1,721,110 research outputs found
Interaction between R 56865 and α-adrenoceptors in the pithed rat
No full textIn pithed normotensive rats, the benzothiazolamine derivative R 56865 in high doses exhibits a competitive antagonism of α1-adrenoceptor-mediated vasoconstrictions. The absence of a depression of the maximum of the dose-response curve of ST 587 and the very moderate attenuation of the maximal B-HT 920-induced increase in diastolic blood pressure (BP) confirms the lack of major calcium entry blocking properties of R 56865 for α-adrenoceptor-activated calcium channels in vitro. In doses up to 10-5mol/kg, the interaction of R 56865 with the sympathetic neurotransmission can solely be explained by α1-adrenoceptor blockade. This was confirmed by the comparable antagonism of the selective α1-adrenoceptor antagonist prazosin in a concentration of 6 x 10-8mol/kg. In contrast to the isolated rat aorta, where R 56865 showed an allosteric interaction with the NA binding site on the α1-adrenoceptor, R 56865 acts like an α1-adrenoceptor antagonist of the competitive type in vivo
The negative inotropic and chronotropic effects of intravenous R 56865 during percutaneous transluminal coronary angioplasty
No full textThe present study was designed to evaluate the potential anti-ischaemic activity of R 56865 in patients with coronary artery disease, scheduled to undergo percutaneous transluminal coronary angioplasty (PTCA). At baseline a complete haemodynamic profile, including cardiac output and coronary sinus blood flow (CSBF) was obtained. In addition, left ventricular pressure and contractility parameters were measured. These parameters were also measured before and after additional balloon inflations, preceded by placebo and R 56865 i.v. R 56865 was infused intravenously at three different dosages, namely: 20 mg (n = 8), 30 mg (n = 2), 40 mg (n = 2). No significant differences were observed between placebo and R 56865 (20 mg) concerning time to onset and duration of ST-segment changes and symptomatic angina pectoris, respectively. The other parameters did not show differences compared with the baseline values when R 56865 (20 and 30 mg) was infused. However, the two patients receiving a dose of 40 mg R 56865 developed a dramatic decrease in systolic and diastolic blood pressure, left ventricular (LV) systolic pressure, peak positive dP/dt and the CSBF (ranging from 30-50%), while the LV end-diastolic pressure increased by 100%. The two patients who received this dose became pale and cyanotic and did not respond to verbal commands. In summary, no anti-ischaemic effects of R 56865 were observed under these conditions, whereas at the highest dose (40 mg) R 56865 induced hypotension and a reduction in cardiac contractile forc
Interaction between R 56865 and α-adrenoceptors in the pithed rat
No full textIn pithed normotensive rats, the benzothiazolamine derivative R 56865 in high doses exhibits a competitive antagonism of α1-adrenoceptor-mediated vasoconstrictions. The absence of a depression of the maximum of the dose-response curve of ST 587 and the very moderate attenuation of the maximal B-HT 920-induced increase in diastolic blood pressure (BP) confirms the lack of major calcium entry blocking properties of R 56865 for α-adrenoceptor-activated calcium channels in vitro. In doses up to 10-5mol/kg, the interaction of R 56865 with the sympathetic neurotransmission can solely be explained by α1-adrenoceptor blockade. This was confirmed by the comparable antagonism of the selective α1-adrenoceptor antagonist prazosin in a concentration of 6 x 10-8mol/kg. In contrast to the isolated rat aorta, where R 56865 showed an allosteric interaction with the NA binding site on the α1-adrenoceptor, R 56865 acts like an α1-adrenoceptor antagonist of the competitive type in vivo
Differential effect of r-56865 on ouabain binding to isolated sarcolemma and intact atrial tissue of guinea-pig
No full text1 R 56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl]-N-methyl-2-benzolamine) is a compound known to antagonize cardiac glycoside intoxication. Therefore, the effect of the compound on ouabain binding to intact cardiac tissue as well as cardiac membrane preparations was investigated. 2 The binding of ouabain to highly purified sarcolemmal membranes was not influenced by R 56865 1 x 10(-6) moll-1 (ouabain: K(D) = 1.3 x 10(-7) moll-1, B(max) = 160 pmol mg-1; ouabain + R 56865: K(D) = 1.4 x 10(-7) moll-1, B(max) = 168 pmol mg-1). 3 In contrast to the results in purified membranes, the binding of ouabain (10(-8) moll-1 to 5 x 10(-7) moll-1) to intact atria was significantly reduced. 4 Ouabain, 5 x 10(-7) moll-1, led to a transient positive inotropic effect of about 220% followed by a developing negative inotropic effect after 3 h. R 56865, 10(-7) moll-1, led to a maximal positive inotropic effect of about 290% also followed by a delayed decline of contractile force. A tenfold higher concentration of R 56865 led to sustained positive inotropic effect of about 250% in the same time interval. 5 The different effects of R 56865 on ouabain binding in subcellular preparations and intact tissue do not support the view that R 56865 interferes directly with the action of ouabain on Na/K-ATPase. An indirect effect, which may be mediated by a lowered intracellular sodium load is discussed
Differential effect of r-56865 on ouabain binding to isolated sarcolemma and intact atrial tissue of guinea-pig
No full text1 R 56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl]-N-methyl-2-benzolamine) is a compound known to antagonize cardiac glycoside intoxication. Therefore, the effect of the compound on ouabain binding to intact cardiac tissue as well as cardiac membrane preparations was investigated.2 The binding of ouabain to highly purified sarcolemmal membranes was not influenced by R 56865 1 x 10(-6) moll-1 (ouabain: K(D) = 1.3 x 10(-7) moll-1, B(max) = 160 pmol mg-1; ouabain + R 56865: K(D) = 1.4 x 10(-7) moll-1, B(max) = 168 pmol mg-1).3 In contrast to the results in purified membranes, the binding of ouabain (10(-8) moll-1 to 5 x 10(-7) moll-1) to intact atria was significantly reduced.4 Ouabain, 5 x 10(-7) moll-1, led to a transient positive inotropic effect of about 220% followed by a developing negative inotropic effect after 3 h. R 56865, 10(-7) moll-1, led to a maximal positive inotropic effect of about 290% also followed by a delayed decline of contractile force. A tenfold higher concentration of R 56865 led to sustained positive inotropic effect of about 250% in the same time interval.5 The different effects of R 56865 on ouabain binding in subcellular preparations and intact tissue do not support the view that R 56865 interferes directly with the action of ouabain on Na/K-ATPase. An indirect effect, which may be mediated by a lowered intracellular sodium load is discussed.</p
Different effects of R 56865 and calcium entry blockers on K+- and noradrenaline-induced contractions and45Ca uptake in rat aorta
No full textThe effects of R 56865, nifedipine, verapamil, diltiazem and flunarizine on K+- and NA-induced contractions and K+-induced45Ca uptake were compared in the isolated rat aorta. The calcium entry blockers concentration dependently inhibited the K+-induced contraction and45Ca uptake over the same dose-range. R 56865 inhibited the K+-induced45Ca uptake, but only partly inhibited the K+-induced contraction. The calcium entry blockers caused a slight rightward shift and a depression of the maximum of the concentration-response curve for the NA-induced contraction. In contrast, R 56865 caused a strong, dose-dependent rightward shift and a depression of the maximum, 10-6and 10-5M being equieffective. The effects of R 56865 and nifedipine were independent of each other. Nevertheless, the NA-induced increase in45Ca uptake, a putative model for Ca influx, was attenuated by R 56865. In conclusion, R 56865 is a weak inhibitor of the K+-induced Ca influx but is without effect on the NA-induced Ca influx. The discrepancy between its effects on K+-induced contractions and45Ca uptake may be explained by an inhibition of the uptake of45Ca from the cytosol into the45Ca pool. The interaction between R 56865 and the α1-adrenoceptor-mediated contractions may be explained by an action at a site that is distinct from the NA-binding-site on the α1-adrenoceptor
Effects of R-56865 on transient inward current, Na(+)-Ca2+ exchange, and Ca2+ release from SR in cardiac myocytes
No full text Voltage-clamp studies were performed on guinea pig ventricular myocytes to clarify the action of N-(1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl)-N-methyl-2-benzothiazo lamine (R-56865), an inhibitor of cardiac glycoside-induced arrhythmias. Transient inward current ((Iti)) was induced using low-K+/high-Ca2+ Tyrode solution. R-56865 (1 mM) was found to abolish I(ti). R-56865 had no influence on the peak Ca2+ current, steady-state current during the clamp, holding current, or the Ni(2+)-sensitive electrogenic Na(+)-Ca2+ exchange current. Fluorescence transients after repolarization (temporally related to the I(ti)) were abolished by R-56865 without affecting the fluorescence transients during depolarization. In separate experiments, the threshold of Ca2+ release from sarcoplasmic reticulum (SR) by the Ca2+ current was found to be unchanged, whereas Ca2+ transients (presumably triggered by Ca2+ entry through the Na(+)-Ca2+ exchanger) were depressed. Our results suggest that R-56865 inhibits spontaneous Ca2+ release from the SR when it is mediated by Ca2+ entry through the Na(+)-Ca2+ exchanger but that it has no direct effect on the well-known “physiological” Ca(2+)-induced Ca(2+)-release mechanism from SR. </jats:p
Flunarizine and R 56865 suppress veratridine-induced increase in oxygen consumption and uptake of45Ca2+in rat cortical synaptosomes
No full textThe effect of the anti-ischemic compounds flunarizine and R 56865 on the veratridine-induced uptake of Ca2+and Na+was observed in cortical synaptosomes in the rat. The veratridine-induced uptake of Na+and Ca2+was determined by means of a measurement of synaptosomal oxygen consumption and a method for the uptake of45Ca2+, respectively. Veratridine (10-5M) was found to induce a 3-fold increase in synaptosomal oxygen consumption (uptake of Na+) and uptake of45Ca2+, both of which were inhibited by tetrodotoxin (10-5M). Nitrendipine (10-5M) and ω-conotoxin (5 x 10-7M) were ineffective on the veratridine-induced response. Nimodipine (10-5M) suppressed the veratridine-induced uptake of45Ca2+but also diminished the unstimulated uptake of45Ca2+. The veratridine-induced uptake of Na+was not influenced by nimodipine. Flunarizine (3 x 10-6-10-5M), as well as R 56865 (10-6-10-5M), attenuated the veratridine-induced uptake of both Na+and45Ca2+. In conclusion, the veratridine-induced uptake of be N+and45Ca2+was shown to be closely correlated to the activity of Na+channels but not to voltage-oporated Ca2+channels. Secondly, flunarizine and R 56865 seemed to evoke their effects by interfering with the permeability of Na+channels. Since veratridine-induced uptake of Na+and Ca2+shares some similarities with ischaemia-induced uptake of Na+and Ca2+, it is proposed, that flunarizine and R 56865 exert their anti-ischaemic effects by reducing ischaemia-induced Na+and Ca2+load, probably by inhibiting a TTX-sensitive Na+channel
Effects of R-56865 on transient inward current, Na<sup>+</sup>-Ca<sup>2+</sup> exchange, and Ca<sup>2+</sup> release from SR in cardiac myocytes
No full text Pages H511–H520: H. Ichikawa, D. J. Hearse, and W. A. Coetzee. “Effects of R-56865 on transient inward current, Na+-Ca2+ exchange, and Ca2+ release from SR in cardiac myocytes.” The concentration of R-56865 should be 1 μM and not 1 mM as stated in the paper. </jats:p
Effects of R-56865 on transient inward current, Na<sup>+</sup>-Ca<sup>2+</sup> exchange, and Ca<sup>2+</sup> release from SR in cardiac myocytes
No full text Pages H511–H520: H. Ichikawa, D. J. Hearse, and W. A. Coetzee. “Effects of R-56865 on transient inward current, Na+-Ca2+ exchange, and Ca2+ release from SR in cardiac myocytes.” The concentration of R-56865 should be 1 μM and not 1 mM as stated in the paper. </jats:p
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