Role of angiotensin II in injury-induced neointima formation in rats.

Angiotensin converting enzyme inhibition markedly suppresses neointima formation in response to balloon catheter-induced vascular injury of the rat carotid artery. To determine whether this effect was mediated through the vasoactive peptide angiotensin II (Ang II), two approaches were followed. First, the balloon model was used to compare the effects of continuous infusion of Ang II, with and without concurrent converting enzyme inhibition by cilazapril; second, the effects of the orally active nonpeptidic Ang II receptor antagonist DuP 753 were analyzed.

Potential-dependent inhibition of cardiac Ca2+ inward currents by Ro 40-5967 and verapamil: relation to negative inotropy.

Ro 40-5967 is a structurally novel Ca2+ channel blocker which binds to the [3H]desmethoxyverapamil receptor in cardiac membranes with a potency similar to that of verapamil but which has considerably fewer negative inotropic effects. In the present study, the inward Ca2+ current was measured in isolated myocytes with the whole-cell patch-clamp technique. It was found that at a physiological membrane potential (-80 mV) Ro 40-5967 was also less potent than verapamil in inhibiting this current, and that negative inotropy and Ca2+ channel blockade were correlated.

The structurally novel Ca2+ channel blocker Ro 40-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts.

Ro 40-5967 is a structurally novel Ca2+ channel blocker that binds to the verapamil-type receptor of cardiac membranes but that has been shown in isolated guinea-pig hearts to be about ten times less potent a negative inotropic agent than verapamil. The goals of the present study were to confirm these findings in vitro in isolated perfused rat hearts as well as in vivo in conscious rats and to compare Ro 40-5967 to verapamil. The effects of Ro 40-5967 and verapamil were tested not only in normal rats, but also in rats with heart failure induced by chronic myocardial infarction.

Antihypertensive properties of the novel calcium antagonist (1S,2S)-2-[2-[[3-(2-benzimidazolyl)propyl]methylamino] ethyl]-6- fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride in rat models of hypertension. Comparison with verapamil.

(1S,2S)-2-[2-[[3-(2-Benzimidazolyl)propyl]methylamino]ethyl]-6- fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride (Ro 40-5967) is a novel calcium antagonist. Its effect on systolic arterial blood pressure and heart rate was investigated in comparison with verapamil in conscious spontaneously hypertensive rats (SHR), renal hypertensive rats (2K1C), deoxycorticosterone acetate (DOCA)-NaCl hypertensive rats and normotensive Wistar rats. After single oral doses, Ro 40-5967 (3-30 mg/kg) and verapamil (10-100 mg/kg) produced a dose-related decrease in blood pressure in all three types of hypertensive rats.

Effects of Ro 40-5967, a novel calcium antagonist, on myocardial function during ischemia induced by lowering coronary perfusion pressure in dogs: comparison with verapamil.

Ro 40-5967 is a structurally novel calcium antagonist that binds to the verapamil binding site but has very weak negative inotropic effects compared to verapamil. The goals of the present study were to assess the effects of Ro 40-5967 on myocardial function during ischemia, and to compare them to those of verapamil. For this purpose, in anesthetized dogs where the circumflex coronary artery was cannulated and perfused at controlled pressure, myocardial function was measured using piezo electric crystals implanted into the endocardium.

In vitro pharmacologic profile of Ro 40-5967, a novel Ca2+ channel blocker with potent vasodilator but weak inotropic action.

Ro 40-5967 is a structurally novel Ca2+ channel blocker which binds to the verapamil-type receptor of cardiac membranes. Its biological activity was investigated in comparison with verapamil in isolated vascular, cardiac, and gastrointestinal muscle preparations, as well as in isolated perfused hearts. Ro 40-5967 was more potent in increasing coronary artery flow (EC50 = 54 nM) than in suppressing myocardial (IC50 = 14,000 nM) and peripheral vascular (aortic) contractility half-maximal inhibition (IC50 = 275 nM).

Ro 15-4513: partial inverse agonism at the BZR and interaction with ethanol.

The imidazobenzodiazepinone derivative Ro 15-4513 has the activity profile of a partial inverse (low efficacy) agonist at the benzodiazepine receptor (BZR). It reverses central nervous depressant effects of diazepam, and, in part, of phenobarbitone and ethanol in mice, rats and cats in behavioural, electrophysiological, and neurochemical paradigms. The interaction of Ro 15-4513 with barbiturates and ethanol is due to its inverse agonistic (negative allosteric modulatory) property at the BZR, as it was reversed by the selective BZR blocker flumazenil (Ro 15-1788).

Interaction of the cardiotonic agent DPI 201-106 with cardiac Ca2+ channels.

The cardiotonic agent DPI 201-106 was investigated for its effects on (a) contractile force in guinea pig left atria, (b) membrane currents in isolated guinea pig cardiac myocytes, and (c) [3H]nitrendipine binding in guinea pig cardiac membranes. The compound elicited a positive inotropic effect in normally polarized (5.9 mM extracellular KCl) and a negative inotropic effect in partially depolarized (20 mM KCl) isolated, electrically stimulated left atria.

Modification of K+ conductance of heart cell membrane by BRL 34915.

1. The effect of the K+ channel agonist BRL 34915 on membrane conductance was investigated in isolated guinea-pig cardiac myocytes. 2.

9-Amino-1,2,3,4-tetrahydroacridine (THA) is a potent blocker of cardiac potassium channels.

1. 9-Amino-1,2,3,4-tetrahydroacridine (THA) is a compound with structural similarity to the K+ channel blocker 4-aminopyridine. It was investigated for its effects on myocardial membrane currents in guinea-pig isolated ventricular myocytes.

Effects of chronic myocardial infarction on responsiveness to isoprenaline and the state of myocardial beta adrenoceptors in rats.

Responsiveness to catecholamines and alterations in myocardial beta adrenoceptors were determined in rats with chronic myocardial infarction. Myocardial infarction was produced by ligating the left main coronary artery. Three weeks after myocardial infarction, when left ventricular function was impaired, catecholamine responsiveness was determined by measuring the effects of isoprenaline in the conscious animal, the isolated perfused heart, the isolated right atria, and the right papillary muscles.

Inhibition of myocardial Ca2+ channels by three dihydropyridines with different structural features: potential-dependent blockade by Ro 18-3981.

Inhibition of myocardial Ca2+ channels was investigated for three dihydropyridines with different structural features: Ro 18-3981, darodipine (PY 108-068) and nifedipine. Ro 18-3981 contains a sulphamoyl acetyl side-chain. In voltage-clamps experiments with isolated cardiac myocytes of guinea-pig, Ro 18-3981 caused a concentration-dependent inhibition of the Ca2+ current, which was influenced by the membrane holding potential.

Inhibition of the fast Na+ inward current by the Ca2+ channel blocker tiapamil.

The inhibitory effect of the phenylalkylamine-type Ca2+-entry blocker, tiapamil, on the fast Na+ inward current was investigated in guinea-pig papillary muscles by measuring the maximum upstroke velocity (dV/dt)max of transmembrane action potentials. Tiapamil inhibited (dV/dt)max at concentrations above 10(-6) M, with an IC50 value of 7 X 10(-5) M (1 Hz stimulation frequency, 5.9 mM extracellular K+).

o-Isothiocyanate dihydropyridine (oNCS-DHP), a long-acting, reversible inhibitor of the Ca++ channel.

The binding characteristics and pharmacological properties of o-isothiocyanate dihydropyridine [oNCS-DHP; 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-isothiocyanatophenyl)-1, 4-dihydropyridine] were investigated in guinea pig heart and ileum. [3H]oNCS-DHP bound to a single population of high-affinity sites (Bmax = 107 fmol/mg of protein and Kd = 0.99 nM) in cardiac membranes, with a specificity characteristic of dihydropyridine receptors.

Inhibition of the myocardial Ca2+ inward current by the class 1 antiarrhythmic agent, cibenzoline.

Cibenzoline, a class 1 (local anaesthetic-type) antiarrhythmic drug, was investigated for possible effects upon the myocardial Ca2+ inward current. In voltage-clamp experiments with isolated cardiac myocytes of guinea-pig, cibenzoline caused a concentration-dependent inhibition of the Ca2+ current, with an IC50 of 14 microM. Inhibition of the Ca2+ current by cibenzoline (2 microM) was dependent upon stimulation frequency, with a greater block occurring at 2 Hz (approximately 50%) than at 0.

The peripheral, high affinity benzodiazepine binding site is not coupled to the cardiac Ca2+ channel.

Ro 5-4864, the prototype ligand of the peripheral benzodiazepine binding site caused a decrease of the action potential duration in isolated guinea-pig cardiac myocytes. Voltage-clamp experiments showed that, at concentrations below 3 X 10(-6) M, Ro 5-4864 caused a parallel outward shift of the membrane current elicited by depolarization to + 10 mV from a holding potential of -50 mV. The peak inward Ca2+ current (ICa) and the inwardly rectifying K+ current were not affected.

Cardiac membrane currents and energetic state.

Adrenaline, cAMP and cAMP-dependent protein kinase modulate the slow inward Ca current by the same basic mechanism, presumably a phosphorylation of membrane proteins. Protein kinase also seems to play a role in the regulation of K outward currents, but not for the transient inward current.

Beta-adrenergic increase in the calcium conductance of cardiac myocytes studied with the patch clamp.

In bovine, cat and guinea pig myocytes the effect of bath application of adrenaline or isoprenaline and of injection of cAMP on the Ca channel was studied with the patch clamp (Hamill et al. 1981), and the following results were obtained. On beta-adrenergic stimulation more activity of the single channel on repeated depolarizations and less records without activity were observed.

Injection of catalytic subunit of cAMP-dependent protein kinase into isolated cardiac myocytes.

Cyclic adenosine 3',5'-monophosphate (cAMP) or the free catalytic subunit (C) of the cAMP-dependent protein kinase were pressure injected into single guinea pig ventricular cells. The following results were obtained: Injection of cAMP prolonged the action potential and shifted the action potential plateau to a more positive level. Under voltage clamp, cAMP injection increased the amplitude of the slow inward calcium current (Isi).

Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current.

beta-Adrenergic stimulation of the heart is thought to increase cardiac muscle contractility by activation of cyclic AMP-dependent protein kinase and concomitant increase in the phosphorylation of certain proteins (for refs see refs 1-6). Electrophysiological studies have shown that the stimulation of cardiac beta-adrenoreceptors, the external application of cyclic AMP or its analogues to Purkinje fibres, or the injection of cyclic AMP into single myocytes can increase the slow inward current (Isi) during the plateau phase of the action potential (AP). In heart muscle this current is mainly carried by Ca2+ (refs 10, 11) and it has been suggested that cyclic AMP-dependent phosphorylation of some component of the calcium channel increases the amount of Ca2+ which enters the cell during depolarization.

Conductance of the slow inward channel in the rabbit sinoatrial node.

The elementary conductance of the slow inward current channel in the rabbit sinoatrial node was measured by analysis of the current fluctuations. The preparations were voltage-clamped to -30 mV, where d infinity and f infinity of the slow inward current (Isi) intersect. In the presence of Ba, which increases Isi and decreases outward currents, a small steady-state component of Isi could be detected.

Effects of barium on the membrane currents in the rabbit S-A node.

In small preparations of rabbit sinoatrial node voltage clamp experiments with the two microelectrode technique were carried out. The effects of extracellular barium ions on the slow inward current and outward currents were studied and the following results were obtained: 1. Ba increased the amplitude of the slow inward current without a change in the time course of inactivation.

The electrophysiological basis of the bradycardic action of AQA 39 on the sinoatrial node.

The electrophysiological effects of the bradycardic agent AQA 39 (5,6-dimethoxy-2-[3-[[ alpha-(3,4-dimethoxy) phenylethyl] methylamino] propyl] phthalimidine hydrochloride) on small preparations of the S-A node of the rabbit heart were investigated. The following results were obtained: 1. The decrease in the rate of the spontaneous preparation resulted from a lower rate of diastolic depolarization, a slower upstroke and a longer duration of the action potential.