SR 48692, a non-peptide neurotensin receptor antagonist, blocks the cardiovascular effects elicited by neurotensin in guinea pigs.

In guinea pigs anaesthetized with sodium pentobarbital, SR 48692, a non peptide neurotensin receptor antagonist blunted the blood pressure increase induced by exogenous neurotensin in a dose dependent manner. Furthermore, in isolated spontaneously beating guinea pig atria, both the tachycardia and inotropic responses induced by neurotensin were potently antagonized. SR 48692 did not show any intrinsic effect in vivo or in vitro.

Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors.

SR 49059, a new potent and selective orally active, nonpeptide vasopressin (AVP) antagonist has been characterized in several in vitro and in vivo models. SR 49059 showed high affinity for V1a receptors from rat liver (Ki = 1.6 +/- 0.2) and human platelets, adrenals, and myometrium (Ki ranging from 1.1 to 6.3 nM). The previously described nonpeptide V1 antagonist, OPC-21268, was almost inactive in human tissues at concentrations up to 100 microM. SR 49059 exhibited much lower affinity (two orders of magnitude or more) for AVP V2 (bovine and human), V1b (human), and oxytocin (rat and human) receptors and had no measurable affinity for a great number of other receptors. In vitro, AVP-induced contraction of rat caudal artery was competitively antagonized by SR 49059 (pA2 = 9.42). Furthermore, SR 49059 inhibited AVP-induced human platelet aggregation with an IC50 value of 3.7 +/- 0.4 nM, while OPC-21268 was inactive up to 20 microM. In vivo, SR 49059 inhibited the pressor response to exogenous AVP in pithed rats (intravenous) and in conscious normotensive rats (intravenous and per os) with a long duration of action (> 8 h at 10 mg/kg p.o). In all the biological assays used, SR 49059 was devoid of any intrinsic agonistic activity. Thus, SR 49059 is the most potent and selective nonpeptide AVP V1a antagonist described so far, with marked affinity, selectivity, and efficacy toward both animal and human receptors. With this original profile, SR 49059 constitutes a powerful tool for exploring the therapeutical usefulness of a selective V1a antagonist.

Pharmacological characterization of SR 47436, a new nonpeptide AT1 subtype angiotensin II receptor antagonist.

SR 47436, 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, is a new potent and selective AT1 angiotensin II (AII) receptor antagonist. It competitively inhibited [125I]AII binding to AT1 subtype receptors in rat liver membranes (IC50 = 1.7 nM) and did not interact with AT2 subtypes in rat adrenal cortical membranes. In rabbit aorta, SR 47436 inhibited contractions induced by 10 nM AII (IC50 = 4.0 nM) and shifted AII contractile response curves to the right in a parallel fashion, without total recovery of the maximal response. The potency of SR 47436 was higher than that of the lead compound, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole (DuP 753) (rat liver binding: IC50 = 16 nM; rabbit aorta: IC50 = 26 nM), and equivalent to saralasin (IC50 = 1.8 and 2.7 nM, respectively). The high specificity of SR 47436 was demonstrated by its lack of activity (IC50 > 10 microM) on various other receptors, ionic channels and antiports and rabbit aorta contracted by norepinephrine and KCl, and its lack of inhibition of renin and converting enzyme. In conscious rats, SR 47436 as well as DuP 753 (0.1 to 3 mg/kg, i.v., and 0.3 to 30 mg/kg, p.o.) antagonized the AII-pressor response in a dose-related manner. In conscious dogs, SR 47436 (1-10 mg/kg, p.o.) was a more potent antagonist of the AII pressor response than DuP 753. In conscious chronically implanted cynomolgus monkeys, SR 47436 antagonized the AII-pressor response at 1 mg/kg (89% i.v. and 66% p.o.) much more strongly than DuP 753 at 10 mg/kg (83% i.v. and 20% p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of SR 44866, a potassium channel opener, on action potentials of rabbit, guinea pig, and human heart fibers.

The effects of various concentrations (3 x 10(-8) - 1 x 10(-5) M) of SR 44866, a K+ channel opener, on action potential (AP) characteristics were investigated in isolated rabbit sinoatrial node (SAN), rabbit Purkinje fibers, guinea pig ventricle, human atrium, and human papillary muscle. SR 44866 (up to 1 x 10(-5) M), like cromakalim and pinacidil, did not modify SAN AP and automaticity of the rabbit heart. In atrial, Purkinje and ventricular fibers of animal and human hearts, SR 44866 did not significantly change membrane resting potential, AP amplitude, or maximum rate of phase 0 (dV/dtmax). The main AP modifications induced by SR 44866 were concentration-dependent reductions in plateau amplitude and AP duration (APD): IC50 2 x 10(-7), 7 x 10(-7), 1.4 x 10(-6), 2.5 x 10(-6), and much greater than 10(-5) M for human atrium, human ventricle, guinea pig ventricle, rabbit Purkinje, and rabbit atrium, respectively. In isolated guinea pig heart, SR 44866 induced decreases in contractions (IC50 1.7 x 10(-6) M) and coronary perfusion pressure (CPP) (IC50 2.1 x 10(-8) M) with a very slight reduction (5% at 1 x 10(-6) M) in spontaneous heart rate (HR). Negative inotropic effect (guinea pig) and APD shortenings (guinea pigs and humans) of SR 44866 (1 x 10(-6) and 3.10(-6) M) were antagonized by glibenclamide (3 x 10(-7) to 3 x 10(-6) M), a specific blocker of cardiac K+ATP channels. The data support the hypothesis that SR 44866 activates ATP-sensitive K+ channels, which are present in the atria and ventricles of the human heart but not in pacemaker cells of rabbit SAN.

Effects of activation of ATP-sensitive K+ channels in mammalian ventricular myocytes.

A cromakalim analogue, SR 44866, is shown to open ATP-sensitive K+ channels in ventricular myocytes. The channels opened by SR 44866 were closed by internal ATP and had the same current-voltage relationship as ATP-sensitive K+ channels; channels closed by ATP could be opened by SR 44866. SR 44866 was effective when applied to either side of excised membrane patches and when included in the pipette during cell-attached membrane recordings. SR 44866 also opened channels in cell-attached membrane patches when it was applied to the cell membrane outside of the pipette. The current evoked by SR 44866 in whole cell recordings was inhibited by tolbutamide. SR 44866 reduced the duration of action potentials and the amplitude and duration of evoked muscle contractions in guinea pig papillary muscle, with dissociation constants of 6.8 microM at 24 degrees C and 1.9 microM at 34 degrees C and Hill coefficients of 1.72 and 1.71, respectively. We conclude that the opening of ATP-sensitive K+ channels has profound inhibitory effects on the electrical and mechanical activity of cardiac muscle.

Electrophysiological effects of penticainide (CM 7857) in isolated human atrial and ventricular fibers.

The intracellular electrophysiological properties of a new antiarrhythmic agent, penticainide (5 x 10(-6) to 5 x 10(-5) M) were studied in isolated driven human right atrial appendage and papillary muscle superfused with oxygenated Tyrode's solution. In atrial fibers, penticainide decreased the amplitude, maximum rate of rise (dV/dtmax), plateau amplitude, and duration (APD) of action potentials (AP). In ventricular fibers, the main AP modification induced by penticainide was a dV/dtmax diminution. All those effects were frequency and concentration dependent. Penticainide decreased resting potential at 5 x 10(-5) M only. Ventricular APD variations were relatively weak: in most of the cases, 5 x 10(-6) M decreased APD and 5 x 10(-5) M shortened long APD (greater than 300 ms) and lengthened short APD (less than 300 ms). The class I antiarrhythmic property (dV/dtmax decrease) of penticainide was rate dependent in both human fibers and was obtained at lower drug concentrations than those used in other species. The relatively rapid rate of onset and the rather slow recovery kinetics of dV/dtmax block suggest a common mechanism of action of penticainide on sodium channels in human heart and others mammals.

Electrophysiological studies of penticainide (CM 7857), a new antiarrhythmic agent, in mammalian myocardium.

The intracellular electrophysiologic properties of a new antiarrhythmic substance, penticainide, were studied in isolated rabbit, dog, and guinea pig myocardial preparations superfused or perfused with oxygenated Tyrode's solution. "Therapeutic" concentrations of penticainide (1.5 to 3 X 10(-5) M) had little effect on sinus node automaticity; sinoatrial conduction was slightly delayed. In atrial, Purkinje and ventricular fibers, amplitude, and maximal rate of rise of phase O (dV/dtmax) were decreased by penticainide; Purkinje-ventricle conduction velocity was depressed. Penticainide did not significantly modify action potential duration (APD) of rabbit atria and dog ventricle and reduced APD and effective refractory period (ERP) of dog Purkinje and guinea pig ventricular fibers. Penticainide reduced APD heterogeneity of Purkinje-ventricle junction with a preferential effect at the gate and decreased tension amplitude of perfused papillary muscle in dog heart. The effect of penticainide on dV/dtmax was voltage and rate dependent; the resting block was weak. Thus, penticainide is a class 1 antiarrhythmic agent with properties of class 1B agents such as APD reduction and properties of class 1C agents such as slow recovery kinetic of rate-dependent block.

Electrophysiological effects of diclofurime on rabbit and frog atrial heart muscle.

The effects of diclofurime on the electrical activity of the rabbit sinus node, rabbit atria and frog atrial fibres were studied using microelectrode and the double sucrose gap voltage-clamp techniques respectively. In rabbit sinus node, diclofurime (10(-7) M to 10(-6) M) decreased the action potential (AP) amplitude and maximum rate of depolarization (Vmax), increased the AP duration and slowed the sinus rate. In rabbit atria, the drug reduced the amplitude of the depolarizing phase and Vmax, lengthened the AP duration and decreased the resting membrane potential. In frog atrial fibres, the drug (10(-5) M) depolarized the resting membrane potential, decreased Vmax as well as the plateau amplitude. It inhibited the sodium current (INa) with a dissociation constant of 3.7 X 10(-6) M and a one to one relationship between the drug molecule and the Na channel. Diclofurime did not alter the apparent reversal potential for the fast Na current (ENa) but it inhibited the sodium conductance (GNa) in a frequency-dependent manner. Diclofurime also blocked the slow inward current (Islow) without alteration of Eslow. The block of Islow occurred with a dissociation constant of 2 X 10(-5) M and unity stoichiometry. The data suggest that diclofurime might be effective in the control of cardiac arrythmias since it exhibited both local anaesthetic-like and calcium antagonistic properties.