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Biomedical subjects

I L Grupp

Publications and source records attributed to I L Grupp.

At least 55 records · Page 3Linked to original sources
PubMed1988

The calcium dependence of the biphasic inotropic response to ouabain in the isolated rat heart.

From the results of this study the following significant conclusions can be drawn. First, there are two separate inotropic responses to ouabain in the rat ventricle and the isolated rat heart resulting in a biphasic dose-response curve. Second, both the "low dose" and "high dose" inotropic responses of ouabain in the rat heart result from the inhibition of NKA, i.e., NKA is the binding site of ouabain for both "low" and "high" dose effects. Third, biphasic inotropic effects (rat ventricle) go together with alpha + and alpha (high and low affinity) isoforms of NKA, monophasic (rat atrium) with the alpha isoform (low affinity). Fourth, high extracellular calcium concentrations inhibit NKA and mask the full expression of the "low-dos" effect.

Animals↗
PubMed1988

Role of the Na+K+-ATPase in the cardiotonic action of cardiac glycosides.

In terms of evolution, the Na+,K+-ATPase is one of the oldest proteins. It is intriguing that this membrane-based enzyme has become biologically consistent with a multifunctional protein. One of the most interesting aspects of the Na+,K+-ATPase is that it contains a specific receptor domain for the oldest plant origin cardiotonic drug and that it is involved in the regulation of myocardial contractility.

Animals↗
PubMed1987

Benzodiazepine Ro 5-4864 increases coronary flow.

Ro 5-4864 (chlorodiazepam) increased coronary flow in isolated retrograde perfused Langendorff rat heart preparations without affecting heart rate and left ventricular contractility (dP/dt). On the other hand Ro 5-4023 (clonazepam) produced very little effect. PK 11195 which has been shown to inhibit the binding of Ro 5-4864 to cardiac muscle did not antagonize this vasodilatory effect of Ro 5-4864 but increased coronary flow by itself. The data indicate a specific vasodilatory effect of certain benzodiazepines. The mechanism of action remains unknown.

Animals↗
PubMed1986

Effects of bepridil and diltiazem on [3H]nitrendipine binding to canine cardiac sarcolemma. Potentiation of pharmacological effects of nitrendipine by bepridil.

[3H]Nitrendipine binds to canine cardiac sarcolemma in a specific, saturable and rapid manner. Bepridil, a Ca++ channel inhibitor, stimulates this binding at submicromolar concentrations, but inhibits it noncompetitively at higher concentrations (IC50 = 15.8 microM). The increase in binding was due primarily to a 30% increase in the association rate constant (k+1) of [3H]nitrendipine, causing a decrease in the KD from a control value of 0.40 to 0.28 nM. In contrast to bepridil, diltiazem causes only an increase in [3H] nitrendipine binding without any inhibition. The increase was due primarily to an increase in receptor site density (maximum binding). These results show that the regulatory effects of bepridil and diltiazem on [3H]nitrendipine binding to cardiac tissue are different. The stimulatory effects of bepridil appeared to be pharmacologically relevant as low concentrations of bepridil potentiated the negative inotropic effect of nitrendipine in isolated perfused rat hearts.

Animals↗
PubMed1985

Profile of the oppositely acting enantiomers of the dihydropyridine 202-791 in cardiac preparations: receptor binding, electrophysiological, and pharmacological studies.

Receptor binding, electrophysiological, and inotropic effects of the pure dihydropyridine enantiomers (+)S202-791 and (-)R202-791 were studied in cardiac preparations. The KI for (+)S202-791 binding correlated with the ED50's for an increase in contractile force and an increase in calcium current, the latter effect occurring at depolarized as well as resting holding potentials. The KI for (-)R202-791 binding was much lower than the IC50's for inhibition of calcium current measured at holding potentials of -80 or -90 mV and a negative inotropic effect, but correlated closely with the IC50 for inhibition of calcium current measured at -30 mV. Thus, (+)S202-791, is a voltage independent calcium channel activator and (-)R202-791 is a voltage dependent calcium channel inhibitor.

Animals↗
PubMed1985

Reversibility of inotropic effects of ouabain on canine atrial and ventricular tissues.

The experiments reported here were designed to quantitate reversibility of ouabain-induced inotropy in atrial and ventricular trabeculae of the dog heart. At 30 degrees C, 1 Hz, 2 mM Ca2+ and 5.9 mM K+, the positive inotropic effects, measured after a 1 h exposure to a single priming concentration of 0.5 microM ouabain, decreased after the removal of the drug with a half time (t1/2) of washout of 9.52 +/- 2.72 h in atrial and 7.64 +/- 1.58 h in ventricular trabeculae. When toxicity occurred it was of three types: transient toxicity, toxicity resembling a 'fast washout,' and severe toxicity characterized by profound and persistent negative inotropy and contracture. Use of the classical glycoside bioassay (Hatcher's digitalis titration) during and after washout, provided a semiquantitative estimation of ouabain remaining in the trabeculae; after a 4 h washout of the drug, the trabeculae were challenged by the addition of one-half of the initial concentration of ouabain (0.25 microM). Trabeculae, which had responded to ouabain with only positive inotropic effects and no toxicity, still contained substantial concentrations of ouabain. Trabeculae which reacted clearly with toxicity to the priming dose of ouabain, showed a significant loss of contractile force and development of contracture. The fastest ouabain washout we observed was 3.1 h.

Animals↗
PubMed1984

Effects of dihydropyridine calcium channel modulators in the heart: pharmacological and radioligand binding correlations.

Bay k 8644 produced a concentration-dependent positive inotropic effect followed by a negative inotropic effect in isolated and intact cardiac preparations. Nimodipine in low concentrations produced slight positive inotropy and in higher concentrations, the usual negative inotropic action. Radioligand binding experiments revealed equilibrium dissociation constants that, taken together with the pharmacological data, suggest that dihydropyridines bind to receptor subtypes and have varying intrinsic activities.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Effects of Bay k 8644, a dihydropyridine analog, on [3H]nitrendipine binding to canine cardiac sarcolemma and the relationship to a positive inotropic effect.

Equilibrium dissociation constants of Bay k 8644, a calcium agonist, and nitrendipine, a calcium antagonist, were determined in canine cardiac sarcolemma. The equilibrium dissociation constant for Bay k 8644 was compared to the concentration that produced a fifty percent increase, and the equilibrium dissociation constant for nitrendipine was compared to the concentration that produced a fifty percent decrease, in contractile force in canine heart trabecular muscle. Both saturation and inhibition binding data suggest that Bay k 8644 and nitrendipine bind to and compete for a high affinity dihydropyridine-binding site present in isolated cardiac sarcolemma preparations. The equilibrium dissociation constant (7-10 nM) and concentration that produced a fifty percent increase in contractile force in the canine trabecular muscle (30 +/- 8 nM) of Bay k 8644 were in a similar concentration range, but the equilibrium dissociation constant (0.29 +/- 0.025 nM) of nitrendipine binding was more than a thousand-fold lower than the concentration that produced a fifty percent decrease in contractile force in canine trabecular muscle (613 +/- 109 nM). These data suggest that binding of Bay k 8644 to high affinity binding sites is pharmacologically relevant, and is related to a positive inotropic effect.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Analysis of the inotropic action of ouabain in rat ventricles: two apparent ouabain inotropic responses.

Two distinct inotropic effects of ouabain were observed in 68 of 82 right ventricular strips of rats with ED50s of 0.5 and 20 microM referred to as "low-dose" and "high-dose" effects, respectively. The other 14 strips showed monophasic dose-response curves, with an apparent ED50 of 0.3 microM; the inotropic response to ouabain or isoproterenol developed by these atypical strips did not exceed 50% over control. In the strips showing the biphasic inotropic response curves, the proportion of the "low-dose" effect varied from 6 to 89% of the maximum response. After treatment with 160 microM ouabain, followed by 60 min of washout, the maximum developed tension in response to ouabain was unchanged, but the "low-dose" effect was abolished or dramatically reduced. In those cases with a remaining "low-dose" response, the response was only 12% or less of the maximum and the ED50 was shifted from 0.3 to about 3 microM ouabain by the washout. The atypical strips, which showed only the "low-dose" effects during the first ouabain exposure, revealed after washout a consistent "high-dose" effect with an ED50 of about 12 microM ouabain. The data show that the two inotropic responses exist in all ventricular strips and that in some strips, after ouabain washout, a residue of the "low-dose" effect remains.

Animals↗
PubMed1984

Effects of a new positive inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212) and its solvent sulfolane on isolated heart preparations of the rat, guinea pig, and dog.

3,4-Dihydro-6-[4-(3,4- dimethoxybenzoyl )-1-piperazinyl]-2(1H)- qu inolinone ( OPC -8212) has positive inotropic effects in guinea pig and dog isolated heart preparations. The rat heart ventricle does not respond to OPC -8212 but the atria do. OPC -8212 produces positive inotropic effects in the rat heart ventricle made hypodynamic by pretreatment with calcium entry blockers. Sulfolane , the solvent of OPC -8212, produced negative inotropic effects in most preparations. In isolated heart preparations of the rat and guinea pig, OPC -8212 produced increased coronary flow; sulfolane had only minor effects.

Animals↗
PubMed1983

Diltiazem potentiates the negative inotropic action of nimodipine in heart.

In Langendorff perfused rat hearts, nimodipine enhances coronary flow and inhibits contractility. The binding of [3H]nimodipine (160 Ci/mmol) to sarcolemma isolated from dog heart revealed a KD of 0.2 nM. d-cis-Diltiazem, but not 1-cis-diltiazem, a less active stereoisomer, stimulated [3H]nimodipine (0.17 nM) binding to sarcolemmal membranes (ED50 for diltiazem = 1.1 microM). In the presence of 10 microM d-cis-diltiazem, [3H]nimodipine binding sites were doubled, but there was no change in the apparent affinity. Perfused rat hearts were treated with 250 nM d-cis-diltiazem. The negative inotropic response to nimodipine was dramatically potentiated (I50, from 1.1 to 0.033 microM). The pharmacological and binding effects were observed only at 37 degrees C. It is possible that diltiazem in some way converts low affinity to high affinity sites.

Animals↗
PubMed1983

Chronotropic, inotropic, and vasodilator actions of diltiazem, nifedipine, and verapamil. A comparative study of physiological responses and membrane receptor activity.

The three major, chemically distinct calcium channel-blocking drugs, diltiazem, nifedipine, and verapamil, produce coronary vasodilation in the conscious dog. Coronary vascular resistance was reduced by 50% with an intravenous dose of 3 micrograms/kg nifedipine, 30 micrograms/kg verapamil, and 100 micrograms/kg diltiazem. In conscious dogs, nifedipine and verapamil increased heart rate, whereas diltiazem produced a smaller increase in heart rate. The rate of left ventricular pressure development in conscious dogs was unaffected by diltiazem, increased by nifedipine, and decreased by verapamil. Tachycardia was reversed to bradycardia and consistent negative inotropic effects were demonstrated by all three drugs only after combined autonomic blockade with atropine and propranolol in conscious dogs. In isolated dog coronary artery strips contracted ex vivo with 50 mM potassium chloride, the ID50 for relaxation was 0.01 microM for nifedipine, 0.02 microM for verapamil, and 0.30 microM for diltiazem. In isolated ex vivo hearts, all agents produced dose-dependent negative chronotropy with a 25% reduction in spontaneous heart rate achieved by 0.09 microM nifedipine, 0.20 microM verapamil, and 0.40 microM diltiazem. Similarly, the rate of force development in isolated myocardial strips was 50% depressed by nifedipine, 0.03 microM; verapamil, 0.10 microM; and diltiazem, 0.40 microM. On a membrane level, nifedipine, verapamil, and diltiazem interacted with a putative receptor or site associated with a calcium channel specifically labelled with [3H]nimodipine. The specific binding to cardiac sarcolemma was competitively inhibited by nifedipine, only partly inhibited by verapamil, and was stimulated by diltiazem. The effects of verapamil and diltiazem, but not the effect of nifedipine, occurred at pharmacologically active concentrations. Considerable nonspecific binding of dihydropyridines to sarcolemma may account, at least in part, for discrepancies between their dissociation constants on purified sarcolemma and their ED50 in pharmacological effects. Diltiazem and verapamil (1 microM) did not alter [3H]nimodipine nonspecific binding. These results strongly suggest that calcium channel-blocking drugs may have different sites of action.

Animals↗
PubMed1982

Differential cardiovascular effects of calcium channel blocking agents: potential mechanisms.

The three major calcium channel blocking agents, diltiazem, nifedipine and verapamil, inhibit calcium entry into excitable cells. Despite this apparent common action at the cell membrane, these drugs produce quantitative and frequently qualitative differences in cardiovascular variables (for example, heart rate, atrioventricular [A-V] conduction and myocardial inotropic state) when evaluated at equieffective vasodilator doses. All three drugs increase coronary blood flow in a dose-dependent fashion (nifedipine greater than diltiazem = verapamil), and produce a negative inotropic effect in vitro in isolated atria and ventricles, also in a dose-dependent manner (verapamil greater than nifedipine greater than diltiazem). However, in conscious dogs nifedipine increases, verapamil decreases and diltiazem has little effect on the inotropic state. A-V conduction is slowed by diltiazem and verapamil but not by nifedipine in anesthetized dogs and in conscious dogs as judged from the P-R interval in the electrocardiogram. Heart rate is slowed in pentobarbital-anesthetized animals but is accelerated in conscious dogs (nifedipine greater than verapamil greater than diltiazem). Nifedipine also appears to interfere significantly with the arterial baroreceptor reflex by an apparent vagolytic action that is less evident with diltiazem and verapamil. Diltiazem, and possibly verapamil and nifedipine as well, appears to retard myocardial damage that accompanies ischemia. The mechanisms and sites of action of these drugs are presumed to be at the cell membrane; however, intracellular sites may also be involved.

Animals↗