Biomedical subjects

A Leonardi

Publications and source records attributed to A Leonardi.

At least 73 records · Page 4Linked to original sources

PubMed1997

Biphasic control of NF-kappa B activation induced by the triggering of HLA-DR antigens expressed on B cells.

The regulation of NF-kappa B activation following the triggering of HLA-DR antigens by mAb L243 has been studied at various times in Raji cells. Electrophoretic mobility shift assays demonstrated a strong increase of NF-kappa B DNA binding after triggering of HLA-DR antigens. Using TNF-alpha-activity neutralizing antibodies, the authors demonstrated that the upregulation of NF-kappa B was found to depend, at later time point, on an autocrine effect of TNF-alpha secreted following triggering of HLA-DR antigens. In contrast, it was found to be TNF-alpha independent in the early time point. Moreover, the upregulation of NF-kappa B binding activity is regulated by the triggering of selected epitopes of HLA-DR antigens. In fact, mAb L243 but not the staphylococcal superantigens, staphylococcal exotoxin toxic shock syndrome toxin-I or staphylococcal enterotoxin B, regulate the NF-kappa B binding activity.

Antibodies, Monoclonal↗

PubMed1997

Antagonism to noradrenaline-induced lethality in rats is related to affinity for the alpha1A-adrenoceptor subtype.

The potency of several alpha1-adrenoceptor antagonists in preventing the noradrenaline-induced lethality in conscious rats, their binding affinity for the native alpha1A- and alpha1B-adrenoceptors, the recombinant animal alpha1a-, alpha1b- and alpha1d-adrenoceptor subtypes, as well as their functional affinity for the alpha1L-adrenoceptor subtype were evaluated. The potency of the tested compounds as antagonists of noradrenaline-induced lethality was correlated with the affinity for the alpha1A- (and alpha1a-) adrenoceptor subtype, but not with the affinity for the other subtypes. On the contrary, the hypotensive effects of the compounds, assessed in anesthetized rats, were not clearly related with the affinity for any of the alpha1-subtypes. These results suggest that the alpha1A-subtype plays a determining role in preventing lethality induced by noradrenaline in the rats, and that this activity is unrelated to the hypotensive effect of the compounds, which cannot be clearly correlated with affinity for a particular alpha1-adrenoceptor subtype.

Adrenergic alpha-Antagonists↗

PubMed1997

Alpha 1-adrenoceptor subtype selectivity: molecular modelling and theoretical quantitative structure-affinity relationships.

This study constitutes a preliminary rationalization, at the molecular level, of antagonist selectivity towards the three cloned alpha 1-adrenergic receptor (alpha 1-AR) subtypes. Molecular dynamics simulations allowed a structural/dynamics analysis of the seven alpha-helix-bundle models of the bovine alpha 1a-, hamster alpha 1b-, and rat alpha 1d-AR subtypes. The results showed that the transmembrane domains of these subtypes have different dynamic behaviours and different topographies of the binding sites, which are mainly constituted by conserved residues. In particular, the alpha 1a-AR binding site is more flexible and topographically different with respect to the other two subtypes. The results of the theoretical structural/dynamics analysis of the isolated receptors are consistent with the binding affinities of the 16 antagonists tested towards the three cloned alpha 1-AR subtypes. Moreover, the theoretical quantitative structure-affinity relationships obtained from the antagonist-receptor interaction models further corroborates the hypothesis that selectivity towards one preferential subtype is mainly modulated by receptor and/or ligand distortion energies. In other words, subtype selectivity seems to be mainly guided by the dynamic complementarity (induced fit) between ligand and receptor. On the basis of the quantitative models presented it is possible to predict both affinities and selectivities of putative alpha 1-AR ligands as well as to estimate the theoretical alpha 1-AR subtype affinities and selectivities of existing antagonists.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1997

Critical roles for the Bcl-3 oncoprotein in T cell-mediated immunity, splenic microarchitecture, and germinal center reactions.

Chromosomal translocations of bcl-3 are associated with chronic B cell lymphocytic leukemias. Previously, we have shown that Bcl-3, a distinct member of the I kappa B family, may function as a positive regulator of NF-kappa B activity, although its physiologic roles remained unknown. To uncover these roles, we generated Bcl-3-deficient mice. Mutant mice, but not their littermate controls, succumb to T. gondii owing to failure to mount a protective T helper 1 immune response. Bcl-3-deficient mice are also impaired in germinal center reactions and T-dependent antibody responses to influenza virus. The results reveal critical roles for Bcl-3 in antigen-specific priming of T and B cells. Altered microarchitecture of secondary lymphoid organs in mutant mice, including partial loss of B cells, may underlie the immunologic defects. The implied role of Bcl-3 in maintaining B cells in wild-type mice may related to its oncogenic potential.

Animals↗

PubMed1997

Hydrogen-deuterium exchange studies of the rat thyroid transcription factor 1 homeodomain.

The 1H NMR solution structure of the rat thyroid transcription factor 1 homeodomain (TTF-1 HD) showed that the molecule folds like classical homeodomains. The C-terminal extension of helix III (fragment 51-59) appeared to adopt a helical geometry, albeit not as rigid as the preceding portion, but the hydrogen-deuterium exchange of backbone amides and the NOE data provided evidence of a discontinuity between the two moieties of helix III at the highly conserved fragment Asn51-His52-Arg53. Analysis of quantitative measurements of isotope exchange rates allows one to recognize the general occurrence, in that region of HD motifs, of opposite effects to helix III stability. Asparagine, histidine and arginine residues occur most frequently at the beginning and end of protein helices. In TTF-1 HD a local fluctuation is observed in the fragment 51-53 which either kinks or tightens the alpha-helix. A search through the protein structure database reveals that the three most common variants of HD fragments 51-53 are often involved in helices and, frequently, in helix initiation or termination. For homeodomains in general, the nature of the fragment 51-53 may be related to the conformational dynamics of their DNA-recognition helix (helix III). Besides the specific results on fragment 51-53, the complete isotope exchange analysis of TTF-1 HD data shows that the partially solvent-exposed recognition helix is stabilized by hydrophobic interactions, like most of the structured regions of the molecule. Hydrophobic stabilization of the contacting regions meets the requirements of a DNA-interaction mechanism which, as shown with other DNA-protein complexes, should entail negative heat capacity variations due to changes in solvent exposure of the nonpolar protein surface.

Amides↗

PubMed1997

Effect of lodoxamide and disodium cromoglycate on tear eosinophil cationic protein in vernal keratoconjunctivitis.

AIM: To validate the use of tear eosinophil cationic protein (ECP) as a marker for eosinophil activation, and its pharmacological modulation, in addition to evaluating the efficacy of lodoxamide and sodium cromoglycate in the treatment of vernal keratoconjunctivitis (VKC). METHODS: Tears were collected from 30 patients affected by active mild to moderate VKC before and after therapy with disodium cromoglycate 4% (DSCG) (n = 15) or lodoxamide 0.1% (n = 15) for 10 days. Tear cytology and ECP measurement were performed, and ocular signs and symptoms evaluated. RESULTS: While statistically significant changes did not occur after DSCG therapy, mean tear ECP increased from 343 (SD 363) micrograms/l to 571 (777) micrograms/l due to marked elevation in six eyes. The clinical score in DSCG eyes did not improve. After lodoxamide therapy, both clinical signs and symptoms, and tear ECP levels (560 (756) micrograms/l to 241 (376) micrograms/l) decreased significantly (p < 0.0001 and p < 0.01, respectively). Compared with DSCG treatment, lodoxamide was more effective in reducing signs and symptoms (p < 0.005). ECP levels were significantly correlated with signs, symptoms, corneal involvement, and number of eosinophils in tears (p < 0.0001). CONCLUSIONS: In patients with VKC, lodoxamide significantly reduced ECP tear levels, and thus, eosinophil activation, and was more effective than DSCG in reducing clinical signs and symptoms.

Biomarkers↗

PubMed1997

Triggering of HLA-DR antigens differentially modulates tumor necrosis factor alpha release by B cells at distinct stage of maturation.

Triggering of HLA class II antigens by the anti-HLA-DR monoclonal antibody (mAb) L243 significantly (P < 0.05) and differentially enhanced the release of tumor necrosis factor alpha (TNF-alpha) by the non-Hodgkin's lymphoma cells Ri-I, Ci-I, and Sc-I, which are at a distinct stage of B-cell differentiation, and by the more mature Burkitt lymphoma cell Raji; in contrast, it did not induce TNF-alpha release by the pre-B leukemia cells Nalm-6 and BV173. TNF-alpha release peaked at 24 h and decreased thereafter, and it was dose dependent and preceded by an increase of TNF-alpha mRNA detectable after 3 h of stimulation with mAb L243. Secreted TNF-alpha mediated the enhancement of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) binding activity; in fact, the triggering of HLA-DR antigens in the presence of antihuman TNF-alpha-neutralizing antibodies did not upregulate NF-kappa B and AP-1. In contrast, released TNF-alpha was not responsible for the homotypic aggregation of Ri-I, Ci-I, Sc-I, and Raji cells induced by mAb L243, and it did not affect the proliferation of B cells investigated. Altogether, our data demonstrate that: (a) the ability of B cells to release TNF-alpha after triggering of HLA-DR antigens depends on their stage of differentiation; (b) levels of released TNF-alpha seem to correlate with the stage of B-cell maturation but do not correlate with the amounts of cell surface HLA-DR antigens; (c) secreted TNF-alpha regulates the levels of expression of NF-kappa B and AP-1 by an autocrine loop; and (d) intracellular signals mediating TNF-alpha release by B cells are distinct from those regulating homotypic aggregation and proliferation.

Antibodies, Monoclonal↗

PubMed1997

Pharmacological characterization of the uroselective alpha-1 antagonist Rec 15/2739 (SB 216469): role of the alpha-1L adrenoceptor in tissue selectivity, part I.

Alpha adrenoceptor antagonists have been convincingly shown to be beneficial in reducing both subjective and objective indices of urethral obstruction in benign prostatic hyperplasia. Rec 15/2739 (SB 216469) is a novel alpha-1 adrenoceptor (alpha-1 AR) antagonist currently being developed for benign prostatic hyperplasia. When evaluated in radioligand binding assays with expressed animal or human alpha-1 ARs, Rec 15/2739 shows marked to moderate selectivity for the alpha-1a AR subtype. Its affinity for the recombinant alpha-2 AR subtypes or native dopaminergic D2 receptor was about 100-fold lower than that for alpha-1a AR subtype. In canine tissues, Rec 15/2739 was 20-fold more potent as an inhibitor of [3H]prazosin binding to prostate vis-a-vis aorta. Functional studies in isolated rabbit tissues also confirmed the uroselectivity of Rec 15/2739, with substantially higher affinity (Kb = 2-3 nM) being observed in urethra and prostate, compared with ear artery and aorta (Kb = 20-100 nM). The in vitro selectivity observed with Rec 15/2739 was confirmed in vivo in the anesthetized dog, comparing potency against norepinephrine- or hypogastric nerve stimulation-induced urethral contraction with its ability to reduce diastolic blood pressure. In this model, Rec 15/2739 had greater selectivity than any other alpha-1 AR antagonist examined, including terazosin and tamsulosin. Based on the low potency of prazosin and some of its structural analogs in the rabbit and dog lower urinary tract tissues, it appears that norepinephrine contracts these tissues via activation of the alpha-1L AR. Hence this alpha-1 AR subtype, rather than the alpha-1A AR, may mediate the contraction in vivo.

Adrenergic alpha-Antagonists↗

PubMed1997

Pharmacological characterization of the uroselective alpha-1 antagonist Rec 15/2739 (SB 216469): role of the alpha-1L adrenoceptor in tissue selectivity, part II.

The aim of the present work was to investigate whether or not the uroselectivity of Rec 15/2739 and several other alpha-1 adrenoceptor (alpha1-AR) antagonists observed in the anesthetized dog could be related to selectivity of these compounds for a particular alpha-1 AR subtype. The binding affinity of the tested compounds for canine prostate alpha-1 ARs and their in vitro functional affinity for the alpha-1 ARs of rabbit urethra and prostate correlated with their functional affinity for the alpha-1L AR subtype, but not with the binding affinity for recombinant animal and human alpha-1a, alpha-1b and alpha-1d AR subtypes. Similar results were obtained when the in vivo potency on urethral pressure was correlated with the affinity for the alpha-1 AR subtypes; also in this case alpha-1L AR gave the best correlation. No correlation was obtained by considering the other alpha-1 AR subtypes. The in vivo hypotensive effects observed in dog after i.v. administration of the considered compounds correlated only with the binding affinity for the animal and human alpha-1d subtype. In conclusion, the results shown in the present paper indicate that the potencies of different alpha-1 antagonists against the contractions induced by norepinephrine on tissues of the lower urinary tract of rabbits and dogs are better correlated with their affinity for the putative alpha-1L subtype than for the alpha-1a subtype. Only the compounds showing selectivity for the alpha-1L subtype versus the alpha-1d subtype proved highly selective in vivo for the lower urinary tract versus the vascular tissues.

Adrenergic alpha-Antagonists↗

PubMed1996

Synthesis and biological profile of the enantiomers of [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin- 1-yl]furan-2-ylmethanone (cyclazosin), a potent competitive alpha 1B- adrenoceptor antagonist.

The enantiomers of [4-(4-amino-6, 7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin-1-yl]-fu ran- 2-ylmethanone (cyclazosin, 1) were synthesized from the chiral furan-2-yl(cis-octahydroquinoxalin-1-yl)methanone [(+)-2 and (-)-2], which were obtained by resolution of the racemic amine with (S)-(+)- and (R)-(-)-mandelic acid. The binding profile of the enantiomers of 1 was assessed at alpha 1-, alpha 2-, D2, and 5-HT1A receptors as well as at native alpha 1A- and alpha 1B- and cloned alpha 1a-, alpha 1b-, and alpha 1d-adrenoceptor subtypes in comparison with prazosin, spiperone, and AH11110A. (+)-1 displayed a 40-90-fold selectivity for the alpha 1B(alpha 1b)-adrenoceptor relative to alpha 1A(alpha 1a) and alpha 1d subtypes. A significant enantioselectivity was observed at the alpha 1A(alpha 1a)-adrenoceptor and particularly at alpha 1d-adrenoceptors since (-)-1 was 11-14- and 47-fold, respectively, more potent than (+)-1. Furthermore the enantiomer (+)-1 displayed selectivities of 1100-, 19000-, and 12000-fold in binding to alpha 1b-adrenoceptors relative to alpha 2-adrenoceptors and 5-HT1A and D2 receptors. These results indicate that (+)-1, [(+)-cyclazosin] is the most potent and selective ligand for the alpha 1B-adrenoceptor subtype so far described and may be a valuable tool in the characterization of alpha 1-adrenoceptor subtypes.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1996

Analysis of the solution structure of the homeodomain of rat thyroid transcription factor 1 by 1H-NMR spectroscopy and restrained molecular mechanics.

The solution structure of the rat thyroid transcription factor 1 (TTF-1) homeodomain has been elucidated by 1H-NMR and restrained modeling. The TTF-1 homeodomain folds in the same manner as classical homeodomains, with three helices, a loose loop between the first two helices, and a tight turn between helix II and helix III. The typical assembly of the hydrophobic core is maintained and N-capping motifs are identified in helix I and helix III. The N-terminal stretch of helix II exhibits some mobility, similar to the preceding loop region, which may be related to its anomalous capping. The N-terminal decapeptide and the C-terminal octapeptide of the molecule (68 residues long) are disordered. All the previous characteristics are shared by all known isolated homeodomain structures. An important difference among these structures occurs at the C-terminal extension of helix III, which is either disordered or helically folded. In the TTF-1 homeodomain, the C-terminal extension of helix III (residues 51-59) appears structured, albeit not as rigidly as the preceding portion. Analysis of the NOEs and hydrogendeuterium exchange of backbone amides provides evidence for discontinuity between the two moieties of helix III, which is introduced by a tightening or a kink of residues 51-53.

Animals↗

PubMed1996

In the TTF-1 homeodomain the contribution of several amino acids to DNA recognition depends on the bound sequence.

The thyroid transcription factor-1 homeodomain (TTF-1HD) shows a peculiar DNA binding specificity, preferentially recognizing sequences containing the 5'-CAAG-3' core motif. Most other homeodomains instead recognize sites containing the 5'-TAAT-3' core motif. Here, we show that TTF-1HD efficiently recognizes another sequence, called D1, devoid of the 5'-CAAG-3' core motif. Different experimental approaches indicate that TTF-1HD contacts the D1 sequence in a manner which is different to that used to interact with sequences containing the 5'-CAAG-3' core motif. The binding activities that mutants of TTF-1HD display with the D1 sequence or with the sequence containing the 5'-CAAG-3' core motif indicate that the role of several DNA-contacting amino acids is different. In particular, during recognition of the D1 sequence, backbone-interacting amino acids not relevant in binding to sequences containing the 5'-CAAG-3' core motif play an important role. In the TTF-1HD, therefore, the contribution of several amino acids to DNA recognition depends on the bound sequence. These data indicate that although a common bonding network exists in all of the HD/DNA complexes, peculiarities important for DNA recognition may occur in single cases.

Amino Acids↗

PubMed1996

Synthesis, absolute configuration, and biological profile of the enantiomers of trans-[2-(2,6-dimethoxyphenoxy)ethyl] [(3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2-yl)methyl]amine (mephendioxan), a potent competitive alpha 1A-adrenoreceptor antagonist.

The enantiomers of trans-[2-(2,6-dimethoxyphenoxy)ethyl] [(3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2-yl) methyl]amine (mephendioxan, 2) were synthesized from the chiral trans-3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2-carboxylic acids [(+)-3 and (-)-3] which in turn were obtained through the resolution of the racemic acid with (R)- and (S)-alpha-methylbenzylamine. Comparison of CD spectra of the enantiomers of 2 with that of (2S,3S)-3-methyl-2-phenyl-1,4-benzodioxane allowed the assignment of the 2S,3S configuration to the (-)-enantiomer of 2 and of the 2R,3R configuration to the other enantiomer. The binding profile of the enantiomers of 2 was assessed at alpha 1, alpha 2, D2, and 5-HT1A receptors, in comparison to WB 4101 (1), 5-methylurapidil, and (+)-niguldipine. In addition, the two enantiomers were investigated at native and cloned alpha 1-adrenoreceptor subtypes. (-)-2 was 10-30 times as potent as the (+)-enantiomer at alpha 1-adrenoreceptor subtypes in both functional and binding assays. It was 36-fold selective for the alpha 1A- versus alpha 1B-adrenoreceptor and 60- and 20-fold selective in binding to the alpha 1a-adrenoreceptor relative to alpha 1b and alpha 1d subtypes, respectively. Furthermore, the enantiomer (-)-2 displayed selectivities of 12000-, 2500-, and 250-fold in binding to alpha 1a-adrenoreceptors relative to alpha 2-adrenoreceptors and 5-HT1A and D2 receptors. These results indicate that (-)-2 may be a valuable tool in the characterization of alpha 1-adrenoreceptor subtypes.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1996

Functional antagonistic activity of Rec 15/2739, a novel alpha-1 antagonist selective for the lower urinary tract, on noradrenaline-induced contraction of human prostate and mesenteric artery.

The aim of this study was to compare with known reference standards the functional in vitro alpha-1 antagonistic activity of Rec 15/2739 on noradrenaline-induced contractions of human prostate and mesenteric artery. We also characterized these tissues with regard to the alpha-1 adrenoceptor subtypes present. Comparing the apparent pKB values revealed Rec 15/2739 to be one of the most potent compounds action on the prostate. Its potency was slightly lower than that of tamsulosin and was higher than the potencies of prazosin, terazosin and 5-methylurapidil. On the mesenteric artery, tamsulosin was the most potent compound. Comparing the results from the functional studies with those obtained from radioreceptor binding studies, we found that the potency (pKB value) in inhibiting the contraction of prostatic tissue showed a close and significant correlation with the affinity for native and recombinant alpha-1A adrenoceptors. No significant correlation was found with affinity for either the native or the recombinant alpha-1B adrenoceptor subtype, or for recombinant alpha-1d receptors. Similar results were obtained for mesenteric artery. In order to characterize further the alpha-1 adrenoceptor subtypes present in the examined tissues, we investigated the functional effects of chloroethylclonidine, an alpha-1B-D subtypes selective alpha-1 adrenoceptor irreversible antagonist, and those of nifedipine, which antagonizes the extracellular calcium influx primarily mediated by alpha-1A adrenoceptor stimulation. The results indicate the presence of both chloroethylclonidine-sensitive and -insensitive alpha-1 adrenoceptor subtypes in the human prostate, whereas in mesenteric artery the alpha-1A subtype seems to be present exclusively. The possibility that the functionally relevant alpha-1 adrenoceptor subtype could be classified as alpha-1L in both tissues shoul also be considered.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1996

Antihypertensive effects of lercanidipine in experimental hypertensive rats and dogs.

The antihypertensive action of lercanidipine (CAS 132866-11-6, Rec 15/2375), a new 1,4-dihydropyridine (1,4-DHP) calcium entry blocker (CEB), was examined in spontaneously hypertensive rats (SHR) and renal hypertensive dogs after acute and repeated administration, in comparison to several reference 1,4-DHPs. In acute experiments in SHR, lercanidipine reduced diastolic blood pressure showing a potency similar to felodipine and 2-3 fold higher than those of nicardipine and nitrendipine, after both intravenous and oral administration. Analysis of the area under the curves of percent reduction of diastolic blood pressure exerted for 3 and 8 h after intravenous and oral administrations, respectively, showed that the duration of the antihypertensive effect of lercanidipine was longer than that of the reference dihydropyridines. After repeated administrations to SHR no tachyphylaxis was observed, as indicated by the marked and persistent decrease in systolic blood pressure elicited by lercanidipine, given orally once a day for 21 days. Moreover, starting from the first week of treatment, the daily basal values of systolic blood pressure of the rats treated with lercanidipine were significantly lower than those of the placebo-treated group. In renal hypertensive dogs, after acute oral administration, lercanidipine was as potent as nitrendipine. After repeated administration, the action of lercanidipine was longer lasting than that of nicardipine and no decrease in the antihypertensive effects was observed. The in vivo studies show that lercanidipine has a potent and long-lasting antihypertensive profile, suggesting that this compound may be used for once-a-day treatment.

Administration, Oral↗

PubMed1996

Pharmacological in vitro studies of the new 1,4-dihydropyridine calcium antagonist lercanidipine.

The present studies were undertaken to examine the in vitro calcium antagonistic properties of lercanidipine (CAS 132866-11-6, Rec 15/2375) in vascular and non-vascular tissues, as well as its binding profile and in particular its affinity to the calcium channel binding sites. Lercanidipine proved to be endowed with high affinity for the dihydropyridine subunit of the L-type calcium channel, where it was much more potent than on the other receptors tested. The nature of the interaction of lercanidipine with the calcium channel appears competitive, as evidenced by a progressive increase in the apparent Kd of the ligand with no change in Bmax. The performed functional in vitro studies in isolated vascular and cardiac tissues demonstrated that lercanidipine has a slower onset and offset of calcium antagonistic activity compared with other calcium antagonists. The time-course of inhibition of vascular smooth muscle contraction showed substantial differences after addition of lercanidipine with regard to the other calcium antagonists tested (nitrendipine and amlodipine). On repeated washing of rat aorta to remove the drugs from the preparation, the effects of nitrendipine disappeared rapidly. After amlodipine incubation, contractility of the tissue was still impaired after 6 h washout with the highest concentrations tested, but completely recovered in 1-3 h after washout of the lowest concentration. On the contrary, the preparations incubated with lercanidipine showed a decrease in contractility that reached the maximum 1 to 3 h after the removal of the compound from the bath at all the active concentrations tested. The functional calcium antagonistic activity of lercanidipine was also evaluated as relaxing potency against the tonic contractions induced by preincubation of rat aorta, bladder and colon with 80 mmol/l K+. In rat aorta, lercanidipine proved more potent than nitrendipine. Comparing the IC50 values evaluated after 3 h of contact time, lercanidipine resulted more active on the vascular tissue with potency ratios of 177 and 8.5 for aorta vs bladder and aorta vs colon, respectively. In contrast, nitrendipine showed about the same activity in the three tested tissues, and potency ratios of 2.0 and 0.8 for aorta vs bladder and aorta vs colon were calculated. In rat aortic strips maintained during the incubation with lercanidipine at different degrees of depolarization, the functional calcium antagonistic activity markedly increased by raising the tissue depolarization and the potency ratio between the IC50 values evaluated at 5 and 100 mmol/l K+ resulted 138. Nitrendipine provided very similar results, whereas nifedipine activity did not seem to be affected by raising the tissue depolarization. The negative inotropic effects of lercanidipine on normally and partially depolarized rabbit ventricular strips, as well as in guinea-pig atria, were negligible in comparison to its effects on vasculature. On the whole these characteristics suggest a slow onset of action and long duration of effects also after in vivo administration. In addition, the unique vascular selectivity of lercanidipine implies that the therapeutically desirable vasodilator activity is not or scarcely associated with a decrease in cardiac contractile force.

Adrenergic alpha-Agonists↗

PubMed1996

Inhibition of bovine cathepsins L and S by stefins and cystatins.

Inhibition of bovine cathepsins L and S by bovine stefin B, human stefins A and B and cystatin C was studied under pseudo-first-order conditions by continuous fluorimetric assay. All inhibitors formed very tight complexes with the enzymes (Ki < or = 29 pM). The binding was reversible (kdiss = 0.52 - 16.7 x 10(-4) s-1) and very fast (kass = 2.8 - 6.2 x 10(7) M-1 S-1). Cystatin C was the strongest inhibitor of the enzymes, but the affinity was too tight to be measured accurately by this method. Consistently weaker inhibition of cathepsin S by all the stefins is apparent due mainly to the higher dissociation rate constants.

Animals↗

PubMed1996

Haemodynamic effects of lercanidipine in anaesthetized open-chest dogs.

In this study, the haemodynamic effects of lercanidipine (CAS 132866-11-6, Rec 15/2375) in anaesthetized open-chest dogs were investigated in comparison with nitrendipine. Intravenously administered lercanidipine induced a dose-related, long-lasting reduction in systemic and coronary vascular resistances, with concomitant decrease in arterial blood pressure and increase in coronary blood flow. The hypotensive ED25 was 6.1 micrograms/kg and 4.2 micrograms/kg (decrease of mean blood pressure and of total peripheral resistances, respectively) and the ED50 on coronary vasodilation, 4.8 micrograms/kg 7.8 micrograms/kg (increase of coronary blood flow and decrease in coronary vascular resistances, respectively). The time-course of the haemodynamic effects was investigated after administration of 5 micrograms/kg. A slow onset of haemodynamic vasodilation and long-lasting activity were observed, since peak effects on mean blood pressure and coronary blood flow occurred at 20 and 30 min after the administration, respectively, and the effects on systemic and coronary resistances were still significant at 30 and 150 min after administration, respectively. A reflex, non-dose-dependent increase in heart rate was observed after the administration of 10 and 30 micrograms/kg, which was absent with the 5 micrograms/kg dose. As far as cardiac contractility was concerned, the contractile index dP/dtmax and dP/dt/P were analyzed. In the dose-response study, dP/dtmax was practically not affected. In the time-course study, dP/dtmax was not modified after administration of 5 micrograms/kg, and dP/dt/P showed a slight but long-lasting increase. Haemodynamic investigation confirmed in vivo the high vascular selectivity of lercanidipine and a lack of sympathetic reflex activation at vasodilating doses.

Anesthesia↗