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Biomedical subjects

E Ragazzi

Publications and source records attributed to E Ragazzi.

At least 37 records · Page 2Linked to original sources
PubMed1999

Morphological features of regeneration of rabbit aortic endothelium after cryoinduced vascular damage.

Regeneration of endothelium after damage is an important factor, which limits the development of atherogenesis. This study examines the topographical characteristics of regenerating endothelial cells (EC) in rabbit aorta after de-endothelialization by cryodestruction. The effects of cloricromene on these processes were also studied. Vessels were harvested from 6-month-old NZW rabbits, 1 and 3 days after cryodestruction. The vessels were evaluated using scanning electron microscopy (SEM). One day after cryodestruction, there were defects in the endothelial monolayer in the zone of injury in saline treated animals. Large numbers of platelets and monocytes were observed in association with endothelium in the damaged zone. Three days after de-endothelialization the size of the area of the damage had decreased. On the surface of the new endothelial layer and below this defect, the number of adhering monocytes was increased, and many microdefects between endothelium could be seen. Administration of cloricromene for 1 or 3 days after damage reduced the number of endothelium-adherent platelets and monocytes, and microdefects in endothelium. The feature of endothelial repair in rabbits is a relatively large involvement of monocytes and platelets, which are visible below regenerated endothelium. Administration of cloricromene essentially restored re-endothelialization and significantly decreased the number of adherent monocytes and microdefects in the new endothelium.

Animals↗
PubMed1998

Functional response of cavernosal tissue to distension.

We studied rabbit isolated erectile tissue responses to changes in preload and to active tension development with norepinephrine. The effects of antagonists of endothelin-1, prostaglandins E2 and F2alpha and of nitric oxide were also tested on normal and de-endothelialized preparations. Tissue distension was found to elicit spontaneous rhythmic contractions. Increase in preload diminished the latency of the spontaneous activity and augmented the developed force. Active tension development and the inhibitor of the Na+,K+ pump, ouabain, opposed the spontaneous activity. A marked reduction in the resting tension with abolition of the spontaneous activity was observed on normal, but not on de-endothelialized tissues, following the addition of the specific prostaglandin E2 and F2alpha receptor antagonist, SC-19220. At 3 x 10(-4) M, the highest concentration used, the endothelin-A receptor antagonist BQ-123 failed to change the pattern of the spontaneous activity and the resting tension of normal tissues. The nitric oxide synthesis inhibitor, L-NAME, did not produce reliable effects. These findings point to a causal relation between cavernosal tissue distension and phasic and tonic contractions. Phasic contractions appear to be elicited by smooth muscle cells through the enzyme Na+,K+-ATPase. Increase in the resting tone could be mediated, at least in part, by the endothelium, through the release of prostaglandins E2 and/or F2alpha but not of endothelins. We discuss the hypothesis that, in cavernosal tissue, mechanotransduction of distension to contractile responses is an important determinant of detumescence.

Acetylcholine↗
PubMed1998

Pharmacological characterization of endothelial cell nitric oxide synthase inhibitors in isolated rabbit aorta.

Different receptors mediating the release of endothelium-derived nitric oxide (EDNO) have been identified at endothelial level. In the present study we aimed to characterise, on rabbit aorta by means of pharmacological tools, the generation of EDNO by receptors located on endothelial cell membrane (M3, P2u, P2y) and by direct activation of Ca2+ entry into the endothelial cell. Four vasodilating drugs were tested (acetylcholine, UTP, A23187 and 2-methyl-thio-ATP); they were active only if the endothelial layer was intact, suggesting that they act through endothelial receptors. The effect of different nitric oxide synthase (NOS) inhibitors (0.1 mM: L- and D-NAME, L-NMMA, L-NIO and 7-NI) was investigated on NO-mediated relaxation induced by the relaxants in vessels with intact endothelium. NOS inhibitors differently affected relaxation mediated by the vasoactive drugs in isolated rabbit aorta. Reversibility of the inhibition by using a fixed concentration of L-arginine (0.1 mM) was different depending on the relaxing drug and NOS-inhibitor. The data obtained support the coexistence in aortic vessel of more than one endothelial cell NOS isoform, each provided with different receptor coupling.

Animals↗
PubMed1998

Possibilities of conveying a cationic drug in Carbomer hydrogels.

A drug with cationic characteristics such as procaine can be conveyed in a Carbomer hydrogel in two different ways: (i) in the form of salt in solution in the aqueous phase, and (ii) in the base form salified with the same polymer. Introduction of the drug into the hydrogel with different concentrations of polymer produced, in both cases, a reduction in viscosity in relation to drug concentration. The gels with procaine salified with the polymer showed greater viscosity. The drug release rate, in general, diminished with the increase in polymer concentration. Nevertheless, when this concentration was maintained, there was no variation in release rate when the viscosity produced as a consequence of drug concentration was changed. Gels with procaine salified with the carboxyvinylic polymer had a faster release rate than those with procaine in the hydrochloride form dissolved in the aqueous phase. These results have also been confirmed by a simulated absorption test.

Acrylic Resins↗
PubMed1998

Cryodamage of the vessel wall accelerates the development of atherosclerotic lesions in arterial vessels of Watanabe hyperlipidemic rabbits.

In the present study we developed an experimental model, resembling human atherosclerosis, by removing the endothelial layer in Watanabe heritable hyperlipidemic (WHHL) rabbits (10 months old) by application of cryodamage on the external surface of arterial vessels. In age-matched New Zealand white (NZW) rabbits, used as control, after two months following cryodamage, carotid artery and infrarenal segments of abdominal aorta did not show any particular change in the ultrastructure of vessel wall. In WHHL rabbits, two months after cryodamage, atherosclerotic lesions (fatty streaks and fibrous plaques) were observed in both arteries. Many lipid-laden endothelial cells, subendothelial foam cells and smooth muscle cells were found in cryodamaged areas. In some areas, the cap of plaques appeared to be thinned and ruptured. Increased number of collagen and elastic fibrils was also observed in atherosclerotic regions. We conclude that this simple technique on WHHL rabbits provides a model of atherosclerosis with a high degree of morphological similarity between the artificially-induced plaque and human atherosclerotic plaque.

Animals↗
PubMed1997

Prolonged inhibition of nitric oxide synthesis in Yoshida hyperlipidemic rat: aorta functional and structural properties.

To test whether inhibition of nitric oxide synthesis, associated with high levels of plasmatic lipids, can induce atherosclerotic lesions and phenotypic changes in smooth muscle cell composition in the aortic wall of an atherosclerotic-resistant species such as the rat, an inbred strain of hyperlipidemic Pittsburgh Yoshida rat was subjected to prolonged treatment (2 months) with the nitric oxide-synthase inhibitor L omega-nitro-arginine-methyl ester or with L-arginine. The two types of in vivo treatments were not able to modify in vitro aortic endothelium-mediated relaxation induced by acetylcholine or calcium-ionophore A-23187, the endothelium-independent sodium nitrite relaxation and the contractile response to serotonin. Histology and lipid infiltration of vascular specimens showed that L omega-nitro-arginine-methyl ester in vivo treatment did not induce any significant change in the aortic wall. Monoclonal antibodies to myosin isoforms and immunofluorescence procedures revealed the presence of an immature smooth muscle cell subpopulation in aortic specimens from saline-treated Pittsburgh Yoshida rats, whose expansion has been related in other species to atherogenesis. This peculiar cell phenotype disappeared in our animal model after prolonged L omega-nitro-arginine-methyl ester treatment. These data indicate that, despite interference with endothelium-mediated nitric oxide synthesis, atherosclerosis does not develop in this animal model and furnish for the first time a biological justification for atherogenesis resistance of rat, i.e., the lack of activation of an immature aortic smooth muscle cell population which in atherosclerosis-prone species is involved in lesion formation.

Acetylcholine↗
PubMed1997

P2X-purinoceptors in the heart: actions of ATP and UTP.

Positive inotropic effects of ATP and UTP (1 microM - 1mM) were studied in isolated rat and guinea pig cardiac tissues. The potency order obtained was ATP>UTP in both species, suggesting possible interaction with P2X-purinoceptors. Binding studies using [(3)H]alpha,beta-methylene ATP as marker of P2X-purinoceptors revealed two receptor sites: one high-, the other low-affinity, in atria and ventricles from rat and guinea pig. Both ATP and UTP were found to bind high-affinity sites of [(3)H]alpha,beta-methylene ATP. The effects of various calcium inhibitors such as nifedipine, dantrolene, ryanodine and TMB-8 on positive inotropic effects induced by ATP and UTP were also studied. The results suggest that ATP and UTP may increase inotropism by interaction with P2X-purinoceptors by means of a calcium-dependent mechanism.

Adenosine Triphosphate↗
PubMed1997

Inhibition of platelet activation by MM-706, a stable carbacyclin analog, in the conscious rat.

A new stable analog of carbacyclin, 13,14-dihydro-15,16,17,18,19,20-hexanor-14-(1-hydroxycyclohexyl) carbacyclin, identified as MM-706, was investigated in vivo in the conscious rat. MM-706 as single bolus (200 micrograms/kg, equivalent to 546 nmol/kg) prevented the reduction of circulating platelets induced by adenosine diphosphate (ADP) (1 mumol/kg as IV bolus). 2. A similar effect on free platelet numbers also was observed with iloprost (20 and 200 micrograms/kg IV bolus). However, MM-706 did not induce any significant variation of mean arterial blood pressure (MABP) or heart rate, unlike iloprost, which reduced MABP within 10 min of administration. 3. In conclusion, MM-706 is effective in interfering with in vivo platelet activation induced by ADP without influencing other cardiovascular parameters, such as arterial pressure and heart rate.

Adenosine Diphosphate↗
PubMed1996

Characterization of in vitro relaxant mechanisms in erectile tissue from rabbits of different ages.

In the present study we investigated the in vitro relaxant response of erectile tissue obtained from rabbits of different ages (3, 7 and 24 months) in order to detect the progression with age of cavernosal activity in response to substances acting via endothelium-dependent or -independent mechanisms. Noradrenaline induced a concentration-dependent contraction (0.1 microM-3 mM), with an increase in the contractility in the 24-month-old group. Acetylcholine produced a concentration-dependent relaxant effect in the three age groups, with a reduction of the maximal relaxant effect in older animals. ATP (10 microM-1 mM) and adenosine (10 microM-1 mM) induced a concentration-dependent relaxant effect that was higher in the older group. The presence of the NO2-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) (0.1 mM) or of the P2-purinoceptor antagonist suramin did not affect ATP relaxation. Relaxation induced by sodium nitrite and nifedipine was reduced in older animals. In conclusion, aging selectively alters the in vitro responsiveness of rabbit erectile tissue. Purinergic system remains more active despite a decrease in the maximal endothelial cholinergic activity and the direct smooth muscle relaxant component.

Acetylcholine↗
PubMed1996

Chronic treatment with cyclosporine A in New Zealand rabbit: aortic and erectile tissue alterations.

Transplanted patients frequently present erectile impotence. In order to test any interference by cyclosporine A (CsA), which is commonly used in the post-transplantation management, we investigated the in vitro contractile and relaxant responses of corpus cavernosum and aorta from rabbits chronically treated with CsA. Male New Zealand White rabbits 6 months of age were treated with CsA (25 mg/kg per day s.c.) or solvent (corn oil) for 3 weeks. Descending thoracic aorta and erectile tissue were studied in vitro at the end of treatment. Isometric tension was recorded. In thoracic aorta, noradrenaline (0.1-30 mM) induced a concentration-dependent contraction with no difference between the two groups. Acetylcholine (30 nM-3 mM) produced relaxation (52 +/- 4% at 1 mM) that was significantly reduced in comparison to controls (67 +/- 4%, P < 0.05). ATP (3-10 mM) relaxation was not significantly different (maximal 78 +/- 10% and 62 +/- 12% in CsA-treated and controls). The relaxation produced by sodium nitrite was reduced in CsA-treated rabbits (at 10 mM and 0.1 mM concentrations). In erectile tissue, no significant variation in the response of isolated erectile tissue to the above drugs was observed between CsA-treated and control animals. These data indicate that chronic treatment with CsA in rabbits, despite alteration of the in vitro response of thoracic aorta, does not directly influence the function of penile tissue with relaxants.

Animals↗
PubMed1996

Effects of N omega-nitro-L-arginine methyl ester on benzodiazepine binding in some limbic areas of hyperlipidaemic rats.

Quantitative autoradiography techniques were used to evaluate the chronic effects of the potent nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester, on the binding pattern of [3H]flunitrazepam (benzodiazepine agonist) in some behaviorally key limbic areas of the genetic hyperlipidaemic Pittsburg Yoshida rat. Administration of this potent synthase inhibitor was capable of supplying higher and moderately higher binding levels in the basolateral amygdala nucleus (+52%) and in the oriens-pyramidalis CA1 hippocampus layer (+38%), respectively. When we tested for the binding changes in the presence of GABA (principal benzodiazepine modulator) we noticed that a physiological concentration (20 microM) of this inhibitory neurotransmitter was sufficient to induce notable changes in other limbic areas. In fact, lower binding values (-65%) were reported for the bed nucleus of stria terminalis whereas moderately higher values (+38%) were obtained for the radiatum-lacunosum molecular CA1 hippocampus layer. From the saturation studies, it was possible to observe that the major receptor variations provoked by the potent synthase inhibitor were not only due to changes in the total number of binding sites because there were variations, as in the case of the basolateral amygdala nucleus, that were instead due to differences in the affinity binding state. These results provide evidences of a GABAergic-nitric oxide synthase inhibitor interaction that might also be involved in the regulation of convulsive, anxiolytic, and aggressive behaviors that are modulated at the benzodiazepine site.

Animals↗
PubMed1996

Kinetics of release and simulated absorption of methyl nicotinate from different ointment formulations: in vitro-in vivo correlations.

The influence of the vehicle on release and simulated absorption of methyl nicotinate (MN) was evaluated using in vitro systems in order to find a correlation with data previously obtained in vivo. Simulation of drug absorption was carried out using a porous polymer membrane soaked with lipophilic phases such as n-dodecanol and isopropyl myristate. Ointment composition influenced differently both release and absorption of MN independent of drug concentration. The degree of skin redness induced by MN was found to be significantly correlated to in vitro simulated drug absorption but not to in vitro drug release.

Absorption↗
PubMed1995

Heparin: pharmacological potentials from atherosclerosis to asthma.

1. Heparin belongs to a family of polysaccharide species, whose best known property is, undoubtedly, anticoagulant activity. However, heparin has many other pharmacological effects, particularly on the cardiovascular system. 2. The therapeutic use of chronically inhaled heparin has been suggested as prophylaxis in atherosclerosis. 3. Heparin, physiologically stored in mast cells of the respiratory system, has also been recently studied in the prevention of immunological and non-immunological asthmatic attacks. 4. Experimental findings and new hypotheses of heparin action in asthma and atherosclerosis are discussed.

Animals↗
PubMed1995

Pharmacological properties of MM-706, a new prostacyclin derivative.

1. In human platelet-rich plasma, platelet aggregation induced in vitro by collagen (10 micrograms/ml) or thrombin (50 mU/ml) was dose-dependently inhibited by increasing concentrations of prostacyclin or of the new derivative (+/-)(5E)-13,14-didehydro-omega-hexanor(1-hydroxycyclo hexyl)-9a- carbaprostacyclin (MM-706) with an IC50 of 20-50 nM and 250-500 nM, respectively. In human platelets loaded with fura-2, the intracellular rise of [Ca2+] induced by thrombin was dose-dependently inhibited by MM-706 with an approximate IC50 of 100 microM. 2. In rabbit isolated femoral artery, MM-706 (10 nM-10 microM) was completely ineffective in relaxing the vessel, which was different to prostacyclin which was able to relax vessels at the same concentrations. 3. In in vitro guinea-pig ileum, prostacyclin produced a contractile effect in the concentration range 1 nM-10 microM, but the derivative MM-706 was ineffective at the same concentrations. Preventive addition of MM-706 did not inhibit prostacyclin contraction. 4. On isolated guinea-pig tracheal preparation, prostacyclin induced a concentration-dependent contraction but the new compound MM-706 showed a lower activity, in the concentration range 10 nM-10 microM. The activity of prostacyclin was not affected by the contemporary presence of MM-706. 5. It is concluded that MM-706 is a prostacyclin analogue with antiaggregating properties but without evident effects on smooth muscle of different regions.

Animals↗
PubMed1995

Endothelial nucleotide-mediated aorta relaxation in aged Watanabe heritable hyperlipidemic rabbits.

We investigated the activity of muscarinic and purinergic endothelial receptors during atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbit aorta. Experiments were performed on isolated thoracic aorta from WHHL rabbits aged 1 and 2.5 years. The relaxant response to acetylcholine (ACh) was progressively reduced with aging, being almost completely abolished in 2.5-year-old rabbits. The relaxant effect of ATP was not affected by the P2-purinoceptor antagonist suramin, thus excluding any involvement of relaxant P2y purinoceptors in both considered ages. The pyrimidine UTP, acting on nucleotide (P2U) receptors, produced concentration-dependent relaxation in 1-year-old WHHL rabbit aorta only in the presence of endothelium; relaxation was reduced in older animals. In 1-year-old WHHL rabbits, the endothelium-dependent relaxant effect of UTP was not antagonized by suramin, but was by the inhibitors of nitric oxide (NO) effect, methylene blue (MB) and L-NG-nitroarginine methyl ester (L-NAME), suggesting involvement of NO in the UTP-mediated relaxation. Morphological data from electron microscopy observations indicated the presence of typical atherosclerotic lesions and extensive dystrophic changes in endothelial cells, gradually evolving at 1 and 2.5 years of age. The present data suggest that progressive atherosclerosis differentially affects the activity of endothelial receptors: The most precociously altered is the P2y-purinoceptor, followed by an impairment of the muscarinic and finally of the P2U-purinoceptor.

Acetylcholine↗
PubMed1995

Influence of ointment formulation on skin erythema induced by nicotinate esters.

The influence of the chemico-physical nature of the vehicle on the skin penetration of topically applied drugs was evaluated in vivo. Five different ointment formulations containing nicotinate esters as model penetrants were tested on human skin. The degree of drug penetration allowed by the various formulations was revealed by means of the erythema induced by the drug, detected by a X-Rite tristimulus reflection colorimeter. The excipient influenced the penetration of the nicotinate esters used to various extents. The concentrations of the tested drugs were found to be an important factor influencing drug penetration and persistence of erythema.

Administration, Topical↗
PubMed1995

Hidden fractals in pharmacodynamics.

The present report is an attempt to give relevance to the fractal theory in pharmacodynamics. It is shown, that analysis and discussion of pharmacological in vitro data keeping in mind that a pharmacological process is just a resultant of many different, also fractal, components, would sometimes lead to a more detailed examination of raw patterns of experimental data.

Animals↗