Biomedical subjects

F Rossi

Publications and source records attributed to F Rossi.

At least 181 records · Page 10Linked to original sources

PubMed1998

Role of AT2 receptors in the cardiovascular events following microinjection of angiotensin II into the superior colliculus of anaesthetised rats.

Central injection of angiotensin II (ANGII) induces pressor and regional haemodynamic effects. Here we have investigated the systemic and regional cardiovascular changes induced by injection of ANGII into the superficial layer of the superior colliculus (SC) of male rats anaesthetised with urethane. In addition, we have used the AT1 receptor-selective antagonist, losartan, and the AT2 receptor-selective antagonist, PD123319 to characterise the receptor(s) mediating these effects. Injection of ANGII (0.1, 1 and 100 nmol/rat) into the superficial layer of the SC significantly (P < 0.05) increased, in a dose-dependent manner, the mean arterial blood pressure (MAP) while decreasing the heart rate, (e.g. by 37+/-4 beats min(-1), at 1 nmol, P < 0.05). The increases in blood pressure induced by ANGII (1 nmol; 43+/-6 mmHg, n = 5) were greatly reduced (> 85%) by pre-administration to the SC of PD123319 (50 nmol/rat), but were unaffected by losartan (50 nmol/rat). Similarly, PD123319 prevented the decrease in heart rate induced by ANGII while losartan did not affect it. Injection of ANGII (1 nmol) also increased (P < 0.01) total peripheral resistance (TPR; control, 2.36+/-0.1 mmHg ml(-1) min 100 g body weight) by 130+/-10% (n = 5) and reduced the cardiac output (CO; control, 99.8+/-1.3 ml min[-1]) by 51+/-3% (n = 5), as determined by radioactive microspheres. The increase in TPR was associated with increases in the vascular resistances of organs, such as the left and right kidney (390+/-15%, P < 0.01 and 352+/-12%, P < 0.01 respectively), the skeletal muscle (91+/-7%, P < 0.05, n = 5), the stomach (43+/-2%, P < 0.01, n = 5), the colon (50+/-3%, P < 0.05, n = 5) and the caecum (65+/-5%, P < 0.05, n = 5). Pre-treatment of the SC with PD123319 reduced (P < 0.01) the increases in TPR and vascular resistance, and the reduction in CO caused by ANGII. Losartan did not affect the responses to ANGII. Thus, injection of ANGII into the SC causes complex haemodynamic changes which are sensitive to AT2 receptor antagonism. AT2 receptors are, therefore, the predominant mediators of the actions of ANGII into the superior colliculus of the rat.

Anesthesia, General↗

PubMed1998

Role of vasopressin on excitatory amino acids mediated pressor responses in the periaqueductal gray area.

In order to evaluate the role played by vasopressin on pressor responses elicited by stimulation of the periaqueductal gray (PAG) area by excitatory amino acids we carried out in vivo studies in genetically vasopressin deficient rats (Brattleboro). Microinjections of 1-glutamic acid (glutamate, 0.6 to 60 nmol/rat) or N-methyl-d-aspartic acid (NMDA, 0.07 to 7 nmol/rat) into the PAG area of freely moving Brattleboro rats induced increases of arterial blood pressure values significantly lower than those obtained in Long Evans rats (control) (glutamate in Brattleboro rats: from +2+/-1 mmHg to 16+/-3 mmHg; glutamate in Long Evans rats: from +16+/-2 mmHg to +36+/-4 mmHg; NMDA in Brattleboro rats: from +5+/-2 mmHg to +34 +/-8 mmHg; NMDA in Long Evans rats: from +18+/-7 mmHg to 80+/-9 mmHg; n=5). Similarly, in anaesthetized Brattleboro rats (urethane 1.2 g/kg i.p.) pressor responses to NMDA microinjections (0.7 nmol/rat) into the PAG area were significantly lower than in Long Evans rats (controls) (+15+/-3 mmHg vs +24+/-4 mmHg). In Long Evans rats NMDA injection also reversed blood pressure decrease induced by ganglionic blocker, hexamethonium and/or losartan (3 mg/kg i.v.), an AT1 receptor antagonist. In Brattleboro rats, NMDA injection did not reverse blood pressure decreases induced by hexamethonium (5 mg/kg i.v.). Moreover, hexamethonium induced blood pressure decrease was not reversed by acetylcholine injection (137 nmol/rat) into the PAG area of anaesthetized Long Evans rats, but if injected before hexamethonium, acetylcholine was able to increase blood pressure (+25+/-3 mmHg). Our results document: i) the importance of the PAG area in the control of cardiovascular system; ii) the involvement of excitatory amino acids in the neural control of vasopressin release; iii) the close relationship between glutamate and vasopressin in the central blood pressure regulation.

Acetylcholine↗

PubMed1998

Metabotropic glutamate receptors modulate serotonin release in the rat periaqueductal gray matter.

The role of metabotropic (mGluRs) and N-methyl-D-aspartate (NMDA) glutamate receptors on 5-hydroxytryptamine (5-HT) release has been studied in rat periaqueductal gray (PAG) matter by using in vivo microdialysis. (1S,3R)-aminocyclopentane- 1,3-dicarboxylic acid [(IS,3R)-ACPD; 0.5 or 1 mM], a group I/group II mGluRs agonist, increased the dialysate 5-HT concentration. (2S)-alpha-ethylglutamic acid (EGlu; 1 mM), an antagonist of group II mGluRs, but not (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 1 mM), an antagonist of group I mGluRs, antagonized the 1S,3R-ACPD-induced effect. (S)-3,5-dihydroxyphenylglycine (DHPG; 0.5 and 1 mM), an agonist of group I mGluRs, did not modify dialysate 5-HT. (2S, 3S, 4S)-alpha-(carboxycyclopropyl)-glycine (L-CCG-I; 0.5 and I mM), an agonist of group II mGluRs, increased extracellular 5-HT. This effect was antagonized by EGlu. Similarly, L-serine-O-phosphate (L-SOP; 1 and 10 mM), an agonist of group III mGluRs, increased extracellular 5-HT and this effect was antagonized by (RS)-(alpha-methylserine O-phosphate (M-SOP; 1 mM), an antagonist of group III mGluRs. Out of the several N-methylD-aspartate concentrations used (NMDA; 10, 50, 100, 500 and 1000 microM) only the 50 microM infusion significantly decreased dialysate 5-HT. The GABA(A) receptor agonist, bicuculline (30 microM), increased 5-HT release on its own and antagonized the decrease caused by the opiate antagonist, naloxone (2 mM), as well as the increases caused by CCG-I or L-SOP. These data show that stimulation of PAG's group II/group II mGluRs increases 5-HT release, while stimulation of NMDA glutamate receptors may decrease it. We speculate that glutamate does not modulate 5-HT release in the PAG directly, but via activation of tonically active GABAergic interneurons.

Animals↗

PubMed1998

Endothelin-1 and bronchial hyperresponsiveness in the rabbit.

Endothelins (ETs) are a family of peptide mediators that have a number of biological properties, including the ability to act as potent bronchoconstrictors of isolated human airways. Moreover, elevated concentrations of ET-1 in the bronchoalveolar lavage fluid from patients with symptomatic asthma have also been detected. We investigated the possible contribution of ET-1 in the development of bronchial hyperresponsiveness and the role of inflammatory cell accumulation in rabbit lungs. Our data show that ET-1 challenge to rabbits does not modify basal lung function but results in an increased airway responsiveness to inhaled histamine. Endothelin-treated rabbits were 3-fold (P<0.01) more responsive to inhaled histamine when compared with vehicle-treated rabbits. This hyperresponsiveness was not associated with an alteration in either total or differential inflammatory cell numbers as assessed by bronchoalveolar lavage (BAL). Pre-treatment with capsaicin (80 mg/kg s.c.) did not alter basal lung function or basal responsiveness to inhaled histamine. While capsaicin had no significant effect on the acute bronchoconstriction induced by endothelin-1, this dose was sufficient to significantly inhibit the increase in airway responsiveness to inhaled histamine, achieved 24 h following endothelin-1 challenge. These results indicate that ET-1 may play a role in the development of bronchial hyperresponsiveness to inhaled histamine and that the maintenance of this state is unrelated to a detectable alteration in cellular infiltration within the airway lumen, but probably via the involvement of capsaicin-sensitive nerves.

Airway Resistance↗

PubMed1998

Possible functional modulation by acetylcholine of nitric oxide on guinea pig isolated trachea.

The aim of this study was to evaluate whether acetylcholine induces NO release. We determined the responses on the cholinergic component of the response to electrical field stimulation (EFS) the effects of L-nitro-arginine-methyl-ester (L-NAME; 1 mM), an inhibitor of NO synthase, of L-Arginine (L-ARG; 1 mM), a precursor of NO synthesis, and methoctramine (0.01-0.1-1 microM), an antagonist of M2 receptors, alone or associated with L-NAME. The experiments were performed on guinea pig isolated intact- or denuded-epithelium tracheal rings contracted in a frequency-dependent manner to EFS. At the maximum frequency tested (30 Hz), the contractile response elicited was 60.36 +/- 0.61% of acetylcholine (100 microM) contraction, while the maximal relaxant effect induced by EFS was -28.40 +/- 0.61% in epithelium intact preparations. A pretreatment with L-NAME significantly (P<0.05) increased the contraction (76.08 +/- 1.39%) and reduced the relaxation elicited by EFS. L-NAME effect on both EFS induced responses were statistically (P<0.05) reversed by the association L-NAME + L-ARG. Methoctramine (1 microM) enhanced contractile (P<0.05) (79.20 +/- 2.21%), as well as relaxant responses (-38.73 +/- 0.99%) elicited by EFS in guinea pig epithelium-intact tracheal rings; in a separate series of experiments, performed on guinea pig epithelium-intact rings, L-NAME increased the contractile responses to methoctramine (82.6 +/- 2.31), but reduced the relaxant ones (26.38 +/- 1.29). In contrast, at the maximum frequency tested, it increased only the contractile response, but not modify the relaxant one, in epithelium denuded rings. In conclusion, the present data showed that the release of acetylcholine from postganglionic cholinergic nerves plays an important role on NO formation and this effect may be modulate by epithelium.

Acetylcholine↗

PubMed1998

Endothelin-1 in the superior colliculus of rats induces depressor responses due to peripheral hemodynamic changes.

Microinjection of endothelin-1 (ET-1; 10 pmol) into the superficial layer of the superior colliculus caused systemic and regional hemodynamic changes, as measured by injection of radioactive microspheres at the peak of the hypotensive effect of endothelin-1. Endothelin-1 decreased total peripheral resistance by 39 +/- 2% (n=5); the vascular resistances were decreased in the spleen, the mesentery, the large intestine and the small intestine. Moreover, we found that in consequence of the increased fraction of cardiac output received by the above organs, decreases in vascular resistances were associated with increases in blood flows in them. Interestingly, ET-1 also decreased the vascular resistances and increased the total blood flows in the kidneys. The haemodynamic changes induced by injection of endothelin-1 to the superior colliculus were associated with significant decreases in the mean arterial blood pressure (37 +/- 4 mmHg, n=6) and no changes in heart rate. Exogenous ET-1, therefore, within the SC decreases blood pressure due to peripheral hemodynamic changes.

Animals↗

PubMed1998

Cardiotoxicity of doxorubicin: effects of 21-aminosteroids.

The purposes of this study were to investigate in vivo the effects of two lazaroids,U-74389G (21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-pregna-1,4,9 (11)-triene-3,20-dione (2)-2-butenenedionate) and U-83836E (-)-2-[[4-(2,6-di-1-pyrrlidinyl-4-pyrimidinyl)-1-piperazinyl]methy l]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, dihydrochloride against the cardiotoxicity induced by doxorubicin in rat and the mechanisms underlying such a toxicity. Doxorubicin (DXR) administered intraperitoneally (5 mg/kg 4 times per week for 1 week) induced significant decrease of body weight, ECG alterations and 100% mortality. The lazaroids used in this study did not protect from DXR-induced cardiotoxicity. Our results showed that the compound U-74389G delayed, but did not reduce DXR-induced mortality, and did not prevent body weight loss and ECG changes. The compound U-83836E was unable to modify any toxic effects induced by DXR. These data indicate that oxygen free radicals and the subsequent increase in intracellular calcium are only steps of DXR progressive general toxicity that leads to cardiac injury. In conclusion, we propose that the 21-aminosteroids, potent inhibitors of membrane lipid peroxidation, alone are not enough to protect from DXR toxic effects.

Animals↗

PubMed1998

Characterisation of mGluRs which modulate nociception in the PAG of the mouse.

The contribution of metabotropic glutamate receptors (mGluRs) to the modulation of nociception by the periaqueductal gray (PAG) matter was investigated in mice. Intra-PAG microinjection of (IS,3R)-ACPD, an agonist of groups I and II mGluRs, as well as (S)-3,5-DHPG, a selective agonist of group I mGluRs, increased the latency of the nociceptive reaction (NR) in the hot plate test. (RS)-AIDA, an antagonist of group I mGluRs, antagonized the effect of (S)-3,5-DHPG, but changed the effect induced by (1S,3R)-ACPD in that a decrease in the latency for the NR could now be observed. L-CCG-I and L-SOP, which are agonists of groups II and III mGluRs respectively, decreased the latency of the NR. (2S)-alpha-EGlu and (RS)-alpha-MSOP, which are antagonists of groups II and III mGluRs, respectively, antagonized the effect of L-CCG-I and L-SOP. (RS)-AIDA and (RS)-alpha-MSOP alone decreased and increased, respectively, the latency of the NR with the highest doses used. (2S)-alpha-EGlu alone did not change significantly the latency of the NR. Intra-PAG microinjection of LH, an agonist of ionotropic glutamate receptors, induced a dose-dependent analgesia which was blocked by pretreatment with DL-AP5, a selective antagonist of NMDA receptors. No mGluRs antagonists were able to prevent LH-induced analgesia. These results emphasize the possible involvement of mGluRs in the modulation of nociception. It seems that activation of group I mGluRs potentiates, while groups II and III mGluRs decrease, the activity of the PAG for the modulation of nociception.

2-Amino-5-phosphonovalerate↗

PubMed1998

Effects of diethylenetriamine on NMDA-induced increase of blood pressure in rats.

We investigated the effects of three doses of diethylenetriamine (DET; 0.1-1-10 nmol/rat), putative ligand at the polyamine site on NMDA receptors, on blood pressure increase induced by N-methyl-D-aspartate (NMDA, 2 nmol/rat) microinjected at the periaqueductal gray (PAG) matter. Said doses of DET did not modify basal arterial blood pressure. Pretreatment with DET, depending on the dose used, either potentiated (DET, 0.1 nmol/rat), reduced (DET, 1 nmol/rat) the NMDA effects or left them unchanged (DET, 10 nmol/rat). DET 10 nmol/rat, microinjected 5 min before spermidine (SPD, 0.02-2 nmol/rat), significantly antagonized SPD modulation on the NMDA-induced pressor changes. These data, in agreement with the functional findings in vitro, suggest that also in vivo DET has pharmacological activities quite different from a pure antagonist but shows multiple actions on the NMDA receptors.

Analysis of Variance↗

PubMed1998

Plasticity of the olivocerebellar pathway.

The adult olivocerebellar axons and their terminal arbours, the climbing fibres, are capable of remarkable structural plasticity, regulated through their interaction with Purkinje cells. When these cells are deleted,terminal climbing fibre branches retract. In contrast,there is a vigorous outgrowth of entire terminal arbours when extra postsynaptic neurones are available. The new connections lead to a functional, highly specific pattern of innervation at the single Purkinje cell level and are topographically organized according to the principles of the original projection map.A reversible climbing fibre retraction occurs following depression of electrical activity of the cerebellar cortex. These remarkable plastic properties, together with the fact that these neurones express several growth-associated genes constitutively, suggest that the climbing fibre synapses might be adjusted dynamically to participate in physiological plasticity.

Animals↗

PubMed1998

Transglutaminase-synthesized gamma-(glutamyl5) spermidine derivative of substance P is a selective tool for neurokinin-2 receptors characterization.

The ability of transglutaminase-synthesized 1,3-diaminopropane, spermidine (Spd), spermine (Spm), and monodansylcadaverine gamma-(glutamyl5)derivatives of substance P (SP) to produce bronchoconstriction was investigated. In urethane-anaesthetized guinea pigs, intravenous injections of SP derivatives contracted differently bronchial smooth muscle and caused hypotension. The most effective bronchoconstrictor among SP analogs was the gamma-(glutamyl5)Spd derivative of SP (Spd-SP; EC50 = 5.3 nmol/kg), which was more potent than the native peptide (EC50 = 26.5 nmol/kg). In contrast, the gamma-(glutamyl5)Spm derivative of SP (Spm-SP) was found completely unable to cause bronchoconstriction and was significantly less effective than SP in determining hypotension. The contractile effect of Spd-SP and Spm-SP was investigated in vitro on rat isolated colon, a well-characterized preparation rich in NK2 receptors. In addition, Spd-SP was tested on the endothelium-denuded rabbit pulmonary artery (RPA) and the hamster isolated trachea (HT), both tissue preparations containing only a single functional receptor subtype (NK2A and NK2B, respectively). The results obtained showed that Spd-SP recognizes NK2 receptors occurring on rat isolated colon more effectively (EC50 = 11 nM) than the native peptide (EC50 = 45 nM). Conversely, Spm-SP evokes a contractile response less effective than that elicited by SP (EC50 = 312 nM). Furthermore, Spd-SP (0.1-10 microg kg(-1)) produced a concentration-dependent contraction of both HT and RPA, exhibiting a potency respectively 12 and 30 times higher than SP in contracting HT and RPA. Our results indicate that the introduction of a Spd moiety at the level of glutamine-5 of SP gives rise to an analog that possesses a different capability to recognize NK2 receptors than the parent peptide. Moreover, since Spd-SP seems to contract more effectively RPA than HT, we conclude that it preferentially recognizes the NK2A receptor subtype.

Animals↗

PubMed1998

Degenerative phenomena and reactive modifications of the adult rat inferior olivary neurons following axotomy and disconnection from their targets.

Adult olivocerebellar axons are capable of vigorous regeneration when provided with growth-permissive environmental conditions. To elucidate the contribution of intrinsic properties to the regenerative capabilities of inferior olivary neurons, we have examined the cellular modifications occurring in these neurons following axotomy and target deprivation in the absence of exogenous growth-promoting influences. Axotomized inferior olivary neurons undergo perikaryal shrinkage, dendritic atrophy and a loss of anti-calbindin immunoreactivity. A conspicuous cell death occurs during the first few weeks after lesion, but about 35% of the affected neurons survive up to 60 days. Coincidentally, a subset of the injured nerve cells become strongly reactive for NADPH diaphorase histochemistry, and this expression is correlated with survival in the medial accessory olive and in the principal olive. In addition, the affected neurons express or maintain the expression of several markers related to regenerative processes, including transcription factors c-Jun, JunD and Krox-24, the growth-associated protein GAP-43 and the developmentally regulated calcitonin gene-related peptide (CGRP). The expression of all these markers is sustained up to two months after lesion, the longest survival time examined. These results show that although adult axotomized inferior olivary neurons undergo severe regressive modifications leading to a conspicuous cell loss, at least a subset of them is resistant to the lesion. In addition, the long-lasting expression of several axon-growth associated markers expressed in these neurons in response to injury reveals that they are endowed with a strong intrinsic regenerative potential.

Animals↗

PubMed1998

Shoulder impingement syndromes.

OBJECTIVE: Not all shoulder pain conditions are a consequence of rotator cuff injuries secondary to anterior subacromial impingement. Additional causative forms have been identified and classified as posterosuperior glenoid rim, subcoracoid and suprascapular nerve (at spinoglenoid notch) impingement syndromes. MATERIAL AND METHODS: We reviewed 206 consecutive magnetic resonance examinations carried out with conventional T1- and T2-weighted spin-echo and gradient-echo sequences in patients complaining of shoulder pain. Adjunctive sequences were acquired with the involved arm positioned in abduction and external rotation. RESULTS: Anterior subacromial impingement is only one of the possible causes of shoulder disorders. Posterosuperior glenoid rim impingement is the most frequent cause of shoulder pain in young throwers. Subcoracoid and spinoglenoid notch suprascapular nerve impingement are additional forms that must be considered in the differential diagnosis because of their frequent occurrence in routine clinical practice. CONCLUSION: Magnetic resonance imaging is the most useful diagnostic modality for shoulder disorders.

Disease Progression↗

PubMed1998

The role of A3 adenosine receptors in central regulation of arterial blood pressure.

1. Pharmacological studies have suggested that A3 receptors are present on central neurons. Recently this adenosine receptor subtype has been identified in the rat and its presence in the central nervous system has been confirmed. 2. In this study we investigated the effects of acute intracerebroventricular (i.c.v.) injections of N6-2-(4-aminophenyl)-ethyladenosine (APNEA), a non-selective A3 adenosine receptor agonist, on arterial blood pressure (ABP) and heart rate (HR), after treatment with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective antagonist of A1 adenosine receptors. 3. Anaesthetized rats, after DPCPX (12 microg(-1) kg i.c.v.), were treated with APNEA (0.4-4 microg kg(-1) i.c.v.) resulting in a transitory and dose-dependent decrease in arterial blood pressure without a change in heart rate. APNEA also induced hypotensive responses after i.c.v. pretreatment with aminophylline, at a dose of 20 microg kg(-1). In contrast, pretreatment 48 h before, with 4 microg kg(-1) i.c.v. of pertussis toxin reduced the hypotensive effect induced by APNEA. Administration of APNEA at a higher dose (20 microg kg(-1) i.c.v.), after DPCPX, induced a decrease in ABP of -66+/-5.4 mmHg and after 3 min a decrease in heart rate of -62+/-6.0 beats min(-1). Transection of the spinal cord abolished this significant fall in ABP, but not the decrease of HR. 4. These results suggest that a population of A3-receptors is present in the CNS, whose activation induces a decrease in blood pressure with no change of heart rate.

Animals↗

PubMed1998

Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications.

Intracerebral vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients who develop delayed headache in response to the drug. The headache is purportedly due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in NO generation. Indomethacin also decreases cerebral blood flow by constricting precapillary resistance vessels. In the present study, the hemodynamic effects of indomethacin were evaluated in migraine patients and healthy controls by means of transcranial Doppler monitoring. Indomethacin caused a significant decrease in mean flow velocity in the middle cerebral artery. This was an additional effect to the mean velocity decrease induced by IDN. The interactions between the two drugs suggest that their effects on cerebral hemodynamics (and pain) may be of relevance both in understanding the role of NO in migraine pathogenesis and in evaluating symptomatic treatments for migraine attacks.

Adult↗

PubMed1998

Combined evaluation of pupillary and cardiovascular responses to cold pressor test in cluster headache patients.

Little is known about the structures and mechanisms involved in the pathophysiology of cluster headache (CH). In this study, pupillary and cardiovascular responses to the cold pressor test (CPT) were monitored in CH patients during either an active phase of disease or a remission period in order to evaluate the oculocephalic and cardiovascular functioning of the autonomic nervous system in this form of idiopathic headache. CH patients showed a specific pattern of pupillary response on both sides during both phases of the disease. This response differed from that of controls because of an absent miosis. The pressor response to CPT was more marked in CH patients than in controls. Naloxone pretreatment caused specific and selective changes in both the pupillary and cardiovascular responses of CH patients. These data suggest a systemic sympathetic hyperactivation in response to CPT in CH patients. An oculocephalic sympathetic hypofunction is possibly associated as well as an altered opioid neuromodulation.

Adult↗

PubMed1998

Specific interaction between bovine cyclophilin A and synthetic analogues of cyclolinopeptide A.

Like cyclosporin A, cyclolinopeptide A binds specifically bovine cyclophilin A, inhibiting its peptidyl-prolyl cis-trans isomerase activity. We describe here the protein interaction with several synthetic analogues of cyclolinopeptide A, which are either homodetic or disulphide bridged heterodetic cyclopeptides characterized by different ring dimensions, in terms of dissociation and inhibition constants evaluated by fluorescence and inhibition of the enzyme activity, respectively. Dissociation constants from fluorescence experiments are practically identical and about 20-fold lower than for cyclosporin A. On the other hand, inhibition constants differ from compound to compound and are higher than for cyclosporin A. This result is therefore difficult to rationalize, but we would suggest decoupling between binding and inhibitory ability of cyclopeptides. The Pro1 residue of cyclolinopeptide A seems to play a fundamental role in determining the inhibition of the rotamase activity of cyclophilin A, as the homodetic analogue lacking this residue does not show any inhibitory ability. Similarly, heterodetic analogues with a ring size smaller than 7 residues do not display inhibition. We presume that the sequence -Pro-Pro-Phe-Phe- and a ring size of 8 residues for homodetic cyclic peptides could be used as starting points in the targeted synthesis of cyclopeptides able to bind both cyclosporin A and calcineurin. The only peptide showing similar values of the dissociation and inhibition constant is cyclolinopeptide A. This compound can be considered a novel model for the molecular design of immunosuppressant drugs.

Amino Acid Sequence↗

PubMed1998

Effects of hyperbaric oxygen exposure on a zymosan-induced shock model.

OBJECTIVE: To evaluate the effects of hyperbaric oxygen (HBO) therapy on zymosan-induced shock in rats. Zymosan, a cell wall component of the yeast Saccharomyces cerevisiae, induces inflammation by causing the production of various cytokines and pro-inflammatory mediators. The administration of zymosan to rats represents a new experimental shock model by inducing acute peritonitis, severe hypotension, and signs of systemic illness. However, it has been recently proposed that the zymosan-induced shock, like septic shock, may be mediated by overproduction of nitric oxide. DESIGN: Experimental study. SETTING: Institute of Pharmacology and Toxicology, 2nd University of Naples, Naples, Italy. SUBJECTS: Male rats were treated with zymosan (500 mg/kg) by intraperitoneal route, with HBO (2 Absolute Atmosphere) or with zymosan and HBO (2 Absolute Atmosphere). MEASUREMENTS AND MAIN RESULTS: Peritoneal exudate, plasma, and peritoneal nitric oxide metabolites (NOx) and zymosan determined a time-dependent increase in peritoneal and plasma NOx concentrations, and peritoneal leukocytes were determined. Moreover, symptomatology was observed. The administration of zymosan caused the appearance of a severe illness in the rats characterized by ruffled fur, lethargy, conjunctivitis, diarrhea, and a significant loss of body weight. All zymosan-treated rats developed an acute peritonitis, producing turbid exudate. Zymosan determined a time-dependent increase in peritoneal, plasma NOx, and tumor necrosis factor (TNF)-alpha concentrations. Morbidity of zymosan shocked rats has been attenuated and no mortality was observed by treatment with HBO. These findings were associated with a significant reduction either of peritoneal leukocytes and exudate, or plasma and peritoneal NOx concentrations. Moreover, TNF-alpha levels were significantly reduced in animals shocked by zymosan and treated with HBO.

Animals↗