A contractile-based model was constructed to represent responses to changes in left ventricular (LV) volume in a heart with constantly activated myocardium. Hearts were isolated from rabbits, the myocardium was put into a state of constant activation by perfusion with Krebs Henseleit solution containing 0.5 mM Ba2+, and recordings were taken of LV pressure responses to step and sinusoidal changes in LV volume. Pressure responses to volume steps were divided into five characteristic phases. An elastance frequency spectrum was calculated from pressure responses to sinusoidal volume changes. Values of features of the elastance frequency spectrum were in accord with values of corresponding features of the step response. Using an explicit homology between elements responsible for LV pressure development (pressure generators) and elements responsible for muscle force development (myofilament cross-bridges), mathematical models were constructed to re-create the data. Basic assumptions were that (1) pressure was the summed effect of pressure generators undergoing volumetric distortion; (2) changes in volume brought about changes in both generator numbers (recruitment) and generator distortion; (3) pressure generators cycle through states that variously do and do not generate pressure. An initial two-step model included a cycle with one attachment step and one detachment step between non-pressure-bearing and pressure-bearing states. Predictions by the two-step model had many similarities with the experimental observations, but were lacking in some important respects. The two-step model was upgraded to a multiple-step model. In addition to multiple attachment and detachment steps within the cycle, the multiple-step model incorporated distortion-dependent detachment steps. The multiple-step model re-created all aspects of the experimentally observed step and frequency responses. Furthermore, this model was consistent with current theories of contractile processes.

Animals↗

PubMedDate not supplied

In vitro evaluation of acute effects of mitoxantrone (Novantrone) in rat and guinea pig atria.

Since guinea pig and rat atria have been used as models to study acute anthracycline-induced cardiotoxicity, experiments were carried out in these preparations to evaluate possible acute cardiac effects mediated by mitoxantrone (MTX). After a latency period of approximately 90 min, MTX (10(-5)-10(-4) M) promoted a concentration-related and time-dependent decrease of spontaneous rate in guinea pig atria. A similar but less intense effect after a longer latency interval was observed in rat atria. In this preparation, MTX (10(-5)-10(-4) M) incubated up to 150 min., induced a gradual competitive beta-adrenergic blocking effect on the positive chronotropic action of isoproterenol. This was characterized by a progressive decline of pD2 values without altering Emax. A similar and stronger effect was found in isolated guinea pig atria incubated under same conditions with MTX, except that 10(-4) M exposed for 150 min. was able to depress the Emax to isoproterenol by 21.2%. In addition, MTX (10(-4) M) in this model promoted a non-competitive antagonistic effect on the chronotropic action of histamine. These data are compatible with the idea that MTX could induce cardiac acute effects qualitatively similar to but of lower potency than those produced by doxorubicin in these two models. In addition, guinea pig atria seemed to display higher sensitivity to MTX compared to rat atrial preparations.

Animals↗

PubMedDate not supplied

Adverse reactions to acetaminophen, ASA, and NSAIDs in children: what alternatives?

ASA and NSAIDs are responsible for a large number of adverse reactions. The association of adverse reactions to acetaminophen and to ASA is uncommon, especially in children, and raises the problem of finding alternative treatments. We present a case report of a 7-year-old boy with combined adverse reaction to acetaminophen and ASA/NSAIDs. The child, who had no history of atopy, first displayed the condition at age 6, when he suffered two episodes of urticaria and angioedema, 2 hours after administration of 500 mg of acetaminophen, following two earlier doses of 500 mg (total 1500 mg). At age 7 he suffered a third episode 3 hours after administration of 180 mg of ASA. The patient submitted to oral challenges with acetaminophen (positive at a cumulative dose of 2,040 mg), ASA (positive at a cumulative dose of 204 mg) and nimesulide (negative at a cumulative dose of 119 mg). In conclusion, nimesulide (an NSAID not available in the United States) may be regarded as an alternative treatment in such patients, but more research is needed in pediatric age groups.

Acetaminophen↗

PubMedDate not supplied

Characterization of extracellular pH drop due to the activation of the secretory process by acetylcholine in the bovine adrenal medulla.

A progressive and reversible decrease of external pH accompanied the catecholamine release elicited by acetylcholine in decorticated bovine adrenal glands perfused with buffer-free Locke solution adjusted to an initial pH of 7.4. Both the secretory response as well as the extracellular acid shift promoted by the cholinergic agonist were antagonized by hexamethonium plus atropine, Mg2+ and verapamil. Experiments performed to assess the effects of the reduction of external pH on acetylcholine-induced release of catecholamines revealed that increasing the extracellular concentration of H+ significantly and reversibly reduced this secretory response. These findings are consistent with the idea that adrenomedullary activation of secretion by acetylcholine could be associated with a transient acidification of the extracellular fluid. This release of protons, arising mainly from the chromaffin granules, may be involved in a local automodulatory mechanism of the regulated secretory process.

Acetylcholine↗

PubMedDate not supplied

Acute effects of doxorubicin on chronotropic and inotropic mechanisms in guinea pig atria.

This study was designed to test the possible acute effects of doxorubicin (DOX) on isolated guinea pig atria incubated in Locke's solution. Different concentrations of DOX (10(-6) to 10(-4) M) were added to the medium 30 minutes before the concentration-response curves to noradrenaline and histamine were carried out. DOX (10(-4) M) significantly reduced spontaneous atrial rate. Atropine (10(-6) g/ml) was unable to modify this cardiodepressant effect. DOX (10(-4) M) produced a competitive beta blocking effect, shifting to the right the concentration-response curve to noradrenaline without altering the maximal chronotropic response. On the other hand, this anthracycline (10(-4) M) not only antagonized chronotropic responses to histamine, but significantly reduced the maximal effect mediated by this amine. Isolated left guinea pig atria electrically paced were used to determine the effects of DOX on positive inotropic activity promoted by noradrenaline and histamine. Similarly to what was observed in chronotropic experiments, DOX (10(-4) M) produced a competitive beta blocking action and a noncompetitive inhibition of the positive inotropic action developed by histamine. Lower concentrations of DOX failed to modify the chronotropic responses to both amines. However, after 60 minutes of incubation with DOX, 10(-5) M of this drug produced a shift to the right of the concentration-response curves to noradrenaline and histamine and depressed the maximal chronotropic response to these amines. These effects were not observed with 3 X 10(-6) M DOX. These results are compatible with the idea that a nonspecific interaction of DOX with cardiac beta and histaminergic receptors could be involved in the acute cardiotoxic mechanism produced by this anthracycline.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

[Sympathomimetic effects of Lactrodectus poison].

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Animals↗