Effects of omapatrilat on blood pressure and insulin sensitivity in an animal model of insulin resistance.

OBJECTIVE: To assess the effects of omapatrilat, fosinopril and placebo on blood pressure, plasma insulin, glucose and triglycerides concentrations in Zucker rats, a model for insulin resistance. DESIGN: Double blind, parallel, prospective trial. METHODS: Forty-two male obese Zucker (falfa) rats (aged 13-18 week) initially weighing 400-600 g were used for the experiments. Omapatrilat (n = 14), placebo (n = 14) or fosinopril (n = 14) were administrated once daily at 10 micromol/kg oral for 15 days. At baseline and at the end of the study, a tail-cuff blood pressure measurement was performed; an oral glucose tolerance test was done at the end of the study. RESULTS: Omapatrilat and fosinopril resulted in significant lower systolic blood pressure compared to the placebo group (p < 0.001). This parameter was significantly lower in the omapatrilat group compared with fosinopril-treated rats (116+/-9 vs 125+/-4 mmHg, p < 0.05). After an overnight fast, there was no difference in the fasting glucose concentrations among treatment groups. The basal and post-glucose challenge insulin concentrations were lower in the omapatrilat group compared to the placebo group. No difference was observed in the fasting triglycerides concentrations between the treatment groups. CONCLUSIONS: Compared to placebo and fosinopril treatment, omapatrilat results in lower arterial blood pressure in an animal model of insulin resistance. The results suggest that omapatrilat may have a positive effect on insulin sensitivity.

Pharmacology of Casimiroa edulis IV. Hypotensive effects of compounds isolated from methanolic extracts in rats and guinea pigs.

Bioassay-directed fractionation of the methanolic extract of seeds of Casimiroa edulis led to the isolation of seven constituents with cardiovascular activity, namely the new compound synephrine acetonide and the known compounds N-monomethylhistamine, N,N-dimethylhistamine, proline, N-methylproline, gamma-aminobutyric acid and casimiroedine. In anesthetized rats, both histamine derivatives produced transient hypotension mediated via H1-histaminergic receptors and in the case of N,N-dimethylhistamine, via nitric oxide release. Synephrine acetonide produced transient hypertension and tachycardia, mediated via alpha- and alpha- and beta-adrenergic receptores, respectively. The chromatographic zone containing N-methyproline, proline and gamma-aminobutyric acid elicited marked and prolonged hypotension. Finally, casimiroedine did not modify the blood pressure of anesthetized rats, but lowered it persistently in anesthetized guinea pigs. It was concluded that hypotension produced by C. edulis is due to several active components. The immediate effect can be attributed to the histamine derivatives acting on H1-receptors. More prolonged hypotension would be produced by the mixture of amino acids through an unknown mechanism, as well as by casimiroedine, possibly by activation of H3-receptors. Hypotension is partially offset by synephrine acetonide through adrenergic mechanisms.

Pharmacology of Casimiroa edulis; III. Relaxant and contractile effects in rat aortic rings.

The relaxant and contractile effects of an aqueous extract of the seeds of the hypotensive plant Casimiroa edulis were investigated in rat aortic rings. The extract inhibited contractions elicited by noradrenaline, serotonin and prostaglandin F2 alpha, but did not affect responses to KCl. Inhibition did not require the presence of intact vascular endothelium and was not affected by histamine antagonists. In this preparation, the extract also elicited concentration-related contractions which were more marked in the absence of endothelium, were not blocked by histamine antagonists, and were completely suppressed by alpha-adrenergic blockade. It was concluded that the relaxant effect of the extract is not exerted through release of an endothelial relaxing factor nor through blockade of calcium channels or of specific smooth muscle receptors, and does not involve histaminergic mechanisms. The contractile effect is modulated by vascular endothelium and is alpha-adrenergic in nature.

Pharmacology of Casimiroa edulis; II. Cardiovascular effects in the anesthesized dog.

The cardiovascular effects of an aqueous extract of seeds of Casimiroa edulis were assessed in pentobarbital-anesthetized dogs. The extract produced marked hypotension which lasted more than two hours; it was accompanied by moderate and less persistent bradycardia. The histaminergic nature of these effects was investigated in animals pretreated with the specific antagonists diphenhydramine, cimetidine, or a combination of both agents. These experiments showed that both H1- and H2-receptors were involved in the hypotensive response, while the bradycardia was mediated solely through an H1-mechanism. In open-chest dogs instrumented for recording cardiac output (ascending aortic flow), left ventricular contractility (dp/dt), central venous pressure (superior vena cava), systemic blood pressure, heart rate, total peripheral resistance and stroke volume, the extract decreased blood pressure and peripheral resistance and increased cardiac output and stroke volume, without modifying the other parameters. It was concluded that the cardiovascular pattern of Casimiroa edulis in the dog is that of a peripheral arterial vasodilator and that it increases cardiac output by reducing left ventricular afterload.

Pharmacology of Casimiroa edulis; Part I. Blood pressure and heart rate effects in the anesthetized rat.

The effect of an alcoholic extract of seeds of Casimiroa edulis on blood pressure and heart rate was determined in rats anesthetized with pentobarbital and compared with that of histamine. The extract induced hypotension, accompanied at high doses by tachycardia. Hypotension after histamine was more transient and was not accompanied by changes in heart rate. Experiments with a variety of autonomic antagonists revealed that extract-induced hypotension was not mediated by histamine H2, muscarinic, or beta-adrenergic receptors, but involved an H1 mechanism. After H1 blockade, the depressor response was reversed to a pressor effect, mediated by alpha-adrenoceptor stimulation. The increase in heart rate was due in part to H1 and in part to beta-adrenergic receptor activation. It was suggested that imidazole derivatives could be responsible for the depressor effect observed. The pressor response could be caused by these or other components of the extract.

Toluene and benzene inhalation influences on ventricular arrhythmias in the rat.

We have previously found that toluene did not share the capacity of benzene for increasing the arrhythmogenic action of epinephrine in the rat, but appeared to elicit the opposite effect. The present experiments were carried out to verify this observation in rats subjected to more severe ventricular arrhythmias. In animals previously inhaling either air, toluene or benzene and anesthetized with pentobarbital, arrhythmias were produced by coronary ligation or aconitine. In both models, toluene decreased and benzene increased the number of ectopic ventricular beats in the 30 min following induction of arrhythmia. Gas chromatographic measurement of toluene levels in the heart during and after inhalation revealed essentially constant concentrations at the time of arrhythmia evaluation, equivalent to approximately one-third the peak levels observed at the end of inhalation. Although the mechanism of the effect of toluene on arrhythmia could not be ascertained, nonspecific membrane stabilization or central serotonergic stimulation were considered as possible explanations. Since both mechanisms could be operant also in the case of benzene, the opposite effects of the solvents on arrhythmia could not be readily accounted for.

Repeated administration of adenosine increases its cardiovascular effects in rats.

Hypotensive and negative chronotropic responses to adenosine in anesthetized rats increased after previous administration of the nucleoside. Bradycardia after adenosine in the isolated perfused rat heart was also potentiated after repeated administration at short intervals. This self-potentiation could be due to extracellular accumulation of adenosine and persistent stimulation of receptors caused by saturation or inhibition of cellular uptake of adenosine.

Electrocardiographic effects of toluene in the anesthetized rat.

The influence of inhalation of near lethal quantities of toluene on some ECG parameters, as well as the possible cardiac sensitizing effect of the solvent, were determined in chloralose-anesthetized rats. These actions were compared with those of its close analogue benzene. Both solvents produced tachycardia; toluene increased the duration of QRS and specially PR, while benzene decreased P wave duration. No other systematic changes in ECG morphology or evidence of arrhythmia were observed. Toluene appeared to decrease the number of ectopic beats induced by epinephrine, in contrast to benzene, which increased it markedly. These results suggest that toluene administered by inhalation up to near lethal doses is devoid of untoward ECG effect in the chloralose-anesthetized rat, its only action being a decrease in intraventricular and particularly AV conduction. It does not share the myocardial sensitizing properties of benzene and in fact appears to elicit some protection from the arrhythmogenic effects of epinephrine, although no definite conclusions as to this action can be derived due to limitations in the experimental model used.