Biomedical subjects

M Astolfi

Publications and source records attributed to M Astolfi.

46 records · Page 3Linked to original sources

PubMed1988

The antagonism induced by ruthenium red of the actions of capsaicin on the peripheral terminals of sensory neurons: further studies.

Ruthenium Red, an inorganic dye which blocks transmembrane calcium (Ca) fluxes in neural tissues, reduced the capsaicin-induced release of substance P-like immunoreactivity from muscle strips of the guinea-pig urinary bladder in a concentration-dependent (30 nM - 3 microM) manner, and protected the sensory fibers from capsaicin-induced densensitization. A similar antagonism of the actions of capsaicin was observed in functional experiments (capsaicin-induced contraction of the isolated guinea-pig bladder or inhibition of twitches of the isolated rat vas deferens). In view of its established action on the depolarization-coupled entry of Ca into synaptosomes and the secretion of transmitter, we propose that Ruthenium Red could antagonize the action of capsaicin on the peripheral terminals of sensory nerves by a similar mechanism, thereby suppressing transmitter secretion and preventing the establishment of desensitization.

Animals↗

PubMed1988

Simultaneous release of substance P- and calcitonin gene-related peptide (CGRP)-like immunoreactivity from isolated muscle of the guinea pig urinary bladder.

Capsaicin (10 microM) induced a tetrodotoxin (TTX)-resistant release of substance P (SP)- and calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) from muscle strips of the guinea pig isolated urinary bladder. A second application of capsaicin had no effect, indicating a specific effect on sensory nerves (desensitization). In functional experiments, capsaicin produced a phasic contraction of isolated bladder strips. This response was TTX-resistant, exhibited desensitization and was specifically antagonized by [D-Pro4, D-Trp7.9, Phe11] SP(4-11) a SP antagonist which also reduced, at a similar extent, the contraction induced by exogenous SP. These findings provide direct neurochemical and functional evidence for a transmitter role for a SP-like peptide(s) from peripheral sensory terminals in the guinea pig urinary bladder.

Animals↗

PubMed1988

Differential temperature-dependency of electrophysiological and inotropic actions of nifedipine, verapamil and cinnarizine in K+-depolarized ventricular myocardium.

1. Temperature dependency (in the range 27-37 degrees C) of inotropic and electrophysiological effects of equieffective (EC30 at 37 degrees C) concentrations of nifedipine, verapamil and cinnarizine was assessed in potassium depolarized isoprenaline-reactivated guinea-pig ventricular strips. 2. Lowering temperature greatly enhanced nifedipine inhibition of (a) maximal rate of depolarization (Vmax) of slow action potentials and (b) amplitude of contractions. 3. Electrophysiological and inotropic actions of verapamil was virtually unaffected by temperature changes. 4. Negative inotropic action of cinnarizine was greater at 37 degrees C than at lower temperature. At 37 degrees C, but not at 32 degrees C, cinnarizine reduced Vmax of slow action potentials.

Action Potentials↗

PubMed1988

Neurokinin receptors in the rat lower urinary tract.

The effects of neurokinins (NKs), tachykinins and some NK-related peptides (selective agonists for the NK-1, NK-2 or NK-3 receptors) have been investigated in the various sections of the rat lower urinary tract. In the isolated bladder, all peptides were substantially equipotent with the exception of senktide, an NK-3 agonist, which was distinctly less potent than the other compounds. Similar results were obtained in the isolated urethra. In these tissues, the maximal response to NK-1 agonists was distinctly less intense than that to the other peptides. In the bladder, exposure to phenoxybenzamine (30 microM for 90 min) reduced the response to NK-A but not that to substance P, KCl or field stimulation. In the isolated ureter, peptides active at both the NK-2 and the NK-3 sites [including senktide and [MePhe7]-NKB(4-10)] activated, at nanomolar concentrations a series of rhythmic contractions, whereas peptides active at the NK-1 site, were active only at micromolar concentrations. These findings provide further evidence that multiple NK receptors are present in the rat lower urinary tract. In the bladder, NK-2 and NK-1 sites mediate the direct response to NKs, in accordance with binding and autoradiographic data. In the ureter, both NK-2 and NK-3 sites may activate the direct contractile response to these substances.

Animals↗

PubMed1987

The presence of mucosa reduces the contractile response of the guinea-pig urinary bladder to substance P.

The contractile response to substance P in-vitro is greater in strips of guinea-pig bladder freed of mucosa than in normal strips, while the response to field stimulation, histamine or KCl is unaffected by the presence of mucosa. Substance P has no inhibitory effect on histamine-induced contractions of the guinea-pig bladder. These findings support the possibility that the presence of mucosa may reduce accessibility of substance P to the muscle layer.

Animals↗

PubMed1986

Positive inotropic effect of Mg2+ in K+-depolarized isoprenaline-reactivated guinea-pig ventricular strip.

In K+-depolarized isoprenaline-reactivated guinea-pig ventricular strips increase in external Mg2+ concentration produced a biphasic inotropic effect i.e. at low concentrations (2.5-7.5 mM) a slight negative inotropic effect was observed, while at higher Mg2+ concentrations (10-17.5 mM) a strong positive inotropic effect become predominant. Variation in extracellular K+ concentration (17-22 and 25 mM) determined a concentration related reduction in Mg2+-induced positive inotropic effect. Increase in extracellular Ca2+ concentration (2.5-3.6 and 5.4 mM) prevented the development of Mg2+-induced negative inotropic effect but did not affect the magnitude of the positive inotropic effect. Mg2+-induced positive inotropic effect was unaffected by TTX (3 mg/l) and even enhanced by nifedipine (65 nM). Caffeine (0.2-15 mM) antagonized in a concentration dependent manner the positive inotropic effect of Mg2+. On the other hand in the presence of Mg2+ (15 mM) caffeine (0.2 mM) was unable to exert its positive inotropic effect. Mg2+ (15 mM) determined a "Ca2+ entry blocking"--like modifications of electrophysiological parameters of slow action potentials elicited by isoprenaline in K+-depolarized preparations. Such effects of Mg2+ were also present during the positive inotropic effect. The possible mechanisms responsible for these complex inotropic effects of Mg2+ are discussed.

Action Potentials↗

PubMedDate not supplied

Role of D-tryptophan for affinity of MEN 10207 tachykinin antagonist at NK2 receptors.

The role of the D-Trp residues in the sequence of the NK2-selective tachykinin antagonist, MEN 10207 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2). has been examined by replacement of each D-Trp with either the L-isomer or the residue naturally occurring in the same position of neurokinin A(4-10). The biological activity of the analogues thus obtained has been characterized, with special attention to the selectivity for the three tachykinin receptors and for the two subtypes of the NK2 receptor recently described. We conclude that the simultaneous presence of the three D-Trp residues of MEN 10207 is crucial both for affinity and for selectivity.

Amino Acid Sequence↗

PubMedDate not supplied

Structure-activity study of the C-terminal residue of MEN 10207 tachykinin antagonist.

The role of the C-terminal residue in the sequence of the NK-2-selective tachykinin antagonist, MEN 10207 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2), has been examined by systematic amino acid substitutions. Biological activity has been measured on two in vitro preparations chosen as paradigms of the recently described NK-2 receptor subtypes, namely the rabbit pulmonary artery and the hamster trachea, in order to define the structural requirements necessary for antagonist subtype selectivity. We conclude that in the presence of a C-terminal hydrophilic residue, affinity is maximal for the NK-2A subtype, while hydrophobic, bulky and aromatic residues increase affinity for the NK-2B subtype.

Amino Acid Sequence↗

PubMedDate not supplied

Pharmacology of MEN 11467: a potent new selective and orally- effective peptidomimetic tachykinin NK(1) receptor antagonist.

We have investigated the pharmacological properties of MEN 11467, a novel partially retro-inverse peptidomimetic antagonist of tachykinin NK(1) receptors. MEN 11467 potently inhibits the binding of [(3)H] substance P (SP) to tachykinin NK(1) receptors in the IM9 limphoblastoid cell line (pK(i) = 9.4 +/- 0.1). MEN 11467 is highly specific for the human tachykinin NK(1) receptors, since it has negligible effects (pK(i) <6) on the binding of specific ligands to tachykinin NK(2) or NK(3) receptors and to a panel of 30 receptors ion channels unrelated to tachykinin receptors. The antagonism exerted by MEN 11467 at tachykinin NK(1) receptors is insurmountable in saturation binding experiments, both K(D) and B(max) of SP were significantly reduced by MEN 11467 (0.3-10 nM). In the guinea-pig isolated ileum, MEN 11467 (0.03-1 nM) produced a nonparallel rightward shift of the concentration-response curve to SP methylester with a concomitant reduction of the Emax to the agonist (pK(B) = 10.7 +/- 0.1). Moreover the antagonist activity of MEN 11467 was hardly reversible despite prolonged washout. In vivo, MEN 11467 produced a long lasting (> 2-3h) dose-dependent antagonism of bronchoconstriction induced by the selective tachykinin NK(1) receptor agonist, [Sar(9), Met(O(2))(11)]SP in anaesthetized guinea-pigs (ID(50)s' = 29+/-5, 31+/-12 and 670+/-270 microg/kg, after intravenous, intranasal and intraduodenal administration, respectively), without affecting bronchoconstriction induced by methacholine. After oral administration MEN 11467 produced a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar(9), Met(O(2))(11)] (ID(50) = 6.7 +/- 2 mg/kg) or by antigen challenge in sensitized animals (ID(50) = 1.3 mg/kg). After i.v. administration MEN 11467 weakly inhibited the GR 73632-induced foot tapping behaviour in gerbil (ED(50) = 2.96 +/- 2 mg/kg), indicating a poor ability to block central tachykinin NK(1) receptors. These results demonstrate that MEN 11467 is a potent, highly selective and orally effective insurmountable pseudopeptide antagonist of peripheral tachykinin NK(1) receptors with a long duration of action.

Administration, Oral↗

PubMedDate not supplied

Long-term molecular remission after conventional chemotherapy in a patient with Philadelphia-negative acute lymphoblastic leukemia.

Adult Philadelphia (Ph1) negative acute lymphoblastic leukemia (ALL) is usually treated with conventional chemotherapy regimens. Long-term disease-free survival is often achieved. The rearrangement of immunoglobulin heavy-chain genes has been used to evaluate minimal residual disease. A novel nested-polymerase chain reaction (PCR) approach was used here to study a patient in long-term complete remission (CR) after the BFM regimen. No evidence of tumor cell contamination was found in bone marrow cells collected after 93 months of CR. This finding supports the hypothesis that conventional chemotherapy can induce long-term molecular remission and cure in Ph1 negative ALL.

Acute Disease↗