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curves to acetylcholine were ''u'' shaped, the result of endothelium-mediated relaxation at low concentrations, superseded by subsequent smooth muscle contractile responses.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.

Medicalization of pharmacology teaching: an urgent need in the medical curriculum.

Information overload, proliferation of new drugs and curricular reforms have been recognized as three of the major factors contributing to the insufficient pharmacological education of medical students. To remedy this situation, it has been recommended that a curriculum more selective in knowledge content coupled with a restricted list of drugs be developed. Based on our own teaching experience, common educational objectives, competencies to be achieved, profiles of morbidity and mortality of the Mexican population, and knowledge of the literature, we have identified what should constitute the core content of pharmacology courses in medical schools. Selected themes were grouped in three categories and the number of drugs that undergraduate medical students have to manage is limited to 139. We have developed a concrete, medicine-focused, core pharmacology program dealing with themes and drugs that will best constitute the primary teaching/learning material for undergraduate medical students.

[The teaching of pharmacology in medical schools: current status and future perspectives]. / La enseñanza de la farmacología en las escuelas de medicina. Situación actual y perspectivas.

Pharmacology is a core course in all medical school curricula. In most medical schools, pharmacology is taught during the second year and teaching covers both basic aspects and useful drugs for the treatment of human diseases. It is assumed that relevant pharmacologic knowledge is revisited during the clinical clerkships and that students are adequately trained to prescribe drugs upon graduation. However, for many years it has been noted that pharmacological training is sometimes insufficient and that inadequate and irrational prescription of drugs is a very common problem in clinical settings. Information overload and proliferation of new drugs have been recognized as two of the major contributing factors. To address this issue, many authors have recommended the development of a core curricula in pharmacology which all students would have to complete coupled with a restricted list of drugs. Based on our own teaching experience we have identified what should constitute the core content of pharmacology courses in medical schools and have written a study guide for this discipline. Both documents provide an organizational framework to help second year medical students ascertain what part of the vast knowledge in pharmacology they need to learn. The number of drugs that students have to manage is limited to 168. Our program constitutes the first effort to medicalize the teaching of pharmacology in medical schools. We expect that most medical schools will follow our guidelines as our program is applicable to all curricula modalities.

La enseñanza de la farmacología en las escuelas de medicina: situación actual y perspectivas / The teaching of pharmacology in medical schools: current status and future perspectives

La farmacología es una ciencia básica que estudia las interacciones entre los fármacos y la materia viva. En las escuelas de medicina se imparte en el segundo año y su estudio se centra en los fundamentos de la disciplina y en los fármacos útiles en el tratamiento de las enfermedades del hombre. Se asume que este conocimiento farmacológico se repasa y expande en los cursos clínicos y que los estudiantes están preparados para prescribir fármacos apropiadamente cuando se gradúan. Sin embargo, desde hace varios años se sabe que la educación farmacológica es insuficiente y que la prescripción irracional de medicamentos es muy frecuente. La sobrecarga de información y la proliferación de nuevos medicamentos son dos factores que contribuyen a este problema. Para enfrentar esta situación se ha recomendado la elaboración de programas básicos de farmacología y una lista de fármacos prototipo. Con base en nuestra experiencia docente identificamos el contenido de lo que debe constituir un programa básico de farmacología, y publicamos una guía para orientar el estudio de la disciplina. Ambos documentos permiten a los estudiantes apreciar qué necesitan aprender del conocimiento farmacológico y los fármacos que deben manejar; el total de ellos se limita a 168. Nuestro programa representa el primer esfuerzo para medicalizar la enseñanza de la farmacología en las escuelas de medicina; esperamos que la mayoría de ellas lo consideren, ya que se puede aplicar a todas las modalidades curriculares vigentes.

Pharmacology is a core course in all medical school curricula. In most medical schools, pharmacology is taught during the second year and teaching covers both basic aspects and useful drugs for the treatment of human diseases. It is assumed that relevant pharmacologic knowledge is revisited during the clinical clerkships and that students are adequately trained to prescribe drugs upon graduation. However, for many years it has been noted that pharmacological training is sometimes insufficient and that inadequate and irrational prescription of drugs is a very common problem in clinical settings. Information overload and proliferation of new drugs have been recognized as two of the major contributing factors. To address this issue, many authors have recommended the development of a core curricula in pharmacology which all students would have to complete coupled with a restricted list of drugs. Based on our own teaching experience we have identified what should constitute the core content of pharmacology courses in medical schools and have written a study guide for this discipline. Both documents provide an organizational framework to help second year medical students ascertain what part of the vast knowledge in pharmacology they need to learn. The number of drugs that students have to manage is limited to 168. Our program constitutes the first effort to medicalize the teaching of pharmacology in medical schools. We expect that most medical schools will follow our guidelines as our program is applicable to all curricula modalities.

Endothelium protectant and contractile effects of the antivaricose principle escin in rat aorta.

The triterpene saponin escin is the active component of the extract of seeds of Aesculus hippocastanum used in the treatment of chronic venous insufficiency. Escin is also used experimentally to increase membrane permeability in isolated cells. Since endothelial dysfunction is postulated to be involved in venous insufficiency, the possible endothelium-protectant effect of escin was explored in rat aortic rings, a model widely used to study such effects with cardiovascular agents. Escin enhanced endothelium-dependent relaxation induced by acetylcholine when such relaxation had been reduced by exposure to the superoxide ion generator pyrogallol. This effect was attributed to enhanced nitric oxide production by endothelial nitric oxide synthase, a calcium-dependent enzyme, activated by the increased endothelial cell permeability to calcium induced by escin. Another effect of escin thought to contribute to its therapeutic activity is its ability to produce venous contraction. The compound was found to induce concentration-related contraction also in rat aortic rings. This response was partially inhibited by removal of the endothelium or by preincubation with indomethacin, and was completely abolished by incubation in a calcium-free perfusion fluid. Contraction was considered to be due mainly to the aforementioned effect on calcium permeability, with some mediation by release of endothelial vasoconstrictor prostanoids. It was concluded that, in rat aorta, escin possesses an endothelium-protectant action and a direct contractile effect. The former could contribute to its beneficial effect in the treatment of venous insufficiency, while the latter could constitute a limiting side effect.

Antivasoconstrictor effect of the neuroprotective agent dexrazoxane in rat aorta.

Dexrazoxane is used clinically to reduce the cardiotoxicity of anthracycline cancer chemotherapeutic agents, acting by an iron-chelating antioxidant mechanism. In a study designed to explore the possible mechanism of the recently described neuroprotective effect of the drug in cerebral ischemia, its influence on vascular reactivity was determined in rat aortic rings. Dexrazoxane was found to be devoid of direct contractile or relaxant activity and to have no influence on responses to acetylcholine or histamine (relaxation), or to angiotensin or serotonin (contraction). In contrast, it decreased contractions to norepinephrine, as evidenced by rightward displacement of the concentration-response curves. The effect was prevented by the removal of the endothelium and by the alpha(2)-adrenoceptor antagonist yohimbine; it was partially antagonized by the endothelium-derived depolarizing factor inhibitor clotrimazole, but was not affected by L-NAME or indomethacin, inhibitors of endothelial nitric oxide and prostacyclin production. The anti-contractile effect did not occur in rings stimulated with the alpha(1)-adrenoceptor agonist phenylephrine. It was concluded that dexrazoxane opposes norepinephrine vascular contraction by enhancing endothelial alpha(2)-adrenoceptor-mediated release of relaxing factor(s). The drug could thus offset the deleterious vasoconstriction elicited by the increased circulating catecholamines present during cerebral ischemia, and by this mechanism produce neuroprotection.

2-bromoethylamine, a suicide inhibitor of semicarbazide-sensitive amine oxidase, increases hydralazine hypotension in rats.

Previous work has shown that inhibitors of the predominantly vascular enzyme semicarbazide-sensitive amine oxidase (SSAO) potentiate the hypotensive response to hydralazine, itself a SSAO inhibitor, in anesthetized rats. The present study was carried out to determine whether the recently described suicide SSAO inhibitor 2-bromoethylamine shares this effect. Hypotensive responses to hydralazine, 0.1 mg/kg IV, were obtained in chloralose-urethane-anesthetized rats, either unpretreated or receiving bromoethylamine at different doses and pretreatment intervals. Parallel experiments were run with semicarbazide, the prototypical hydrazine SSAO inhibitor. Both inhibitors potentiated hydralazine hypotension, bromoethylamine having a longer latency and a shorter duration of action than semicarbazide. High doses of bromoethylamine did not produce potentiation, a phenomenon attributed to SSAO inactivation by excess substrate and decreased formation by the enzyme of the inhibitor product. Experiments with combined administration of both inhibitors were also carried out. When semicarbazide was administered before bromoethylamine, potentiaton was prevented, apparently by a mechanism similar to the above; when it was given after the amine, potentiation was increased. This was attributed to enzyme inhibition by interaction with 2 different active sites. The charactertistics of hydralazine potentiation by bromoethylamine were considered compatible with the mechanism of SSAO inhibition by the amine.

Metamizol acts as an ATP sensitive potassium channel opener to inhibit the contracting response induced by angiotensin II but not to norepinephrine in rat thoracic aorta smooth muscle.

Clinically metamizol (MZ) has been related to alteration on haemodynamic parameters and modifications on blood pressure in humans when administered intravenously. These effects have been observed at MZ therapeutic doses. Experimentally, MZ is able to induce relaxation on several types of vascular smooth muscles and modulates the contraction induced by phenylephrine. However, the mechanism underlying the MZ effects on vascular reactivity is not clear. Potassium channels (K) present on vascular smooth muscle cells closely regulate the vascular reactivity and membrane potential. There are four described types of K in vascular tissue: K voltage sensitive (K(V)), K calcium sensitive (K(Ca)2+), K ATP sensitive (K(ATP) and K inward rectification (K(IR), voltage sensitive). The aim of this work was to investigate MZ effects on angiotensin II (AT II) and noradrenaline (NA) induced contraction and to evaluate the K participation on MZ modulating effect on vascular smooth muscle contraction, using isometric and patch clamp techniques. MZ induces relaxation in a concentration dependent manner. Furthermore, MZ strongly inhibits in a concentration dependent fashion the contraction induced by AT II. However, MZ inhibition on NA induced contraction was moderated compared with that observed on AT II. MZ effects on AT II induced contraction was blocked by glybenclamide (a specific K(ATP) blocker, 3 microM, *p < 0.01). In patch clamp experiments, MZ (3 mM) induces an increase on potassium current (K+) mediated by K(ATP) in similar way as diazoxide (a specific K(ATP) opener, 3 microM). Our results suggest that MZ induces relaxation and inhibits contraction induced by AT II acting as a K(ATP) opener.

Hydralazine decreases sodium nitroprusside-induced rat aortic ring relaxation and increased cGMP production by rat aortic myocytes.

Association of hydralazine with nitrova-sodilators has long been known to be beneficial in the vasodilator treatment of heart failure. We previously found that hydralazine appeared to reduce the increase in cGMP induced by sodium nitroprusside in cultured rat aortic myocytes. In order to further explore this seemingly paradoxical interaction, we extended our initial observations in rat aortic myocytes and also determined the influence of hydralazine on sodium nitroprusside-induced relaxation of rat aortic rings. Hydralazine produced a concentration-dependent inhibition of sodium nitroprusside stimulation of cGMP production and caused a rightward shift of concentration-relaxation curves in aortic rings. A possible mechanism of the hydralazine-nitroprusside interaction could be the interference with bioactivation of the nitro-vasodilator to release nitric oxide. Recent evidence indicates that vascular NADH oxidase, an enzyme known to be inhibited by hydralazine, could be involved in this process. Accordingly, hydralazine was found to inhibit NADH oxidase activity in rat aortic myocytes at concentrations similar to those reducing sodium nitroprusside responses. It was concluded that antagonism of sodium nitroprusside action by hydralazine could be a consequence of interference with bioactivation of the former, apparently through inhibition of vascular NADH oxidase.

Semicarbazide-sensitive amine oxidase substrates potentiate hydralazine hypotension: possible role of hydrogen peroxide.

The relation between inhibition of semicarbazide-sensitive amine oxidase (SSAO) and vasodilation by hydralazine (HYD) was evaluated in chloralose/urethane-anesthetized rats pretreated with various substrates of the enzyme and subsequently administered a threshold hypotensive dose of the vasodilator. The SSAO substrates benzylamine, phenethylamine, and methylamine potentiate the hypotensive response to HYD. Methylamine, which was studied in greater detail because of its status as a possible endogenous SSAO substrate, does not influence the response to the reference vasodilator pinacidil; it does enhance HYD relaxation in aortic rings obtained from pretreated rats. Experiments designed to identify the product of SSAO activity responsible for potentiation by methylamine suggest involvement of hydrogen peroxide (H2O2), as evidenced by the findings that such potentiation is abolished by additional pretreatment with the H2O2-metabolizing enzyme catalase, and that the plasma concentration of H2O2 is increased by methylamine and decreased by HYD. These results are interpreted as a substantiation of the relation between the known SSAO inhibitory effect of HYD and its vasodilator activity. Pretreatment with the SSAO substrates would increase production of H2O2 in vascular smooth muscle and thus magnify the influence of this vasoconstrictor agent on vascular tone. In these conditions, the decrease in H2O2 production and hence in vascular tone caused by SSAO inhibition by HYD would also be magnified. It is speculated that inhibition of vascular SSAO could represent a novel mechanism of vasodilation.

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.

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.

Tachyphylaxis and sensitization to nicotine-induced tachycardiac and pressor effects after nicotine infusions

This work examined the effects of nicotine on mean arterial pressure and heart rate in non-anesthetized as a single bolus, as infusions lasting 7.5, 15 or 30 min, and as a post-infusion bolus. A nicotine bolus increased pressure and rate. These effects were less marked as the rate of infusion decreased. The infusions affected differentially the effects of a subsequent bolus. Thus, while tachycardia was decreased, the blood pressure rise was increased. An initial transiet bradycardia was observed after bolus administration, but not during infusions; this effect was unchaged after post-infusion boluses. Pharmacological analysis indicated that tachycardia and bradycardia were predominantly due to ganglionic stimulation, while adrenal and sumpathetic nerve catecholamine release played a major role in the pressor response., These results indicate that slow nicotine infusions do not induce tachyphylaxis for all of the cardiovascular effects of a subsequent bolus, and that development of acute tolerance appears to depend on the mechanism of action of the response

Patterns of heart rate responses to hydralazine in normotensive and hypertensive rats

Hydralazine (H) induces hypotension acompanied by cardiac stimulation due to activation of ther arterial baroreflex. Both clinical and experimental observations suggest, however, that in certain conditions H hypotension can be accompanied by unchanged or even depressed cardiac performance. The present study determined whether varying petterns of heart rate responses could be detected in large populations of conscious normotensive (n=61) and renal hypertensive (n = 59) rats receiving a single dose of H. These patterns were compared with those of normotensive pentobarbital-anesthetized rats (n = 43). In the three groups, hypotension was accompanied by either tachycardia, unchanged heart rate or bradycardia. Tachycardia was found in 52 percent of normotensive conscious rats, in 51 percent of hypertensives and in only 14 percent of anesthetized animals. Heart rate did not change in 26, 35 and 23 percent, while bradycardia was detected in 22, 14 and 63 percent, respectively . These results were explained by postulating the initiation by H of two reflexes with opposite effects on heart rate: the arterial baroreflex producing tachycardia and a cardiac mechanoreceptor reflex producing bradycardia. These reactions would compete with each other, with results depending on their relative sensitivity in a given animal

Trabajos de investigación 1990 / Research works 1990

El estudio surgío con la necesidad de revisar la confiabilidad diagnóstica de los pacientes (82 expedientes primer trimestre 1988) el tratamiento y la evolución hospitalaria que se ha brindado a pacientes con diagnóstico de esquizofrenia, siendo que este diagnóstico es uno de los más frecuentes en el Hospital Psiquiátrico "Fray Bernardino Alvares". Se encuestaron 44 pacientes masculinos y 38 del sexo femenino, 30-36 promedio de edad, escolaridad 15.9% primaria completa, 13.4% con secundaria, 7.3% con preparatoria, 2.4% educación profesional y 2.4% analfabeta; 56.1% no tenian ocupación, la mayoria provenian del D.F. o Valle de México; 74.4% su estado civil eran solteros, 23 pacientes se hospitalizaron por primera vez; 32 pacientes provenian de familias desintegradas, 25 de familias integradas y 2 no se corroboró. El promedio de estancia en el hospital es de 68-93 días. El uso de fármacos demostró que la perfenazina tuvo un 92% de resultados satisfactorios,los medicamentos más usados fueron los neviolepticos (125 ocasiones). A su egreso se ha controlado el brote agudo de enfermedad y diagnóstico emitido es concordante en un 71% con el