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D Mitolo-Chieppa

Publications and source records attributed to D Mitolo-Chieppa.

At least 19 recordsLinked to original sources
PubMed1999

Functional characterization of endothelin receptors in hypertensive resistance vessels.

OBJECTIVE: The physiological and pathophysiological functions of endothelin-1 in modulating the regional blood flow of normal and spontaneously hypertensive rats (SHR) were studied in the perfused mesenteric vascular bed, a useful model for investigating resistance vessels. DESIGN AND METHODS: We used 12-week-old SHR and Wistar-Kyoto (WKY) rats. Endothelin A (ETA) receptor responsiveness was evaluated by endothelin-1 (0.2-2 mumol/l) concentration-response curves, and repeated in the presence of indomethacin and the ETA and endothelin B (ETB) receptor antagonists BQ-485 and BQ-788, respectively. ETB receptor responsiveness was tested by sarafotoxin S6c concentration-response curves, obtained in the noradrenaline-precontracted mesenteric vascular bed, and repeated after treatment with BQ-788 and after endothelial denudation. RESULTS: In both groups, endothelin-1 induced concentration-dependent contraction; SHR exhibited a markedly increased maximal effect compared with WKY rats (P < 0.01). BQ-485 produced a shift to the right for endothelin-1 concentration-response curves in both groups, with a higher pA2 (negative common logarithm of the antagonist that produces an agonist dose ratio of 2) value in SHR than in WKY rats (P < 0.01). The increase in the maximal effect produced by endothelin-1 in SHR was prevented by indomethacin, which also induced a significant increase in the endothelin-1 concentration producing the half-maximal response (EC50) in SHR (P < 0.05). Sarafotoxin S6c produced an ETB-dependent endothelium-mediated relaxant effect in WKY rats, which was not observed in SHR. CONCLUSIONS: The higher vasoconstriction induced by endothelin-1 in SHR may be related to a greater number of available ETA receptors, due to the presence of an ETA receptor subtype. This mechanism may be linked to the production of prostanoids that add to the direct endothelin-1-evoked vasoconstriction. These results, together with the lack of relaxation in response to sarafotoxin S6c in SHR, suggest that an imbalance in the endothelin-1 ability to induce both contraction and relaxation is present in SHR with sustained hypertension, manifesting as a greater contractile effect evoked in this strain.

Animals↗
PubMed1998

Cholinergic stimulation and nonadrenergic, noncholinergic relaxation of human colonic circular muscle in idiopathic chronic constipation.

The aim of our study was to further investigate the pathophysiological mechanism underlying idiopathic chronic constipation (ICC), a disorder of colonic motility. A possible alteration of excitatory and inhibitory neurotransmission and also the role of inhibitory neurotransmitters such as nitric oxide (NO), 5'-adenosine triphosphate (ATP), and vasoactive intestinal peptide (VIP) has been evaluated on preparations of distal colon from patients with or without ICC. The isometric tension was recorded from isolated circular muscle strips of both experimental groups during pharmacological and electrical field stimulation (EFS). The contractile response obtained by acetylcholine (ACh 20 microM), EFS (20 Hz, 20 V, 1 msec, pulse trains lasting 1 min) and substance P (SP 1 microM) was significantly lower in ICC than in control preparations. The effect of inhibitory nonadrenergic, noncholinergic innervation was evaluated using EFS at low frequencies (0.5-8 Hz), after cholinergic and sympathetic blockade with atropine (3 microM) and guanethidine (3 microM). The maximum relaxation value expressed as percentage of inhibition of SP-induced contraction was significantly higher in ICC than in control preparations (87+/-2.4 and 67+/-6.3, respectively; P<0.05). Experiments with substances that antagonize or reduce the effect of putative inhibitory mediators (VIP 6-28, apamin and N(G)-nitro-L-arginine) suggest that an alteration in NO and ATP release is present in ICC preparations. In particular at a higher inhibitory frequency NO-mediated relaxation is enhanced in ICC vs control, supporting the hypothesis that excessive NO production may be involved in pathophysiological mechanism of constipation.

Acetylcholine↗
PubMed1998

Functional evaluation of 5-hydroxytryptamine receptor activity in rat resistance vessels.

1. To characterize 5-hydroxytryptamine (5-HT) receptors in rat perfused mesenteric vascular bed (MVB), the effect of 5-HT and related compounds was investigated by functional assay. 2. In quiescent preparations, 5-HT elicited a concentration-dependent conctractile response. After addition of ketanserin, a 5-HT2 receptor antagonist, EC50 values were significantly higher than in controls. 3. In noradrenaline (NA)-precontracted preparations, under continuous infusion of ketanserin, 5-HT, 5-carboxamidotryptamine (5-CT) and sumatriptan produced relaxation. Their rank order of relaxant potency and maximum effect were sumatriptan > 5-HT > 5-CT. Methysergide (1 microM) and spiperone (20-100 nM) caused a rightward shift of the relaxation curve to sumatriptan. These data suggest that vasodilatation in rat MVB is mediated by an 'atypical' subtype of 5-HT1-like receptor, which reveals a pharmacological profile similar to that of the 5-HT1D receptor. The involvement of both 5-HT3 and 5-HT4 receptors can be ruled out, since tropisetron (up to 10 microM) was not able to antagonize the relaxant effect by sumatriptan. 4. Under granisetron infusion (3 microM), the contractile response evoked by perivascular nervous stimulation, but not exogenous NA contraction, was significantly reduced (P < 0.001). These data demonstrate the presence of 5-HT3 receptors in peripheral neurones, modulating neurotransmitters release.

Animals↗
PubMed1996

Hyporeactivity of mesenteric vascular bed in endotoxin-treated rats.

Vascular reactivity and activation of the nitric oxide (NO) pathway were investigated in perfused mesenteric vascular bed removed from rats 5 h after i.p. injection of bacterial lipopolysaccharide (E. coli lipopolysaccharide, 30 mg kg -1). Lipopolysaccharide treatment induced hyporesponsiveness to noradrenaline. Maximal noradrenaline-induced vasoconstriction was significantly reduced in lipopolysaccharide-treated vs. untreated preparations. Continuous infusion of L-arginine (L-Arg) (0.2 mM) enhanced noradrenaline hyporeactivity of lipopolysaccharide-treated rats. N omega-Nitro-L-arginine methyl ester (L-NAME) (0.2 mM), a non-selective inhibitor of NO synthase, failed to completely restore the noradrenaline hyporeactivity of lipopolysaccharide-treated + L-Arg-infused mesenteric vascular bed. After L-NAME treatment. Methylene blue (10 microM), a guanylate cyclase inhibitor, produced no additional increase of noradrenaline vasoconstriction in lipopolysaccharide-treated + L-Arg-infused mesenteric vascular bed, suggesting that an NO-independent activation of guanylate cyclase may be excluded. In lipopolysaccharide-treated preparations, L-Arg (0.2 mM) elicited a significant increase in nitrite production, which was antagonized by L-NAME. In conclusion, lipopolysaccharide-induced noradrenaline hyporesponsiveness of rat resistance vessels can only be partially explained by NO overproduction. Other mechanisms, probably related to vasoconstriction, may be involved.

Animals↗
PubMed1996

Prenatal exposure to carbon monoxide and vascular responsiveness of rat resistance vessels.

The aim of the present study was to investigate the influence of prenatal exposure to carbon monoxide (CO) on vascular reactivity of rat resistance vessels, in different stages of neurogenesis. Both prenatally CO-exposed and control male Wistar pups (5-7, 9-11, 14-16, 20-22 days) were tested vs respective 60 day adult rats. The results showed that: (i) at 5-7 days of age, TTX caused a more marked inhibition of perivascular nerve stimulation (PNS)-evoked vasoconstriction in CO-exposed animals with respect to controls; (ii) the NO-related relaxant effect by ACh in CO-exposed group appeared earlier (5-7 days) than in control group (9-11 days); (iii) the contractile response evoked by ACh on resting tone disappeared earlier (after 14-16 days) than in control group (after 20-22 days). These observations suggested that CO-exposure might induce changes in nerve electrophysiological properties and might cause a precocious maturation of the NO-related enzymatic mechanism implicated in ACh-relaxation.

Acetylcholine↗
PubMed1996

Postnatal developmental changes of receptor responsiveness in rat mesenteric vascular bed.

1. The response to perivascular nervous stimulation (PNS) and the responsiveness to receptor agonists, in different stages of neurogenesis, on rat mesenteric vascular bed (MVB), was investigated. Rats of different age groups (5-7, 9-11, 14-16, 20-22 days) were tested, using 60-day-old rats as controls. 2. In the 5-7 days age group, the response to PNS was resistant to TTX treatment (1 x 10(-6) M). The TTX inhibition increased with age and became almost complete in 60-day-old rats. 3. In the 1st week of postnatal life (pre-innervation period), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) produced contraction, whereas isoprenaline (ISO) and dopamine (DA) caused relaxation. During the 1st and 2nd week, pD2 values of NA and ISO were significantly higher than in adult control rats. No significant difference in pD2 values of 5-HT and DA was observed during postnatal development. 4. At 5-7 days, the relaxation by acetylcholine (ACh), typical of adult age, was absent and ACh evoked only contractile responses. The relaxant effect by ACh appeared at 9-11 days, increased with age and, by the end of the 2nd week, did not differ from that of the adult group. 5. These results provide evidence that responsiveness of all tested receptors in the MVB is already present in the pre-innervation period (1st week). Adrenergic receptor responsiveness is higher at birth and decreases by the end of the 3rd week of postnatal life, when connections between the central nervous system and effector organs are established. Only muscular muscarinic receptors, responsible for ACh-induced contraction, are functional in the 1st week, while endothelial muscarinic receptors, responsible for ACh-induced relaxation, become gradually responsive later in postnatal life.

Acetylcholine↗
PubMed1996

Beta-adrenoceptor responsiveness of splenic macrophages in normotensive and hypertensive rats.

The aim of the present study was to investigate putative mechanisms implicated in the impaired phagocytic response of spontaneously hypertensive rats (SHR)1. The effect of in vitro treatment with isoproterenol (ISO), a beta-adrenergic drug, on phagocytosis and respiratory burst by splenic macrophages (SpMø) from normotensive Wistar-Kyoto rats (WKY) and SHR with established hypertension, respectively, was evaluated. Furthermore, the relaxant effect of ISO was determined in phenilephrine-precontracted thoracic aorta strips from SHR compared with age-matched WKY rats. Results indicate that exposure of rat SpMø to ISO generate a significant and dose-dependent reduction of phagocytosis and oxidative burst which was antagonized, almost completely, by the beta-adrenergic antagonist propranolol (PRO). Unlike normotensive, in hypertensive rats treatment with ISO fail to modulate phagocytosis and respiratory burst activity by SpMø. At vascular level, aortic relaxation by ISO was reduced in SHR when compared to WKY rats. These findings suggest that SHR exhibit changes not only in vascular, but also in macrophage beta-adrenoceptor-mediated responses. It is postulable that sympathetic overactivity could be responsible for impaired phagocytic functions and beta-receptor alterations observed in SHR.

Animals↗
PubMed1994

Decrease of phagocytic functions in hypertensive rats.

The present investigation was aimed to examine non-specific immunologic capabilities of spontaneously hypertensive rats (SHR) during the development of hypertension. In vitro phagocytosis and oxidative killing exerted by monocytes, polymorphonuclear cells (PMN) and splenic macrophages (SpM0) were evaluated in SHR at 5-, 8-, and 24-weeks of age. Age-matched normotensive Wistar-Kyoto (WKY) rats were used as controls. Results showed that in pre-hypertensive stage (5-wk) there was no difference between SHR and WKY rats with regard to non-specific immunologic functions. Statistically significant differences in both phagocytosis and oxidative killing arose in early hypertensive stage (8-wk) and became more marked in adult SHR with established hypertension (24-wk). In conclusion, our data provide evidence of novel immunologic abnormalities in SHR in terms of ingestion and bactericidal phagocytic capabilities. The mechanisms responsible for these impaired immunologic functions may depend on various suppressive factors which will be object of discussion.

Aging↗
PubMed1992

The effects of (+/-)-idazoxan and its stereoisomers on mouse vas deferens motility in vitro. A comparison with yohimbine.

The effects of idazoxan (IDZ) and its stereoisomers were compared to that of a classical alpha 2-antagonist, yohimbine (YOH), on para-aminoclonidine (PAC)- and norepinephrine (NE)-mediated inhibition of the twitch response evoked in the mouse vas deferens by low-frequency (0.1 Hz) field stimulation. (+/-)-IDZ and (+)-IDZ antagonized the inhibitory effects of PAC, (+)-IDZ being twice as potent as (+/-)-IDZ; in contrast, antagonism by (-)-IDZ failed to meet Schild criteria for a competitive mechanism. YOH completely reversed the inhibition of twitch response induced by NE, but not that induced by PAC; in the latter case, residual inhibition was almost fully reversed by (+)-IDZ and to a lesser extent by (+/-)-IDZ, while (-)-IDZ proved ineffective. These results provide pharmacological evidence of alpha 2-receptor heterogeneity at the vas deferens level. A possible additional mechanism involving imidazoline binding sites is discussed.

Adrenergic alpha-Antagonists↗
PubMed1991

Comparative evaluation of lisuride and terguride, ergot alkaloid derivatives, on the field-stimulated vas deferens of mouse.

The ergot alkaloid derivatives, lisuride (LIS) and terguride (TDHL), known to interact with central dopamine receptors as agonist and partial agonist, respectively, were studied on the field-stimulated mouse vas deferens, where recently the existence of presynaptic dopamine receptors has been evidenced. LIS was a competitive antagonist at prejunctional alpha 2 and DA1 receptors situated on the sympathetic nerve terminals of the mouse, with a pA2 value of 9.2 and 9.1, respectively. LIS was also able to antagonize the effects of LY 171555, selective DA2 agonist, but the type of interaction cannot be conceptualized in terms of competitive antagonism. Likewise, the type of interaction of TDHL with dopaminergic and adrenergic agonist-activated sites is not suggestive of a competitive antagonism. Based on these results, it seems that central and peripheral pharmacologic profiles of LIS and TDHL cannot be overlapped, LIS being a potent DA1- and alpha 2-antagonist with a high degree of specifity for these receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Multiple forms of synaptic coordinative interactions in the autonomic neurotransmission. Tensiometric evaluations in peripheral tissues.

The existence of co-transmitters interacting in the complex regulation of autonomic neurotransmission, has led to investigate the interactive effects between the conventional neurotransmitters and other drugs, such as histamine, serotonin, substance P, strictly related to inflammatory mediators, in both vas deferens and urinary bladder of guinea pig. The results suggest that synergistic interactions, involving post-synaptic sites, exist between co-transmitters; furthermore, inflammatory mediators are able to modify the responses to endogenous (via intramural nerves stimulation) and exogenous conventional neurotransmitters. It is conceivable that inflammatory mediators, released by activation of mast cells either within or delivered to the tissues by the vascular supply, may alter the physiological responses of several organ systems.

Acute-Phase Proteins↗
PubMed1990

Pre-junctional regulation of sympathetic neurotransmission in the mouse vas deferens: assessment of agonist and antagonist potencies.

Dopaminergic agonists and antagonists were tested on the field-stimulated mouse vas deferens. Both LY 171555 and SK & F 38393, relatively selective DA2 and DA1 receptor agonists, respectively, produced concentration-dependent inhibition of the field stimulation-induced contractions, without modifying the baseline tone nor the contractile responses to the exogenous noradrenaline. Both LY 171555 and SK & F 38393 concentration-response curves were shifted rightward in a parallel manner by sulpiride (relatively specific DA2 antagonist) and SCH 23390 (relatively specific DA1 antagonist), respectively. The results are suggestive of the existence of pre-junctional dopamine receptors involved in the regulation of sympathetic neurotransmission in rodent vasa.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

[Effects of the partial dopamine receptor agonist, terguride, on the field-stimulated vas deferens in the mouse].

Transdihydrolisuride (terguride), a 9,10-dihydrogenated analogue of the ergot dopamine agonist lisuride, is characterized as partial dopamine receptor agonist at CNS level. This compound was investigated for its effects on peripheral neurotransmission in the attempt to delineate its pharmacological profile. The contractile responses of field-stimulated mouse vas deferens were slightly inhibited by terguride at very high concentrations (10(-5)-10(-2) M); the selective antagonists for alpha 2-adrenergic and dopamine receptors failed to counteract this effect. Terguride was very effective in blocking the inhibitory effects of LY 171555 (selective DA2 agonist), SK&F 38393 (selective DA1 agonist) and clonidine (selective alpha 2 agonist). In no case the antagonism was competitive: the control dose-response curves were not shifted in a parallel and dose-dependent manner. Therefore terguride displays a mixed DA1, DA2 and alpha 2 antagonistic activity.

Animals↗
PubMed1990

[Multiple receptor interactions in the electrically stimulated ductus deferens of the guinea-pig].

The evidence that ATP is released with noradrenaline as a cotransmitter from sympathetic nerve endings in the isolated guinea-pig vas deferens, had led to investigate the potential interactive effects of P2 and alpha 1 receptors, extending the observations to potentially synergistic interactions of histamine-, acetylcholine- and serotonin-receptors. Ineffective concentrations of histamine, carbachol and serotonin increase the neurogenic response to field stimulation; this effect is prevented by the specific antagonist. The responses to the exogenously applied ATP and noradrenaline are increased as well, suggesting that this synergistic interaction of carbachol is less specific. It can be envisaged that receptor complex is a multicomponent system with subunits specific for the primary neurotransmitter and accessory subunits which may interact to increase the responsiveness of the target cell to simultaneous afferent stimuli.

Adenosine Triphosphate↗
PubMed1989

Interaction between bradykinin and voltage-sensitive sodium channels in myelinated nerve fibers.

The effects of externally and internally applied bradykinin on the excitability of single myelinated nerve fibers were studied. External bradykinin (10 microM) slightly prolongs the action potential of a single myelinated nerve fiber; hence, when the fibers are stimulated by long-lasting pulses, this raises the frequency of repetitive firing in sensory fibers and evokes repetitive activity in motor fibers. Under voltage-clamp conditions, sodium channel inactivation is slowed, while sodium channel activation remains unaffected. Prolonged depolarization of the membrane leads to a maintained sodium current. The voltage dependence of the steady-state sodium current inactivation (h infinity) is shifted in the depolarized direction by approximately 10 mV. Internally applied bradykinin produces a frequency-dependent block of the sodium current. The phenomena described here imply that more than one site on the sodium channel is modified by bradykinin.

Action Potentials↗
PubMed1989

Evidence for the existence of prejunctional receptor sites for dopamine in the mouse vas deferens.

The present work is focused on the effects of newly developed dopaminergic agonists and antagonists on the field-stimulated vas deferens. Both LY 171555 and SK&F 38393, relatively selective DA2 and DA1 receptor agonists, respectively, produced concentration-dependent inhibition of the field stimulation-evoked contractions in the mouse vas deferens; both compounds did not modify the baseline tone nor the contractile responses to exogenous noradrenaline. Control LY 171555 and SK&F 38393 concentration-response curves, were shifted rightward in a parallel manner in the presence of sulpiride (relatively specific DA2 antagonist) and SCH 23390 (relatively specific DA1 antagonist), respectively. Control concentration-response curves for dopaminergic agonists were not modified in the presence of specific blockers for H1 and H2 histamine receptors, serotonin receptors and alpha 2-adrenoceptors. These preliminary findings are suggestive of the existence of two dopaminergic receptor types both presumably located prejunctionally.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Mechanism of action of a structural analog of alphaxalone on myelinated nerve fibre.

The action of alphadolone acetate (0.05-5 mM), a steroid anaesthetic and structural analog of alphaxalone, was investigated on frog myelinated axons under voltage-clamp conditions. When applied externally, alphadolone acetate reduced K and Na currents, with apparent dissociation constants of 0.70 and 1.74 mM, respectively, and without noticeable modification in their time course. In addition, Na conductance-voltage and steady-state inactivation-voltage curves were shifted towards negative voltages. This effect was more pronounced on the steady-state inactivation-voltage relationship. These results suggest that alphadolone acetate blocked K channels indifferently in their resting or open state, and Na channels preferentially in their inactivated state. Alphaxalone has been shown to preferentially block open K and inactivated Na channels (Benoit et al., 1988, Br. J. Pharmacol. 94, 635). Thus, a structural change of a steroid molecule can lead to differences in its mechanism of action. This supports the hypothesis of direct interactions between steroid molecules and target membrane proteins with resulting anaesthetic activity.

Anesthetics↗