Association between heterozygous alpha 1-antitrypsin deficiency and genetic hemochromatosis.
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Genetic Linkage↗
Biomedical subjects
I Graziadei
Publications and source records attributed to I Graziadei.
Different stereoselective effects of (R)- and (S)-propafenone: clinical pharmacologic, electrophysiologic, and radioligand binding studies.
Propafenone is a class 1c antiarrhythmic agent with moderate beta-blocking activity as a result of a structural similarity to beta-adrenoceptor antagonists. In a randomized, double-blind crossover exercise study, eight healthy volunteers were examined before and 2 1/2 hours after oral administration of 300 mg (R,S)-, 150 mg (R)-, and 150 mg (S)-propafenone hydrochloride. The mean rate pressure product was significantly reduced by (R,S)-propafenone hydrochloride (-5.2%; p = 0.045) and half-dosed (S)-propafenone hydrochloride (-5.9%; p = 0.013), whereas the (R)-enantiomer caused no significant changes. There was a significant difference between the effects of (R)- and (S)-propafenone (p = 0.033). In beta-adrenoceptor-binding inhibition experiments with (S)-(125I)iodocyanopindolol in a sarcolemma-enriched cardiac membrane preparation, the eudismic ratio of (S)- over (R)-propafenone was 54. On the spontaneously beating Langendorff-perfused guinea pig heart, 3 x 10(-6) mol/L of both (R)- and (S)-propafenone resulted in significant changes (p less than 0.01) on His bundle conduction (+79% +/- 27% and +69% +/- 9%), as well as comparable decreases in the maximal rate of pacing with 1:1 conduction of the atrial (-54% +/- 10% and -57% +/- 8%) and ventricular myocardium (-42% +/- 6% and -43% +/- 6%), indicating equal effects in sodium channel-dependent antiarrhythmic class 1 activity. Thus (R)- and (S)-propafenone exert different beta-blocking actions but equal effects on the sodium channel-dependent antiarrhythmic class 1 activity. More specific antiarrhythmic class 1 therapy with reduction of beta-blocking side effects may be attained with optically pure (R)-propafenone hydrochloride instead of the currently used racemic mixture.
Administration, Oral↗
Mitochondrial Ca2+ antagonist binding sites are associated with an inner mitochondrial membrane anion channel.
The inner mitochondrial membrane contains specific Ca2+ antagonist binding sites unrelated to the L-type Ca2+ channel. The mitochondrial 1,4-dihydropyridine (DHP) and phenylalkylamine sites are reciprocally allosterically coupled, require anions (e.g., Cl-, No3-) for optimal binding, and are inhibited by purine and pyrimidine nucleotides in a noncompetitive manner. In mitochondrial swelling experiments, a concentration-dependent inhibition of an inner mitochondrial membrane anion channel (IMAC) by Ca2+ antagonists from different chemical classes can be demonstrated. Under the conditions of the swelling experiments, affinity of different Ca2+ antagonists and amiodarone, a known IMAC inhibitor, for the mitochondrial (+/-)-[3H]nitrendipine binding site (Kd, 7.2 +/- 2.0 microM; Bmax, 1.03 +/- 0.37 nmol/mg of protein) strongly correlated with their inhibitory potency for the IMAC. Linear regression of pIC50 values for IMAC-induced swelling versus pIC50 values for (+/-)-[3H]nitrendipine binding inhibition yielded a correlation coefficient of 0.91 for all tested DHPs (n = 12, p less than 0.001). Amiodarone inhibited (+/-)-[3H]nitrendipine binding and IMAC-induced swelling with pIC50 values of 6.11 and 5.93, respectively. The correlation coefficient between binding and inhibition of IMAC-induced swelling for amiodarone and all tested Ca2+ antagonists (including non-DHP compounds) was 0.76 (n = 20, p less than 0.001), with the slopes approaching unity. These results suggest the association of the mitochondrial Ca2+ antagonist binding sites with an IMAC.
Amiodarone↗
Hydrophobic calcium channel ligands: methodical problems and their solution.
Niguldipine is a 1,4-dihydropyridine derivative that combines L-type Ca2+ channel-blocking effects and alpha 1-adrenolytic activity within a single molecule, exemplifying a novel approach in the treatment of hypertension. As niguldipine is a very hydrophobic compound, it (1) readily adsorbs to surfaces of the plastic-ware often used in radioligand binding assays and (2) partitions into the hydrophobic membrane compartments. Both phenomena decrease the actual free drug concentration in radioligand-binding assays and lead to gross underestimation of the affinity of niguldipine (and other hydrophobic ligands) for the 1,4-dihydropyridine binding domain of the L-type Ca2+ channel or for alpha 1A adrenoceptors, respectively. Partitioning of the hydrophobic molecules into the membrane phase leads to a dependence of the Ki value on "total receptor" concentration despite mathematic corrections of the experimentally determined IC50 values. The Ki dependence was mimicked by adding denatured membranes (devoid of high-affinity receptor-binding activity) to native membrane preparations. Loss to pipet tips and tubes was avoided by a special dilution protocol. Partitioning into the hydrophobic membrane compartments needed more elaborate correction procedures.
Adsorption↗
Stereoselective binding of niguldipine enantiomers to alpha 1A-adrenoceptors labeled with [3H]5-methyl-urapidil.
[3H]5-Methyl-urapidil, a potent antihypertensive derivative of urapidil, binds to alpha 1A-adrenoceptors in rat brain cortex membranes with a dissociation constant (KD) of 0.89 nM and a Bmax of 116 fmol/mg protein. The ligand does not bind to purified liver cell membranes (alpha 1B-adrenoceptors). [3H]5-Methyl-urapidil also labels 5-HT1A receptors in brain membranes (KD: 0.84 nM and Bmax: 235 fmol/mg protein). (+/-)-Niguldipine, a novel 1,4-dihydropyridine with Ca2+-antagonistic as well as alpha 1A-adrenoceptor blocking properties, is a competitive inhibitor of [3H]5-methyl-urapidil binding to alpha 1A-adrenoceptors. In contrast to those for prazosin, the Ki values for niguldipine were highly dependent on the membrane protein concentration, indicating partitioning of niguldipine into hydrophobic compartments unavailable for alpha-adrenoceptor interaction. The extrapolated, 'true' Ki values were as follows: (+/-)-niguldipine: 0.298 nM, (-)-niguldipine: 3.12 nM, (+)-niguldipine: 0.145 nM.
Animals↗
Lack of stereoselectivity in the inotropic and phosphodiesterase inhibitory effects of saterinone enantiomers.
The enantiomers of the positive inotropic and a1-adrenoceptor blocking agent saterinone (+/-)-1,2-dihydro-5-[4-[2-hydroxy-3- [4-(2-methoxyphenyl)-1-piperazinyl]propoxy] phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) have been investigated with in vitro and in vivo models in laboratory animals. In the guinea pig papillary muscle, saterinone enantiomers had equipotent inotropic activity and were also as potent as racemic saterinone; the (R)-enantiomer, however, exhibited a greater efficacy than the related compounds. Saterinone and its enantiomers were equipotent in the inhibition of phosphodiesterase PDE III activity in the guinea pig myocardium. The equipotent inotropic effects were also observed after parenteral and enteral administration in cats. In receptor binding studies, (S)-saterinone was 10-fold more potent than (R)-saterinone by inhibiting [3H]-prazosin binding to specific alpha 1-adrenoceptor sites in rat brain cortex membranes. However, in the isolated thoracic aorta of the rabbit, (S)-saterinone was only 3-fold more potent than (R)-saterinone at preventing the pressor effects of phenylephrine. When the enantiomers were tested in vivo against the pressor effects of phenylephrine in the pithed rat, (S)-saterinone was only 2-fold more potent than (R)-saterinone in its alpha 1-adrenoceptor blocking potency. Thus the enantiomers of saterinone do not display enantio-selectivity in their inotropic and PDE III inhibitory effects in vitro, nor in their cardiotonic effects in vivo. There is a slight enantio-selectivity at alpha 1-adrenoceptors in receptor binding studies, but this is reduced to biologically irrelevant magnitude in functional studies in vitro and in vivo.
3',5'-Cyclic-AMP Phosphodiesterases↗
The mitochondrial high-capacity low-affinity (+/-)-[3H]nitrendipine binding site is regulated by nucleotides.
The high-capacity, low-affinity (+/-)-[3H]nitrendipine binding site in the inner mitochondrial membrane from guinea-pig heart is regulated by purine and pyrimidine nucleotides. The rank order in (+/-)-[3H]nitrendipine binding inhibition assays (with decreasing potency) was: ATP (IC50 11.8 microM) = adenosine 5'-O-(2-thiotriphosphate (ATP gamma S) greater than 5'-adenylylimidodiphosphate (AppNHp) greater than ADP much greater than GTP = ITP = CTP greater than UTP greater than guanosine 5'-tetraphosphate (GT4P) greater than guanosine 5'-O-(2-thiotriphosphate) (GTP gamma S) greater than 5'-guanylylimidodiphosphate (GppNHp) greater than IDP greater than CDP greater than GDP. There was no effect of AMP, adenosine 3':5'-cyclic monophosphate (cAMP), adenosine, UDP, NAD, and NADP. The ATP effect was fully reversible upon wash-out. Adenine nucleotides and analogs had a (+/-)-[3H]nitrendipine binding inhibition profile in mitochondrial membranes from guinea-pig liver or kidney similar to that obtained in heart mitochondrial membranes. In heart mitochondria, 0.3 mM ATP decreased the Bmax from 1.69 +/- 0.04 nmol/mg protein to 0.73 +/- 0.24 nmol/mg protein whilst it decreased the KD only moderately, from 521 +/- 50 to 352 +/- 43 nM, in equilibrium saturation studies. In kinetic studies, ATP slowed down the dissociation rate of the (+/-)-[3H]nitrendipine binding site complex from 0.016 +/- 0.004 to 0.0042 +/- 0.0002 min-1 but it also decreased the association rate constant from 1.52 +/- 0.15 to 0.41 +/- 0.28 10(4).M-1.min-1, yielding a kinetically determined KD (1024 nM) identical to the control KD (1053 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphate↗