RESUMO
The effects of coronary occlusion and of subsequent isoproterenol infusion were examined in conscious dogs. Left ventricular (LV) function was assessed by measurements of LV diameter, pressure, velocity and dP/dt/P, and regional myocardial function was assessed by measurements of segment length (SL) and velocity of SL shortening in normal, border, and ischemic zones. Regional myocardial function was measured from the same sites, along with intramyocardial electrograms and regional myocardial blood flow as determined by radioactive microspheres. Coronary occlusion resulted in graded loss of function from the normal to severely ischemic zones with graded flow reductions and graded increases in ST segment elevation. Isoproterenol improved overall LV function, and function in the normal zone. Isoproterenol also improved function in 19 of 21 border-zone segments and in all moderately ischemic segments, while elevating further the ST segments. These changes were accompanied by increases in myocardial blood flow. In contrast, in severely ischemic segments, isoproterenol resulted in a deterioration of function, in that paradoxical motion occurred in segments previously akinetic during systole, while paradoxical motion was intensified in those segments in which it was already present. These changes were accompanied by further ST segment elevation but not by concurrent increases in blood flow. In addition, in 2 of 21 border zone segments, myocardial blood flow fell and these segments responded to isoproterenol with complete loss of function; paradoxical motion developed. Thus, in the conscious dog, a strong inotropic agent can improve function, even in the ischemic myocardium, as long as the required additional blood flow can be provided wither through primary or collateral channels.
Assuntos
Doença das Coronárias/fisiopatologia , Coração/fisiologia , Isoproterenol/farmacologia , Contração Miocárdica/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Cães , Eletrocardiografia , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Estimulação QuímicaRESUMO
The time relationship for recovery of mechanical function, the intramyocardial electrogram and coronary flow after brief periods of regional myocardial ischemia, was studied in conscious dogs. Total left vemtricular (LV) function was assessed with measurements of LV systolic and diastolic pressures, rate of change of LV pressure (dP/dt), and dP/dt/P. Regional LV function was assessed with measurements of regional segment length and velocity of shortening. An implanted hydraulic occluder on either the left anterior descending or circumflex coronary artery was inflated for 5- and 15-min periods on separate days. A 5-min occlusion depressed overall LV function transiently, but just before release of occlusion overall function had nearly returned to control. At this time regional function in the ischemic zone was still depressed to the point of absent shorteining or paradoxical motion during systole and was associated with marked ST segment elevation (+ 10 +/- 2.2 mV) at the site where function was measured. With release of occlusion and reperfusion the intramyocardial electrogram returned to normal within 1 min, and reactive hyperemia subsided by 5-10 min. In contrast to the rapid return to preocclusion levels for coronary flow and the electrogram, regional mechanical function remained depressed for over 3 h. A 15-min coronary occlusion resulted in an even more prolonged (greater than 6 h) derangement of function in the ischemic zone. Thus, brief periods of coronary occlusion result in prolonged impairement of regional myocardial function which could not have been predicted from the rapid return of the electrogram and coronary flow. These observations indicate that brief interruptions of coronary flow result either in a prolonged period of local ischemia or that alterations of mechanical induced by ischemia far outlast the repayment of the oxygen debt.
Assuntos
Vasos Coronários/fisiologia , Coração/fisiologia , Animais , Constrição , Circulação Coronária , Creatina Quinase/sangue , Cães , Eletrocardiografia , Eletrofisiologia , Perfusão , Pressão , Fatores de TempoRESUMO
Four different interventions were examined in dogs with cardiac tamponade. Infusion of 216 to 288 ml saline solution into the pericardium reduced cardiac output from 3.5 +/- 0.3 to 1.7 +/- 0.2 liters/min as systemic vascular resistance increased from 4,110 +/- 281 to 6,370 +/- 424 dynes . s . cm-5. Left ventricular epicardial and endocardial blood flows were 178 +/- 13 and 220 +/- 12 ml/min per 100 g, respectively, and decreased to 72 +/- 14 and 78 +/- 11 ml/min per 100 g with tamponade. Reductions of 25 to 65% occurred in visceral and brain blood flows and in a composite brain sample. Cardiac output during tamponade was significantly increased by isoproterenol, 0.5 microgram/kg per min intravenously; hydralazine, 40 mg intravenously; dextran infusion or combined hydralazine and dextran, but not by amrinone. Total systemic vascular resistance was reduced by all interventions. Left ventricular epicardial flow was increased by isoproterenol, hydralazine and the hydralazine-dextran combination. Endocardial flow was increased by amrinone and the combination of hydralazine and dextran. Right ventricular myocardial blood flow increased with all interventions except dextran. Kidney cortical and composite brain blood flows were increased by both dextran alone and by the hydralazine-dextran combinations. Blood flow to small intestine was increased by all interventions as was that to large intestine by all except amrinone and hydralazine. Liver blood flow response was variable. The most pronounced hemodynamic and tissue perfusion improvements during cardiac tamponade were effected by combined vasodilation-blood volume expansion with a hydralazine-dextran combination. Isoproterenol had as dramatic an effect but it was short-lived. Amrinone was the least effective intervention.
Assuntos
Aminopiridinas/uso terapêutico , Tamponamento Cardíaco/tratamento farmacológico , Cardiotônicos/uso terapêutico , Dextranos/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hidralazina/uso terapêutico , Isoproterenol/uso terapêutico , Amrinona , Animais , Pressão Sanguínea/efeitos dos fármacos , Volume Sanguíneo/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Microesferas , Radioisótopos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacosRESUMO
A protective effect of intravenous diltiazem pretreatment on transmural histologic damage in ischemic hearts of 30 pigs was determined morphometrically. The pig hearts were rendered ischemic by ligation of the distal left anterior descending coronary artery for 20, 40 and 120 minutes in separate experiments. Heart rate, left ventricular systolic pressure and systemic diastolic pressure decreased slightly during 40 minutes of occlusion, and then recovered to control levels. However, there were no significant differences between control and diltiazem-treated groups. Blood flow, measured by the microsphere technique, was uniformly absent in the ischemic areas in both control and diltiazem-treated hearts. In the few cell layers immediately beneath the endocardium and epicardium, little cellular damage was observed in either group regardless of the duration of ischemia. In the subendocardial, mid-myocardial and subepicardial layers, less cellular damage was detected after all periods of ischemia in hearts exposed to diltiazem in comparison with that observed in control hearts. However, even in the drug-treated hearts, after 2 hours of occlusion, the cells remained severely injured. The protective effect of diltiazem on the cellular integrity in the ischemic myocardial regions appears to be independent of blood flow and may be a reflection of a direct effect of diltiazem on myocytes. The precise mechanism is unresolved. Nevertheless, in the ischemic heart without a significant collateral circulation, pretreatment with the calcium channel blocking drug, diltiazem, results in a delayed onset of cellular damage after acute coronary artery ligation and less cellular damage at ischemic periods up to 40 minutes' duration.
Assuntos
Benzazepinas/farmacologia , Diltiazem/farmacologia , Hemodinâmica/efeitos dos fármacos , Miocárdio/ultraestrutura , Animais , Pressão Sanguínea/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Diltiazem/administração & dosagem , Diltiazem/sangue , Frequência Cardíaca/efeitos dos fármacos , Microscopia Eletrônica , Miocárdio/patologia , Volume Sistólico/efeitos dos fármacos , SuínosRESUMO
The calcium channel blocking agent, diltiazem, improves ischemia-induced conduction delays in the canine heart. It is not known, however, if the improvement of myocardial blood flow caused by diltiazem participates in this response. Accordingly, ischemia-induced conduction delay was measured during brief coronary artery occlusion before and after administration of diltiazem in nine anesthetized pigs with fixed heart rate. Acute coronary occlusion prolonged subendocardial (mean +/- standard error of the mean, 39.9 +/- 3.9 ms) and subepicardial (41.6 +/- 4.1 ms) conduction times (time to peak of the bipolar electrogram in each region) by 51 +/- 4 and 58 +/- 5%, respectively. Regional myocardial blood flow at the ischemic electrode sites was 0.006 +/- 0.002 ml/min per g and was unaffected by diltiazem. Intravenous diltiazem pretreatment (0.01, 0.1, 0.3 and 1.0 mg/kg) 5 minutes before coronary occlusion significantly reduced the ischemia-induced conduction delay in both subendocardial and subepicardial regions during coronary occlusion. The pigs in which ventricular fibrillation occurred within 10 minutes showed a significantly longer conduction delay than that observed in pigs in which ventricular fibrillation occurred later (greater than 10 minutes). Thus, the data suggest that the reduction of ischemia-induced conduction delay produced by diltiazem is independent of blood flow changes and, therefore, that diltiazem may have a beneficial antiarrhythmic action.
Assuntos
Arritmias Cardíacas/tratamento farmacológico , Benzazepinas/uso terapêutico , Doença das Coronárias/complicações , Diltiazem/uso terapêutico , Sistema de Condução Cardíaco/efeitos dos fármacos , Animais , Antiarrítmicos , Arritmias Cardíacas/etiologia , Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/fisiopatologia , Eletrocardiografia , Frequência Cardíaca , SuínosRESUMO
OBJECTIVES: The aim of this study was to characterize fully in vivo aortic compliance over a wide range of passive distending pressures, and to study pharmacologically induced alterations in compliance using an intravascular ultrasound-based technique in the canine model of heart failure. BACKGROUND: Altered aortic compliance may influence considerably the function of the failing heart. Although some studies demonstrate that patients with heart failure have decreased aortic compliance, data from other studies are conflicting. METHODS: Aortic pressures and dimensions in seven dogs were determined both before and after pacing-induced congestive heart failure (CHF) using simultaneous micromanometer and intravascular ultrasound transducers. Decreases in aortic pressure were produced at baseline and after nitroprusside and dobutamine infusions. Inner and outer aortic circumferences were drawn at the lumen-intimal and media-adventitial borders. RESULTS: Aortic pressure-dimension (chamber) stiffness constants were greater after heart failure was produced (10.0+/-1.5 vs. 6.7+/-1.5, p < 0.05), but stress-strain stiffness (material) constants were similar (11.4+/-1.8 vs. 11.3+/-1.0, p=NS). Equivasodilating doses of nitroprusside and 10 microg/kg/min dobutamine decreased pressure-dimension stiffness constants after pacing-induced heart failure but not beforehand. The aortic wall thickness to diameter ratio was significantly greater in CHF than in the control condition (0.30+/-0.08 vs. 0.16+/-0.03, p < 0.01). CONCLUSIONS: Aortic compliance is decreased in this model of CHF, and this change is attributable primarily to vessel geometry rather than material properties. Equivasodilating doses of nitroprusside and equivalent doses of dobutamine increase aortic chamber compliance in dogs with CHF, but not in normal dogs. These data suggest that the beneficial effects of nitroprusside and dobutamine in CHF occur in part from improvement in aortic compliance.
Assuntos
Aorta/diagnóstico por imagem , Tecido Elástico/diagnóstico por imagem , Endossonografia , Insuficiência Cardíaca/diagnóstico por imagem , Animais , Aorta/patologia , Aorta/fisiopatologia , Estimulação Cardíaca Artificial , Complacência (Medida de Distensibilidade) , Cães , Dopamina/farmacologia , Tecido Elástico/patologia , Tecido Elástico/fisiopatologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Nitroprussiato/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Effects of myocardial ischaemia on sarcoplasmic reticulum (SR) of dog hearts were investigated. Regional ischaemia was produced by occlusion of the left circumflex artery, and a microsomal fraction enriched in vesicles of SR was isolated from subendocardium (Endo) and subepicardium (Epi) of control and ischaemic areas of the heart. No significant changes occurred in ischaemic Epi. A loss of in vitro activities (ie calcium transport and ATPase) was found for SR from ischaemic Endo which paralleled the changes in the histology of the tissue. At 5 min of coronary occlusion, Ca2+ binding and Ca2+-ATPase activities of SR from ischaemic Endo were normal. A decrease in the activities of SR was first evident at 15 min after the occlusion, decreased further at about 30 min and remained at that level at 60 min of ischaemia. The maximal rate of Ca2+ uptake did not parallel the Ca2+-binding and Ca2+-ATPase activities. The degree of cAMP-dependent phosphorylation by endogenous and exogenous protein kinase was not different between SR from control and ischaemic areas. A participatory role of SR in the ischaemic impairment of left ventricular systolic and diastolic performance is discussed.
Assuntos
Doença das Coronárias/metabolismo , Miocárdio/metabolismo , Retículo Sarcoplasmático/metabolismo , Animais , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Doença das Coronárias/patologia , Cães , Técnica de Fratura por Congelamento , Microscopia Eletrônica , Miocárdio/ultraestrutura , Proteínas Quinases/metabolismo , Retículo Sarcoplasmático/ultraestruturaRESUMO
We investigated the mechanism of hydrogen peroxide (H2O2) action on myocardial injury in relation to hydroxyl radical (.OH) formation. Isolated rat hearts were perfused with a concentration of H2O2 (300 microM) known to produce cardiac injury. Perfusion of H2O2 for 15 min caused severe myocardial dysfunction, morphological damage, ATP depletion, and lipid peroxidation. Hydrogen peroxide concentration in the coronary effluent was reduced approximately 40% reflecting a myocardial H2O2 consumption of 12.7 +/- 0.9 mumol/15 min/g wet tissue (n = 12). One of the .OH-generated derivatives, 2,3-dihydroxybenzoic acid (2,3-DHBA), formed from reaction with salicylic acid, was detected in the coronary effluent by high-performance liquid chromatography at 23.16 +/- 4.05 nmol/15 min/g wet tissue. Catalase (200 U/ml, n = 6) added to the perfusate attenuated all parameters of myocardial injury by eliminating H2O2 from the perfusate, and thus .OH was not detected in the effluent. Deferoxamine (5 mM, n = 7) added to the perfusate reduced morphological damage and lipid peroxidation, but not dysfunction or ATP depletion. Deferoxamine significantly reduced .OH production; 2,3-DHBA was 5.22 +/- 3.56 nmol/15 min/g wet tissue. The present study provides evidence that .OH is produced in the H2O2-perfused heart. The adverse H2O2-mediated myocardial outcomes documented in this study appear to arise from both .OH-dependent and .OH-independent mechanisms.
Assuntos
Coração/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Hidróxidos/farmacologia , Miocárdio/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Catalase/farmacologia , Circulação Coronária/efeitos dos fármacos , Radicais Livres , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Hidróxidos/análise , Hidróxidos/metabolismo , Hidroxibenzoatos/metabolismo , Radical Hidroxila , Peroxidação de Lipídeos , Masculino , Microscopia Eletrônica , Contração Miocárdica/efeitos dos fármacos , Miocárdio/ultraestrutura , Ratos , Ratos Sprague-Dawley , Tiobarbitúricos/metabolismoRESUMO
UNLABELLED: The mechanisms of myocardial extraction and retention of the new cationic lipophilic radionuclide imaging agent 99mTc-Q12 are currently unknown. We hypothesized that 99mTc-Q12 has satisfactory single-pass extraction independent of active transport processes and longer cellular retention than 201Tl for rapid and sustained cardiac imaging to differentiate perfusion defects. METHODS: Isolated rat hearts were perfused at constant flow with Krebs-Henseleit buffer enriched with bovine red blood cells (30%-40%). The indicator dilution method was used to measure the single-pass maximum extraction (Emax) and net extraction (Enet(t)) of 201Tl and 99mTc-Q12 over 15 min during control perfusion (n = 11) and during normal (1 microM, n = 6) and high cardiotoxic (50 microM, n = 11) dose infusions of the digitalis glycoside, ouabain. RESULTS: The Emax of 201Tl was greater than 99mTc-Q12 Emax (0.73 +/- 0.01 and 0.29 +/- 0.01, respectively). At 3 min of perfusion, 201Tl Enet was greater than 99mTc-Q12 Enet (0.40 +/- 0.01 and 0.11 +/- 0.00, respectively). Between 3 and 15 min, 201Tl Enet was decreasing by a rate of 2% per minute while 99mTc-Q1 2 Enet was decreasing by less than 0.1 % per minute. Ouabain decreased 201TI Emax but did not change 99mTc-Q12 Emax. High-dose ouabain decreased 201Tl Enet at 3 min and 99-Tc-Q12 Enet at 10 and 15 min. CONCLUSION: Ouabain reduced 201Tl Emax but not 99mTc-Q12 Emax. Therefore, the cellular extraction process for 99mTc-Q12 is different from that of 201Tl. Since the Enet(t) of 99mTc-Q12 was reduced in the presence of high doses of ouabain while Emax was unchanged, 99mTc-Q12 extraction and retention appear to be controlled by different processes. Extraction and release kinetics of 99mTc-Q12 were not changed with a low dose analogous to the human therapeutic levels of ouabain.
Assuntos
Cardiotônicos/farmacologia , Furanos , Coração/diagnóstico por imagem , Compostos de Organotecnécio , Ouabaína/farmacologia , Radioisótopos de Tálio , Animais , Bovinos , Eritrócitos , Furanos/farmacocinética , Coração/efeitos dos fármacos , Técnicas de Diluição do Indicador , Masculino , Compostos de Organotecnécio/farmacocinética , Perfusão , Cintilografia , Ratos , Radioisótopos de Tálio/farmacocinéticaRESUMO
UNLABELLED: We postulated that 99mTc-Q3, a cationic imaging agent, produces myocardial activity related to myocardial blood flow during myocardial ischemia and pharmacologic coronary artery vasodilation, and shows little or no myocardial redistribution over 4 hr after intravenous injection. METHODS: In six Group 1 dogs, the chest was opened, the left circumflex coronary artery was acutely ligated, and dipyridamole (0.32, 0.56 or 0.84 mg/kg) was infused into the right atrium, followed by 10 mCi of 99mTc-Q3. Myocardial blood flow was measured by radiolabeled microspheres. The animals were euthanized and 357 myocardial samples were assayed in a well counter for 99mTc activity. One week later, radiolabeled microsphere activity was counted and myocardial blood flow calculated. In nine Group 2 dogs, a variable occluder was placed around the left circumflex coronary artery and an ischemic level of circumflex blood flow was maintained constant over 4 hr as measured by an ultrasonic flow meter. Dipyridamole (0.56 mg/kg) was then infused into the right atrium followed by 10 mCi of 99mTc-Q3. Gamma camera images were acquired at 5, 15, 30, 60, 120 and 240 min following 99mTc-Q3 injection. Microsphere blood flow and endocardial biopsies (n = 6 dogs) were performed at 30, 60, 120 and 240 min following 99mTc-Q3 injection. RESULTS: In the Group 1 animals, 99mTc activity (y) was related to myocardial blood flow (x) from 0 to 6.1 ml/min/g by the relationship y = 0.83X + 0.18, r = 0.95, p = 0.0001. The scintigraphic ratio of myocardial perfusion defect zone counts-to-normal myocardial zone counts (0.54 +/- 0.05 at 30 min) remained constant over 4 hr, as did technetium counts from direct endocardial sampling. Scintigraphic count ratios allowed discrimination between perfusion defect and normal myocardial regions beginning at 5 min following 99mTc-Q3 injection. CONCLUSIONS: Over a range of myocardial blood flows from 0 to 6.1 ml/min/g, 99mTc-Q3 myocardial activity is related to myocardial flow at the time of tracer injection. Technetium-99m-Q3 shows no evidence of myocardial redistribution over a 4-hr period.
Assuntos
Coração/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico por imagem , Compostos de Organotecnécio , Fosfinas , Animais , Circulação Coronária/efeitos dos fármacos , Circulação Coronária/fisiologia , Dipiridamol , Cães , Masculino , Microesferas , Cintilografia , Fatores de TempoRESUMO
UNLABELLED: We investigated the myocardial flow kinetics of six putative radioperfusion agents (99mTc-Q3, 99mTc-Q4, 99mTc-Q12, 99mTc-sestamibi, 99mTc-tetrofosmin and 99mTcN-NOET) and 201Tl in a canine model of myocardial ischemia with pharmacologic coronary artery vasodilation. METHODS: In 31 open-chest dogs with acute coronary occlusion, dipyridamole (approximately 0.56 mg/kg) was infused intravenously, followed by a perfusion tracer injection and radioactive microspheres for myocardial blood flow (MBF) measurement. The paired data were normalized using three techniques; average, normal or maximum myocardial tracer activity and MBF. RESULTS: The upper limit of MBF obtained for the group of tracers ranged from 4.2 ml/min/g to 8.2 ml/min/g. There was a statistically significant (p < 0.0001) linear correlation (r = 0.87-0.98) between the normalized myocardial activity and the normalized MBF values of each of the tracers. The slope of the curve normalized by average for 201Tl (0.83) was greater than those for the 99mTc tracers, and the intercept (0.07) was lower than those for the 99mTc tracers. Slopes and intercepts for the 99mTc agents were as follows: 99mTc-Q3, 0.81 and 0.18; 99mTc-Q4, 0.61 and 0.41; 99mTc-Q12, 0.63 and 0.39; 99mTc-sestamibi, 0.62 and 0.34; 99mTc-tetrofosmin, 0.68 and 0.32; and 99mTcN-NOET, 0.71 and 0.29, respectively. CONCLUSION: In an anesthetized open-chest canine model of regional myocardial ischemia with dipyridamole induced hyperemia, 201Tl shows a more ideal relationship between tracer uptake and MBF than do the 99mTc-based agents. Of the various 99mTc-based imaging agents studied, the myocardial flow kinetics of 99mTc-Q3 appear to be closest to ideal. This relationship is maintained regardless of the normalization technique used. This may, in theory, imply a higher sensitivity in discerning ischemic from normal myocardium and a role in diagnostic nuclear imaging for 99mTc-Q3.
Assuntos
Coração/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico por imagem , Compostos de Organotecnécio , Compostos Radiofarmacêuticos , Radioisótopos de Tálio , Animais , Circulação Coronária/fisiologia , Dipiridamol , Cães , Masculino , Isquemia Miocárdica/fisiopatologia , Compostos de Organotecnécio/farmacocinética , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Radioisótopos de Tálio/farmacocinética , VasodilatadoresRESUMO
The effects of amlodipine (0.3 mg/kg administered intravenously, n = 5) and placebo (n = 5) on recovery of myocardial function and respiration of isolated mitochondria were examined in "stunned" myocardium of normotensive pentobarbital-anesthetized dogs. Measures of myocardial wall motion, using sonomicrometers, and tissue blood flow, by radioactive microspheres, were obtained at baseline, 15 minutes after administration of amlodipine or placebo, after 10 minutes of left circumflex artery ligation and at 60 minutes of reperfusion. Mean aortic pressure decreased from 115 +/- 6 to 101 +/- 5 mm Hg after administration of amlodipine and remained decreased throughout the experiment. Heart rate was not significantly affected at any time. Both groups showed similar degrees of ischemia: elevation of ST segment to 4.7 +/- 1.4 vs 6.2 +/- 1.9 mV; reduction of ischemic zone shortening fraction to 0.6 +/- 1.9 vs -3.4 +/- 2.7%; and reduction of epicardial and endocardial blood flows (epicardial = 40 +/- 13 vs 43 +/- 13 ml/100 g/min; endocardial = 7 +/- 4 vs 13 +/- 6 ml/100 g/min [values for amlodipine vs placebo]). Mitochondrial state 3 rate of respiration and respiratory control index indicative of rate of adenosine triphosphate synthesis and membrane integrity in myocardial samples taken after 10 minutes of ischemia were significantly reduced in the placebo but not in the amlodipine group. Myocardial function showed significantly greater improvement in amlodipine vs placebo at 60 minutes of reperfusion as indicated by shortening fraction (17.7 +/- -1.4 vs 5.8 +/- -3.5%, amlodipine vs placebo), which may have been related to increased myocardial blood flow and decreased blood pressure during reperfusion. Thus, amlodipine pretreatment prevented mitochondrial dysfunction during ischemia and accelerated recovery of both myocardial mechanical function and blood flow when compared with placebo.
Assuntos
Doença das Coronárias/fisiopatologia , Mitocôndrias Cardíacas/metabolismo , Anlodipino , Animais , Fenômenos Biomecânicos , Bloqueadores dos Canais de Cálcio , Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/metabolismo , Cães , Eletrofisiologia , Feminino , Hemodinâmica/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/fisiologia , Nifedipino/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Fatores de TempoRESUMO
Myocardial blood flow was studied in 10 closed chest, anesthetized pigs after an acute balloon catheter occlusion of the left anterior descending coronary artery. With use of radioactive microspheres (15 mu), myocardial blood flow was measured before and during an intravenous nitroglycerin infusion and during a combined nitroglycerin-phenylephrine infusion. A significant zone of ischemis (myocardial blood flow less than 50 percent of normal zone flow) was produced by the occlusion and involved 15 percent of the combined left ventricular and interventricular septal mass. More than 50 percent of this ischemic zone was intensely ischemic (myocardial blood flow 0 to 3 percent of normal). Nitroglycerin resulted in a 20 to 30 mm Hg decrease in systolic blood pressure. Myocardial blood flow was unchanged in intensely ischemic areas but varied directly with the product of heart rate and systolic blood pressure in the moderately ischemic area (myocardial blood flow 26 to 50 percent of normal). S-T segment elevation was significantly increased during nitroglycerin infusion and returned to control level with the added infusion of phenylephrine sufficient to restore the systemic blood pressure to prenitroglycerin values. No improvement in ischemic zone perfusion could be demonstrated during the infusion of nitroglycerin alone or with phenylephrine. The endocardial-epicardial flow ratio in moderately ischemic areas was slightly lower than the normal zone flow ratio and decreased slightly during infusion of nitroglycerin. With the addition of phenylephrine, the ratios rose slightly and no longer differed from prenitroglycerin values. Blood flow distribution in acutely ischemic pig myocardium differs considerably from that observed in the dog. Nitroglycerin was not shown to have any beneficial effects with or without its relative hypotensive effect. More extensive study in animal models other than the dog is needed.
Assuntos
Circulação Colateral/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/tratamento farmacológico , Nitroglicerina/uso terapêutico , Animais , Doença das Coronárias/fisiopatologia , Modelos Animais de Doenças , Cães , Sistema de Condução Cardíaco/fisiopatologia , Hemodinâmica , Infusões Parenterais , Nitroglicerina/administração & dosagem , Fenilefrina/administração & dosagem , Fenilefrina/uso terapêutico , Especificidade da Espécie , Suínos , SístoleRESUMO
The effect of diltiazem on creatine kinase release and tissue adenosine triphosphate content was investigated during calcium paradox in the isolated perfused rat heart. Creatine kinase loss was minimal during the calcium-free phase, but there was a 100-fold increase in creatine kinase release after reperfusion with normal calcium-containing medium. Diltiazem reduced creatine kinase loss by 35 percent when added to calcium-free medium and by approximately 80 percent when added to both calcium-free and reperfusion media. Adenosine triphosphate content was significantly increased from 2.98 mumol in untreated calcium paradox hearts to 5 mumol/g dry weight in diltiazem-treated hearts. With hypothermia the calcium paradox injury was completely inhibited if the temperature of calcium-free perfusion was maintained at 15 degrees C. Diltiazem appears to exert its protective effect through its ability to prevent the cellular separation and alterations in the gap junctions during calcium deprivation of cells and to limit calcium entry into the cells after reperfusion with calcium-containing medium.
Assuntos
Benzazepinas/farmacologia , Circulação Coronária/efeitos dos fármacos , Diltiazem/farmacologia , Canais Iônicos/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Creatina Quinase/metabolismo , Hipotermia Induzida , Miocárdio/enzimologia , Ratos , Ratos EndogâmicosRESUMO
The effects of amlodipine (300 micrograms/kg administered intravenously), a new, long-acting, dihydropyridine class, calcium channel blocking drug, were studied in atrially paced (120 beats/min), autonomically blocked dogs. Hemodynamic and electrophysiologic parameters were measured before and up to 3 hours after amlodipine. Coronary blood flow was significantly increased 10 and 30 minutes after drug administration, whereas cardiac output and mean arterial pressure were unaffected. Coronary vascular resistance was decreased but total systemic vascular resistance did not change. Atrioventricular (AV) nodal conduction was slightly prolonged, as reflected by increases in atrial-His bundle and AV conduction times and PR interval, 30 minutes after administration. All parameters returned toward their control values within 3 hours after drug administration. Comparison of coronary vascular resistance and AV conduction changes with those previously reported for other calcium channel blocking drugs where autonomic blockade existed suggests that at equivalent levels of coronary vasodilation, amlodipine's effects more closely resemble the effects of diltiazem or verapamil than other dihydropyridines.
Assuntos
Sistema de Condução Cardíaco/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Anlodipino , Animais , Bloqueio Nervoso Autônomo , Bloqueadores dos Canais de Cálcio , Cães , Eletrofisiologia , Feminino , Sistema de Condução Cardíaco/fisiologia , Masculino , Nifedipino/farmacologia , Fatores de TempoRESUMO
The effects of amlodipine, a novel, long-lasting calcium channel blocking agent, on ischemia-induced myocardial conduction delay was studied in anesthetized pigs paced at a constant heart rate. Acute coronary occlusion (3 minutes) significantly lengthened time to onset, time to peak and duration of bipolar electrograms recorded from both subendocardial and subepicardial left ventricular sites. After intravenous injection of amlodipine (0.3 mg/kg, n = 6), subsequent periods of ischemia greatly reduced (p less than 0.01) all indexes of subepicardial conduction delay. In the subendocardium, amlodipine decreased only time to onset (-25 +/- 4%, p less than 0.01) within the ischemic zone. Significant delays in all indexes were present during repeated ischemic periods in the placebo-treated control group (n = 5). Amlodipine also increased regional myocardial blood flow within the nonischemic myocardium by 25 +/- 10% and decreased mean aortic pressure by 7 +/- 2% without altering flow in the ischemic region. Left atrial pressure remained unchanged. Indexes of ischemia-induced conduction delay were more rapidly restored after reperfusion in amlodipine-pretreated than in control animals. In conclusion, amlodipine produced a beneficial blood flow-independent effect on ischemia-induced injury potentials. The effect may help to reduce the likelihood of development of lethal ventricular arrhythmias in the early stage of myocardial ischemia in the clinical setting.
Assuntos
Doença das Coronárias/tratamento farmacológico , Sistema de Condução Cardíaco/efeitos dos fármacos , Coração/efeitos dos fármacos , Anlodipino , Animais , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio , Doença das Coronárias/fisiopatologia , Eletrofisiologia , Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Ventrículos do Coração , Nifedipino/farmacologia , Reperfusão , Suínos , Fatores de TempoRESUMO
The three major calcium channel blocking agents, diltiazem, nifedipine and verapamil, inhibit calcium entry into excitable cells. Despite this apparent common action at the cell membrane, these drugs produce quantitative and frequently qualitative differences in cardiovascular variables (for example, heart rate, atrioventricular [A-V] conduction and myocardial inotropic state) when evaluated at equieffective vasodilator doses. All three drugs increase coronary blood flow in a dose-dependent fashion (nifedipine greater than diltiazem = verapamil), and produce a negative inotropic effect in vitro in isolated atria and ventricles, also in a dose-dependent manner (verapamil greater than nifedipine greater than diltiazem). However, in conscious dogs nifedipine increases, verapamil decreases and diltiazem has little effect on the inotropic state. A-V conduction is slowed by diltiazem and verapamil but not by nifedipine in anesthetized dogs and in conscious dogs as judged from the P-R interval in the electrocardiogram. Heart rate is slowed in pentobarbital-anesthetized animals but is accelerated in conscious dogs (nifedipine greater than verapamil greater than diltiazem). Nifedipine also appears to interfere significantly with the arterial baroreceptor reflex by an apparent vagolytic action that is less evident with diltiazem and verapamil. Diltiazem, and possibly verapamil and nifedipine as well, appears to retard myocardial damage that accompanies ischemia. The mechanisms and sites of action of these drugs are presumed to be at the cell membrane; however, intracellular sites may also be involved.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Circulação Coronária/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Canais Iônicos/efeitos dos fármacos , Animais , Cálcio/metabolismo , Vasos Coronários/efeitos dos fármacos , Diltiazem/farmacologia , Cães , Relação Dose-Resposta a Droga , Cobaias , Parada Cardíaca Induzida , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Nifedipino/farmacologia , Verapamil/farmacologiaRESUMO
We sought to determine whether the calcium antagonist, diltiazem, increased regional myocardial collateral blood flow in a dog model in which the physiologic conditions thought to be associated with angina pectoris had been induced, and to determine if such changes would be reflected in alterations in function of the collateral-dependent myocardium. Regional myocardial function and blood flow were measured with instruments in dogs for weeks as the left circumflex artery was progressively stenosed to occlusion by an implanted ameroid constrictor. The extent of collateral development was determined in terms of the reduction in regional function induced by brief, total test occlusions. When collaterals had developed adequate for the metabolic requirements at rest, pacing tachycardia stress test produced ischemia-related hypofunction. Under these conditions, diltiazem, 20 mirogram/min/kg, increased blood flow via collateral channels from approximately 140 to 190 ml/min/100 g tissue (epicardium) and from 80 to 140 ml/min/100 g tissue (endocardium) in the colateral-dependent area without significant modification in hypofunction. Similar results were obtained in dogs with greater collateral flow reserve later in the collateral development process when the ameroid constrictor had completely occluded the vessel and stress testing did not produce hypofunction. Thus, diltiazem increased collateral flow to collateral-dependent myocardium under conditions simulating unstable angina pectoris.
Assuntos
Angina Pectoris/fisiopatologia , Benzazepinas/farmacologia , Cálcio/antagonistas & inibidores , Circulação Colateral/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Diltiazem/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Frequência Cardíaca/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacosRESUMO
RATIONALE AND OBJECTIVES: Perfluorocarbon (PFC) aerosols present the opportunity for simultaneous analysis of lung structure and pulmonary oxygenation patterns. The authors investigated techniques to nebulize neat liquid PFCs for inhalation as a new method of PFC administration and tested the hypothesis that PFC aerosols may be developed for efficient delivery to the lung in an experimental rat model allowing the potential for sequential monitoring of pulmonary status via quantitative fluorine-19 (19F) magnetic resonance (MR) partial pressure of oxygen (pO2) imaging. METHODS: Pneumatic aerosol generators were configured to produce a neat liquid PFC perfluorotributylamine (FC-43) aerosol. Perfluorocarbon inhalation breathing protocols for the rat model included: spontaneous direct breathing from an aerosol chamber, and use of a tracheotomy tube to bypass nasal breathing. The PFC aerosol delivery into the rat lung was documented through 19F MR imaging in correlation with high-resolution anatomic proton MR images. Theoretical model calculations for PFC mass deposition were compared with experimental results. RESULTS: The pneumatic generator produced a PFC aerosol droplet within the theoretically targeted range (geometric mean particle diameter of 1.2 microns; concentration of approximately 4 x 10(7) droplets per cm3). No measurable aerosol reached the lungs during spontaneous breathing because of the efficient filtering capabilities of the turbinated nasal passages. With tracheotomy, aerosol depositions within the lung were achieved in mass quantities consistent with theoretical expectations; however, the distribution patterns were nonuniform and unpredictable. Oxygen-enhanced 19F imaging was demonstrated. CONCLUSIONS: Perfluorocarbon aerosols of controlled size distribution can be produced at sufficient concentration with pneumatic generators for distribution to the terminal pulmonary architecture and visualization using 19F MR imaging. The potential exists for in vivo oxygen-sensitive imaging in the pulmonary system and development of sophisticated experimental animal models of systemic oxygen transport as a function of pulmonary status.
Assuntos
Sistemas de Liberação de Medicamentos , Fluorocarbonos/administração & dosagem , Pulmão/anatomia & histologia , Imageamento por Ressonância Magnética/métodos , Oxigênio/metabolismo , Administração por Inalação , Aerossóis , Animais , Humanos , Aumento da Imagem , Pulmão/fisiologia , Troca Gasosa Pulmonar , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos TestesRESUMO
RATIONALE AND OBJECTIVES: Direct comparison of myocardial perfusion tracers has been made difficult by variability in experimental models, and by a virtual absence of data comparing tracer uptake to myocardial blood flow under conditions of increased myocardial oxygen consumption, similar to what occurs with dynamic exercise. METHODS: Tracer uptake versus myocardial blood flow was evaluated for thallium-201 (201TI) and six technetium-99m (99mTc) myocardial-imaging agents in 24 open-chest canines with an occluded left-anterior descending coronary artery during dobutamine infusion. Data were fitted to the exponential model y = ax(1 - exp[-PSc/x]), where y is the tissue tracer/g normalized to normal (activity at 1 mL/minute/g) and x is the blood flow measured by the radioactive microsphere method. RESULTS: With dobutamine, myocardial tracer uptake was linear across a wide range of ischemic and hyperemic flows for each tracer. Based on the permeability surface area product, 201TI and 99mTc Q3 provided the best tracer estimate of myocardial blood flow (5.30+/-0.86 mL/minute/g, r = 0.91; 5.46+/-0.58 mL/minute/g, r = 0.94, respectively). Correlation coefficient (r) values for other tracers studied were 99mTc Q4 (r =0.93), 99mTc Q12 (r = 0.93), 99mTc sestamibi (r = 0.90), 99mTc tetrofosmin (r = 0.96), and 99mTc-N-Noet (r = 0.82). CONCLUSIONS: Of the 99mTc tracers examined under conditions of dobutamine-altered myocardial contractility, the myocardial uptake properties of 99mTc Q3 were most similar to those of 201TI.