[Role of opioid peptides in the peripheral regulation of cardiovascular function].
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Cardiovascular Physiological Phenomena↗
Biomedical subjects
F Ledda
Publications and source records attributed to F Ledda.
Clinical findings and follow-up evaluation of an outbreak of mushroom poisoning--survey of Amanita phalloides poisoning.
One hundred and sixty cases of mushroom poisoning during the period July-November 1981 are reported. The survey details 116 observations of short incubation syndromes and 44 cases of delayed syndrome, identified as Amanita Phalloides poisoning. Of the latter, 40 patients were adult (mean age 46 years, range 20-77; 18 females and 22 males) and 4 were children (less than or equal to 12 years old; 3 females and 1 male). All the patients with Amanita Phalloides poisoning were treated according to a therapeutic protocol, based on the infusion of high doses of penicillin G, administration of dexamethasone and thioctic acid, careful correction of water and electrolyte unbalance. The severity of the disease varied in the population of 44 patients: 4 patients died (2 females, 10 and 77 years old; 2 males, 56 and 64 years old); 26 patients were discharged from the hospital as clinically cured; 14 were discharged with persistently abnormal levels of transaminases and they were advised of a follow-up evaluation. The average length of stay in hospital was 2 weeks. Of the patients followed-up, 6 were symptom-free after 6 months, with normal transaminase values and a normal histopathological picture of liver biopsy specimens. In the remaining patients, there was no normalization of transaminase values and liver biopsy specimens showed a picture of chronic active hepatitis. These patients displayed abnormal immunological tests, with presence of immune complexes and of anti-smooth muscle autoantibodies. The results indicate that Amanita Phalloides poisoning represents a threat not only in the high mortality acute phase, but also in the development of chronic active hepatitis in some survivors.
Adolescent↗
In vitro evaluation of the beta-blocking and electrophysiological properties of mepindolol.
The electrophysiological and beta-blocking effects of mepindolol have been examined in isolated guinea-pig preparations and sheep cardiac Purkinje fibers. Mepindolol did not show selectivity for blocking the chronotropic and inotropic responses to isoprenaline on isolated guinea-pig preparations, and was practically equally potent in blocking the effect of isoprenaline on isolated guinea-pig trachea. Mepindolol 10(-7) M fully antagonized the positive chronotropic effect of isoprenaline (10(-7) M) in Purkinje fibers. However, normal automaticity, action potential characteristics, effective refractory period, membrane responsiveness of Purkinje fibers were unaffected by mepindolol up to 10(-6) M. On the whole, mepindolol appears to be a potent beta-blocker with no cardioselectivity, exerting membrane depressant effect only at concentrations 100-1000 times higher than those exerting effective beta-blockade.
Adrenergic alpha-Antagonists↗
Effects of dl-methadone on the response to physiological transmitters and on several functional parameters of the isolated guinea-pig heart.
The effects of high concentrations of dl-methadone (1-10 microM) on several parameters of cardiac function were studied in isolated guinea-pig heart preparations. The opioid agonist dose-dependently potentiated the inotropic cardiac response to sympathetic nerve stimulation; this effect was naloxone-insensitive and was antagonized by an increase in extracellular calcium concentration. Moreover, methadone enhanced the dose-inotropic response curve of exogenous noradrenaline. The cardiac response to parasympathetic stimulation was antagonized by the drug through a postsynaptic effect; the responses to histamine and isoprenaline were also antagonized in a noncompetitive way. The spontaneous rate and contractility of atrial preparations were depressed by methadone concentrations above 1 microM; the functional refractory period was increased and the maximal driving rate was reduced at the same range of concentrations. All the above mentioned effects were naloxone-insensitive. In isolated sheep Purkinje fibers methadone, at concentrations of 10 microM and higher, significantly affected the transmembrane action potential parameters, by chiefly decreasing the maximum rate of depolarization and increasing the action potential duration. It was concluded that high concentrations of dl-methadone are able to affect several parameters of cardiac function through an unspecific mechanism different from the stimulation of opiate receptors.
Action Potentials↗
Sensitivity to dynorphin-(1-13) of the presynaptic inhibitory opiate receptors of the guinea-pig heart.
Dynorphin-(1-13) at the concentrations of 1-10 microM, produced a dose-dependent inhibition of the cardiac response to field stimulation of the adrenergic nerve terminals in guinea-pig atria pretreated with peptidase inhibitors. This inhibitory effect was competitively antagonized in a dose-dependent manner by 5 and 10 microM naloxone. Since dynorphin-(1-13) did not modify the dose-inotropic effect curve of exogenous noradrenaline, it was concluded that the depressant effect of the opioid agonist was due to the stimulation of the presynaptic inhibitory opiate receptors belonging to the kappa subtype.
Animals↗
Cardiodepressant effects of ethanol on guinea-pig atria: presynaptic and postsynaptic components.
Ethanol, at concentrations ranging from 0.5 to 1.5%, depressed myocardial contractility of electrically-stimulated guinea-pig atria. This effect was evident in preparations bathed with a low calcium concentration, but was progressively reduced by increasing the extracellular calcium. The same concentrations of ethanol produced a dose-dependent inhibition of the cardiac response to field stimulation of the adrenergic nerve terminals. This effect was again calcium-dependent. These results support the hypothesis that the pre- and postsynaptic components of the cardiodepressant effects of ethanol are due to a reduction in calcium availability both at the nerve endings and in the contractile cells.
Animals↗
Influences of age on the positive inotropic effect mediated by alpha- and beta-adrenoceptors in rat ventricular strips.
The positive inotropic effect of phenylephrine (in the presence of atenolol) and isoprenaline was studied in isolated right ventricular strips obtained from Wistar rats aged 2 weeks, 3 months, and 26 months. The positive inotropic effects induced by phenylephrine and isoprenaline were higher in the 2-week-old than in the 3- or 26-month-old rats. The typical 'alpha-type' or 'beta-type' responses were induced by phenylephrine (plus atenolol) or isoprenaline, in all the age groups. The EC50 values for the alpha-mediated positive inotropic effect decreased with age, while the EC50 value for the positive inotropic effect of isoprenaline increased in the senescent heart. These results suggest an enhanced alpha-adrenergic sensitivity in the senescent heart.
Aging↗
Amanita poisoning: a clinical-histopathological study of 64 cases of intoxication.
In the last few years new and effective therapeutic schedules have been employed in the treatment of patients intoxicated by mushrooms of the genus Amanita. As a result, the survival rate has considerably increased and clinical-histopathological correlation studies, such as the present one, have become feasible. The fate of these patients was once wrongly considered to be either complete recovery (rarely) or death (frequently). According to the results of the present study, Amanita intoxication can also progress to chronic liver damage. This latter evolution of the disease seems to depend on the severity of the acute phase of the intoxication, as clinical, laboratory and biopsy findings of liver alteration testify. The correct evaluation of evolving liver damage involves histopathological investigations, which should be performed 6 months after the acute episode, in those patients who overcome a moderate to severe acute intoxication.
Amanita↗
Inhibition of the cardiac response to sympathetic nerve stimulation by opioid peptides and its potentiation by morphine and methadone.
[D-Ala2,D-Leu5]enkephalin (1-10 microM) and [Met5]enkephalin-Arg-Phe (1-10 microM) produced concentration-dependent inhibition of the cardiac response to field stimulation of the adrenergic nerve terminals in preparations pretreated with peptidase inhibitors (captopril 10 microM, bestatin 10 microM, thiorphan 0.3 microM and L-leucyl-L-leucine 2 mM). The inhibitory response to the opioid agonists was evident in preparations superfused with solutions containing 1.8 mM calcium, but not in those containing 3.6 mM calcium. Moreover the inhibition was antagonized by naloxone 10 microM. [D-Ala2,Met5]enkephalinamide (1-3 microM) and beta-endorphin (1-3 microM) did not significantly affect the sympathetic response. The cardiac response to sympathetic stimulation was not inhibited but, on the contrary, was potentiated by morphine (3-10 microM) and methadone (3-10 microM). It is suggested that the depressant effect of the opioid peptides was due to stimulation of presynaptic inhibitory opiate receptors on adrenergic nerve terminals of the heart, and that the potentiation of the sympathetic response by morphine and methadone was probably attributable to an unspecific inhibitory effect on the neuronal uptake of noradrenaline.
Animals↗
Alterations of drug toxicity in cardiovascular disease.
The past ten years have seen a rapid expansion in the field of cardiovascular pharmacology. New indications for old agents have appeared and new powerful drugs have been introduced, including entirely new classes of compounds. The availability of so many agents has considerably expanded the risk of life-threatening adverse reactions due to overdosage or to inappropriate drug associations. The liability to encounter severe side effects is often enhanced in patients with underlying cardiovascular diseases, which may change the usual drug action either by inducing modifications of the drug pharmacolinetic or by altering the receptor sensitivity. In most cases these kind of reactions are predictable on the ground of the knowledge of both the drug mechanism of action and the functional alterations induced by the disease. However entirely unexpected adverse reactions may also occur in cases in which unrecognized alterations exist, whose pathophysiology has not been fully elucidated. Recent demonstrations that some physiopathological influences, as well as prolonged drug treatment, can modulate the number of adrenergic receptors in the cardiovascular system has offered a clue to a better understanding of at least some episodes of altered responsiveness to cardiovascular drugs, previously considered of unknown origin. The possibility of obtaining some indications of the adrenoceptor status in man, by the assessment of the receptor density in circulating blood cells, seems to represent a promising diagnostic approach to the problem of disease induced adrenergic regulation and its possible consequences in terms of altered drug responsiveness.
Anti-Arrhythmia Agents↗
On the presence of H1-receptors in various sections of guinea-pig heart: a correlation between binding and functional studies.
The binding of 3H-mepyramine in different sections of guinea-pig heart was examined. 3H-mepyramine binds to a single class of binding sites to guinea-pig ventricular membranes and to right atrial suspension with an apparent dissociation constant (Kd) of 4.35 nM and 14.90 nM respectively. When treated as those obtained from the right atrium, the left atrial suspensions do not seem to bind 3H-mepyramine specifically.
Aminopyridines↗
Differences between the prejunctional effects of phenylephrine and clonidine in guinea-pig isolated atria.
The prejunctional effects of clonidine and phenylephrine were studied in guinea-pig isolated atria by means of field stimulation of the sympathetic nerve terminals during the cardiac refractory period, in the presence of 1 microM atropine. Clonidine (10-100 nM) produced a dose-dependent decrease in the stimulus-inotropic response curve; the IC50 for clonidine was increased about 70 times by the pretreatment of the preparations with 1 microM yohimbine. The effect of clonidine was not modified by 0.5 microM prazosin. Unlike clonidine, phenylephrine (1-10 microM) induced a statistically insignificant increase in the contractile force of preparations stimulated at 4 Hz. The inhibitory effect of phenylephrine (1-10 microM) was partially prevented by either 1 microM yohimbine or 0.5 microM prazosin. However, it was antagonized, to about the same degree as that observed with clonidine, by the pretreatment of the preparations with both 1 microM yohimbine and 0.5 microM prazosin. The results seem to indicate that one component of the prejunctional effects of phenylephrine may be mediated by presynaptic alpha-adrenoceptors belonging to the alpha 1-subtype.
Animals↗
[Electrophysiologic and anti-arrhythmia properties of propafenone deducible from experimental studies in vitro].
The aim of our study was to analyze which of the basic "in vitro" properties of Propafenon could be relevant to the antiarrhythmic action, as well as to contribute to its classification among the antiarrhythmic drugs. Propafenon belongs to class 1 of Singh and Hauswirth's classification and its characteristics are similar to those of lidocaine; Propafenon may act mainly on ventricular arrhythmias caused by a reentry circuit or by increased automaticity including those which occur in the post-ischemic state and those due to digitalis toxicity. A peculiar aspect of Propafenon seems, however, to be the beta-receptor blocking activity (especially beta-2) shown at therapeutical doses. Such property can induce a depression of heart rate and contractility mainly in patients with a compensatory increase of the sympathetic tone. On the contrary, the calcium-antagonist action of Propafenon is very weak, as it is detected only at doses 80-100 times higher than those that exert an electrophysiologic action. It is also possible that the pharmacological activity of the drug "in vivo" can assume aspects different from those expected from "in vitro" experiments, because of the various metabolites of Propafenon demonstrated in human beings.
Anti-Arrhythmia Agents↗
Differences between the effects of phenylephrine and other inotropic interventions on post-rest contraction in guinea-pig ventricular strips.
The influence of several inotropic interventions on the strength of the post-rest contraction (PCR) was studied in isolated guinea-pig ventricular strips. In preparations stimulated at 1 Hz and incubated in 3.6 mM Ca++, the PRC-maximum potentiation was obtained after a rest interval of 2 sec (optimum resting time: ORT); a post-rest potentiation was present until 15 sec of rest. An increase in stimulation rate and in Ca++ concentration induced a shift in the ORT towards 15-20 sec, and an increase in the potentiation of PRC. At a low stimulation rate (0.33 Hz) the PRC was lower than steady-state contraction (SSC) at all rest intervals tested. Phenylephrine (5 X 10(-6) M) did not modify the ORT either at 1 or 2.5 Hz, and reduced the height of PRC at 0.33, 1 and 2.5 Hz. These results are discussed in terms of the different effects induced by the various inotropic interventions on cellular calcium availability.
Animals↗
Reoxygenation dysrhythmias in the isolated guinea-pig heart: sensitivity to prazosin, atenolol and practolol.
Isolated guinea-pig hearts were perfused aerobically for 60 min, then made anoxic for 30 min and finally reoxygenated for 30 min. The effects of prazosin, atenolol and practolol on contractility, coronary pressure, ECG and LDH release were examined. Prazosin and atenolol were able to reduce significantly the incidence of ventricular fibrillation and LDH release. The same two drugs increased the recovery of normal electrical activity after 30 min of reoxygenation. Practolol, on the other hand, was ineffective in reducing the incidence of ventricular arrhythmias and LDH release.
Animals↗
Overall evaluation of treatment modalities for heroin addiction in a toxicology unit.
A survey of treatment results is presented, using a variety of guidelines for the therapy of different features of heroin addiction in a toxicology unit. Data on 3,211 inpatients under treatment from 1972 are analyzed separately, as well as the follow-up status of 1,262 outpatients who were enrolled in a methadone treatment program. The results are discussed in terms of reliability of the programs and their risk-benefit ratios for the community.
Clonidine↗
Possible presynaptic inhibitory effect of etorphine on sympathetic nerve terminals of guinea-pig heart.
Etorphine (1-4 microM) dose dependently reduced the sympathetic response induced by trains of field pulses in guinea-pig isolated atria stimulated at 4 Hz; this effect was antagonized by 10 microM naloxone. Since etorphine did not modify the dose-inotropic effect curve of exogenous noradrenaline in the same preparation, it is suggested that the depressant effect of the opioid agonist was due to stimulation of presynaptic inhibitory opiate receptors on adrenergic nerve terminals of the heart.
Animals↗
Some characteristics of the inotropic effects of histamine H1- and H2-receptor agonists in comparison with those of alpha- and beta-adrenoceptor agonists.
The positive inotropic effects of 2-pyridyl-ethylamine (PEA) and of 4-methylhistamine (4MeH) were studied in isolated guinea-pig ventricular strips electrically stimulated at a rate of 60 and 150/min. The increase in contractile tension induced by PEA (10(-7)-3 X 10(-4) M) in the presence of cimetidine (10(-5) M) was associated with a slight increase in time to peak tension and with a lengthening of the relaxation phase; the positive inotropic effect of PEA was significantly higher at a frequency of 60/min than at 150/min. Conversely, the inotropic response to 4MeH (10(-8)-3 X 10(-6) M) was not frequency dependent, and was associated with an evident decrease in relaxation time. Moreover, 4MeH consistently antagonized, in dose-dependent manner, the negative inotropic effects induced by the calcium antagonistic drug D600 and by lowering calcium concentration in the medium, and was able to restore the contractility abolished by treatment of preparations with a high K+ medium. On the other hand PEA, in the presence of cimetidine, scarcely antagonized the negative inotropic effects induced either by D600 or by low calcium solution, and was unable to restore the contractility of K+-depolarized preparations. The characteristics of the inotropic response of the H1-receptor agonist were very similar to those of the alpha-adrenoceptor agonist phenylephrine. This observation suggests that a common mechanism is probably involved in the inotropic effects mediated by H1 and by alpha receptors, and that this mechanism does not include a stimulation of the calcium transmembrane influx.
Adrenergic alpha-Agonists↗