levels about 4 fold. These effects were abolished by ODQ (50 μM). In cardiomyocytes, SNAP (100 μ…
cGMP-Dependent Protein Kinase I Mediates the Negative Inotropic Effect of cGMP in the Murine Myocardium
2002
To study the role of cGMP-dependent protein kinase I (cGKI) for cardiac contractility, force of contraction (F c ) was studied in electrically driven heart muscle from wild-type (WT) mice and from conventional and conditional cGKI knockout mice. Both 8-Br-cGMP and 8-pCPT-cGMP reduced Fc in cardiac muscle from juvenile WT but not from juvenile cGKI-null mutants. Similarly, the cGMP analogues reduced F c in forskolin-stimulated ventricular muscle from WT mice but not from cGKI-null mutants. In contrast, carbachol reduced F c in both groups of animals. 8-Br-cGMP reduced F c also in heart muscle from adult WT mice but not from adult cardiomyocyte-specific cGKI-knockout mice. These results demo…
Cardiac effects of isoliquiritigenin
1997
The effects of isoliquiritigenin on force of contraction (Fc), L-type Ca2+ current (I(Ca)) and intracellular Ca2+ concentration ([Ca2+]i) were investigated in rat ventricular heart muscle. Isoliquiritigenin increased Fc and I(Ca) and, after longer exposure times, resting tension and [Ca2+]i. The effect of isoliquiritigenin (100 microM) on I(Ca) was diminished by Rp-cAMPS (30 microM). 1H-[1,2,4]oxa- diazolo[4,3-a]quinoxalin-1-one (50 microM) did not influence the effects of isoliquiritigenin on Fc and I(Ca). The positive inotropic effects of isoprenaline and forskolin, but not of 3-isobutyl-1-methylxanthine, were potentiated by isoliquiritigenin (100 microM). In the presence of milrinone (10…
Activation of soluble guanylyl cyclase by YC-1 in aortic smooth muscle but not in ventricular myocardium from rat
1997
1 The effects of YC-1 (3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole), an activator of soluble guanylyl cyclase, on tension, levels of cyclic GMP and cyclic AMP, and cardiac L-type Ca2+-current (ICa(L)) were investigated in aortic smooth muscle and ventricular heart muscle from rat. 2 YC-1 (0.1–30 μM) induced a concentration-dependent relaxation in aortic rings precontracted with phenylephrine (3 μM). The relaxant effects of YC-1 were reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (30 μM; ODQ), potentiated by zaprinast (10 μM) and antagonized by Rp-8-Br-cGMPS (100 μM). 3 In ventricular heart muscle strips, YC-1 (30 μM) exhibited no effects on force of contraction (Fc) in the abse…
Kinetics and state-dependent effects of verapamil on cardiac L-type calcium channels.
1996
The voltage dependence and the kinetics of block by verapamil of L-type calcium current (ICa) were investigated in ventricular myocytes from rat hearts using the whole-cell patch-clamp technique. ICa was elicited repetitively in response to depolarizing voltage pulses from -80 mV to 0 mV at different pulse intervals and durations. Verapamil reduced the magnitude of ICa in a frequency-dependent manner without tonic component. The time course of ICa remained unchanged suggesting that not open but inactivated channels were affected by the drug. The interaction of verapamil with inactivated channels was investigated by the application of twin pulses. In the presence of verapamil, the duration o…
Differences in the nitric oxide/soluble guanylyl cyclase signalling pathway in the myocardium of neonatal and adult rats
2000
Abstract The effects of a nitric oxide-donor, S -nitroso- N -acetylpenicillamine, and a direct activator of soluble guanylyl cyclase, 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1), on force of contraction ( F c ) and L-type Ca 2+ currents ( I Ca(L) ) were investigated in myocardial preparations from neonatal and adult rats. Since hearts from adult and neonatal animals contained 160 and 47 mg/100 g wet weight myoglobin, respectively, its possible interaction with both drugs was also investigated. Both S -nitroso- N -acetylpenicillamine (100 μM) and YC-1 (30 μM) were ineffective in myocardial preparations from adult rats but reduced the magnitude of I Ca(L) and F c in preparations fr…
Extracellular site of action of phenylalkylamines on L-type calcium current in rat ventricular myocytes.
1995
The effects of the phenylalkylamines verapamil, gallopamil, and devapamil on L-type calcium currents (ICa) were studied in ventricular myocytes from rat hearts using the whole-cell patch-clamp technique. In particular, the question was addressed, whether the pharmacological binding sites for these drugs were located at the inner and/or at the outer surface of the cell membrane. Therefore, tertiary verapamil, gallopamil, and devapamil and their corresponding quaternary derivatives were applied either from the outside or the inside of the cell membrane. Extracellular application of verapamil, gallopamil and devapamil (each at 3 microM) reduced ICa to 16.1 +/- 8.6%, 11 +/- 8.9%, and 9.3 +/- 6%…
Differential effects of isoliquiritigenin and YC-1 in rat aortic smooth muscle.
1997
We investigated the effects of isoliquiritigenin and YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole) on tension in endothelial-free rat aortic rings precontracted with phenylephrine (3 microM). Both compounds induced a concentration-dependent relaxation (EC50 of YC-1 1.9 microM and of isoliquiritigenin 9.4 microM). The effects developed faster with YC-1 than with isoliquiritigenin, and the effects of YC-1 were potentiated by isoliquiritigenin (10 microM). 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (30 microM) inhibited the effect of YC-1, but not of isoliquiritigenin. These results suggest that the effects of YC-1 are due to stimulation of soluble guanylyl cyclase activity, whereas …
Inhibition by Fendiline of the Transient Outward Current in Rat Ventricular Cardiomyocytes
1999
The effects of fendiline on the transient outward current (Ito) were investigated in rat ventricular cardiomyocytes. Extracellularly applied fendiline reduced peak and steady-state current amplitude of Ito; the inactivation of Ito was accelerated by the drug, which reflects onset of block. The described effects were concentration dependent: half-maximal effects were achieved at approximately 3 microM fendiline. Intracellularly applied fendiline (3 microM) did not affect Ito within 5 min. The steady-state current amplitude of Ito was more efficiently suppressed by the drug at 22 +/- 1 degrees C than at 36 +/- 1 degrees C. The recovery of Ito was analyzed by the application of twin depolarizi…
Involvement of K+ channels in the relaxant effects of YC-1 in vascular smooth muscle
1999
This study addresses the question whether K(+) channels are involved in the vasorelaxant effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl-indazole (YC-1 ). In rat aorta, guinea pig aorta, and guinea pig a. carotis, YC-1 inhibited contractions induced by phenylephrine (3 microM) more potently than those induced by K(+)(48 mM). In rat aorta, tetraethylammonium (10 mM), charybdotoxin (0.2 microM), and iberiotoxin (0.1 microM), but not glibenclamide (10 microM), attenuated the relaxant effects of YC-1. In guinea pig a. carotis, YC-1 (30 microM) induced a hyperpolarisation which was antagonised by 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ; 50 microM). In rat aorta, YC-1 (30 microM) incr…
Effects of nitric oxide donors on cardiac contractility in wild-type and myoglobin-deficient mice
2002
1. The effects of the nitric oxide (NO) donors S-nitroso-N-acetylpenicillamine (SNAP), sodium(Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate), and (Z)-1-[N-(2-Aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate) on force of contraction (F(c)) were studied in atrial and ventricular muscle strips obtained from wild-type (WT) and myoglobin-deficient (myo(-/-)) mice. 2. SNAP slightly reduced F(c) in preparations from WT mice at concentrations above 100 microM; this effect was more pronounced in myo(-/-) mice. 3. DEA-NONOate reduced F(c) in preparations from myo(-/-) mice to a larger extent than those from WT mice. 4. DETA-NONOate reduced F(c) in preparations…
Barnidipine block of L-type Ca2+ channel currents in rat ventricular cardiomyocytes
2000
The effects of barnidipine and nifedipine on L-type Ca2+ current (ICa(L)) were investigated in ventricular cardiomyocytes from rats. Both barnidipine and nifedipine reduced ICa(L) in a concentration and voltage dependent manner; the EC50 were 80 and 130 nM at a holding potential of −80 mV, respectively, and 18 and 6 nM at −40 mV, respectively. Both drugs induced a leftward shift of the steady-state inactivation curve of ICa(L). Using a twin pulse protocol, the relationships between the amount of block of ICa(L) by either drug, seen during the second pulse, and the length of the first pulse were described by monoexponential functions reflecting onset of block, dependent on drug concentration…
Voltage dependence of L-arginine transport by hCAT-2A and hCAT-2B expressed in oocytes from Xenopus laevis.
2000
Membrane potential and currents were investigated with the two-electrode voltage-clamp technique in Xenopus laevisoocytes expressing hCAT-2A or hCAT-2B, the splice variants of the human cationic amino acid transporter hCAT-2. Both hCAT-2A- and hCAT-2B-expressing oocytes exhibited a negative extracellularl-arginine concentration ([l-Arg]o)-sensitive membrane potential, additive to the K+diffusion potential, when cells were incubated in Leibovitz medium (containing 1.45 mM l-Arg and 0.25 mM l-lysine). The two carrier proteins produced inward and outward currents, which were dependent on the l-Arg gradient and membrane potential. Ion substitution experiments showed that the hCAT-induced curren…
Mechanism of Block by 4-Aminopyridine of the Transient Outward Current in Rat Ventricular Cardiomyocytes
1998
The effects of 4-aminopyridine (4-AP) on the transient outward current (I to ) were investigated in rat ventricular cardiomyocytes at different values of intracellular pH (pH i ) and extracellular pH (pH o ). The 4-AP was administered either extracellularly (bath application) or intracellularly (diffusion from the intrapipette solution). The 4-AP diminished I to given either from inside or outside the cell membrane. The block by extracellularly applied 4-AP (4-AP o ) of the peak amplitude of I to was decreased by external acidification but increased by external alkalinization: conversely. the block by 4-AP o was decreased by internal alkalinization but increased by internal acidification. I…
Effects of Quinine and Quinidine on the Transient Outward and on the L-Type Ca<sup>2+</sup> Current in Rat Ventricular Cardiomyocytes
2002
The effects of the enantiomers quinine and quinidine on the transient outward current (I<sub>to</sub>) and on the L-type Ca<sup>2+</sup> current (I<sub>Ca</sub>) were investigated in rat ventricular cardiomyocytes using the patch-clamp technique. At a stimulation frequency of 2 Hz, both quinine and quinidine depressed the magnitude of I<sub>to</sub> and I<sub>Ca</sub>; the half-maximal effects on I<sub>to</sub> were achieved at 11 and 15 µmol/l, respectively, and those on I<sub>Ca</sub> at 14 and 10 µmol/l, respectively. At 0.2 Hz, both drugs depressed the magnitude of I<sub>to</sub>, but not tha…
Voltage-Dependent Effects of Barnidipine in Rat Vascular Smooth Muscle
2003
The effects of the dihydropyridine nifedipine and its more lipophilic congener, barnidipine, were investigated in smooth muscle preparations from the rat in resting and depolarizing conditions. Both drugs relaxed precontracted aortic rings more potently in depolarizing conditions, barnidipine being more potent than nifedipine. Currents through Ca 2+ channels in rat vascular smooth muscle cells (A7r5) and in isolated rat cardiomyocytes were reduced more potently by both drugs at a holding potential of-40 mV than at -80 mV. However, barnidipine and nifedipine were more effective in reducing the current in A7r5 cells than in cardiomyocytes. The IC 50 obtained in aortic rings and in A7r5 cells …
Action of tertiary phenylalkylamines on cardiac transient outward current from outside the cell membrane.
1996
The effects of the phenylalkylamines verapamil (V), gallopamil (G), and devapamil (D) and their corresponding quaternary derivatives on the transient outward current (Ito) were examined in rat ventricular cardiomyocytes using the whole-cell patch-clamp technique. The question was addressed, whether phenylalkylamines act on Ito from the inside or the outside or from both sides of the cell membrane. To this end, the myocytes were either superfused extracellularly or perfused intracellularly with drug-containing solutions. In addition, the effects of verapamil were investigated at different pH-values. V, G, and D (30 microM each), applied extracellularly, reduced the steady state current of It…