RESUMO
The purpose of this study was to determine if there is flow-mediated vasodilation of the femoral artery in response to progressive increases in flow within a physiological range observed in the in vivo experiments. Femoral artery blood flow was determined in conscious rabbits (n = 5) using chronically implanted flowprobes. Resting blood flow was 8.3 +/- 0.6 ml/min and increased to 39.9 +/- 5.4 ml/min during high intensity exercise. Femoral arteries (n = 12, 1705 +/- 43 microm outer diameter) harvested from a separate group of rabbits were mounted on cannulas and diameter was continuously monitored by video system. Functional integrity of the endothelium was tested with acetylcholine. The arteries were set at a transmural pressure of 100 mm Hg and preconstricted with phenylephrine to 73 +/- 3% of initial diameter. Using a roller pump with pressure held constant, the arteries were perfused intraluminally with warmed, oxygenated Krebs' solution (pH = 7.4) over a physiological range of flows up to 35 ml/min. As flow increased from 5 ml/min to 35 ml/min, diameter decreased significantly (p < 0.05) from 1285 +/- 58 microm to 1100 +/- 49 microm. Thus, in vessels with a functional endothelium, increasing intraluminal flow over a physiological range of flows produced constriction, not dilation. Based on these results, it seems unlikely that flow-mediated vasodilation in the rabbit femoral artery contributes to exercise hyperemia.
Assuntos
Artéria Femoral/fisiopatologia , Hiperemia/fisiopatologia , Músculo Esquelético/irrigação sanguínea , Esforço Físico , Vasodilatação , Acetilcolina/farmacologia , Adaptação Fisiológica , Animais , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Artéria Femoral/efeitos dos fármacos , Coelhos , Fluxo Sanguíneo Regional , Vasoconstrição , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
The constancy of cerebral blood flow and volume relies heavily upon the cerebral arteries' intrinsic ability to respond to changes in the partial pressure of arterial CO2. The physiologic mechanisms underlying these responses have not been determined, although changes in extracellular and intracellular pH, mediation by prostanoids and neural activity have been suggested. CO2 reactivity can be influenced by oxygen status and blood pressure and can vary according to age and brain region. In certain pathological conditions or diseases, it can be severely altered. Modern techniques, which measure CBF in cases of cerebral hemodynamic insufficiency, head injury or tumor, rely on the inherent ability of the cerebral circulation to respond to changing levels of CO2.
Assuntos
Dióxido de Carbono/fisiologia , Artérias Cerebrais/fisiologia , Circulação Cerebrovascular , Transtornos Cerebrovasculares/fisiopatologia , Envelhecimento/fisiologia , Anestésicos/farmacologia , Animais , Pressão Sanguínea , Artérias Cerebrais/fisiopatologia , Humanos , Concentração de Íons de Hidrogênio , Pressão ParcialRESUMO
We used an isolated, pressurized, and perfused feline middle cerebral artery preparation to measure how changes in intraluminal pressure and alterations in O2 and CO2 affect vessel diameter and myogenic contractile activation before and after treatment with indomethacin (IND). Vessel diameters were measured over the pressure range 60-140 mm Hg. The arteries were then exposed to low O2 (50 torr) and/or high CO2 (65 torr) and diameters remeasured over the same range. Under control conditions, the arteries exhibited myogenic contractile activation. Exposure to low O2, high CO2, or a mixture of low O2/high CO2, increased vessel diameter but did not change the vessels' myogenic contractile responsiveness to changes in pressure. Arteries exposed to IND decreased in diameter but retained myogenic contractile activity. In the presence of IND, vessels dilated to both low O2 and a mixture of low O2/high CO2, but did not dilate to high CO2 alone. Under all conditions, vessels retained myogenic contractile activity. Results obtained under control conditions and low O2 confirm those of others using similar systems. Myogenic contractile activity in the presence of high CO2 or a mixture of low O2/high CO2 has not been previously reported. The dilation to low O2 but not to high CO2 in the presence of IND suggests that this drug's effects in cerebral arteries are not limited solely to inhibition of prostaglandin synthesis.
Assuntos
Dióxido de Carbono/fisiologia , Artérias Cerebrais/efeitos dos fármacos , Indometacina/farmacologia , Contração Muscular/efeitos dos fármacos , Oxigênio/fisiologia , Animais , Gatos , Artérias Cerebrais/fisiologia , Feminino , Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efeitos dos fármacosRESUMO
Kinetics and distribution of K-43 and Tl-201 were studied in isolated myocardial tissue from rats to assess the effects of exercise. The experimental design was as follows. Rats in some groups were forced to swim for 2 hr; immediately after swimming, they were injected with 0.2 mCi of 43KCl or 201TlCl; at 0.5 or 3 hr after injection they were killed and a myocardial segment was obtained and subjected to washouts with nonradioactive Krebs fluid in a special chamber. The radioactivity remaining in the tissue was recorded continuously for 1 hr. In control groups ("rested") the exercise was omitted. Altogether there were four groups of ten animals each for both K-43 and Tl-201. A three-compartment model (extracellular, main intracellular, and subcellular) was used; transport rate constants and relative compartment sizes were determined. The most striking finding was the unchangeability of K-43 parameters with regard to experimental condition (rest compared with exercise) and sampling time (0.5 compared with 3 hr after radionuclide injection). On the other hand, Tl-201 parameters were modified by exercise and sampling time. Notable differences between K-43 and Tl-201 kinetics were found. The hypothesis that alterations at the cellular level may affect regional myocardial distribution of a radionuclide is discussed.
Assuntos
Miocárdio/metabolismo , Esforço Físico , Radioisótopos de Potássio/metabolismo , Radioisótopos/metabolismo , Tálio/metabolismo , Animais , Espaço Extracelular/metabolismo , Coração/diagnóstico por imagem , Técnicas In Vitro , Cinética , Masculino , Modelos Biológicos , Cintilografia , Ratos , Fatores de TempoRESUMO
Kinetics and distribution of TI-201 were studied in myocardium of rats with chronic dietary induced Mg deficiency. Rats were fed the Mg-deficient diet for 30 days and were then injected intravenously with 0.2 mCi of TI-201. Comparable control animals were fed a standard laboratory diet. One-half hour after injection, rats were killed and a segment of myocardium was washed with nonradioactive Krebs solution in a special chamber. Radioactivity in the tissue was recorded continuously for 1 hr. A three-compartment model (extracellular, main intracellular, and subcellular) was found to describe adequately the kinetics of TI-201. In myocardium of Mg-deficient animals, significant changes in values of transport rate constants and compartment sizes for TI-201 indicated a moderate decrease in extracellular compartment and a threefold enlargement in subcellular compartment (presumably mitochondrial) at the expense of the main intracellular compartment, which underwent a marked reduction. Bulk TI-201 uptake in myocardium of Mg-deficient rats was unchanged. The findings are interpreted as being consistent with mitochondrial alterations reported in Mg-deficient animals. Clinical implications are discussed.
Assuntos
Coração/diagnóstico por imagem , Deficiência de Magnésio , Miocárdio/metabolismo , Tálio/metabolismo , Animais , Transporte Biológico , Doença das Coronárias/diagnóstico por imagem , Dieta , Cinética , Magnésio , Masculino , Radioisótopos/metabolismo , Cintilografia , Ratos , Ratos EndogâmicosRESUMO
We have devised a computer-assisted method for objective estimation of liver mass from the right lateral projection of radiocolloid images of the liver. Gamma-camera images were digitized, preprocessed, and stored in computer memory. The definition of liver for area measurement was adaptively determined by means of a Laplacian operator that measures change in radioactivity slope associated with the liver margin. Individual thresholds were calculated for each of 16 subregions. A liver-mass index was derived from a linear regression model correlating the area of the right lateral projection with liver weight at autopsy in 50 patients whose livers weighed between 0.8 to 3.0 Kg. The correlation coefficient found for this method was 0.83 using the equation: Liver Mass [kg] = Area [cm2]/275 [kg/cm2]--0.215 [kg]. Liver-mass estimates using an alternative computer-assisted method or representative manual methods adapted for gamma-camera images showed lower correlation with liver weight at autopsy.
Assuntos
Diagnóstico por Computador , Hepatopatias/diagnóstico por imagem , Fígado/patologia , Adulto , Idoso , Humanos , Fígado/diagnóstico por imagem , Hepatopatias/patologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Cintilografia , Análise de RegressãoRESUMO
The kinetics and distribution of TI-201 in isolated myocardial tissue of rats injected i.v. with this radionuclide are compared at rest and after exercise (2 hr of forced swimming). At 1/2 and 3 hr after injection, a myocardial segment was obtained and subjected to continuous washout with the radioactivity remaining in the tissue recorded each 10 sec for 1 hr. Altogether there were four groups of ten animals each. A three-compartment model (extracellular, main intracellular, and subcellular) was found to describe adequately the kinetics of TI-201. In the groups studied 1/2 hr after TI-201 injection the most dramatic effect of exercise was a translocation of TI-201 into the subcellular compartment. The change was also present but less marked in samples from exercised rats obtained 3 hr after TI-201 injection, which suggests a transition to the resting stage. The findings suggest the possibility of structural subcellular differences in myocardial uptake for TI-201 in clinical images visualized after exercise and at rest.
Assuntos
Miocárdio/metabolismo , Esforço Físico , Tálio/metabolismo , Animais , Citoplasma/metabolismo , Espaço Extracelular , Coração/diagnóstico por imagem , Injeções Intravenosas , Cinética , Mitocôndrias/metabolismo , Miocárdio/ultraestrutura , Radioisótopos , Cintilografia , Ratos , Descanso , Tálio/administração & dosagemRESUMO
Using specially fabricated muscle myographs, we examined electrical and mechanical responses to reduction of PO2 in small (less than 300 micron) pulmonary arteries excised from cat lungs. Upon lowering PO2 from 400 to 50 mm Hg, these preparations consistently developed contractile responses concomitant with membrane depolarization and action potential generation. The largest changes in electromechanical responses to reduction of PO2 occurred between 150 and 50 mm Hg. These data strongly suggest that hypoxic activation of small pulmonary arteries is mediated by direct effects of reduced PO2 on muscle cell membrane ionic conductance systems.
Assuntos
Hipóxia/fisiopatologia , Artéria Pulmonar/fisiopatologia , Vasoconstrição , Animais , Dióxido de Carbono/fisiologia , Gatos , Membrana Celular , Músculo Liso Vascular/fisiopatologiaRESUMO
Small pulmonary arteries (less than 300 micron) from cats were mounted in myographs to record mechanical and electrical responses to hypoxia. When these preparations were exposed to a PO2 of 30-50 Torr after equilibration at 300 Torr they consistently developed active force, which increased or decreased in amplitude as [Ca2+] was raised or lowered, respectively, and was blocked on addition of verapamil. Intracellular electrical recording with glass microelectrodes demonstrated membrane depolarization and action potential generation when PO2 was lowered. Steady-state voltage vs. applied current curves obtained before and during hypoxia showed a significant reduction in input resistance. The relationship between membrane potential and extracellular K+ was not different during hypoxia compared with control, suggesting that there were not marked changes in K+ permeability under this condition. In the presence of verapamil to block Ca2+ inward current the hypoxia-induced action potentials were abolished concomitant with partial membrane repolarization. The results of these studies suggest that in certain isolated pulmonary arteries hypoxia induces contraction by a mechanism involving an increased Ca2+ conductance. These data suggest that the sensor involved in hypoxic pulmonary vasoconstriction may lie within the vessel wall and somehow mediates changes in smooth muscle ionic conductances.
Assuntos
Cálcio/metabolismo , Hipóxia/fisiopatologia , Artéria Pulmonar/fisiopatologia , Potenciais de Ação , Animais , Gatos , Hipóxia/metabolismo , Técnicas In Vitro , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Artéria Pulmonar/metabolismoRESUMO
Effects of hypoxia on force development and membrane potential were studied in isolated small (less than 300 microns diam) and large (greater than 500 microns diam) pulmonary arteries from cats. There was a consistent and reproducible hypoxic constrictor response in small pulmonary arteries that began at PO2 values between 350 and 300 Torr and reached a maximum at PO2 between 50 and 30 Torr. In the small artery smooth muscle cell the membrane potential, which was -51 +/- 1.4 mV at a PO2 of 400 Torr, was depolarized to -37 +/- 2 mV at a PO2 of 50 Torr. In contrast, larger arteries did not exhibit significant hypoxic constriction or depolarization upon exposure to low PO2. Constriction in small arteries was not blocked by phentolamine. Treatment with a low dose of indomethacin (10(-9) M) augmented the response; however, a larger dose of indomethacin (10(-3) M) blocked the constriction to hypoxia but not to 30 mM KCl. Depolarization during hypoxia was not blocked by ouabain. Results of this study suggest that the hypoxic response of these isolated small pulmonary vessels may be like that seen in the intact lung. Furthermore, these data suggest that hypoxic vasoconstriction may be mediated by electrical events occurring at the pulmonary arterial muscle cell membrane either directly or via mediators released from the vessel wall.
Assuntos
Hipóxia/fisiopatologia , Artéria Pulmonar/fisiopatologia , Animais , Gatos , Feminino , Técnicas In Vitro , Indometacina/farmacologia , Membranas Intracelulares/fisiologia , Masculino , Potenciais da Membrana , Oxigênio , Fisiologia/instrumentação , Vasoconstrição/efeitos dos fármacosRESUMO
Isolated, cannulated, endothelium-intact cat pulmonary arteries, averaging 692 +/- 104 microns in diameter, were set at a transmural pressure of 10 mmHg and monitored with a video system. Intraluminal flow was increased in steps from 0 to 1.6 ml/min by using a syringe pump. An electronic system held pressure constant by changing outflow resistance. Flow-diameter curves were generated in physiological saline solution. At constant transmural pressure, the arteries constricted in response to increased intraluminal flow. Constriction was not affected by removing extracellular Ca2+ but was abolished after treatment with ryanodine to deplete intracellular Ca2+ stores, with the endothelin-1 synthesis inhibitor phosphoramidon, with the endothelin A-receptor antagonist BQ-123, with the protein kinase C inhibitor staurosporine, or with glutaraldehyde to reduce endothelial cell deformability. The results indicate that isolated pulmonary arteries can constrict in response to intraluminal flow and suggest that constriction is mediated by endothelin-1 and depends on intracellular Ca2+ release and protein kinase C activation.
Assuntos
Artéria Pulmonar/fisiologia , Acetilcolina/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Cálcio/fisiologia , Gatos , Endotélio Vascular/fisiologia , Inibidores Enzimáticos/farmacologia , Feminino , Glicopeptídeos/farmacologia , Técnicas In Vitro , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico/fisiologia , Norepinefrina/farmacologia , Peptídeos Cíclicos/farmacologia , Cloreto de Potássio/farmacologia , Inibidores de Proteases/farmacologia , Artéria Pulmonar/anatomia & histologia , Artéria Pulmonar/efeitos dos fármacos , Estaurosporina/farmacologia , Resistência Vascular/efeitos dos fármacos , Resistência Vascular/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
Prenatal cocaine exposure has been reported to cause neurovascular complications in the developing fetus. To determine the effect of cocaine on the fetal neurovasculature, we studied the in vitro response of fetal sheep cerebral arteries to cocaine and cocaine metabolites. The change in diameter of cannulated pressurized cerebral artery segments from fetal sheep was measured using a video microscaler system. Cumulative dose-response curves (10(-12)-10(-4) M) were generated for cocaine and the major cocaine metabolites in fetal sheep cerebral artery segments. Benzoylecgonine (> 10(-10) M) also caused concentration-dependent constriction, and cerebral artery segments were significantly more sensitive to benzoylecgonine than to cocaine and the other cocaine metabolites. Benzoylecgonine-induced vasoconstriction appeared to be mediated through alpha-adrenergic stimulation, predominantly through stimulation of alpha 1-adrenergic receptor subtypes. We conclude that cocaine and benzoylecgonine cause significant fetal cerebral artery vasoconstriction in vitro. Cocaine and benzoylecgonine-induced cerebral vasoconstriction may contribute to the perinatal neurovascular complications associated with prenatal cocaine exposure.
Assuntos
Artérias Cerebrais/efeitos dos fármacos , Cocaína/análogos & derivados , Cocaína/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Cateterismo , Artérias Cerebrais/embriologia , Feminino , Técnicas In Vitro , Gravidez , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Ovinos , Vasoconstrição/efeitos dos fármacosRESUMO
To determine whether altered NO production contributes to attenuated distensibility (alpha), vasoreactivity, and acetylcholine (ACh) dilation in pulmonary arteries from monocrotaline (MCT)-treated rats (J.A. Madden, P.A. Keller, R. M. Effrosa, C. Sequitte, J.S. Choy, and A.D. Hacker. J. Appl. Physiol. 76: 1589-1593, 1994), intralobar and sidebranch arteries from rats 21 days after MCT treatment were cannulated and pressurized and their diameter changes in response to KCl, norepinephrine, angiotensin II, and pressure were measured in the presence of N omega-nitro-L-arginine (NLA) and L-arginine. NLA treatment decreased MCT artery diameters more than normal arteries (P < 0.05) and abolished ACh dilation in both. Agonist responses were greater in normal but not MCT arteries. The alpha increased in NLA-treated normal (P < 0.05) but not MCT arteries. After L-arginine, normal and MCT arteries returned to control diameters and dilated to ACh. Agonist responses returned to control in normal but not MCT arteries. Normal but not MCT arteries dilated in calcium-free solution (P < 0.05). These results suggest that pulmonary arteries from rats with MCT-induced pulmonary hypertension produce more NO than do pulmonary arteries; inhibiting NO does not increase contractility; and decreased vasoreactivity and alpha values are not due to smooth muscle cell tone but may be due to abnormal vascular remodeling.
Assuntos
Pressão do Ar , Arginina/análogos & derivados , Inibidores Enzimáticos/farmacologia , Monocrotalina/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Arginina/farmacologia , Cálcio/fisiologia , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/fisiopatologia , Masculino , Tono Muscular/efeitos dos fármacos , Tono Muscular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Óxido Nítrico/agonistas , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/fisiologia , Nitroarginina , Artéria Pulmonar/anatomia & histologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
To obtain in situ measurements of the distensibility of small (100- to 1,000-microns-diam) pulmonary arterial vessels of the dog lung, X-ray angiograms were obtained from isolated lung lobes with the vascular pressure adjusted to various levels. The in situ diameter-pressure relationships were compared with the diameter-pressure relationships for small arteries that were dissected free from the lungs and cannulated with small glass pipettes for the measurement of diameter and transmural pressure. The diameter-vascular or diameter-transmural pressure curves from both in situ and cannulated vessels were sufficiently linear in the pressure range studied (0-30 Torr) that they could be characterized by linear regression to obtain estimates of D0, the diameter at zero vascular pressure, and beta, the change in diameter (micron) per Torr change in pressure. The vessel distensibility coefficient (alpha) was defined as alpha = beta/D0. The mean values of alpha were approximately 2.0 +/- 0.8%/Torr (SD) for the in situ vessels and 1.7 +/- 0.6%/Torr for the cannulated vessels, with no statistically significant difference between the two methods. The influence of vasoconstriction elicited by serotonin was evaluated in the in situ vessels. Serotonin-induced vasoconstriction caused a decrease in D0 and little change in alpha.
Assuntos
Artéria Pulmonar/fisiologia , Animais , Pressão Sanguínea , Cães , Técnicas In Vitro , Perfusão , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/efeitos dos fármacos , Circulação Pulmonar , Radiografia , Serotonina/farmacologia , Vasoconstrição/efeitos dos fármacosRESUMO
Intralobar and side branch pulmonary arteries removed from rats 7, 14, and 21 days after injection with monocrotaline (MCT) were cannulated and pressurized, and their responses to potassium chloride, norepinephrine, acetylcholine, and angiotensin II were measured. Static pressure-diameter curves were also performed, and arterial distensibility was calculated. Arteries from all three MCT-treated groups showed reduced responses to potassium chloride and angiotensin II compared with control arteries (P < 0.05). The norepinephrine response was significantly reduced in arteries from the 14- and 21-day groups (P < 0.05). Dilations in response to acetylcholine were similar in arteries from the control and 7-day groups but were reduced compared with those in control vessels from the 14- and 21-day groups (P < 0.05). Compared with control values, the slopes of the pressure-diameter curves and the arterial distensibility decreased significantly with time after MCT treatment (P < 0.05). Values for arterial distensibilities obtained in the isolated pulmonary arteries support the theory that structural changes that occur as a result of MCT administration contribute to vessel stiffness. The acetylcholine-induced dilation of vessels from MCT-treated rats indicates that endothelium-derived factors are still produced, but diminished vasodilation coupled with decreased distensibilities after MCT suggest that abnormal vascular remodeling rather than a change in agonist sensitivity may be responsible for the reduced responsiveness seen in these arteries.
Assuntos
Monocrotalina/farmacologia , Artéria Pulmonar/fisiologia , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Animais , Técnicas In Vitro , Masculino , Norepinefrina/farmacologia , Cloreto de Potássio/farmacologia , Pressão , Artéria Pulmonar/anatomia & histologia , Artéria Pulmonar/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
To determine some of the cellular mechanisms of opiate receptor stimulation in cat middle cerebral arterial muscle, intracellular electrical measurements and force development were monitored before and after addition of morphine. Addition of morphine resulted in a dose-dependent hyperpolarization of the muscle cells in the middle cerebral artery with a concomitant relaxation, indicating a high degree of electromechanical coupling in this preparation. The curve relating membrane potential vs. morphine was shifted to the right and downward by naloxone, demonstrating competitive inhibition at receptor sites. When middle cerebral arteries were studied from animals which had been injected with morphine prior to sacrifice, a significant hyperpolarization of the membrane was recorded when studied in an organ bath. This hyperpolarization was abolished if the animal had been pretreated with naloxone prior to morphine injection, suggesting that morphine may act in vivo as we have observed it to act in vitro. Morphine-induced hyperpolarization could be blocked in the organ bath when potassium conductance (gk) was inhibited. Similarly, the reduction in the slope of the voltage/current curve induced by morphine was blocked by agents which reduced gk. These data suggest the presence of opiate receptors on cat cerebral artery and suggest that morphine relaxes these vessels through a mechanism involving increased gk. These findings suggest a role for opiate-mediated systems in cerebral vascular control.
Assuntos
Músculo Liso Vascular/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Animais , Gatos , Artérias Cerebrais/efeitos dos fármacos , Estimulação Elétrica , Eletrofisiologia , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Morfina/farmacologia , Ouabaína/farmacologia , Potássio/fisiologia , Compostos de Tetraetilamônio/farmacologia , Vasodilatação/efeitos dos fármacos , VasodilatadoresRESUMO
The predominant cocaine metabolites were tested for central nervous system effects by intracerebroventricular (ICV) administration in rats. We found two types of responses: cocaine, norcocaine (NC), benzoylecgonine (BE), and benzoylnorecgonine (Nor BE) produced stimulatory effects, whereas ecgonine methyl ester (EME) and ecgonine (EC) resulted in no specific effect or sedation. A novel metabolite interaction was revealed when rats were pretreated with EME, which inhibited both analgesia and seizures by subsequently administered cocaine. Pretreatment with EC inhibited both cocaine and BE seizures and seizure-associated death. Direct injection of EME into the nucleus accumbens significantly suppressed systemic cocaine potentiation of intracranial electrical self-stimulation of the ventral tegmental area, whereas corticotropin releasing hormone injected ICV selectively potentiated BE-induced seizures and death. These results confirm multiple, metabolite-mediated activities in the central nervous system. Pharmacological interactions of the metabolites with each other and/or with neurohormones may help explain some of the pathophysiological effects seen in human chronic cocaine abuse.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/análogos & derivados , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Sistemas Neurossecretores/fisiologia , Animais , Encéfalo/fisiologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Estimulação Elétrica , Hormônios/administração & dosagem , Hormônios/farmacologia , Injeções Intraventriculares , Masculino , Potenciais da Membrana/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , AutoestimulaçãoRESUMO
Cocaine has pronounced peripheral vasoconstrictor effects. Despite the short half life of cocaine in the body these effects are relatively long-lived. The role of cocaine metabolites in vasoconstriction attributed to cocaine has not been reported. We evaluated the contractile ability of cocaine and its major metabolites in isolated cat cerebral arteries. The primary cocaine metabolite, benzoylecgonine was a potent contractile agent, causing a 50% decrease in cross sectional area at 10(-5) M. This was less than caused by serotonin, but greater than caused by norepinehrine. Ecgonine and cocaine were less active contractile agents than was benzoylecgonine, and ecgonine methyl ester was a mild relaxant.
Assuntos
Artérias Cerebrais/efeitos dos fármacos , Cocaína/farmacologia , Vasoconstritores , Animais , Gatos , Cocaína/análogos & derivados , Feminino , Técnicas In Vitro , Masculino , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Serotonina/farmacologia , Vasoconstritores/farmacologiaRESUMO
This study was designed to determine possible mechanisms underlying the vasoconstrictor activity of cocaine and its principal metabolite, benzoylecgonine (BE) in cat isolated cerebral arteries. The arteries constricted significantly in response to single doses of cocaine, BE and norepinephrine (NE; (P < 0.05). After 6-OHDA treatment to remove adrenergic nerve endings, NE-induced constrictions were essentially unchanged from those before treatment. Denervated arteries exposed to cocaine dilated significantly (P < 0.05) but those exposed to BE constricted as much as before denervation. Following exposure to prazosin and yohimbine, arterial constrictions to NE and cocaine were significantly reduced from control (P < 0.05) but the BE-induced constriction was unchanged. Ryanodine eliminated the cocaine-induced contraction (P < 0.05) whereas verapamil eliminated the BE response (P < 0.05). These data suggest that while cocaine's vasoconstrictor action may be significantly mediated through adrenergic transmission, BE may act through a mechanism involving calcium (Ca2+) channels. Cocaine levels peak and decline in the body more rapidly than BE levels which can remain detectable for days. This study suggests there may also be different pharmacological mechanisms as well as temporal differences underlying the vasoreactivity of these two substances. Our findings may have implications for pharmacological management of cocaine-induced toxic vascular events.
Assuntos
Artérias Cerebrais/efeitos dos fármacos , Cocaína/análogos & derivados , Cocaína/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Cálcio/metabolismo , Gatos , Artérias Cerebrais/inervação , Artérias Cerebrais/fisiologia , Feminino , Masculino , Norepinefrina/farmacologia , Oxidopamina/farmacologia , Prazosina/farmacologia , Rianodina/farmacologia , Simpatectomia Química , Sistema Vasomotor/fisiologia , Verapamil/farmacologia , Ioimbina/farmacologiaRESUMO
Hot plate testing of rats was performed to determine the optimal analgesic doses of intracerebroventricularly (ICV) administered cocaine, significant cocaine metabolites, and selected structurally similar molecules. Optimal, (subseizure) analgesic doses for cocaine and selected cocaine analogues were (in microM): cocaine, 0.37; cocaethylene, 0.09; benzoylecgonine, 0.35; norcocaine, 0.43; and ecgonine, 2.1. Ecgonine methyl ester was not analgesic at < or = 3.7 microM. These results, in conjunction with findings on other structurally similar molecules suggest that, of the molecules tested, (a) a hydrophobic group at the C-3 attached carbon is critical for analgesia; (b) a hydrophobic C-2 ester group can enhance analgesic activity (e.g., cocaethylene); (c) the N-methyl position is minimally important for analgesia; and (d) isomeric configurational changes can influence analgesia.