Biomedical subjects

P Schaeffer

Publications and source records attributed to P Schaeffer.

At least 37 records · Page 2Linked to original sources

PubMed1999

Experimental studies on guanosine 3',5'-cyclic monophosphate levels and airway responsiveness of the novel phosphodiesterase type 5 inhibitor SR 265579 in guinea-pigs.

The effect of 1-cyclopentyl-3-ethyl-6-(3-ethoxypyrid-4-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-one (SR 265579), a potent inhibitor of guanosine 3',5'-cyclic monophosphate (cyclic GMP) phosphodiesterase (PDE5), was examined regarding its specificity toward the other cyclic nucleotide phosphodiesterases, the effect on cyclic nucleotide levels and the bronchodilatory activity, both in vitro and in vivo in guinea-pigs. The effects were compared to those obtained with zaprinast (CAS 37762-06-4), a known PDE5 inhibitor. Anion-exchange chromatography of the soluble fraction of guinea-pig homogenates revealed 5 peaks which corresponded to PDE1, PDE2, PDE3, PDE4 and PDE5. SR 265579 produced a potent and competitive inhibition, with respect to cyclic GMP, of PDE5 with a Ki of 6.4 nmol/l. The compound was 25 fold more potent than zaprinast and demonstrated selectivity toward PDE5. The selectivity index was 14 and 33 with respect to PDE4 and 3, respectively. PDE1 and 2 were only inhibited at considerably higher concentrations. SR 265579 specifically increased the intracellular cyclic GMP levels in guinea-pig tracheal epithelial cells (EC50 = 117 nmol/l). Moreover, in the guinea pig, plasma cyclic GMP levels were significantly increased after the intravenous or oral administration of doses as low as 1 mg/kg. Isolated guinea-pig trachea were relaxed by the addition of SR 265579 as evaluated by measuring either spontaneous tone or relaxation of histamine and acetylcholine-precontracted preparations. PD2 values were of 7.64, 6.52 and 5.25, respectively. In vivo, after i.v. administration, bronchodilatory activity was demonstrated in an artificially-ventilated guinea-pig histamine-induced bronchospasm model with an ED50 of 0.63 mg/kg. In all experiments, SR-265579 was proved to be more active than zaprinast. These results demonstrate that SR 265579 is an orally active, potent and specific inhibitor of PDE5.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1998

Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo.

The binding of 125I-factor Xa to human aortic smooth muscle cell (SMC) monolayers was studied. At 4 degreesC, 125I-factor Xa bound to a single class of binding sites with a dissociation constant value of 3.6+/-0.7 nM and a binding site density of 11,720+/-1,240 sites/cell (n = 9). 125I-factor Xa binding was not affected by factor X, thrombin, or by DX9065, a direct inhibitor of factor Xa, but was inhibited by factor Xa (IC50 = 5.4+/-0.2 nM; n = 9) and by antibodies specific for the effector cell protease receptor 1 (EPR-1), a well-known receptor of factor Xa on various cell types. A factor X peptide duplicating the inter-EGF sequence Leu83-Leu88-(Gly) blocked the binding of 125I-factor Xa to these cells in a dose-dependent manner (IC50 = 110+/-21 nM). Factor Xa increased phosphoinositide turnover in SMCs and when added to SMCs in culture was a potent mitogen. These effects were inhibited by DX9065 and by antibodies directed against EPR-1 and PDGF. Increased expression of EPR-1 was identified immunohistochemically on SMCs growing in culture and in SMCs from the rabbit carotid artery after vascular injury. When applied locally to air-injured rabbit carotid arteries, antibodies directed against EPR-1 (100 mug/ artery) strongly reduced myointimal proliferation 14 d after vascular injury (65-71% inhibition, P < 0.01). DX9065 (10 mg/kg, subcutaneous) inhibited myointimal proliferation significantly (43% inhibition, P < 0.05). These findings indicate that SMCs express functional high affinity receptors for factor Xa related to EPR-1, which may be of importance in the regulation of homeostasis of the vascular wall and after vascular injury.

Animals↗

PubMed1998

SR142948A is a potent antagonist of the cardiovascular effects of neurotensin.

The novel compound SR142948A was compared with SR48692 as an antagonist of neurotensin-induced cardiovascular effects both in vitro and in vivo. SR142948A inhibited [125I]-neurotensin binding [median inhibitory concentration (IC50) = 0.24 +/- 0.01 nM], neurotensin-induced cytosolic free Ca2+ increase (IC50 = 19 +/- 6 nM), and prostacyclin production in human umbilical vein endothelial cells (IC50 = 17 +/- 3 nM) at much lower concentrations than did SR48692 (respective IC50 values, 14 +/- 5, 41 +/- 16, and 86 +/- 16 nM). Oral administration of SR142948A (10 microg/kg) resulted in significant inhibition of neurotensin-induced blood pressure changes, whereas SR48692 was active only at 10-fold higher doses. Furthermore, SR142948A administered i.v. in microg/kg quantities in the rat was as active as mg/kg doses of SR48692 on neurotensin-induced increase in hematocrit. SR142948A injected intradermally also significantly inhibited neurotensin-induced plasma extravasation at concentrations as low as 10 pmol/site, whereas 1,000 pmol/site of SR48692 were necessary to reach a significant inhibition. These data show that SR142948A is a novel, extremely potent antagonist of neurotensin-induced cardiovascular responses both in vitro and in vivo. SR142948A and SR48692 constitute a pair of nonpeptide neurotensin antagonists of different potency, which may be used to probe for the implication of neurotensin receptors in physiologic or pathologic phenomena.

Adamantane↗

PubMed1997

Neurotensin induces the release of prostacyclin from human umbilical vein endothelial cells in vitro and increases plasma prostacyclin levels in the rat.

Human umbilical vein endothelial cells express high affinity neurotensin receptors which are coupled to phosphoinositide turnover and 45Ca2+ efflux (Schaeffer et al., 1995. J. Biol. Chem. 270, 3409-3413). In order to assess the physiological significance of neurotensin receptor activation in endothelial cells, we have compared the in vitro effect of neurotensin on prostacyclin release and cytosolic free calcium increase ([Ca2+]i) as determined by fura-2 fluorescence experiments to the in vivo effect of neurotensin on blood pressure and haematocrit. Neurotensin increased [Ca2+]i levels at low concentrations (EC50 = 4.2 +/- 0.2 nM, n = 3). At similar concentrations, neurotensin was also able to induce prostacyclin release from human umbilical vein endothelial cells (EC50 = 14 +/- 1 nM, n = 3) as determined by a 6-keto-prostaglandin F1 alpha enzyme immunoassay. The neurotensin (100 nM)-induced [Ca2+]i increase and prostacyclin release were inhibited by the specific non-peptide neurotensin receptor antagonist SR 48692 at similar concentrations (IC50 = 41 +/- 16 nM and 86 +/- 17 nM, respectively, n = 3), confirming that these responses were mediated by high affinity neurotensin receptors. Intravenous injection of neurotensin (1-4 nmol/kg i.v.) in the rat resulted in a drop of blood pressure and increased haematocrit, and nearly doubled the plasma levels of 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin. Whereas indomethacin (10 mg/kg i.v.) pretreatment significantly reduced the effect of neurotensin on blood pressure, it did not alter its effect on haematocrit. These results suggest that prostacyclin release plays a role in the hypotensive effects of neurotensin, but is not involved in its effects on haematocrit.

6-Ketoprostaglandin F1 alpha↗

PubMed1997

Nonproteolytic activation of the thrombin receptor promotes human umbilical vein endothelial cell growth but not intracellular CA2+, prostacyclin, or permeability.

Both thrombin and the synthetic tetracapeptide thrombin receptor-activating peptide (TRAP), recently described as a peptide mimicking the new amino terminus created by cleavage of the thrombin receptor, stimulated the proliferation of human umbilical vein endothelial cells (HUVEC) in culture. Although to a lesser extent, F-14, a tetradecapeptide representing the residues 365-378 of human prothrombin, also promoted HUVEC growth, thereby demonstrating that thrombin can stimulate HUVEC growth via both a proteolytic and a nonenzymatic pathway. Thrombin-TRAP, and F-14-induced HUVEC growth were inhibited by a thrombin receptor oligodeoxynucleotide antisense, showing that the growth-inducing effects of all 3 compounds were mediated through the same thrombin receptor. Thrombin and TRAP also stimulated intracellular Ca2+ increase, monolayer permeability increase, and prostacyclin release in HUVEC. None of these effects was observed with F-14 suggesting that thrombin-induced intracellular Ca2+ release, permeability increase, and prostacyclin release in HUVEC required catalytic cleavage of the receptor, whereas thrombin-induced growth might also be due to activation of the thrombin receptor through a nonproteolytic pathway.

Calcium↗

PubMed1997

Human umbilical vein endothelial cells express high affinity receptors for factor Xa.

The binding of [125I]-factor Xa to human umbilical vein endothelial cell (HUVEC) monolayers was studied. At 7 degrees C, [125I]-factor Xa bound to a single class of binding sites with a dissociation constant value of 6.6 +/- 0.8 nM and a binding site density of 57,460 +/- 5,200 sites/cell (n = 3). Association and dissociation kinetics were of a pseudo-first order and gave association and dissociation rate constant values of 0.15 x 10(6) M-1 s-1 and 4.0 x 10(-4) s-1, respectively. [125I]-factor Xa binding was inhibited by factor Xa but was not affected by factor X, thrombin or monoclonal antibodies against factor V, antithrombin-III or tissue factor pathway inhibitor (TFPI) but was inhibited by an antibody specific for the effector cell protease receptor-1 (EPR-1), a well-known receptor of factor Xa on various cell types. [125I]-factor Xa binding to HUVEC was not affected by various inhibitors of factor Xa such as DX 9065, pentasaccharide-antithrombin-III or TFPI. Factor Xa increased intracellular free calcium levels and phosphoinositide turnover in endothelial cells and, when added to HUVEC in culture, factor Xa was a potent mitogen, stimulating an increase in cell number at a 0.3 to 100 nM concentration. HUVEC-bound factor Xa promoted prothrombin activation in the presence of factor Va only. This effect was inhibited by both indirect and direct inhibitors of factor Xa. These findings indicate that HUVEC express functional high affinity receptors for factor Xa, related to EPR-1, which may be of importance in the regulation of coagulation and homeostasis of the vascular wall.

Calcium↗

PubMed1997

Coagulation factor Xa induces endothelium-dependent relaxations in rat aorta.

The relaxing effect of coagulation factor Xa on phenylephrine-contracted rat aortic rings was compared with the effect of thrombin and trypsin. All three proteases induced a dose-dependent relaxation in the presence of an intact endothelium. EC50 values were 3 +/- 1, 24 +/- 9, and 16 +/- 1 nmol/L for thrombin, trypsin, and factor Xa, respectively. Whereas thrombin induced rapid relaxations followed by partial recontraction, trypsin and factor Xa induced slower sustained effects. Factor Xa-induced relaxations were not affected by hirudin at high concentrations (1 mumol/L) but were abolished by DX9065A, a specific inhibitor of the catalytic activity of factor Xa. Furthermore, no relaxations to factor Xa could be elicited in the presence of the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (100 mumol/L), whereas relaxations were not altered in the presence of the inactive enantiomer N omega-nitro-D-arginine methyl ester (100 mumol/L). Addition of factor Xa together with thrombin induced relaxations that were larger than those induced by thrombin alone, whereas factor Xa had no additional effects on trypsin-induced relaxations. Further-more, factor Xa relaxed thrombin-desensitized aortic rings but was ineffective in trypsin-desensitized tissues. These data suggest that factor Xa acts on a cleavable endothelial receptor that induces NO release, resulting in the relaxation of precontracted rat aortic rings. Factor Xa does not act through endothelial thrombin receptors but may activate another cleavable trypsin-sensitive receptor.

Animals↗

PubMed1996

Structural correlates of speed and endurance in skeletal muscle: the rattlesnake tailshaker muscle

The western diamondback rattlesnake Crotalus atrox can rattle its tail continuously for hours at frequencies approaching 90 Hz. We examined the basis of these fast sustainable contractions using electromyography, data on oxygen uptake and the quantitative ultrastructure of the tailshaker muscle complex. The tailshaker muscle has no apparent unique structures; rather, the relative proportions of the structures common to all skeletal muscles appear to be present (1) to minimize activation, contraction and relaxation times via an extremely high volume density of sarcoplasmic reticulum (26 %) as well as, (2) to maximize ATP resysnthesis via a high volume density of mitochondria (26 %). The high rate of ATP supply is reflected in the in vivo muscle mass-specific oxygen uptake of this group of muscles which, at 585 ml O2 kg-1 min-1 during rattling at 30 °C body temperature, exceeds that reported for other ectotherm and many endotherm muscles. Since the change in oxygen uptake paralleled that of the rattling frequency over the range of measured body temperatures, there was a nearly constant O2 cost per muscle contraction (0.139±0.016 µl O2 g-1). Electromyo-graphic analysis suggests that each of the six muscles that make up the shaker complex may be a single motor unit. Finally, the maximum rate of mitochondrial oxygen uptake is similar to that of various mammals, a hummingbird, a lizard, an anuran amphibian and of isolated mitochondria (at 10 000-40 000 molecules O2 s-1 µm2 of cristae surface area, when normalized to 30 °C), suggesting a shared principle of design of the inner mitochondrial membrane among the vertebrates.

Journal Article↗

PubMed1995

Effect of SR 33805 on arterial smooth muscle cell proliferation and neointima formation following vascular injury.

The possible activity of SR 33805 ([[N-[dimethoxy-3,4-phenethyl]-N- methylamino-propoxyl]-4-benzenesulfonyl]-2-isopropyl-3-methyl-1-in dole), a novel Ca2+ channel blocker, in early atherogenesis was investigated. In vitro, SR 33805 strongly inhibited fetal calf serum-induced proliferation of cultured human aortic smooth muscle cells with an IC50 value of 0.3 +/- 0.1 microM (n = 3). In this respect, SR 33805 was several fold more active than the reference compounds: diltiazem, verapamil, nifedipine and fantofarone. SR 33805 was also a potent inhibitor of platelet-derived growth factor- or basic fibroblast growth factor-induced proliferation of human smooth muscle cells. SR 33805 inhibited serum-stimulated 45Ca2+ uptake in these cells, with an IC50 value of 47 +/- 18 nM. The effect of SR 33805 on intimal smooth muscle hyperplasia in rabbit carotid arteries subjected to air-drying endothelial injury was then investigated. After a 16-day treatment, SR 33805 (6.0 mg/kg/day p.o.) inhibited the development of intimal thickening. Under the same experimental conditions, nifedipine, verapamil, diltiazem (2 x 6 mg/kg/day p.o.--16 days) and fantofarone (12 mg/kg/day p.o.--16 days) were inactive. These results show that SR 33805, a novel and potent Ca2+ channel blocker, can reduce myointimal thickening following endothelial injury.

Animals↗

PubMed1995

Human umbilical vein endothelial cells express high affinity neurotensin receptors coupled to intracellular calcium release.

The binding of 125I-neurotensin (NT) to human umbilical vein endothelial cell monolayers was studied. At 20 degrees C, 125I-NT bound to a single class of binding sites with a dissociation constant of 0.23 +/- 0.08 nM and a binding site density of 5500 +/- 1300 sites/cell (n = 3). 125I-NT also bound to human aortic endothelial cells with a dissociation constant of 0.6 +/- 0.26 nM and a binding site density of 32000 +/- 1700 sites/cell. Association and dissociation kinetics were of a pseudo-first order and gave association and dissociation rate constant values of 1.6 x 10(6) M-1 s-1 and 3.5 x 10(-4) s-1, respectively. 125I-NT binding was inhibited by NT analogues with a rank order of potency similar to that characterizing brain high affinity NT binding sites (K0.5, nM): NT8-13 (0.11) > NT (0.35) > acetyl-NT8-13 (1.5) > [Phe11]NT (12) > [D-Tyr11]NT (> 1000). 125I-NT binding was also inhibited by the non-peptide NT antagonist SR 48692 (Ki = 16 nM) but was not affected by levocabastine, an inhibitor of low affinity brain NT binding sites. NT had no effect on cGMP levels in endothelial cells but NT and its analogues increased 45Ca2+ efflux from endothelial cells at nanomolar concentrations with a rank order of potency which was identical to that observed in binding experiments. This effect was inhibited by SR 48692 (IC50 = 8 nM). NT was able to increase phosphoinositide turnover in these cells, and this effect was blocked by SR 48692. The correlation between dissociation constants of NT analogues in binding experiments and IC50 values in 45Ca2+ efflux experiments was very high (r = 0.997) with a slope near unity, indicating that 125I-NT binding sites are functional NT receptors coupled to phosphoinositide hydrolysis and Ca2+ release in human umbilical vein endothelial cells.

Binding Sites↗

PubMed1995

Effect of SR-49059, a vasopressin V1a antagonist, on human vascular smooth muscle cells.

The effects of SR-49059, a new nonpeptide and selective arginine vasopressin (AVP) V1a antagonist, were investigated in binding and functional studies on cultured human aortic vascular smooth muscle cells (VSMC). Characterization of human vascular V1a receptors, using a specific V1a radioiodinated ligand, showed that [125I]-linear AVP antagonist binding to human VSMC membranes was time dependent, reversible, and saturable. A single population of high-affinity binding sites (apparent equilibrium dissociation constant = 15 +/- 6 pM; maximum binding density = 36 +/- 5 fmol/mg protein, i.e., approximately 3,000 sites/cell) with the expected V1a profile was identified. Exposure of these cells to AVP dose-dependently produced cytosolic free [Ca2+] increase [AVP concentration required to obtain a half-maximal response (EC50) = 23 +/- 9 nM] and proliferation (EC50 = 3.2 +/- 0.5 nM). SR-49059 strongly and stereospecifically inhibited [125I]-linear AVP antagonist binding to VSMC V1a receptors [inhibition constant (Ki) = 1.4 +/- 0.3 nM], AVP-evoked Ca2+ increase [concentration of inhibitor required to obtain 50% inhibition of specific binding (IC50) = 0.41 +/- 0.06 nM], and the mitogenic effects induced by 100 nM AVP (IC50 = 0.83 +/- 0.04 nM). OPC-21268, another nonpeptide V1a antagonist, was more than two orders of magnitude less potent than SR-49059 in these models. However, the consistent affinity (Ki = 138 +/- 21 nM) and activity found with OPC-21268 on human VSMC in comparison with the inactivity already observed for other human V1a receptors (liver, platelets, adrenals, and uterus) strongly suggested the existence of human AVP V1a-receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aorta↗

PubMed1994

CCK-JMV-180 acts as an antagonist of the CCKA receptor in the human IMR-32 neuroblastoma cell line.

[125I]Cholecystokinin-8-S (CCK-8-S) bound to a single class of saturable binding sites on the human neuroblastoma cell line IMR-32 (KD = 4 +/- 1.5 nM, Bmax = 10,500 +/- 3,500 sites/cell (n = 6)). These binding sites were of the CCKA type, as demonstrated by the differential inhibition of the binding of [125I]CCK-8-S and CCK-8-S-induced 45Ca2+ efflux by the specific CCKA antagonist SR 27897 and the specific CCKB antagonist PD 134,308. CCK-JMV-180, an analogue of CCK-8-S which has been shown to activate 45Ca2+ efflux in rat cells in a manner similar to CCK-8-S, acted as a potent antagonist of CCK-8-S-induced 45Ca2+ efflux (IC50 = 50 nM) and inhibited [125I]CCK-8-S binding to IMR-32 cells (IC50 = 1.7 nM). These results show that, unlike its CCK-like effect in various animal systems, CCK-JMC-180 acts as an antagonist of CCKA receptors in the human neuroblastoma cell line IMR-32.

Calcium Radioisotopes↗

PubMed1994

Effect of SR 47436, a novel angiotensin II AT1 receptor antagonist, on human vascular smooth muscle cells in vitro.

Proliferation of smooth muscle cells within the intima plays a key role in vascular occlusive disorders such as atherosclerosis and restenosis following balloon angioplasty. Among the factors that may be important in the development of vascular lesions, several authors have reported that the local angiotensin system participates in modulating the proliferation of smooth muscle cells after arterial injury. This study was therefore designed to characterize the antagonistic properties and to investigate the antiproliferative effect of a newly developed non-peptide angiotensin II AT1 receptor antagonist, SR 47436. This compound is a potent and competitive antagonist of the binding of [125I]angiotensin II to its receptor on cultured human aortic smooth muscle cells, exhibiting an IC50 value of 1.7 +/- 0.6 nM. SR 47436 was 10-fold more potent than DuP 753 (Losartan) (IC50 = 20.8 +/- 3.7 nM). In these same cells, SR 47436 potently inhibited the angiotensin II-induced [Ca2+]i increase (IC50 = 0.53 +/- 0.13 vs. 7.4 +/- 1.3 nM for DuP 753). Angiotensin II is a potent mitogen for human aortic smooth muscle cells in culture, exhibiting a maximum proliferative response at 1 microM. SR 47436 and Losartan prevented angiotensin II-induced proliferation of these cells in a dose-dependent manner (IC50 = 0.32 +/- 0.09 and 0.71 +/- 0.08 microM, respectively). SR 47436 displayed a marked in vitro inhibition of serum-induced smooth muscle cell proliferation (IC50 = 5.5 +/- 0.8 microM). A selective AT2 receptor antagonist, PD 123177 did not affect angiotensin II-induced responses in these cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1993

Characterization of cardiac angiotensin AT1 receptors by [3H]SR 47436.

[3H]SR 47436, a selective and potent novel non-peptide antagonist of angiotensin receptors, was used to characterize the cardiac angiotensin AT1 receptors. In neonatal rat heart cells, Scatchard analysis showed a single class of high affinity binding sites (Kd = 0.24 nM, Bmax = 28 fmol/mg protein). The binding was saturable, reversible and prevented by angiotensin II and the AT1 subtype receptor antagonist DuP 753 whilst unaffected by the AT2 receptor antagonist PD123177. In the same cells, angiotensin II induced a twofold increase in the intracellular free Ca2+ concentration ([Ca2+]i), with a half-maximal effect (EC50) at 14 nM. This increase was prevented by SR 47436 (IC50 = 1.03 nM) and by the AT1 receptor antagonist DuP 753, but at higher concentrations (IC50 = 15.6 nM) and was unaffected by PD123177. These data directly demonstrate the presence of cardiac AT1 receptors in rat neonatal cardiomyocytes and confirm the involvement of AT1 receptors in cardiac Ca2+ homeostasis.

Angiotensin I↗

PubMed1992

[The consequences of demographic trends for urban growth].

"The large cities of Switzerland have lost population for the last twenty to thirty years. Now it appears that the number of employers and jobs may also start to stagnate, or even decline. At the present time the large Swiss cities have a population with an unbalanced demographic and economic structure.... It is important that the cities remember that their inhabitants are part of the tax base and try to achieve a population structure that will not burden them in the effort to compete in a changing economic environment. Failure to do so could result in long-term economic decline for some core cities." (SUMMARY IN ENG AND FRE)

Demography↗

PubMed1991

Interactions of calmodulin antagonists with calcium antagonists binding sites.

Calmodulin antagonists have calcium entry blocking properties. In order to quantitatively investigate the interactions of these drugs with calcium channels, their effect on [3H]nitrendipine and [3H]d-cis-diltiazem binding to rat cerebral cortex membrane preparations was compared to their inhibitory effect on the activation of cyclic nucleotide phosphodiesterase by calmodulin. The potency of most antagonists to inhibit [3H]nitrendipine binding was correlated with their calmodulin inhibitory potency. However, bepridil (K0.5 = 280 nM), chlorpromazine (K0.5 = 3 microM), triflupromazine (K0.5 = 1.5 microM), imipramine (K0.5 = 3 microM) and propranolol (K0.5 = 14 microM) were much more active on [3H]d-cis-diltiazem binding than on either [3H]nitrendipine binding or calmodulin, suggesting that these compounds bind to higher affinity sites on the calcium antagonist target protein. Moreover, the potencies of these compounds to compete with [3H]d-cis-diltiazem and to inhibit calcium-induced contractions in depolarized smooth muscle were correlated (R = 0.76, p less than 0.02). These data suggest that low concentrations of these hydrophobic drugs which have calcium and calmodulin antagonistic properties inhibit smooth muscle contraction through calcium entry blockade, not calmodulin antagonism.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed1991

K+ efflux pathways and neurotransmitter release associated to hippocampal ischemia: effects of glucose and of K+ channel blockers.

Ischemia of hippocampal slices leads to 86Rb+ efflux and to amino acid neurotransmitter release. This 86Rb+ efflux which corresponds to the massive K+ efflux from neuronal cells observed in ischemic animals is inhibited by glucose (IC50 = 1.7 mM). Glucose also inhibits the ischemia induced liberation of GABA and aspartate. 86Rb+ efflux is insensitive to any type of known blockers for ATP-sensitive, Ca2(+)-sensitive and voltage-sensitive K+ channels.

4-Aminopyridine↗

PubMed1990

Identification and pharmacological properties of binding sites for the atypical thiazide diuretic, indapamide.

[3H]Indapamide bound to a single class of binding sites in pig renal cortex membranes with a dissociation constant Kd = 35 +/- 13 nM and a binding site density Bmax = 40 +/- 9 pmol/mg of protein. [3H]Indapamide binding was inhibited by the carbonic anhydrase inhibitor, acetazolamide, and by thiazide diuretics with the following rank order of potency: chlorothiazide greater than hydrochlorothiazide approximately metolazone greater than hydroflumethiazide. The effect of the latter drugs to inhibit [3H]indapamide binding was not related to their activity as thiazide diuretics, but was significantly correlated with their inhibitory effect on carbonic anhydrase II. These results suggest that the major renal binding site of [3H]indapamide is a membrane form of carbonic anhydrase. Inhibition of carbonic anhydrase may play a role in the antihypertensive effect of indapamide.

Animals↗