Biomedical subjects

M Grima

Publications and source records attributed to M Grima.

71 records · Page 4Linked to original sources

PubMed1988

Inhibitory effects of some cyclohexylaralkylamines related to perhexiline on sodium influx, binding of [3H]batrachotoxinin A 20-alpha-benzoate and [3H]nitrendipine and on guinea pig left atria contractions.

The antagonist activities of some cyclohexylaralkylamines derived from perhexiline on the fast Na+ channel and slow Ca2+ channel in rat brain and rat heart were examined and compared to the antagonist activities of nifedipine, verapamil, prenylamine and perhexiline. Prenylamine, perhexiline and the cyclohexylaralkylamine derivatives inhibited the [3H]batrachotoxinin A 20-alpha-benzoate binding more than the [3H]nitrendipine binding in rat brain. The nature of the interaction of the cyclohexylaralkylamines with the binding of [3H]batrachotoxinin and [3H]nitrendipine was non-competitive. The synaptosomal 22Na uptake induced by protoveratrine B, a Na+ channel agonist, was also inhibited. Prenylamine, perhexiline and perhexiline derivatives were more potent on the fast Na+ channel than on the Ca2+ channel in contrast to nifedipine and verapamil. The inhibition of Na+ and Ca2+ channels was also shown in guinea pig left atria. Perhexiline, prenylamine and the perhexiline derivatives inhibited the protoveratrine B-induced contraction more than they inhibited that induced by CaCl2, in contrast with nifedipine and verapamil. Our results showed that prenylamine, perhexiline and its related cyclohexylaralkylamines inhibited the fast Na+ channel far more than the slow Ca2+ channel in rat brain, rat heart and guinea pig atria.

Animals↗

PubMed1988

Effects on the sodium channel of some new cardiotonic drugs: the 4-, 5-, and 6-pyridyl-2(1H)-quinolone derivatives.

To study the action of some new cardiotonic drugs, the 4-, 5-, and 6-pyridyl-2(1H)-quinolone series, on the fast Na+ channel, we compared the effects of eight compounds of this series and milrinone on 22Na uptake in rat brain synaptosomes and in rat heart muscle cells in culture. The action of tetrodotoxin, a specific Na+ channel blocker, on the positive inotropic effect of these compounds on guinea pig atria was also examined. The new positive inotropic agents enhance 22Na uptake in synaptosomes in a dose-dependent manner. The activities, expressed as percentage of the maximum activity of protoveratrine B, a classic Na+ channel agonist, reached 70% for milrinone, 60% for compound 7, 57% for compound 6, and less than 50% for the other drugs. For compound 8, but not for milrinone, it was possible to observe a stimulatory effect of the 22Na uptake on heart muscle cells in culture. Tetrodotoxin (1 and 100 microM) inhibited the stimulatory effects of the inotropic drugs on both preparations. The positive inotropic activities of protoveratrine B, milrinone, and compounds 5 and 8, in guinea pig atria, were inhibited by tetrodotoxin. The affinity and the activity of the other compounds were unchanged in the presence of tetrodotoxin. Our results showed that the stimulation of Na+ influx through the fast Na+ channel might represent a part of the mechanism of action of the inotropic effect of some new cardiotonic drugs.

Animals↗

PubMed1988

Soft drug derivatives related to perhexiline. Part I: In vitro studies.

A series of cyclohexylaralkylamines derived from perhexiline was synthesized according to the "soft drug" concept. An amide function was introduced as a labile centre to give non-toxic moieties in vivo after the "soft drugs" had attained their therapeutic aims. Compounds were evaluated for their alpha-adrenolytic, calcium antagonist and vasodilator activities in vitro. Some of them, 2, 3, 7 and 15 on rat aorta had alpha-adrenolytic effects comparable to that of perhexiline. Most of them were about 10 times more active calcium antagonists on depolarized pig coronary artery than perhexiline. All derivatives produced concentration-related coronary dilation in the perfused guinea pig heart. Compound 2 was equipotent to perhexiline. The decrease in coronary resistance might, at least partly, be attributable to the alpha-blocking properties of the molecules. In conclusion, the introduction of an amide function into the perhexiline skeleton does not markedly alter the in vitro pharmacological properties.

Adrenergic alpha-Antagonists↗

PubMed1988

Soft drug derivatives related to perhexiline. Part II: In vivo studies.

A series of cyclohexylaralkylamines derived from perhexiline and synthesized according to the "soft drug" concept were evaluated for haemodynamic effects and myocardial oxygen consumption in vivo. In anaesthetized rabbits, the most active compounds, 2, 5, and 11 decreased arterial blood pressure, to a greater extent dp/dtmax and, to a lesser extent heart rate. The decrease in cardiac work and the decrease in cardiac output varied concomitantly. The cardiac effort index decreased in all cases to a greater degree than with perhexiline. In anaesthetized open-chest dogs, the potential antianginal properties of compounds 2, 5 and 11 were due to a decrease in cardiac work via a decrease in cardiac output and myocardial oxygen consumption. None of these compounds reduced arterial blood pressure. Compounds 2 and 5 decreased myocardial oxygen consumption more than perhexiline. Compound 5 was the most promising molecule of this series both as regards cardiac work and myocardial oxygen consumption, being active at a lower dose than perhexiline and having a long active span. These studies suggest that compounds 2, 5 and 11 might be beneficial to patients with angina pectoris.

Animals↗

PubMed1987

Effects of various antianginal drugs on sodium influx in rat brain synaptosomes and in rat heart muscle cells in culture.

This paper describes the inhibitory effects of several antianginal drugs on 22Na uptake of the fast Na+ channel in rat brain synaptosomes and in rat heart muscle cells in culture. Calcium antagonists like verapamil, flunarizine, perhexiline, two perhexiline derivatives IPS 629 and IPS 672, and beta-adrenoceptor antagonists like propranolol and practolol were tested. IPS 672 was the most active compound on synaptosomes and heart muscle cells (IC50 = 2.0 X 10(-6) and 2.4 X 10(-6) M respectively). The relative potencies of the Ca2+ antagonists tested on heart muscle cells were found to be IPS 672 greater than IPS 629 greater than perhexiline greater than flunarizine greater than verapamil. Verapamil was 55 and 10 times less active than IPS 672 on synaptosomes and heart cells respectively. Propranolol had an inhibitory activity comparable to that of flunarizine and was 100 times more active than practolol. It can be concluded that several antianginal drugs seems to interfere with the Na+ fast channel on rat brain and heart.

Angina Pectoris↗

PubMed1987

Effects of some antianginal and vasodilating drugs on sodium influx and on the binding of 3H-batrachotoxinin-A 20-alpha-benzoate and 3H-tetracaine.

The effects of antianginal drugs, especially arylalkylamines and structurally related derivatives, on 3H-batrachotoxinin-A 20-alpha-benzoate (3H-BTX-B) binding and on 3H-tetracaine binding were studied on rat synaptosomal and heart membrane preparations. The effect of the same drugs on the Na+ influx induced by protoveratrine B was studied on the rat synaptosomal preparation. Antianginal drugs tested inhibited 3H-BTX-B binding in rat synaptosomes, arylalkylamine derivatives being the most potent: IC50 values were 27 nM for flunarizine, 32 nM for prenylamine, 79 nM for cinnarizine. Similarly, these drugs were the most potent when tested in cardiac membrane preparations. All the drugs tested were very weak inhibitors of 3H-tetracaine binding (IC50 ranging from 0.01 mM to more than 1 mM) except for guanabenz, which was more potent (IC50:0.3 microM on the synaptosomal preparation). The various drugs tested inhibited the 22Na+ influx induced by protoveratrine B, with IC50 values ranging from 15 microM (prenylamine) to 110 microM (verapamil), with the exception of nifedipine which had an IC50 of more than 0.1 mM. The inhibition of 22Na+ influx correlated well with the inhibition of 3H-BTX-B binding. These findings suggest that some antianginal drugs, especially the arylalkylamines may have, in addition to their calcium antagonist activity, direct effects on sodium channels.

Angina Pectoris↗

PubMed1987

A novel positive inotropic series. 1st communication: in vitro studies of 3-, 4-, 5-, 6-, 7- and 8-pyridyl-2(1H)-quinolone derivatives.

A series of 3-, 4-, 5-, 6-, 7- and 8-pyridyl-2(1H)-quinolones and related compounds were evaluated for positive inotropic and vasodilatory activities in vitro. Most of them produced dose-related increases in myocardial contractility on guinea pig isolated atria and perfused heart. In guinea pig atria, the 6-pyridyl molecules were more active than the 5-pyridyl ones; the mean ED50 of compounds 14, 32 and 33 was 4.0 x 10(-7) mol/l i.e. 33 times that of sulmazole; that of compounds 6 and 7 was 2.0 x 10(-5) mol/l. The potencies of the 5- and the 6-pyridyl series also differed by 2 log units on perfused guinea pig heart. The 5- and 6-pyridyl series induced relaxation in precontracted pig coronary artery and coronary vasodilation on perfused guinea pig heart. Compounds 14, 32 and 33 also showed alpha-adrenolytic properties, which were by 0.7 log unit lower than that of phentolamine. These results indicate that this novel cardiotonic series exert positive inotropic and coronary vasodilatory effects.

Animals↗

PubMed1987

A novel positive inotropic series. 2nd communication: in vivo studies of 5- and 6-pyridyl-2(1H)-quinolone derivatives.

In the anaesthetized rabbits and dogs, the 6-pyridyl compounds 14, 32 and 33 (0.1-3 mg/kg) and the 5-pyridyl compounds 6 and 7 (1-10 mg/kg), administered i.v., produced dose-related increases in cardiac contractile force lasting more than 30 min. They also produced relatively minor and shorter-lasting increases in heart rate. Only the 6-pyridyl series decreased blood pressure. The effects were not blocked by propranolol. In the normal haemodynamic states, myocardial oxygen consumption did not increase. When the haemodynamic characteristics of heart failure were produced by propranolol in anaesthetized rabbits and dogs, compounds 14, 32 and 33 reversed these effects, increasing in particular cardiac output. These studies suggest that compounds of the 6-pyridyl series might be beneficial in patients with congestive heart failure.

Anesthesia↗

PubMed1986

Anti-anginal arylalkylamines and sodium channels: [3H]-batrachotoxinin-A 20-alpha-benzoate and [3H]-tetracaine binding.

[3H]-batrachotoxinin-A 20-alpha-benzoate ([3H]-BTX-B) and [3H]-tetracaine are useful ligands for the study of sodium channels. Inhibition of their binding by various anti-anginal drugs was tested on a rat synaptosomal preparation and on a heart membrane preparation. Diphenylalkylamines and structurally related drugs inhibited [3H]-BTX-B binding in both the synaptosomal preparation and heart membrane preparation. They were almost inactive on [3H]-tetracaine binding. These results suggest that activity of arylalkylamines could be mediated by an interaction on the sodium channel.

Angina Pectoris↗

PubMed1986

Inhibition of some new cardiotonic agents by tetrodotoxin.

The effects of sulmazole, milrinone and 1,5-dihydro-6-chloro-3-methylimidazo[2,1-b]quinazolone-2 on guinea pig left atria were studied, measuring the force of contraction in the absence and in the presence of 1 x 10(-5) mol/l octahydro-12-(hydroxymethyl)-2-imino-5,9: 7,10a-dimethano-10aH-[1,3]-dioxocino[6,5-d]pyrimidine- 4,7,10, 11,12-pentol (tetrodotoxin, TTX). The dihydropyridine derivative methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-tri-fluoromethylphenyl) pyridine-5-carboxylate, a Ca2+ agonist, was also tested. Protoveratrine B, which prolongs the Na+ current phase, was inhibited by TTX. Isoprenaline, whose activity is mediated by cyclic adenosine monophosphate and consequently by the increase in slow inward Ca2+ current, was not. TTX antagonized competitively sulmazole, milrinone and the quinazolone drug and reduced only the activity of the dihydropyridine derivative. These results suggest an interference of the new cardiotonic drugs with the fast Na+ channel.

Animals↗

PubMed1986

Effect of some new cardiotonic agents on synaptosomal sodium uptake.

The new positive inotropic agents sulmazole, piroximone, milrinone and 1,5-dihydro-6-chloro-3-methy-limidazo [2,1-b]quinazolone-2 enhance 22Na uptake in rat brain synaptosomes. In comparison, theophylline, a cyclic nucleotide phosphodiesterase inhibitor, has no effect on synaptosomal 22Na uptake. Tetrodotoxin inhibits the stimulation induced by the new inotropic agents. The quinazolone is about three times more potent than protoveratrine B and milrinone and ten times more potent than sulmazole and piroximone. There is a direct correlation between the 22Na uptake and the positive inotropic effect on guinea pig left atria of the new cardioactive drugs. The dose-response curves for synaptosomal 22Na uptake and for the inotropic effect on guinea pig left atria are parallel for sulmazole and the quinazolone drug, with first an increase and then a decrease in activity.

Animals↗

PubMed1985

[3H]-tetracaine binding on rat synaptosomes and sodium channels.

[3H]-tetracaine binding was studied in a rat synaptosomal preparation. [3H]-tetracaine bound to a single class of binding sites with a mean KD of 188 +/- 28 nM and a mean maximal binding capacity of 13 +/- 0.7 pmol mg-1 protein. [3H]-tetracaine binding was inhibited by tetracaine, procaine and by beta-adrenoceptor blocking agents which possess local anaesthetic properties. [3H]-tetracaine binding was not modified by neurotoxins interacting specifically with the sodium channels.

Adrenergic beta-Antagonists↗

PubMed1984

Modulation of renal ATPase activities by cyclic AMP.

A possible link between cellular cyclic AMP content and Na+K+ATPase activity was investigated in homogenates of rat kidney. Enzyme kinetics of Mg2+ and Na+K+ATPase were run in the presence of cyclic AMP, dibutyryl cAMP and compounds expected to elevate cyclic AMP levels such as forskolin, a potent adenylate cyclase activator, IBMX, an inhibitor of phosphodiesterases, and the beta-agonist isoproterenol. Medullary Na+K+ATPase is strongly inhibited by cyclic AMP whereas cortical Na+K+ATPase was stimulated in the same conditions. The correlation between ATPase activity and cellular cyclic AMP content supports the concept of a possible regulation of the enzyme by cyclic AMP.

1-Methyl-3-isobutylxanthine↗

PubMed1983

Blood oxygen consumption and erythrocyte types in embryonic and postnatal chicken.

In an extension of previous work showing that oxygen consumption (MO2) of chick blood cells declines from 5 to 14-15 days incubation age, declines more steeply to hatching, rises abruptly up to 4-6 posthatch days, and declines thereafter, we investigated the succession of embryonic and posthatch erythrocytic types by performing differential erythrocyte (RBC) counts. MO2 of RBC groups separated by density gradients and fractionation into younger and older RBC populations were measured in 1- to 22-day-old posthatch chicks. The embryonic MO2 decline can be attributed to the appearance of erythrocytic types with successively lower metabolism. The MO2 slope change at 14-15 days incubation coincides with the predominance of definitive erythrocytes with oval nuclei over other cell types. The posthatch MO2 rise is due to a temporary invasion of immature RBC, especially postnatal polychromatic erythroblasts. MO2 then decreases as these cells mature.

Animals↗

PubMedDate not supplied

Renal tissue angiotensins during converting enzyme inhibition in the spontaneously hypertensive rat.

To compare the effects of an angiotensin-converting enzyme inhibitor on circulating and tissue renin-angiotensin system (RAS), we measured different RAS parameters during the first day of treatment (Day1) as well as after two weeks of treatment (Day14). Ramipril was given orally once daily to adult male spontaneously hypertensive rats (SHR). Renin activity (RA), angiotensin converting enzyme (ACE) activity and levels of angiotensin I (ang I) and angiotensin II (ang II) in the plasma, renal cortex and renal medulla were assessed at Day1 and Day14 of the treatment. In the plasma, both RA and ang I increased 10 to 15 fold one to four hours after acute as well as at Day14 of ramipril treatment and then returned to basal values within 24 hours. Plasma ang II levels were not significantly decreased at Day1 or Day14. The decrease in the ang II/ang I ratio suggested a sustained inhibition of plasma ACE at Day14. In the renal cortex and medulla, a clearly different pattern was observed: in ramipril treated rats, RA in the renal cortex and medulla did not change at Day1 but at Day14 we observed a slight and sustained increase in RA. Despite very high basal levels of RA, ang I levels in the renal cortex were comparable to those in the plasma. The ang I level increased only one-fold one hour after ramipril intake at Day1 and Day14. This suggests that angiotensinogen may have a limiting role in the synthesis of ang I in the kidney. Ang II levels were slightly higher in the renal cortex and medulla than in the plasma suggesting local synthesis of the peptide. In the kidney, ang II levels decreased one and four hours after the acute or prolonged ramipril treatment and the ang II/ang I ratio was reduced at the same time. Our results show that the responses of the plasma and kidney components of the RAS to ACE inhibition are different in the plasma and the kidney suggesting that the circulating and tissue RAS are at least in part independent.

Angiotensin I↗

PubMedDate not supplied

Coronary vasodilation and positive inotropic effect of non steroidal cardiotonics.

The effects of several cardiotonic agents (ARL-115, Amrinone, RMI 82-249, Milrinone, CI-914, RO 13-6438 and APP 201-533) were compared with those of ouabain on pig isolated coronary artery, guinea-pig isolated atria and guinea-pig perfused heart to compare vasodilatory and inotropic responses. Like ouabain, all compounds tested produce positive inotropic and chronotropic effects in isolated atria and on perfused heart, and induce relaxation in precontracted pig coronary artery and coronary vasodilation on perfused heart, except ouabain which induces vasoconstriction. The results indicate that non steroidal cardiotonics exert positive inotropic and coronary vasodilatory effects.

Animals↗

PubMedDate not supplied

[Aldosterone antagonists: new pharmacologic prospects].

The pharmacology of the mineralocorticoid receptor antagonist spironolactone and analogues is reviewed in the light of recent discoveries regarding the primary structure of corticosteroid receptors and the different isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase. The type 2 isoform of this enzyme functions in some tissues to keep the aldosterone receptor activation specific, i.e. it allows stimulation by aldosterone while eliminating glucocorticoids such as cortisol and corticosterone. The type 2 isoform has been shown in the colon, hypothalamus, kidney, placenta and salivary gland. New clinical uses of aldosterone antagonists may be derived from these developments. Most prominent in this respect appear to be myocardial fibrosis and specific forms of hypertension with altered mineralocorticoid receptor functioning and deficiencies in the protection system of the receptor against glucocorticoids.

Animals↗