Horacio Vidrio

Effects of hydrazine derivatives on vascular smooth muscle contractility, blood pressure and cGMP production in rats: comparison with hydralazine.

Hydralazine is a hydrazine derivative used clinically as a vasodilator and antihypertensive agent. Despite numerous studies with the drug, its mechanism of action has remained unknown; guanylate cyclase activation and release of endothelial relaxing factors are thought to be involved in its vasodilator effect. Other hydrazine derivatives are known to stimulate guanylate cyclase and could therefore share the vasodilator activity of hydralazine, although such possibility has not been assessed systematically. In the present study, hydralazine, hydrazine, phenylhydrazine, and isoniazid were evaluated for vascular smooth muscle relaxation in rat aortic rings with and without endothelium, as well as after incubation with the guanylate cyclase inhibitor methylene blue. They were also tested for enhancement of cyclic guanosine monophosphate (cGMP) production by cultured rat aortic smooth muscle cells and for hypotension in the anesthetized rat. All hydrazines relaxed aortic rings, an action unaffected by endothelium removal and, in all cases except hydralazine, antagonized by methylene blue. Only phenylhydrazine increased cGMP production and only hydralazine markedly lowered blood pressure. It was concluded that hydralazine vascular relaxation is independent of endothelium and is not related to guanylate cyclase activation. The other hydrazines studied also elicit endothelium-independent relaxation, but the effect is related to guanylate cyclase. The marked hypotensive effect of hydralazine contrasts with its modest relaxant activity and is not shared by the other hydrazines. The fact that hydrazine and isoniazid produce methylene blue-sensitive relaxation, yet do not enhance cGMP production suggests the need for activating factors present in aortic rings but not in isolated cells.

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.

Endothelial Function Impairment in Chronic Venous Insufficiency: Effect of Some Cardiovascular Protectant Agents

In segments of human varicose veins, endothelial function was assessed by measuring relaxation induced by acetylcholine in noradrenaline-precontracted preparations. In addition, concentration-response curves to acetylcholine were obtained before and after incubation with the arterial endothelium protectant agents captopril, losartan, troglitazone, pravastatin, or simvastatin. The antivaricose agent escin was also tested. Mean acetylcholine-induced relaxation of varicose venous rings was about 13%, approximately one third of that reported for control saphenous veins. Concentration-response curves to acetylcholine were ‘‘u’’ shaped, the result of endothelium-mediated relaxation at low concentrations, superseded by subsequent smooth muscle contractile responses. Relaxation was enhanced by the endothelium-protecting agents and by escin, troglitazone being the least, and simvastatin the most effective. It was concluded that endothelial dysfunction is present in varicose veins, that this anomaly can be reverted by cardiovascular protecting agents, and that it can play a role in the pathogenesis and treatment of chronic venous insufficiency.

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.

Evaluating knowledge retention of third-year medical students taught with an innovative pharmacology program.

Purpose To explore the degree of retention of pharmacologic knowledge of third-year medical students taught in a new pharmacology teaching program. Method In 1997, the authors administered a retention test consisting of 100 multiple-choice questions, each with only one correct answer, to 457 third-year medical students at the National University of Mexico. Students were not told in advance about this diagnostic evaluation, which was given eight months after they completed the second-year pharmacology course. As a comparison, the authors also analyzed the results obtained by the same students in the three partial examinations taken during the second-year pharmacology course. The Kolmogorov—Smirnov procedure and Wilcoxon and chi-square tests were used to analyze data. Results The distribution of scores obtained in the partial exams well approximated a symmetrical bell-shaped curve, and the mean score was 59.9%. In contrast, in the retention test the distribution was negatively skewed, the mean score (69.8%) was significantly higher (p < .001), and the curve was clearly displaced to the right of that corresponding to the partial exams. The percentage of students obtaining at least a passing score (60%) was considerably higher for the retention test (82.5 versus 51.9). Conclusion These findings, indicating that medical students taught in a new pharmacology program developed adequate basic pharmacologic knowledge, should encourage other medical schools to formally evaluate their teaching programs and continue efforts to improve pharmacologic education of medical students.

Enhancement of hydralazine hypotension by low doses of isoniazid. possible role of semicarbazide-sensitive amine oxidase inhibition

The influence of pretreatment with 1 through 300 mg/kg ip of isoniazid (ISO) on blood pressure and heart rate responses to 0.1 mg/kg iv of hydralazine (HYD) was assessed in rats anesthetized with chloralose--urethane. HYD hypotension was significantly enhanced by ISO at doses between 3 and 300 mg/kg ip. Heart rate was not influenced by HYD in control or pretreated animals. Depressor responses to 0.2 mg/kg iv of pinacidil (PIN) were also potentiated by ISO at 100 and 300, but not at 30 mg/kg. Similarly, ISO decreased cerebral gamma-aminobutyric acid (GABA) at the two highest doses; 30 mg/kg was without effect. Pretreatment of rats with ISO at 1 through 300 mg/kg failed to influence HYD-induced relaxation of aortic rings. These results were interpreted as indicating that potentiation of HYD hypotension by high doses of ISO is not specific for that vasodilator and is related to decreased cerebral GABA, as postulated previously. Lower doses could specifically potentiate the HYD-induced hypotensive effect by inhibition of semicarbazide-sensitive amine oxidase (SSAO), since both ISO and HYD are potent inhibitors of this enzyme. In support of this hypothesis, the SSAO inhibitors, benserazide (100 mg/kg ip) and mexiletine (50 mg/kg ip), were also found to enhance HYD hypotension.

Bilateral Sequential Common Carotid Artery Sectioning in Mice as a New Model for Testing Neuroprotective Drugs

The consequences of cerebral global ischemia induced by right common carotid artery (CCA) sectioning in mice previously subjected to a chronic deficiency of brain blood supply by sectioning of the contralateral artery, as well as the neuroprotector efficacy of 3 5-hydroxytryptamine 1A receptor agonists, were investigated in this study. Left CCA sectioning produced a remarkable increase in the diameter of arteries constituting the cerebral arterial circle; the effect was maximal at 32 days. No neurological deficit or significant brain damage were found in these animals. In mice with previous left CCA sectioning, sectioning of the contralateral artery gave rise to a wide range of motor-behavioral abnormalities, characteristic brain damage, and high mortality rate. Neurological abnormalities ranged from alterations in locomotor activity to lack of coordination, hemiparesis, circling, immobility, and unresponsiveness. Seventeen percent of the animals died within 15 minutes after the acute ischemic event, and the number of deaths progressively increased to 63 at 24 hours and 92 at day 8. In mice killed 72 hours after right artery sectioning, the incidence of infarction was 100, and was more pronounced in the right hemisphere. The 3 5-hydroxytryptamine 1A receptor agonists, tested reduced the severity of neurological alterations and decreased the cumulative mortality rate of the mice. The activity of ±8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide and indorenate was dose-dependent, whereas the protective action of buspirone was more pronounced with lower and higher doses than with intermediate ones. Maximal neuroprotection was obtained with ±8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide. This new model of global ischemia may be relevant to stroke in humans. It incorporates the idea of provoking an acute ischemic insult in animals subjected to chronic hypoperfusion and uses neurological and mortality endpoints to determine the effects of brain ischemia and the degree of neuroprotection. The present findings warrant continued efforts to refine our model to better reflect human stroke and to determine its usefulness in predicting the effectiveness of a particular treatment strategy.

Changing the countenance of pharmacology courses in medical schools

Pharmacology, the science of drugs,is a very complex discipline. In gen-eral, it is the study of the interactionbetween chemical substances andliving matter and its consequences.In particular, it attempts to apply theknowledge and laws derived fromsuch interactions to solve specificproblems. Emerging as a product ofthis discipline is a body of funda-mental knowledge with applicationin many other sciences, primarilymedicine. For the clinician and medical science student, the scope ofpharmacology is, at first glance, lessextensive. The clinician is particu-larly concerned with chemical en-tities that provoke human illness andthose that possess selective biologi-cal activity useful for the treatmentof disease. The medical student isinterested in learning the pharmaco-logical basis of therapeutics.The first pharmacology courses in medical schools were orientedtowards a materia medica content,dealing with drugs of plant or animal origin, and pharmacy

Interaction between isoniazid and diverse vasodilators: role of decreased cerebral GABA

OBJECTIVE To determine if the interaction between isoniazid and hydralazine, consisting of increased hypotension accompanied by bradycardia, occurs with other vasodilators. METHODS Blood pressure and heart rate responses to a number of vasodilators were determined in rats under chloralose-urethane, pretreated or not with 250 mg/kg of isoniazid. The influence of this dose of isoniazid on GABA levels in the hypothalamus and pons-medulla was assessed in other groups of rats. RESULTS Increased hypotension and bradycardia following i.p. isoniazid were observed with dipyridamole, prazosin, pinacidil and hydralazine given i.v. Bradycardia without increased hypotension appeared with papaverine and verapamil, while increased hypotension with unchanged heart rate was observed with minoxidil and captopril. Isoniazid decreased GABA in the hypothalamus and pons-medulla. CONCLUSIONS At the high dose used, isoniazid interacts with various vasodilators, irrespective of their mechanism of action. The interaction could be due to the influence of the drug on GABA levels at cardiovascular regulatory sites.

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.