Assuntos
Ácidos Nucleicos Livres , Aneuploidia , Feminino , Humanos , Gravidez , Diagnóstico Pré-NatalAssuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 5/genética , Translocação Genética/genética , Trissomia/diagnóstico , Adulto , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez , Diagnóstico Pré-Natal , Síndrome da Trissomía do Cromossomo 18RESUMO
1. To investigate possible mechanisms underlying the ability of combined administration of a 5-hydroxytryptamine2 (5-HT2) antagonist and a thromboxane A2 antagonist to reduce reperfusion-induced arrhythmias, the effects of these drugs alone and in combination on platelet aggregation and on cardiac muscle were determined. 2. Platelet aggregation was measured in whole blood obtained from anaesthetized rats. Concentrations of 5-HT (10 microM) and the thromboxane A2 mimetic U46619 (1 microM) which did not cause aggregation themselves, enhanced the responses to ADP (0.1 microM) and to collagen (1 microgram ml-1). For example, the response of 1.0 +/- 0.5 omega to ADP alone was increased significantly to 6.4 +/- 1.0 omega by 5-HT, 15.5 +/- 2.8 omega by U46619, and 17.3 +/- 1.3 omega when U46619, 5-HT and ADP were added together. 3. In further experiments blood was obtained from rats which had received either the 5-HT2 antagonist, ICI 170,809 (1 mg kg-1), or the thromboxane A2 antagonist. ICI 192,605 (1 mg kg-1 min-1), or both in combination. When ADP was used as the primary aggregating agent, the ability of U46619 alone, or together with 5-HT, to enhance responses was reduced significantly by ICI 192,605 alone and in combination with ICI 170,809. Similar results were obtained with lower doses of ICI 170,809 (0.3 mg kg-1) and ICI 192,605 (0.3 mg kg-1 min-1). 4. When collagen was used as the primary aggregating agent ICI 170,809 (1 mg kg-1) reduced the response to 5-HT (5.0 +/- 0.8 omega versus 10.9 +/- 1.2 omega in controls), and ICI 192,605 (1 mg kg-1 min-1) reduced the response to U46619 (6.8 +/- 2.5 omega versus 11.2 +/- 2.2 omega in control). The greatest reduction of platelet aggregation was seen in blood from rats which had received both antagonists, with the response to U46619 plus 5-HT plus collagen being 2.7 +/- 0.6 omega compared to 14.2 +/- 1.7 omega in controls. In contrast, there was no significant attenuation of platelet aggregation in blood from rats which had received the lower doses of each antagonist alone. Only the combination of ICI 170,809 (0.3 mg kg-1) and ICI 192,605 (0.3 mg kg-1 min-1) reduced the response to U46619 plus 5-HT plus collagen (7.6 +/- 1.4 omega versus 15.0 +/- 0.5 omega in controls). 5. In rat isolated ventricular muscle preparations, ICI 170,809 increased the effective refractory period; e.g. from 39 +/- 4 to 86 +/- 18 ms, 10 min after adding 30 microM to left papillary muscles. ICI 192,605 did not increase the effective refractory period itself and did not alter the ability of ICI 170,809 to prolong the effective refractory period. In the presence of 100 microM ICI 192,605, ICI 170,809 (30 microM) increased the effective refractory period from 38 +/- 7 to 100 +/- 30 ms. 6. These results indicate that the previously observed antiarrhythmic activity of combined administration of the higher doses of ICI 170,809 and ICI 192,605 is unlikely to be due to direct effects on cardiac muscle but could be a consequence of reduced platelet aggregation.
Assuntos
Coração/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Tromboxano A2/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Difosfato de Adenosina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Dioxanos/farmacologia , Eletrocardiografia/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Músculos Papilares/efeitos dos fármacos , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Quinolinas/farmacologia , Ratos , Ratos Wistar , Período Refratário Eletrofisiológico/efeitos dos fármacos , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacologia , Vasoconstritores/farmacologiaRESUMO
1. Several unrelated drugs have pro-arrhythmic activity associated with an ability to prolong the QT interval of the ECG. The aim of this work was to examine the effects of the antimalarial drug halofantrine in vivo and in vitro. 2. In anaesthetized guinea-pigs consecutive bolus doses of halofantrine (0.3, 1, 3, 10 and 30 mg kg(-1), i.v.) at 25 min intervals caused dose-dependent prolongation of the rate corrected QTc interval and bradycardia. The change in heart rate became significant after administration of 10 mg kg(-1) halofantrine (-23+/-9 beats min[-1]) whereas the increase in QTc was significant with only 1 mg kg(-1) halofantrine (22+/-10 ms). It was only with the highest dose of halofantrine that the PR interval was increased (from 52+/-3 to 67+/-4 ms) and second degree atrioventricular (AV) block (type 1 Mobitz) occurred in all animals. No changes were observed in any parameters in a separate group of guinea-pigs which received vehicle (dimethylacetamide 60% propylene glycol 40%) at equivalent time points. 3. The blood concentrations of halofantrine ranged from 0.26+/-0.17 microM after administration of 0.3 mg kg(-1) to 2.79+/-0.87 microM after 30 mg kg(-1), i.v. There was a significant correlation between the blood concentrations of halofantrine and the changes in QTc interval. 4 In guinea-pig left papillary muscles the effective refractory period was increased significantly 60 min after addition of halofantrine; from 161+/-4 to 173+/-6 ms with 10 microM, 156+/-8 to 174+/-6 ms with 30 microM and 165+/-6 to 179+/-5 ms with 100 microM halofantrine. However, the vehicle (0.1% Tween 80 in DMSO; final concentration of vehicle in Krebs, 1%) also increased the effective refractory period from 164+/-5 to 173+/-6 ms. Similar results were obtained in right ventricular strips but left atrial effective refractory periods were not altered by either the vehicle or halofantrine. 5. The results of these experiments suggest that any direct effects that halofantrine may have had on the effective refractory period of cardiac muscle cannot be separated from those of the vehicle. The prolongation of QTc and consistent observation of AV block with halofantrine in anaesthetized guinea-pigs suggest that in vivo models may be more useful for further studies investigating the mechanisms underlying the cardiotoxicity of halofantrine.
Assuntos
Antimaláricos/toxicidade , Síndrome do QT Longo/induzido quimicamente , Fenantrenos/toxicidade , Animais , Antimaláricos/sangue , Antimaláricos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Músculos Papilares/efeitos dos fármacos , Fenantrenos/sangue , Fenantrenos/farmacologia , Período Refratário Eletrofisiológico/efeitos dos fármacosRESUMO
1. To examine the possible cardiotoxicity of the antimalarial drug mefloquine, increasing doses (0.3 - 30 mg kg(-1)) were given i.v. to anaesthetized guinea-pigs. Mefloquine did not alter ECG intervals significantly but gradually increased systolic blood pressure (at 3 mg kg(-1)) then had a depressor effect (at 10 mg kg(-1)). Death due to profound hypotension, probably resulting from cardiac contractile failure or AV block, occurred after either 10 mg kg(-1) (2/6) or 30 mg kg(-1) (4/6) mefloquine. 2. In isolated cardiac preparations mefloquine (3 - 100 microM) did not alter the effective refractory period but at the higher concentrations resting tension increased. Developed tension was reduced by 100 microM mefloquine in left atria (from 5.8+/-1.7 to 2.2+/-0.4 mN) whereas in papillary muscles although 30 microM mefloquine reduced developed tension (from 2. 6+/-0.5 to 1.1+/-0.1 mN) subsequent addition of 100 microM caused a marked, but not sustained, positive inotropic effect (from 1.2+/-0.1 to 3.8+/-0.8 mN). 3. In single ventricular myocytes, mefloquine (10 microM) shortened action potential duration (e.g. APD(90) from 285+/-29 to 141+/-12 ms) and reduced the amplitude of the systolic Ca(2+) transient. 4. These effects were accompanied by a decrease in the L-type Ca(2+) current. These results indicate that the main adverse effect of mefloquine on the heart is a negative inotropic action. This action can be explained by blockade of L-type Ca(2+) channels.