RESUMO
To determine residual flow to ischaemic tissue, which is the primary determinant of the rate of development and ultimate size of the myocardial infarct resulting from coronary artery occlusion, the coronary collateral circulation was quantified during acute myocardial ischaemia in eight species in vivo using the radiolabelled microsphere technique. In each case, a prominent branch of the left coronary artery was ligated, and within 5 min microspheres (141Ce labelled, 15 micron diameter) were injected intra-atrially. Hearts were then excised, frozen, and sliced perpendicular to the septum. Using autoradiograms as a guide, tissue samples were obtained from non-ischaemic and ischaemic tissue and the radioactivity of the ischaemic samples measured and expressed as a percentage of the activity in the non-ischaemic myocardium. In the guinea pig heart, despite ligation of a major artery, no zone of significant underperfusion was detected. In the hearts from other species, coronary collateral flow (as a percentage (mean(SEM)) of non-ischaemic flow) was: dog 15.9(1.8) (n = 6); cat 11.8(1.1) (n = 16); rat 6.1(0.7) (n = 6); ferret 2.4(0.6) (n = 6); baboon 2.1(0.3) (n = 6); rabbit 2.0(0.5) (n = 9); pig 0.6(0.2) (n = 6). The dog and cat hearts both possessed transmural gradients of collateral flow with greatest delivery in the epicardium. The patterns of flow distribution in the guinea pig heart were further examined in a Langendorff perfused preparation. Blue dye was injected into the coronary circulation and its distribution over 5 s recorded on cine film. After ligation of the left anterior descending or circumflex arteries, or both, the perfusion field of these arteries was seen to fill retrogradely within seconds. It is concluded that a wide spectrum of collateral flow exists between various mammalian species, a fact that should be taken into account in the study of the pathophysiology and control of regional ischaemia and myocardial infarction.
Assuntos
Circulação Colateral , Circulação Coronária , Doença das Coronárias/fisiopatologia , Mamíferos/fisiologia , Animais , Autorradiografia , Radioisótopos de Césio , Microesferas , Infarto do Miocárdio/fisiopatologia , Especificidade da EspécieRESUMO
The possibility of a component of collateral flow to the ischaemic myocardium that cannot be detected by the radiolabelled microsphere technique was examined in the cat, rat, and rabbit in vivo. Animals were anaesthetised and a coronary artery ligated. The regional distribution of blood flow was assessed by the simultaneous injection of 141Ce labelled microspheres and 86Rb. Blue dye was injected into the circulation to delineate the perfused tissue and the heart removed, frozen, and lyophilised, after which tissue was separated into ischaemic and non-ischaemic fractions and the radioactivity of each assessed. Flow to the ischaemic zone, expressed as a percentage of that in the non-ischaemic tissue, for 86Rb based assessments and 141Ce measurements was: for the cat 21.6(3.9)% and 12.4(1.4)% (n = 12 hearts); the rat 13.2(2.6)% and 5.2(1.8)% (n = 9); and the rabbit 7.2(0.8)% and 1.9(0.8)% (n = 5) respectively. In all species there was a statistically significant difference (p less than 0.01) between the results for the two markers. These results suggest either a microsphere insensitive component of collateral flow or some methodological inadequacy of one of the assessment techniques. The 86Rb data were corrected for possible artefacts due to the flow rate dependent extraction of the isotope. The new 86Rb values for collateral flow in the cat, rat, and rabbit were 15.2(2.9)% (NS vs microspheres), 9.5(1.9)% (p less than 0.05), and 5.2(0.5)% (p less than 0.05) respectively. Although these values were closer to the 141Ce microsphere values, significant differences between the two results still remained, possibly owing to other limitations of the 86Rb method.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Circulação Colateral , Circulação Coronária , Doença das Coronárias/fisiopatologia , Mamíferos/fisiologia , Animais , Gatos , Radioisótopos de Césio , Desipramina , Microesferas , Coelhos , Ratos , Radioisótopos de Rubídio , Especificidade da Espécie , TrítioRESUMO
STUDY OBJECTIVE: The aim was to examine the value of a subthrombolytic maintenance infusion of recombinant double chain tissue plasminogen activator (BW t-PA, Duteplase) in preserving microvascular coronary flow following initial thrombolysis. DESIGN: Coronary arterial thrombi were induced by a copper coil (placed under fluoroscopic control) in the canine left anterior descending coronary artery. Complete vessel occlusion occurred within 10-15 min of coil placement. Following 90 min of thrombotic occlusion, animals received one of three treatments: group 1, vehicle 0.9% saline; group 2, t-PA 1.0 X 10(6) IU.kg-1.h-1 for 1 h; group 3, t-PA 1.0 X 10(6) IU.kg-1.h-1 for 1 h followed by 0.12 X 10(6) IU.kg-1.h-1 throughout the 2 h reperfusion period. Radiolabelled microspheres were administered to assess microvascular coronary flow at various time points throughout the experimental period. SUBJECTS: Experimental subjects were beagle dogs of either sex (n = 30), weight 8.9-14.3 kg. MEASUREMENTS AND MAIN RESULTS: Main vessel patency (assessed fluoroscopically) was achieved within 40.0(SEM 4.0) min and 37.0(3.1) min for group 2 and group 3 animals respectively. Group 1 animals did not reperfuse. Full microvascular coronary flow was achieved following the lytic infusion of t-PA. However, microvascular flow to the ischaemic zone was significantly reduced at the end of the 2 h reperfusion phase in group 2 animals despite "aggressive" anticoagulation with heparin throughout the reperfusion period: subendocardial flow decreased from 0.74(0.14) to 0.24(0.08) ml.min-1.g-1; subepicardial flow decreased from 0.82(0.13) to 0.36(0.09) ml.min-1.g-1, p less than 0.05. Microvascular coronary flow to the ischaemic zone was better preserved following the maintenance infusion of t-PA given throughout the reperfusion phase: subendocardial flow decreased from 0.95(0.07) to 0.50(0.10) ml.min-1.g-1; subepicardial flow decreased from 0.73(0.04) to 0.52(0.08) ml.min-1.g-1. Thrombolytic reperfusion led to salvage of the ischaemic myocardium, with infarct/risk ratio decreasing from 75.0(10.0)% in group 1 to 46.3(11.0)% in group 2, p less than 0.05. Further salvage of the ischaemic myocardium followed a lytic plus maintenance infusion of t-PA, with infarct/risk ratio decreasing to 35.5(6.7)% but this did not reach statistical significance. CONCLUSIONS: t-PA consistently achieved main vessel reperfusion within 40 min (mean) of instituting therapy in our model, leading to marked salvage of ischaemic myocardium. The data also suggest that maintenance infusion of t-PA helps preserve microvascular coronary flow throughout reperfusion and tends to reduce infarct size further.
Assuntos
Circulação Coronária/efeitos dos fármacos , Infarto do Miocárdio/terapia , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/administração & dosagem , Grau de Desobstrução Vascular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Cães , Feminino , Fibrinogênio/análise , Infusões Intravenosas , Masculino , Microcirculação/efeitos dos fármacos , Infarto do Miocárdio/sangue , Reperfusão Miocárdica , Tempo de Tromboplastina Parcial , Proteínas Recombinantes/administração & dosagem , Fatores de Tempo , Ativador de Plasminogênio Tecidual/uso terapêuticoRESUMO
The influence of chronic chemical sympathectomy on the extent of coronary collateral flow delivered to a zone of regional ischaemia following an acute coronary artery occlusion was examined in the rat. Male rats were randomly assigned to either 6-hydroxydopamine treated or vehicle treated groups (n = 20 in each group). Drug treated animals were injected with 6-hydroxydopamine intravenously as follows: day 1, 10 mg.kg-1; day 2, 50 mg.kg-1; days 7, 8, 14, 15, 21, 28, 35 and 42, 100 mg.kg-1. Control animals were injected in a similar manner with vehicle solution. On day 43, animals were anaesthetised, and their hearts were excised and perfused in the Langendorff mode at a perfusion pressure of 10 kPa. After 5 min the left main coronary artery was ligated and after a further 5 min, 153Gd labelled microspheres (10 microCi, 15 microns diameter) were infused via a side arm on the aortic cannula. This was followed within 3 min by the infusion of 3H-desmethylimipramine (5 microCi) via the same route. Disulphine blue dye was injected via the side arm within 1 min of the desmethylimipramine injection so as to delineate the perfused from the ischaemic region. The hearts were frozen in liquid nitrogen and freeze dried. The dried hearts were separated into ischaemic and non-ischaemic tissue on the basis of the blue dye coloration. The weighed samples were assessed for gamma and beta activity and the ratio of radioactive counts.g-1 in the ischaemic tissue to that of the non-ischaemic tissue was taken as an index of relative coronary collateral flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Circulação Colateral , Circulação Coronária , Simpatectomia Química , Animais , Desipramina , Hidroxidopaminas , Masculino , Oxidopamina , Ratos , Ratos EndogâmicosRESUMO
Studies were undertaken to ascertain whether verapamil infusion affords a sustained limitation of myocardial injury in the dog after a 24-hour period of coronary artery occlusion. Regional myocardial ischemia was induced by an embolization procedure which did not involve thoracotomy. Immediately after embolization radioactive microspheres were administered intraventricularly to define any area of myocardial underperfusion (zone at risk of infarction). Verapamil (0.005 mg/kg/min) was then administered and maintained for 24 hours during which time the dogs were allowed to recover from anesthesia. The control group received a corresponding infusion of saline solution. After 24 hours the dogs were killed and transverse myocardial sections (3 mm) were prepared. The resulting area of necrosis was visualized by tetrazolium staining, and risk zones were visualized by autoradiography. In the control heart, 62 +/- 7% of the zone at risk deteriorated to necrotic tissue, whereas in the verapamil-treated group only 18 +/- 4% of the tissue in the zone at risk became necrotic. Verapamil appeared to exert a significant (p less than 0.001) tissue-sparing effect that was sustained for at least 24 hours after the onset of ischemia.
Assuntos
Doença das Coronárias/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/patologia , Verapamil/uso terapêutico , Animais , Circulação Coronária/efeitos dos fármacos , Cães , Feminino , Hemodinâmica/efeitos dos fármacos , Masculino , Necrose , Fatores de TempoRESUMO
We have characterized an isolated rat heart preparation in which particles induce transient coronary vasoconstriction. Exploiting the fact that all commercially available intravenous solutions contain permissible levels of contaminant particles (usually 2 to 20 micron in diameter), we investigated whether these particles have any adverse effect upon coronary flow. A commercially available intravenous solution was modified to produce the St. Thomas' Hospital cardioplegic solution. Constant-pressure infusion of this solution over a 20 minute period caused a 46.2% +/- 5.1% reduction in coronary flow. This flow impairment could be limited to 13.3% +/- 3.5% by the incorporation of a 0.8 micron in-line filter. In hearts perfused with particle-containing solution followed by ultrafiltered solutions, the impairment of coronary flow was reversed within 1 minute. This quick reversal indicates that the particles were impairing flow not by physical occlusion of vessels but by triggering some form of transient vasoconstriction. In studies with filters of varying porosity (between 0.8 and 15.0 micron), the phenomenon was shown to be attributable to relatively small numbers of particles greater than 10.0 micron in diameter. In studies of myocardial protection, it was shown that the impairment of solution delivery and distribution caused by particles could severely reduce the protective properties of a chemical cardioplegic solution; hearts subjected to 180 minutes of hypothermic (20 degrees C) ischemic arrest with multidose (3 minutes every 30 minutes) cardioplegia recovered almost completely upon reperfusion if a filtered (0.8 micron) solution was used, but failed to recover when unfiltered, commercially prepared solutions were used. In an attempt to define the mechanisms underlying the particle-induced vasoconstriction, we conducted dose-response studies in which various vasoactive agents were used in an attempt to combat the effects of the particles. At their optimal concentrations, procaine (10.0 mmol/L), nifedipine (0.1 mumol/L), and adenosine triphosphate (1.0 mmol/L) completely prevented the problem; lidocaine and dipyridamole partially alleviated the effect; verapamil and isosorbide dinitrate were ineffective. These results indicate that several mechanisms acting at a small vessel level might contribute to the particle-induced vasoconstriction.
Assuntos
Bicarbonatos/farmacologia , Cloreto de Cálcio/farmacologia , Circulação Coronária , Magnésio/farmacologia , Cloreto de Potássio/farmacologia , Cloreto de Sódio/farmacologia , Vasoconstrição , Trifosfato de Adenosina/farmacologia , Anestésicos Locais/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Dipiridamol/farmacologia , Contaminação de Medicamentos , Filtração , Técnicas In Vitro , Masculino , Nitratos/farmacologia , Tamanho da Partícula , Ratos , Ratos Endogâmicos , Vasoconstrição/efeitos dos fármacosRESUMO
The purpose of this study was to investigate the pharmacological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration-dependently inhibited radioligand binding in membranes containing rat and human 5-HT3 receptors with estimated pKi values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5-HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycardia (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of approximately 3.0 at 1.0 microg kg-1, = 3-5). Alosetron administered via the duodenum also inhibited this reflex, with duration of action that was significantly longer than that seen with ondansetron (120-60 min, respectively, n = 6). Alosetron had no significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5-HT3 antagonist which normalizes perturbed small intestinal propulsion. Previous clinical data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.
Assuntos
Carbolinas/uso terapêutico , Jejum , Trânsito Gastrointestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Antagonistas da Serotonina/uso terapêutico , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Clonidina/análogos & derivados , Clonidina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ondansetron/farmacologia , Ovalbumina/farmacologia , Ensaio Radioligante , Ratos , Valores de Referência , Reflexo/efeitos dos fármacos , Nervo Vago/efeitos dos fármacosRESUMO
To characterize the temporal and spatial characteristics of transmural gradients of flow, ATP and CP, dogs (n = 17) were subjected to coronary artery ligation for either 30 minutes or 24 hours. Different radioactive microspheres were given at the onset and end of the ischemic period. Simultaneous multiple transmural biopsies (up to 20 per heart) were obtained (in situ freezing) from central ischemic and surrounding normal tissue after either 30 minutes or 24 hours of elapsed ischemia. After lyophilization each biopsy was divided into up to 6 transmural sub-fragments, each of which was analysed for flow, ATP and CP. At the onset of ischemia flow declined to less than 15% throughout the ischemic zone and there was a slight transmural gradient of flow from epi- to endocardium (12.4 +/- 1.6, 13.5 +/- 2.0, 11.0 +/- 1.8, 10.3 +/- 1.7, 8.5 +/- 1.9 and 8.3 +/- 3.1% of non-ischemic tissue). After 30 minutes of ischemia, collateral flow to the epicardial tissue had increased substantially but endocardial flow remained unchanged, the epi- to endo- gradient was 20.8 +/- 2.5, 18.9 +/- 2.4, 13.7 +/- 2.1, 10.8 +/- 1.5, 8.5 +/- 1.2, 7.6 +/- 1.7. After 24 hours there were further increases in the epi- and mid- myocardial regions but the endocardial flow remained severely depressed, the epi- to endo- gradient was 23.9 +/- 3.2, 24.5 +/- 3.0, 23.6 +/- 4.8, 16.4 +/- 3.3, 9.8 +/- 2.9, 5.8 +/- 2.9%. ATP and CP were severely depressed after 30 minutes of ischemia and reflected flow closely with sharp linear epi- to endo- gradients (17.5 to 10.9 muMol/g dry wt for ATP and 7.4 to 3.1 muMol/g dry wt for CP). After 24 hours, the decline in ATP had been slowed and there was a striking recovery of CP in the epi- and mid- myocardial regions which had experienced increasing collateral flow. CP in the endocardium remained severely depressed. Progressive supplementation of collateral flow early and throughout a 24 hour period of regional myocardial ischemia and the selective delivery of this flow to subepi- and mid- myocardial tissue accounts in part for the natural salvage of this tissue and the deterioration of the endocardium to necrosis. Gradients of flow and metabolism further influence these events and account for the "wave front" of cell death.
Assuntos
Circulação Colateral , Doença das Coronárias/fisiopatologia , Metabolismo Energético , Trifosfato de Adenosina/metabolismo , Animais , Biópsia , Doença das Coronárias/metabolismo , Vasos Coronários/fisiologia , Cães , Feminino , Ligadura , Masculino , Microesferas , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Fosfocreatina/metabolismo , Fatores de TempoRESUMO
The role of iron-catalysed hydroxyl radical production in development of myocardial injury was examined in an in vivo rabbit heart with regional ischaemia (45 min) and reperfusion (3 h). Open-chest anaesthetised rabbits were assigned to control (saline) or desferrioxamine-treated [30 mg/kg subcutaneously (s.c.) plus 1, 10, 20, or 100 mg/kg/h intravenously (i.v.) starting 15 min before ischaemia] groups. Haemodynamics and ECG were monitored throughout. Following reperfusion, hearts were excised and perfused in vitro with buffer. The artery was religated, and fluorescent particles were injected to delineate the ischaemic zone. Tetrazolium staining was used to define necrosis. Planimetry was performed on photographed heart slices for calculation of the size of the hearts and of the ischaemic and infarcted zones. Infarct size (as a percentage of ischaemic zone size) in control hearts was 51.2 +/- 5.8% (n = 10) and in the groups treated with desferrioxamine 1, 10, 20, and 100 mg/kg/h it was 53.1 +/- 11.7% (n = 8), 45.3 +/- 6.3% (n = 9), 65.1 +/- 10.1% (n = 6), and 52.5 +/- 9.4% (n = 7), respectively (p = NS vs. control in each instance). In addition, no antiarrhythmic effects were observed at any dose. Thus, iron-catalysed hydroxyl radical damage may not play a role in the pathogenesis of tissue injury under these conditions.
Assuntos
Doença das Coronárias/fisiopatologia , Desferroxamina/farmacologia , Quelantes de Ferro/farmacologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Animais , Doença das Coronárias/patologia , Radicais Livres , Hemodinâmica/efeitos dos fármacos , Hidróxidos/biossíntese , Radical Hidroxila , Técnicas In Vitro , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , CoelhosRESUMO
The effects of BW A4C, a selective arachidonate 5-lipoxygenase (5-LO) inhibitor, on the progression of myocardial tissue injury were examined in anaesthetised, open-chest beagle dogs subjected to 90-min occlusion of the left anterior descending coronary artery (LAD) followed by 120-min reperfusion. Regional myocardial blood flow (RMBF, microspheres), segment shortening (sonomicrometry), and infarct size (tetrazolium stain) as an index of tissue injury were measured. Control animals (group 1, n = 11) received an infusion of vehicle [50% vol/vol glycofurol and distilled water, 47 ml at 12 ml h-1, intravenously (i.v.)] beginning 15 min before ischaemia and continuing until the end of reperfusion. Treated animals received either 10 (group 2, n = 11) or 50 micrograms kg-1 min-1 (group 3, n = 5) BW A4C i.v. in the same period. The infarct/risk zone ratio (I/R) in group 1 (24.1 +/- 6.0%) was not significantly different from that of group 2 (28.0 +/- 8.4%) or group 3 (46.1 +/- 6.7%). The close inverse relationship observed in controls between I/R ratio and collateral flow was not altered by either dose of BW A4C. Segment shortening during ischaemia (-0.2 +/- 2.7, -2.4 +/- 1.7, and -1.5 +/- 1.7%) and reperfusion (4.9 +/- 2.8, 1.0 +/- 1.8, and -1.0 +/- 1.9%) and during an isoprenaline infusion to unmask stunned myocardium (14.7 +/- 3.0, 14.7 +/- 2.6, and 7.4 +/- 1.7%) were not significantly different between groups 1, 2, and 3.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Benzenoacetamidas , Doença das Coronárias/tratamento farmacológico , Ácidos Hidroxâmicos/farmacologia , Inibidores de Lipoxigenase , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologia , Gasometria , Doença das Coronárias/fisiopatologia , Creatina Quinase/metabolismo , Cães , Feminino , Hemodinâmica/efeitos dos fármacos , Lactatos/metabolismo , Masculino , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologiaRESUMO
We studied the ability of two calcium antagonists, nifedipine and verapamil, to limit infarct size in the closed-chest, coronary-embolized dog. Immediately after embolization, 141Ce-labeled microspheres were administered into the left ventricle. Myocardium not receiving microspheres was considered to be the region at risk. The nifedipine group received 16 micrograms/kg, i.v., over 8 min as a loading dose, followed by continuous infusion (0.04 mg/kg per 24 hr) within 10 min after embolization. The verapamil group received a 0.2 mg/kg bolus over 2 min, followed by a continuous infusion of 8 mg/kg per 24 hr. Again, the drug was started within 10 min of embolization. The control groups received an equal volume of saline. At 24 hr after embolization, the dogs were sacrificed, the hearts were sectioned into 3-mm slices, and the slices were stained with tetrazolium to reveal the infarct. The region at risk was determined by autoradiography of the microspheres in the heart slices. Infarct and risk-zone volume were determined by planimetric methods. Infarct size was normalized by expressing it as a percentage of the region at risk. Nifedipine significantly reduced this percentage when compared to matched controls (38.7 +/- 4.7 vs. 79.5 +/- 4.3%, p less than 0.001). Similarly, verapamil also reduced infarct size (18.0 +/- 4.4 vs. 62.0 +/- 7.4%, p less than 0.001). We conclude that both these drugs appear to offer protection in the presence of permanent coronary occlusion.
Assuntos
Infarto do Miocárdio/tratamento farmacológico , Nifedipino/uso terapêutico , Verapamil/uso terapêutico , Animais , Circulação Coronária/efeitos dos fármacos , Cães , Feminino , Hemodinâmica/efeitos dos fármacos , Masculino , Infarto do Miocárdio/patologia , Miocárdio/patologia , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
The cardioprotective effects of the selective adenosine A1-receptor agonist, GR79236 (N-[(1S, trans)-2-hydroxycyclopentyl]adenosine), were examined in a porcine model of myocardial ischaemia-reperfusion injury. When pigs were subjected to a 50-min coronary artery occlusion followed by 3-h reperfusion, GR79236 (10 nmol/kg, i.v.) significantly reduced infarct size whether given 10 min before the onset of ischaemia or reperfusion. This effect was independent of the bradycardia induced by GR79236, as it was also observed in animals in which heart rate was maintained by electrical pacing. However, GR79236 administered 10 min after reperfusion did not reduce infarct size. GR79236 had no effect on the incidence or outcome of ventricular dysrhythmias in this pig model of infarction. Similarly, ischaemic preconditioning (IPC, 2 x 10-min ischaemia and 10-min reperfusion) significantly reduced infarct size. The selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 3.3 micromol/kg, i.v.), abolished the haemodynamic and cardioprotective effects of GR79236 and the cardioprotective effects of IPC in anaesthetised pigs. In conclusion, GR79236 exerted a marked cardioprotective effect in a porcine model of myocardial ischaemia-reperfusion injury, provided that it was administered before reperfusion. This suggests that GR79236 may have clinical utility in the treatment of various aspects of ischaemic heart disease.
Assuntos
Adenosina/análogos & derivados , Pressão Sanguínea/efeitos dos fármacos , Infarto do Miocárdio/patologia , Agonistas do Receptor Purinérgico P1 , Traumatismo por Reperfusão/prevenção & controle , Disfunção Ventricular/patologia , Adenosina/farmacologia , Anestesia , Animais , Doença das Coronárias/patologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Estrutura Molecular , Suínos , Fatores de Tempo , Xantinas/farmacologiaRESUMO
Studies were undertaken to ascertain whether metoprolol, a beta 1-selective adrenergic blocking agent, could offer a limitation of myocardial injury throughout a 24-h period of coronary embolization in the dog. Regional myocardial ischaemia was induced through the use of a bead embolization technique which did not require thoracotomy. In order to delineate the zone at risk of infarction (hypoperfused area), radioactive microspheres (141Ce) were administered intraventricularly immediately after embolization. In the drug-treated group (n = 8) metoprolol administration was initiated by an intravenous bolus injection (0.3 mg X kg-1). This was followed by a continuous infusion (0.003 mg X kg-1 X min-1) during the 24-h experimental period. In the control group (n = 8) saline was administered throughout the 24-h period. Electrocardiographic activity was monitored throughout the experiment and this confirmed the negative chronotropic and antiarrhythmic properties of metoprolol. After 24 h, the hearts were excised and transverse myocardial sections (3 mm) prepared. Areas of necrosis were visualized by tetrazolium staining and risk zones were defined by microsphere autoradiography. In the control and metoprolol-treated groups, 73.3 +/- 7.7% and 68.2 +/- 6.1% of the risk zone became necrotic, respectively. There was no significant difference between these groups.
Assuntos
Metoprolol/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Animais , Circulação Coronária/efeitos dos fármacos , Cães , Eletrocardiografia , Feminino , Masculino , Metoprolol/sangue , Infarto do Miocárdio/fisiopatologiaRESUMO
An isolated perfused rat heart preparation has been used in an attempt to define the mechanisms underlying the coronary vasoconstriction associated with the intraarterial infusion of cardioplegic solutions containing contaminant particles. Coronary infusion of commercially available intravenous solutions, compounded to create the St. Thomas' cardioplegic solution, resulted in a 40.3 +/- 1.9% decline in coronary flow rate at the end of a 20-minute period of infusion. Filtration of the solution through a 0.8 micron filter reduced this decline in flow rate to 23.4 +/- 2.3% of its control value. Inclusion of the 5HT2 receptor antagonist ketanserin (1.0 nanomoles/l), in the unfiltered cardioplegic solution, afforded the same protection as filtration. Inclusion of 5HT (0.1 micromole/l) in a filtered cardioplegic solution resulted in a reduction of coronary flow (49.7 +/- 1.9%) greater than that seen with the unfiltered solution. Studies with antagonists of the histamine receptor (mepyramine and cimetidine) and agonists and antagonists of adrenergic receptors suggested that, although involved in the control of vascular tone, these receptor systems are unlikely to be involved in the process of particle-induced vasoconstriction. Arguments are presented that 5 HT and its receptors may play a critical role and the hypothesis is advanced that particle-induced focal endothelial injury may be the primary lesion in a complex sequence of events leading to induction of transient vasoconstriction.
Assuntos
Circulação Coronária , Contaminação de Medicamentos , Parada Cardíaca Induzida , Animais , Bicarbonatos/administração & dosagem , Cloreto de Cálcio/administração & dosagem , Cimetidina/farmacologia , Circulação Coronária/efeitos dos fármacos , Contaminação de Medicamentos/prevenção & controle , Filtração , Isoproterenol/farmacologia , Ketanserina/farmacologia , Magnésio/administração & dosagem , Masculino , Metisergida/farmacologia , Fenilefrina/farmacologia , Cloreto de Potássio/administração & dosagem , Pirilamina/farmacologia , Ratos , Ratos Endogâmicos , Serotonina/farmacologia , Cloreto de Sódio/administração & dosagemRESUMO
With the use of tetrazolium staining and risk-zone analysis, flurbiprofen has previously been shown to limit infarct size at 6 hr but not at 24 hr following coronary embolization in the dog heart. This study was designed to assess whether this delay in the development of a histologically defined infarct was real or an artifact arising from the effect of the drug on tetrazolium staining characteristics. With the use of a closed-chest bead-embolization model with a capability for reperfusion, hearts were made ischemic for 4 hr by injecting a 2.5 mm bead attached to a silk thread through a special cannula into the coronary vasculature. Immediately following occlusion, radioactive microspheres (141Ce) were administered to define the zone at risk of infarction. Hearts were divided into treatment (flurbiprofen, 1 mg/kg every 6 hr, N = 7) and control (saline, N = 7) groups. Following 4 hr of ischemia, the ischemic area was reperfused by withdrawing the thread and attached bead. Twenty hours later, the hearts were removed and transverse sections (3 mm) were prepared. The area of necrosis was visualized by tetrazolium staining and the risk zone by microsphere autoradiography. In control hearts, 24.7 +/- 5.0% of the zone at risk deteriorated to necrotic tissue; in the flurbiprofen-treated hearts, 17.4 +/- 4.3% of the risk zone became necrotic (NS, p greater than 0.10). Thus, despite earlier findings, these results suggest that the apparent delay in the development of tissue injury may be artifactual.
Assuntos
Circulação Coronária/efeitos dos fármacos , Flurbiprofeno/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Propionatos/uso terapêutico , Animais , Cães , Feminino , Hemodinâmica/efeitos dos fármacos , Masculino , Infarto do Miocárdio/patologia , Miocárdio/patologia , NecroseRESUMO
In previous studies nifedipine has been shown to limit infarct size during 24 h of regional ischemia in the dog. Using a closed chest embolization procedure, autoradiographic (141-cerium at onset of ischemia) microsphere risk zone analysis and tetrazolium staining, the ability of nifedipine to influence collateral flow, energy metabolism and infarct size over 48 h was assessed in the dog. A second microsphere (46-scandium), which did not interfere with the autoradiography, was given after 48 h of ischemia to allow temporal changes in flow to be assessed. Transmural biopsies, taken after 48 h from non-ischemic tissue, ischemic tissue which had become necrotic and ischemic tissue which had survived (tetrazolium-positive tissue within the risk zone) were assayed for flow, adenosine triphosphate (ATP) and creatine phosphate (CP). The results indicate: nifedipine may still afford some small degree of protection up to 48 h of elapsed ischemia, (infarct size as a percent of risk zone size was 86.1 +/- 3.0 in control vs 70.4 +/- 4.5 in drug group (p less than 0.025 n = 9 in each group), 'salvage' in both the control and the nifedipine-treated groups was predominantly subepicardial and in the transmural plane. The extent and location of salvage and necrosis was determined by the epicardial to endocardial distribution of collateral flow. In tissue which was destined to necrosis (mainly in the subendocardium) collateral flow at the onset of ischemia (7.2 +/- 1.2% relative to surrounding non-ischemic tissue) did not increase over 48 h (8.0 +/- 1.4) whereas in tissue which was 'salvaged' (mainly in the subepicardium) flow was greater (27.4 +/- 3.2%) at onset of ischemia) and increased substantially (to 64.6 +/- 5.9%) over 48 h; nifedipine does not increase the amount of flow per g of tissue in salvaged tissue but rather it may increase the amount of tissue receiving sufficient flow to promote salvage; it follows that in nifedipine-treated animals more flow is delivered to the ischemic zone; tissue ATP and CP parallel flow and the results support the concept of a critical threshold of flow (approx. 25% at onset of ischemia) below which tissue eventually deteriorates to necrosis and above which tissue is likely to amenable to salvage. However, for sustained survival this flow level must eventually increase to above 40-50%. In conclusion, while nifedipine can achieve a substantial delay in the onset of tissue necrosis, for sustained salvage there must be early and substantial reflow to the tissue.