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PubMed1982

Effects of calmodulin antagonists on tension and cellular calcium content in depolarized vascular and intestinal smooth muscles.

1 Several putative calmodulin antagonists have been examined for their inhibitory action on muscle tension and cellular Ca content in the K-depolarized vascular and intestinal smooth muscles. 2 The 65.4 mM K-induced sustained contraction in the media-intimal layer of rabbit aorta and the 45.4 mM K-induced sustained contraction in guinea-pig taenia coli were inhibited by the calmodulin antagonists, prenylamine, chlorpromazine, N2-dansyl-L-arginine-4-t-butylpiperadine amide (No. 233), and N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W-7), and also by the organic Ca antagonists, verapamil and diltiazem. 3 The cellular Ca content in rabbit aorta and guinea-pig taenia coli as measured by a modified lanthanum technique increased in the high-K solutions. The increments were inhibited by these antagonists at concentrations similar to those required to inhibit the K-induced contractions. However, W-7 did not change (in aorta) or only slightly decreased (in taenia coli) the K-induced increase in the cellular Ca content. 4 A high concentration (2 X 10(-4)M) of W-7 increased the resting cellular Ca content without increasing the muscle tension in aorta. The increment was inhibited by verapamil, sodium nitroprusside or hypoxia (N2 aeration). 5 It is suggested that the inhibitory effects of prenylamine, chlorpromazine and No. 233 may be attributed mainly to the Ca antagonistic effect whereas W-7 may inhibit the process beyond the transmembrane Ca influx.

Animals↗
PubMed1988

Cardiovascular and renal actions of calcium channel blocker chemical subgroups: a search for renal specificity.

The diuretic and natriuretic responses to structurally distinct classes of Ca2+ channel blockers have been compared, to determine whether any agent provoked K+-sparing natriuresis, and to assess the relation of such responses with drug effects on blood pressure. Conscious normotensive Sprague-Dawley rats received vehicle or one of the following drugs in an oral saline load (40 mL kg-1) nifedipine, nimodipine, nitrendipine, prenylamine, cinnarizine, flunarizine, diltiazem, verapamil, hydrochlorothiazide, amiloride, or hydralazine, at doses from 0.316 to 100 mg kg-1. Urine was collected for 6h. Blood pressure was monitored directly in parallel studies. Diltiazem (31.6, 100 mg kg-1) and flunarizine (100 mg.kg-1) enhanced urine and electrolyte excretion in spite of marked hypotension; diltiazem was the only drug to produce dose-related renal responses. In contrast, equihypotensive doses of hydralazine and nifedipine produced overt urine and electrolyte retention. Nitrendipine and prenylamine (0.316 mg kg-1 each) produced slight diuresis or natriuresis without altering blood pressure; higher doses had no effect. The 31.6 mg kg-1 doses of verapamil, nitrendipine, and nimodipine markedly reduced blood pressure, but neither enhanced nor limited urine and electrolyte excretion. Cinnarizine failed to produce any cardiovascular or renal effects. Diuretic responses evoked by the Ca2+ channel blockers were not class-specific, showed no tendency towards sparing K+, were generally weaker than those produced by low doses of amiloride or hydrochlorothiazide, and were dissociable from drug-induced changes in blood pressure.

Amiloride↗
PubMed1985

Effects of phospholipase A2 inhibitors on ruthenium red-induced Ca2+ release from mitochondria.

The pharmacologic agents verapamil, nifedipine, diltiazem, prenylamine, N-oleoylethanolamine, R 24571, trifluoperazine, dibucaine, and quinacrine are examined as potential inhibitors of rat liver mitochondrial phospholipase A2 acting on endogenous phospholipid. Their potency as inhibitors of the enzyme is compared to their activities as inhibitors of phospholipase A2-dependent swelling and ruthenium red-induced Ca2+ release in intact mitochondria. For verapamil, diltiazem, trifluoperazine, dibucaine, and quinacrine, there is complete agreement between the relative potencies as inhibitors of phospholipase A2 and the two other processes. Nifedipine and prenylamine, which are weak inhibitors of phospholipase A2, produce a permeable inner membrane, provided that the mitochondrial have accumulated Ca2+. R 24571, which strongly inhibits the enzyme, disrupts mitochondria by a Ca2+-independent mechanism. N-Oleoylethanolamine, which is an effective inhibitor of swelling, does not inhibit phospholipase A2 or ruthenium red-induced Ca2+ release. The results support a proposed scheme wherein ruthenium red-induced Ca2+ release is viewed as reverse activity of the Ca2+-uptake uniporter occurring subsequent to decline in the proton motive force. The latter effect is proposed to arise from a specific phospholipase A2-dependent increase in inner-membrane H+ conductance of mitochondrial subpopulations. It is further shown that mitochondrial membranes display cyclic oscillations in free fatty acid content which are not dependent on the presence of Ca2+ or on the capacity to generate acylcoenzyme A.

Animals↗
PubMed1982

Inotropic and chronotropic effects of vasodilators.

Although vasodilators are used with increasing frequency for the treatment of heart failure and myocardial ischemia, their direct effects on cardiac muscle have not been completely characterized. To delineate the action of vasodilators on mammalian myocardium, the chronotropic and inotropic effects of vasodilators on isolated guinea-pig atria (n = 163) have been determined. The spontaneous frequency and the peak rate of isometric force development at a fixed frequency of 200/min were used as indexes of chronotropy and inotropy. The potency series for negative chronotropy was diltiazem greater than D600 greater than verapamil greater than lidoflazine greater than bepridil greater than prenylamine greater than perhexiline greater than nifedipine. The potency series for negative inotropy differed substantially, exhibiting the sequence nifedipine greater than D600 greater than verapamil greater than bepridil greater than lidoflazine greater than prenylamine greater than perhexiline greater than diltiazem. Therefore, nifedipine acted as an "inoselective" and diltiazem as a "chrono-selective" depressant. Other vasodilators, including papaverine, nitroglycerin, nitroprusside, adenosine, dipyridamole, diazoxide and hydralazine exerted no or negligible negative chronotropic or inotropic effects even at high concentration (10(-5) M). Therefore, only vasodilators classified among the calcium antagonists proved to have appreciable direct myocardial effects. This supports the view that these drugs constitute a category of agents distinct from classical vasodilators.

Animals↗
PubMed1982

Effects of various calmodulin antagonists on contraction of rabbit aortic strips.

Effects of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), chlorpromazine, prenylamine and N2-dansyl-L-arginine-4-t-butylpiperidine amide on vascular smooth muscle contraction were compared by using helically cut strips of rabbit aorta. These compounds are reported to be calmodulin antagonists, in vitro. W-7 at a concentration of 1 x 10(-4) M significantly antagonized the contractile responses of aortic strips to the same extent as seen with norepinephrine, serotonin, histamine, prostaglandin F2 alpha, angiotensin II and KCl. On the other hand, the addition of 1 x 10(-4) M N-(6 aminohexyl)-1-naphthalenesulfonamide, an analog of W-7 which has no chloride molecule in the structure and possesses a lower affinity for calmodulin than W-7, did not antagonize aortic contractions. Chlorpromazine at a concentration of 1 x 10(-6) M specifically antagonized the norepinephrine-, serotonin- and histamine-induced contractions, but did not antagonize the prostaglandin F2 alpha-and angiotensin II-induced contractions. Inhibition of prenylamine of the contractile response of aortic strips to KCl was marked compared with the inhibition by this drug of the responses to other agonists. N2-dansyl-L-arginine-4-t-butylpiperidine amide selectively antagonized the serotonin- and KCl-induced contractions at a concentration of 1 x 10(-5) M, however, at this concentration, the responses to norepinephrine, histamine and prostaglandin F2 alpha were not affected by the drug. Thus, each calmodulin antagonist tested has a different spectrum of action and of these only W-7 has a specific interaction with calmodulin.

Animals↗
PubMedDate not supplied

Pathogenesis of isoproterenol-induced lesions in the rat myocardium.

The aim of this study was to investigate the action of isoproterenol (ISP) on the myocardium by means of light microscopy, histochemistry, autoradiography with tritiated ISP and electron microscopy. One hundred and sixty four Wistar rats were divided into 8 groups. Group A, B, C and D were given 10 mg/kg i.p. ISP (plus 5 uC of tritiated ISP). The animals were sacrificed at different intervals. Group E served as control to proceeding groups. Group F was given 10 mg/kg i.p. ISP and subjected to "holding" stress; Group G was its corresponding control. Group H received 9 mg/kg. prenylamine, as inhibiting drug, 1 hour before and hour after ISP injection. Histopathology of "infarct like" lesions presenting localized necrosis, myocytolysis, homogenization and positive tests for ischemia are correlated to the localization of tritiated ISP on sarcolemma and to changes in succine dehydrogenase enzymes in the groups A, B, C and D. Hypercontraction and widening of Z bands of sarcomers are found in electron microscopy. These ischemic changes are inhibited by prenylamine, a drug acting as moderator of catecholamine effects by slowing down Ca transport. It is concluded that myocardial necrosis induced by ISP is probably due to an increased activation of the "calcium pump". The ISP provoked lesions appear to be a promising model to study experimental myocardial necrosis.

Animals↗
PubMed1989

Stimulation by McN-A-343 and blockade by telenzepine of acid secretion in the mouse isolated stomach at histamine-liberating cells.

(1) In the lumen-perfused mouse stomach in vitro, potential sites of gastric antisecretory action of the muscarine M1-receptor antagonist telenzepine were investigated. Acid secretion was stimulated by the muscarinic agonist McN-A-343 (1-1000 mumol/l). Neither basal nor McN-A-343-stimulated acid secretion was affected by 1 mumol/l TTX indicating that neuronal structures were probably not involved. (2) Acid secretion stimulated by 10 mumol/l McN-A-343 was inhibited by telenzepine (0.1-1.4 mumol/l) and cimetidine (10-140 mumol/l). Neither of the antagonists affected basal acid secretion. TTX had no inhibitory influence on the antagonist effect of telenzepine and cimetidine. (3) Compound 48/80 (100 mumol/l), which depletes histamine stores, initially mimicked but subsequently prevented the effect of McN-A-343. Prenylamine (50 mumol/l), which prevents histamine release, also abolished the secretagogue effect of subsequently administered McN-A-343. (4) Up to concentrations greater than 100 mumol/l, McN-A-343 did not stimulate acid production in rabbit isolated fundic glands and guinea-pig isolated parietal cells. Thus, parietal cells are not directly stimulated by McN-A-343. (5) Based on the site of action of the agonist McN-A-343 in the mouse isolated stomach and its failure to stimulate parietal cells from different species directly, it is concluded that telenzepine blocks, in the mouse isolated stomach, muscarine receptors located on paracrine cells to reduce endogenous histamine release.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1975

Uptake of dopamine into fractions of pig caudate nucleus homogenates.

Homogenates of the caudate nucleus of the pig were submitted to differential centrifugation. The 20000 g and 80000 g fractions were isolated and a part of them was osmotically shocked. The highest dopamine content per mg protein was found in the intact 80000 g fraction. Incubation experiments with the intact and the osmotically shocked fractions at 25 degrees C revealed that the particles of the intact 20000 g fraction took up dopamine, the influx of the amine was not enhanced by addition of ATP and magnesium to the incubation medium. On the other hand after osmotic shock the uptake of dopamine into the particles of this fraction was greatly enhanced by addition of ATP and magnesium. The uptake of dopamine into the particles of both intact and osmotically shocked 80000 g fractions was likewise enhanced by ATP and magnesium. The uptake in all fractions was not influenced by ouabain. The influx of dopamine into the particles of the intact 80000 g fraction was competitively inhibited by reserpine (Ki0.96 x 10-8M) and prenylamine (Ki1.74 x 10-8M). It is concluded that the intact 20000 g fraction contains intact synaptosomes; the uptake of dopamine is independent of the presence of ATP and magnesium. The shocked 20000 g fraction and the 80000 g fractions contain synaptic vesicles; the uptake of dopamine into these vesicles is enhanced by ATP and magnesium.

Adenosine Triphosphate↗
PubMed1982

Evidence of multiple receptor sites within the putative calcium channel.

[3H]-Nimodipine a potent calcium channel blocker, binds to an apparently homogenous population of receptors in guinea-pig brain membranes (KD=0.62 nM, Hill coefficient or approximately 1.0). Diltiazem (10(-5) M) lowers the KD for [3H]-nimodipine by a factor of 3 without changing the maximum number of binding sites. Diltiazem decreased the dissociation rate constant of the nimodipine-receptor complex from 0.18 min-1 to 0.049 min-1 and altered the pharmacological profile as revealed by displacement studies with (-) and (+) verapamil, (-) and (+) prenylamine and 1,4 dihydropyridines. In conclusion [3H]-nimodipine binding can be utilized as a tool to evaluate complex molecular interactions between calcium channel blockers.

Animals↗
PubMedDate not supplied

Calmodulin blockers decrease short-term plasticity of the cholinoreceptors of neurons of the edible snail.

A reversible decrease in the rate and depth of the extinction of the reactions of the cholinoreceptive membrane to repeated iontophoretic applications of acetylcholine to the soma by a number of calmodulin blockers was demonstrated in identified RPa3 and LPa3 neurons in the edible snail using the method of recording transmembrane ionic currents: R 24571 (20-50 mumols/liter), trifluoperazine (50-200 mumols/liter), chlorpromazine (20-60 mumols/liter), and prenylamine lactate (30-400 mumols/liter). The results obtained attest to the positive regulation of short-term plasticity of the cholinoreceptors of the neurons in question by calmodulin.

Acetylcholine↗
PubMed1991

Calcium ion mobilization in neuronal cells induced by PAF.

We have reported previously that platelet-activating factor (PAF) interacts with the neuronal cell line NG108-15 (neuroblastoma X glioma hybrid) and the pheochromocytoma cell line, PC12. PAF acts on these cells by raising levels of intracellular free calcium ions. In the present report, we extend these studies. PAF induced the vesicular release of adenosine 5'-triphosphate (ATP) from PC12 cells in a dose-dependent manner. The PAF-induced ATP release was inhibited by the PAF antagonists, CV-3988 and CV-6209, and the calcium antagonist prenylamine. The relevance of the interaction of PAF with neuronal cells was investigated further by using brain synaptosomal preparations and primary cortical and neostriatal cells. Nanomolar concentrations of PAF induced calcium transients in aequorin-loaded synaptosomal preparations, and cortical and neostriatal cells were sensitive to the action of PAF. The possible physiological and pathophysiological roles of PAF in brain function are discussed.

Adenosine Triphosphate↗
PubMed1984

The effect of verapamil and other calcium antagonists on chemotaxis of polymorphonuclear leukocytes.

The calcium antagonists verapamil, D600, prenylamine, diltiazem and perhexiline inhibit chemotaxis and (stimulated) locomotion by rabbit polymorphonuclear leukocytes (PMN's). Inhibition occurs at relatively high concentrations (5.10(-5)-10(-3) M). Inhibition was most pronounced in the absence of extracellular Ca2+. In the presence of extracellular Ca2+ there was also inhibition of chemotaxis, but to a lesser degree than in the absence of Ca2+, thus extracellular Ca2+ partly reverses the inhibition of chemotaxis by calcium antagonists. The results suggest that the mechanism of action of these drugs in PMN chemotaxis differs from that in smooth muscle cell contraction, where much lower concentrations of these drugs are active. The data obtained suggest that calcium antagonists inhibit PMN chemotaxis and locomotion by interference with a Ca2+-dependent intracellular target.

Animals↗
PubMed1986

Intracellular Ca2+-calmodulin system involved in the palytoxin-induced K+ release from rabbit erythrocytes.

Palytoxin (PTX) caused K+ release from rabbit erythrocytes which was dependent on the concentrations of extracellular Ca2+ and PTX. In a Ca2+-free solution, PTX still caused a slow K+ release. An intracellular Ca2+ antagonist, TMB-8, an intracellular Ca2+ chelator, quin 2, and calmodulin inhibitors, prenylamine, W-7 and W-5, inhibited the PTX-induced K+ release in a Ca2+-free solution. These results suggest that the PTX-induced K+ release is dependent on the process including intracellular Ca2+ and calmodulin.

Acrylamides↗
PubMed1983

A simple sensitive radioreceptor assay for calcium antagonist drugs.

A radioreceptor assay for calcium channel antagonist drugs described here is based on the ability of these drugs to affect 3H-nitrendipine binding to calcium channels. All the known calcium channel antagonists may be assayed in this manner. The assay can detect 10-100 nM (4 - 40 ng/ml) nimodipine, 10-100 nM (3.5 - 35 ng/ml) nifedipine, 3-30 microM (1.2 - 12 micrograms/ml) prenylamine, 0.1 - 1.0 microM (49 - 490 ng/ml) verapamil and 3-30 microM (1.2 - 12 micrograms/ml) diltiazem. These values cover the range of concentrations of calcium channel antagonists that are clinically important. As the radioreceptor assay detects active metabolites as well as the parent drugs, it should prove a useful adjunct in cardiovascular therapy. The method is more reproducible, simpler and less expensive than other methods such as high pressure liquid chromatography.

Animals↗
PubMed1986

The effect of antithrombotics in a new model of arterial thrombosis.

A series of drugs representing several groups of antithrombotics was tested in a new model of arterial thrombosis in rats. Thrombosis was produced in the aorta by the combination of local partial obstruction and systemic administration of hypotonic saline with serotonin. High efficacy was demonstrated with heparin, acetylsalicylic acid, troxerutin, prenylamine, antiserotonin agents /pizotifen, ketanserin/ and particularly with the combinations of antiserotonins and the above mentioned antithrombotic drugs. The model showed high sensitivity to all tested drugs in the clinical dose range.

Animals↗
PubMed1993

Calcium mobilization and cell proliferation activated by extracellular ATP in human ovarian tumour cells.

The effects of ATP on cell proliferation and intracellular calcium concentration ([Ca2+]i) were examined in a human ovarian cancer cell line (OVCAR-3). Micromolar concentrations of ATP promoted a biphasic rise in [Ca2+]i representing a phase with a rapid peak followed by a phase in which the rise was slower and sustained. When the influx of extracellular calcium was blocked by calcium chelation to EGTA, the ATP stimulated rise in [Ca2+]i was rapid and monophasic. Voltage-sensitive calcium channel blockers like nifedipine and verapamil had no effect on the action of ATP while prenylamine totally blocked calcium influx. ATP inclusion in the medium significantly stimulated growth of OVCAR-3 cells. Fetal calf serum (FCS) increased [Ca2+]i with similar biphasic kinetics representing both the entry of extracellular calcium and release of calcium from intracellular stores. FCS also caused a substantial increase in cell growth. From these experiments it was concluded that an increase in [Ca2+]i is obligatory for stimulation of cell growth in OVCAR-3 cells and that this increase probably requires a contribution from the entry of extracellular calcium. The involvement of both pertussis toxin sensitive G-protein and protein kinase C in ATP induced responses was indicated by the data showing interference of the response by pertussis toxin and phorbol-myristate acetate.

Adenosine Triphosphate↗
PubMed1990

Calcium-dependent potentials with different sensitivities to calcium agonists and antagonists in guinea-pig hippocampal neurons.

Effects of organic Ca channel blockers, Ca channel activators and omega-conotoxin on guinea-pig hippocampal CA1 neurons in vitro preparations were studied with intracellular recording methods. Most of the Ca channel blockers, such as prenylamine, D 600, flunarizine, nifedipine, cinnarizine and nicardipine (0.2-4 microM), raised the threshold for Na-dependent spike generation and decreased the amplitude of the spike afterhyperpolarization. Verapamil (5 microM) and diltiazem (5 microM) did not significantly alter the threshold and amplitude of the Na spike. Action potentials elicited in the presence of either tetrodotoxin (0.5 microM) and tetraethylammonium (20 mM) or tetrodotoxin (0.5 microM) and Ba (1.25 mM) consisted of an initial spike component followed by a long depolarization. Both responses were abolished by addition of Co (2 mM) or Cd (0.25-0.5 mM), or by superfusion with a low Ca (0.25 mM)-high Mg(15 mM) medium, indicating that the potentials resulted from Ca entry. The Ca-dependent slow depolarization was preferentially blocked by most of the organic Ca channel blockers at approximately one-third the concentrations (0.1-2 microM) which were required to shorten the Ca spike. When the cell in a solution containing tetrodotoxin (0.5 microM), Co (2 mM) and 4-aminopyridine (2 mM) was hyperpolarized and then depolarized by passing current pulses across the membrane, a transient depolarizing hump occurred on the decay phase of the electrotonic potential. This transient depolarization was abolished by Co (2 mM), Ni (2 mM) or most of the organic Ca channel blockers (0.2-5 microM). Diltiazem (5 microM) did not significantly change these Ca-dependent potentials. The evoked excitatory postsynaptic potential was very resistant to the Ca channel blockers. Approximately 2-10 times higher concentrations (0.5-3 microM) were necessary to decrease the excitatory postsynaptic potential amplitude than to shorten the Ca spike. On the other hand, the minimal concentrations and order of potencies of the Ca channel blockers for depressing the evoked inhibitory postsynaptic potential and for elevating the threshold for Na spike generation were almost the same. Dihydropyridine Ca channel activators, such as Bay K 8644, CGP 28 392 and YC 170 at low concentrations (0.1-1 microM), decreased the Ca spike, the Ca-dependent slow depolarization and the evoked synaptic potentials, while the substances augmented the Ca-dependent transient depolarization. On the other hand, omega-conotoxin (5 microM) reversibly depressed the Ca spike and slow depolarization to the same degree, without affecting the transient depolarization and the evoked excitatory or inhibitory postsynaptic potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1986

The effect of calmodulin inhibitors on the release of acetylcholine and protein phosphorylation induced by tityustoxin, K+ and ouabain.

In this paper we describe our studies of the effects of calmodulin inhibitors on the relationship between the release of acetylcholine (ACh) and protein phosphorylation induced by tityustoxin (TsTX), K+ and ouabain. We observed that in cortical slices of brain, the TsTX induced release of ACh was inhibited in the presence of the calmodulin inhibitors trifluoperazine, W-7 and prenylamine, but not by trifluoperazine sulphoxide. The release of ACh elicited by ouabain and K+ (33 mM) was also inhibited by trifluoperazine and chlorpromazine. Studies on protein phosphorylation with crude or purified synaptosome fractions showed that TsTX and K+ (33 mM) increased the incorporation of 32P into a protein with the same apparent molecular weight of synapsin I. Surprisingly, ouabain did not stimulate phosphorylation of this protein. Trifluoperazine, at the same concentrations that inhibited the release of ACh, blocked the stimulatory effect of tityustoxin and K+ on protein phosphorylation. On the other hand, tetrodotoxin inhibited the effect of tityustoxin on protein phosphorylation but had no effect on phosphorylation evoked by K+. Our results demonstrate for the first time that, at least for ouabain, the release of neurotransmitter is not dependent on protein phosphorylation.

Acetylcholine↗