RESUMEN
The majority of women diagnosed with breast cancer will experience some form of drug-related toxicity and subsequent impairments in Health-related Quality of Life (HRQoL). Despite this, HRQoL is assessed inconsistently and there is no validated method to integrate HRQoL data into the assessment of therapeutic agents. This proof of concept study utilizes data from the neoadjuvant I-SPY 2 clinical trial to describe the development of the Quality of Life Index (QoLI) measure. The QoLI represents a single composite score that incorporates validated longitudinal measures of clinical efficacy and QoL and one that permits a more comprehensive, direct comparison of individual therapeutic agents. Preliminary data suggest the QoLI is able to distinguish between agents based on their efficacy and toxicity; with further validation, the QoLI has the potential to provide more patient-centered evaluations in clinical trials and help guide treatment decision making in breast cancer and other oncologic diseases.
RESUMEN
Potential and documented interactions between alternative therapy agents and warfarin are discussed. An estimated one third of adults in the United States use alternative therapies, including herbs. A major safety concern is potential interactions of alternative medicine products with prescription medications. This issue is especially important with respect to drugs with narrow therapeutic indexes, such as warfarin. Herbal products that may potentially increase the risk of bleeding or potentiate the effects of warfarin therapy include angelica root, arnica flower, anise, asafoetida, bogbean, borage seed oil, bromelain, capsicum, celery, chamomile, clove, fenugreek, feverfew, garlic, ginger ginkgo, horse chestnut, licorice root, lovage root, meadowsweet, onion, parsley, passionflower herb, poplar, quassia, red clover, rue, sweet clover, turmeric, and willow bark. Products that have been associated with documented reports of potential interactions with warfarin include coenzyme Q10, danshen, devil's claw, dong quai, ginseng, green tea, papain, and vitamin E. Interpretation of the available information on herb-warfarin interactions is difficult because nearly all of it is based on in vitro data, animal studies, or individual case reports. More study is needed to confirm and assess the clinical significance of these potential interactions. There is evidence that a wide range of alternative therapy products have the potential to interact with warfarin. Pharmacists and other health care professionals should question all patients about use of alternative therapies and report documented interactions to FDA's MedWatch program.
Asunto(s)
Anticoagulantes/efectos adversos , Terapias Complementarias , Warfarina/efectos adversos , Adulto , Interacciones de Hierba-Droga , Humanos , Magnoliopsida/efectos adversos , Fitoterapia , Vitaminas/efectos adversosRESUMEN
The effects of the nitric oxide (NO) synthesis inhibitor L-N5-(1-iminoethyl)-ornithine (L-NIO) on baseline tone and on responses to the endothelium-dependent vasodilator agents were investigated in the pulmonary vascular bed of the cat under constant-flow conditions. When administered in doses of 1 and 5 mg/kg i.v., L-NIO inhibited pulmonary vasodilator responses to acetylcholine, bradykinin, and substance P but did not alter vasodilator responses to adenosine, pinacidil, or adrenomedullin. L-NIO in doses of 1-10 mg/kg i.v. did not significantly affect baseline lobar arterial pressure, and when administered in doses of 10-30 mg/kg i.v. the inhibitory effect on responses to bradykinin and substance P was not greater than that observed when the lower doses of L-NIO were administered. L-NIO in doses of 5-30 mg/kg i.v. reduced plasma reactive nitrogen intermediate levels. The inhibitory effects of L-NIO were similar to the inhibitory effects of N omega-nitro-L-arginine, N omega-nitro-L-arginine methyl ester, and N omega-nitro-L-arginine benzyl ester. The highest dose of L-NIO studied (30 mg/kg i.v.) caused a significant increased in lobar arterial pressure, and the administration of N omega-nitro-L-arginine methyl ester (100 mg/kg i.v.) caused a significant increase in lobar arterial pressure in animals previously treated with L-NIO (1 mg/kg i.v.). The results of the present study show that the effects of L-NIO on endothelium-dependent vasodilator responses and on baseline tone can be separated and may be interpreted to suggest that basal release of NO does not play an important role in the maintenance of baseline tone in the pulmonary vascular bed of the cat.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Endotelio Vascular/fisiología , Ornitina/análogos & derivados , Arteria Pulmonar/fisiología , Circulación Pulmonar/fisiología , Vasodilatación/fisiología , Acetilcolina/farmacología , Adenosina/farmacología , Adrenomedulina , Animales , Arginina/análogos & derivados , Arginina/farmacología , Bradiquinina/farmacología , Gatos , Endotelio Vascular/efectos de los fármacos , Femenino , Guanidinas/farmacología , Masculino , Tono Muscular/efectos de los fármacos , Tono Muscular/fisiología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Ornitina/farmacología , Péptidos/farmacología , Pinacidilo , Arteria Pulmonar/efectos de los fármacos , Circulación Pulmonar/efectos de los fármacos , Sustancia P/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
The inhibitory effects of the oral sulfonylurea, glibenclamide, on vasoconstrictor responses to the thromboxane A2 mimic, U46619, were investigated in the pulmonary and hindquarters vascular beds of the cat under constant flow conditions. When lobar arterial tone was at resting conditions (14 +/- 2 mm Hg), intralobar injections of U46619, prostaglandin F2alpha, prostaglandin D2, angiotensin II, norepinephrine, and BAY K 8644 caused dose-related increases in lobar arterial pressure without altering left atrial pressure. Following an intralobar infusion of glibenclamide (5 mg/kg), vasoconstrictor responses to U46619, prostaglandin F2alpha and prostaglandin D2 were significantly reduced, whereas vasoconstrictor responses to norepinephrine and angiotensin II were not altered and responses to BAY K 8644 were significantly enhanced. When tone in the pulmonary vascular bed was raised to a high steady level (36 +/- 3 mm Hg), glibenclamide in a dose of 5 mg/kg i.a. markedly attenuated responses to injections of U46619 and reduced the vasodilator responses to the K+-ATP channel opener, levcromakalim, whereas responses to acetylcholine and S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide donor, were not changed. In the hindquarters vascular bed of the cat, administration of glibenclamide in a dose of 5 mg/kg i.a. had no significant effect on vasoconstrictor responses to U46619, norepinephrine or angiotensin II. Hindquarters vasodilator responses to levcromakalim, but not to nitric oxide, were decreased significantly following administration of glibenclamide. These data suggest that glibenclamide, in addition to inhibiting K+-ATP channels, has thromboxane A2 receptor blocking activity in the pulmonary vascular bed of the cat. These data also suggest that vasoconstrictor responses to U46619 may be mediated by different thromboxane A2 receptors with different binding affinities in the pulmonary and in the hindquarters vascular beds of the cat.
Asunto(s)
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Gliburida/farmacología , Miembro Posterior/irrigación sanguínea , Hipoglucemiantes/farmacología , Circulación Pulmonar/efectos de los fármacos , Tromboxano A2/fisiología , Vasoconstrictores/farmacología , Animales , Análisis de los Gases de la Sangre , Gatos , Relación Dosis-Respuesta a Droga , Femenino , Miembro Posterior/efectos de los fármacos , Masculino , Flujo Sanguíneo Regional/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
The effects of the vascular selective nonsulfonylurea guanidine ATP-sensitive K+ (KATP+) channel-blocking agent U-37883A on vasodilator and vasoconstrictor responses were investigated in the pulmonary and hindlimb vascular beds of the cat. Under elevated tone conditions, both U-37883A and the sulfonylurea KATP+ antagonist, glibenclamide, attenuated pulmonary vasodilator responses to the KATP+ channel openers without altering responses to vasodilator agents that are reported to act by KATP(+)-independent mechanisms. However, under low resting-tone conditions, U-37883A enhanced pulmonary vasoconstrictor responses to the thromboxane mimic U-46619 and to prostaglandin (PG) F2 alpha and PGD2, whereas glibenclamide antagonized responses to U-46619 and the vasoconstrictor PG. In the hindlimb vascular bed, U-37883A and glibenclamide had no effects on responses to U-46619 in doses that inhibited vasodilator responses to the KATP+ channel opener levcromakalim. U-37883A and glibenclamide had no significant effect on baseline tone in the pulmonary or hindlimb vascular beds, and neither U-37883A nor glibenclamide altered pulmonary vasodilator responses to PGE1. The results of the present investigation show that U-37883A and glibenclamide, agents that are used in the study of vascular smooth muscle KATP+ channel mechanisms and attenuate vasodilator responses to the KATP+ channel openers, have pronounced effects on thromboxane/PG receptor-mediated vasoconstrictor responses in the pulmonary vascular bed of the cat.
Asunto(s)
Adamantano/análogos & derivados , Vasos Sanguíneos/efectos de los fármacos , Extremidades/irrigación sanguínea , Morfolinas/farmacología , Bloqueadores de los Canales de Potasio , Circulación Pulmonar/efectos de los fármacos , Adamantano/farmacología , Animales , Vasos Sanguíneos/metabolismo , Gatos , Femenino , Gliburida/farmacología , Masculino , Vasodilatación/efectos de los fármacosRESUMEN
Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.
Asunto(s)
Óxido Nítrico Sintasa/antagonistas & inhibidores , Péptidos/farmacología , Circulación Pulmonar/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Adrenomedulina , Secuencia de Aminoácidos , Animales , Arginina/análogos & derivados , Arginina/farmacología , Péptido Relacionado con Gen de Calcitonina/química , Péptido Relacionado con Gen de Calcitonina/farmacología , Gatos , Femenino , Isoproterenol/farmacología , Masculino , Datos de Secuencia Molecular , NG-Nitroarginina Metil Éster/farmacología , Nitroglicerina/farmacología , Péptidos/química , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Vasodilatadores/farmacologíaRESUMEN
Adenosine produces tone-dependent pulmonary vascular responses; however, the adenosine receptor subtype mediating these responses is unknown. In the present study, the adenosine receptor subtypes mediating tone-dependent responses were investigated, Intralobar injections of adenosine,ATP, and analogues under low-tone conditions caused dose-related increases in lobar arterial pressure; the order of potency was alpha,beta-methylene ATP (alpha,beta-metATP) > N6-cyclopentyladenosine (CPA) > ATP > adenosine. Under low-tone conditions, pressor responses to adenosine, ATP, and CPA, an adenosine A1-receptor agonist, were reduced by KW-3902, an adenosine A1-receptor antagonist, whereas KW-3902 and meclofenamate had no effect on responses to alpha,beta-metATP, norepinephrine, serotonin, or angiotensin II. Under elevated-tone conditions, injections of adenosine, ATP, and analogues caused dose-related decreases in lobar arterial pressure, and adenosine was 10-fold less potent than 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), an A2-receptor agonist, and ATP. KF-17837, an A2-receptor antagonist, reduced vasodilator responses to adenosine and CPCA, whereas responses to ATP, isoproterenol, diethylamine-NO, lemakalim, and bradykinin were not changed. The vasodilator responses to adenosine were not attenuated by Nw-nitro-L-arginine benzyl ester, methylene blue, or U-37883A. These results suggest that vasoconstrictor responses to adenosine are mediated by A1 receptors and the release of vasoconstrictor prostanoids, and that, under elevated-tone conditions, vasodilator responses are mediated by A2 receptors but not the release of nitric oxide or the activation of guanylate cyclase or K+ATP channels.
Asunto(s)
Tono Muscular/fisiología , Músculo Liso Vascular/fisiología , Circulación Pulmonar/fisiología , Receptores Purinérgicos P1/fisiología , Adamantano/análogos & derivados , Adamantano/farmacología , Adenosina/farmacología , Adenosina Trifosfato/farmacología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Gatos , Femenino , Masculino , Azul de Metileno/farmacología , Morfolinas/farmacología , Músculo Liso Vascular/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/metabolismo , Circulación Pulmonar/efectos de los fármacos , Agonistas del Receptor Purinérgico P1 , Xantinas/farmacologíaRESUMEN
OBJECTIVE: Current evidence suggests that thromboxane plays a role in pathophysiologic processes in the lung. Efforts to find effective, specific therapy to modify these effects have led to the development of a new class of thromboxane receptor blockers. This present investigation examined the selectivity and duration of the inhibitory effects of one of these novel agents in the pulmonary vascular bed of anesthetized cats. DESIGN: Prospective, randomized, controlled study with repeated measures. SETTING: University research laboratory. SUBJECTS: Twenty-nine adult cats obtained from the Tulane University School of Medicine vivarium. INTERVENTIONS: The effects of GR32191, a thromboxane receptor antagonist, were investigated under constant-flow conditions in the intact-chest cat, using a triple-lumen, 6-Fr, balloon perfusion catheter that was placed by means of fluoroscopic guidance. Data were analyzed using a paired or unpaired t-test or analysis of variance. A p < .05 was considered statistically significant. MEASUREMENTS AND MAIN RESULTS: Aortic, left atrial, and left lobar arterial pressures were measured. After administration of GR32191 (0.25 and 1.0 mg/kg iv), pulmonary vasoconstrictor responses to U46619, a thromboxane mimic, were significantly decreased. Blockade was overcome with higher doses of the thromboxane mimic. GR32191 was without significant effect on the responses to prostaglandin (PG) D2, PGF2 alpha, serotonin, the calcium-channel agonist BAY K8644, or norepinephrine. Additionally, GR32191 did not alter baseline vascular pressures. Responses to U46619 returned to 50% of control value 90 mins after administration of 0.25 mg/kg of U46619. Responses to GR32191 returned to 50% of control value 180 mins after administration of 1.0 mg/kg of GR32191. These data suggest that GR32191 selectively blocks thromboxane A2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed of the cat. CONCLUSIONS: These results are consistent with the hypothesis that discrete thromboxane A2 receptors, unrelated to receptors activated by PGF2 alpha or PGD2, are present in the feline pulmonary vascular bed. Specific thromboxane receptor antagonists, such as GR32191, could be useful therapeutic agents in the treatment of pulmonary hypertensive and thromboembolic disorders.
Asunto(s)
Presión Sanguínea , Circulación Pulmonar/fisiología , Receptores de Tromboxanos/fisiología , Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Animales , Compuestos de Bifenilo/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Gatos , Dinoprost/farmacología , Ácidos Heptanoicos/farmacología , Norepinefrina/farmacología , Estudios Prospectivos , Prostaglandina D2/farmacología , Distribución Aleatoria , Receptores de Tromboxanos/antagonistas & inhibidores , Serotonina/farmacología , Vasoconstricción/efectos de los fármacosRESUMEN
Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide initially isolated from human pheochromocytoma cells, an ADM analog (ADM15-52), and a structurally related peptide, calcitonin gene-related peptide (CGRP), were compared in the pulmonary vascular bed of the cat and rat under constant flow conditions. When tone was increased with U46619, intraarterial injections of ADM (0.03-0.3 nmol), ADM15-52 (0.03-0.3 nmol), and of CGRP (0.03-0.3 nmol) caused dose-related decreases in pulmonary arterial perfusion pressure. When the relative vasodilator activity of the peptides was compared on a nmol basis, ADM was approximately 10-fold more potent in the cat than in the rat, whereas vasodilator responses to CGRP were very similar in both species. CGRP was slightly more potent than ADM in the rat, whereas ADM was slightly more potent than CGRP in the cat. ADM and ADM15-52 had similar pulmonary vasodilator activity in the cat, whereas the full sequence peptide was slightly more potent than ADM15-52 in the rat. The present data demonstrate that ADM has significant vasodilator activity in the pulmonary vascular beds of the cat and of the rat, and that the relative potency of the vasodilator effects of ADM and ADM15-52 are different in the two species.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/farmacología , Péptidos/farmacología , Circulación Pulmonar/efectos de los fármacos , Vasodilatadores/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Adrenomedulina , Animales , Gatos , Femenino , Humanos , Masculino , Péptidos/química , Endoperóxidos de Prostaglandinas Sintéticos/farmacología , Ratas , Ratas Sprague-Dawley , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacología , Vasoconstrictores/farmacologíaRESUMEN
Responses to des-Arg9-bradykinin, a selective kinin B1 receptor agonist, were characterized in the pulmonary vascular bed of the intact-chest cat. Injections of des-Arg9-bradykinin into the perfused lobar artery under low-resting tone conditions caused dose-related increases in lobar arterial pressure; whereas in the same experiment under elevated tone conditions, injections of the B1 agonist caused dose-related decreases in lobar arterial pressure. Vasoconstrictor responses to des-Arg9-bradykinin under low-tone conditions and vasodilator responses under elevated-tone conditions were antagonized by des-Arg9,[Leu8]-bradykinin, a kinin B1 receptor antagonist, whereas responses under low- and high-tone conditions were not altered by Hoe 140, a kinin B2 receptor antagonist. Vasoconstrictor responses to des-Arg9-bradykinin under low-tone conditions were attenuated by phentolamine, prazosin, and reserpine but not by sodium meclofenamate, suggesting that release of catecholamines and activation of alpha-adrenergic receptors are involved. Pulmonary vasodilator responses under elevated-tone conditions were inhibited by N omega-nitro-L-arginine methyl ester, suggesting that des-Arg9-bradykinin stimulates the release of nitric oxide, whereas meclofenamate and U-37883A, a nonsulfonylurea ATP-sensitive K+ channel antagonist, did not alter vasodilator responses to the B1 receptor agonist. These results suggest that vasoconstrictor responses to des-Arg9-bradykinin under low-tone conditions are mediated by the activation of kinin B1 receptors, the release of catecholamines within the lung, and the activation of alpha-adrenergic receptors, whereas vasodilator responses under elevated tone conditions are mediated by activation of B1 receptors and the release of nitric oxide from the endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Bradiquinina/análogos & derivados , Pulmón/irrigación sanguínea , Pulmón/fisiología , Receptores de Bradiquinina/metabolismo , Animales , Bradiquinina/antagonistas & inhibidores , Bradiquinina/farmacología , Gatos , Femenino , Masculino , Circulación Pulmonar , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
Responses to angiotensin IV were investigated and compared with responses to angiotensin II in the pulmonary vascular bed of the intact-chest cat under constant flow conditions. Under low resting tone conditions, intralobar injections of angiotensin IV caused dose-related increases in lobar arterial pressure. Angiotensin II also increased lobar arterial pressure and was 100 fold more potent than angiotensin IV. Dose-response curves for both peptides were parallel, and the time-to-peak increase in lobar arterial pressure in response to angiotensin IV and angiotensin II was similar whereas the duration of the response to angiotensin IV was significantly shorter. Following administration of the angiotensin receptor subtype 1 (AT1) antagonist, DuP 532 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4- yl)-methyl]imidazole), responses to angiotensin IV and angiotensin II were reduced in a similar manner, whereas pulmonary pressor responses to serotonin were not altered. In contrast to the inhibitory effects of the angiotensin AT1 receptor antagonist, administration of PD 123,319 ((S)-1-[[4-(dimethylamino)-3-methyl-phenyl]methyl-5-(diphenylacetyl++ +)- 4,5,6,7-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxylic acid), an angiotensin AT2 receptor antagonist, did not change responses to angiotensin II and angiotensin IV. The results of the present study demonstrate that angiotensin IV has significant vasoconstrictor activity in the pulmonary vascular bed, and suggest that pressor responses to angiotensin IV are mediated by the activation of angiotensin AT1 receptors. These data indicate that angiotensin IV is 100-fold less potent than angiotensin II and suggest that the hexapeptide may have a lower apparent affinity for the angiotensin AT1 receptor than does angiotensin II in the pulmonary vascular bed of the cat.
Asunto(s)
Angiotensina II/análogos & derivados , Circulación Pulmonar/efectos de los fármacos , Angiotensina I/farmacología , Angiotensina II/antagonistas & inhibidores , Angiotensina II/farmacología , Antagonistas de Receptores de Angiotensina , Animales , Análisis de los Gases de la Sangre , Presión Sanguínea/efectos de los fármacos , Gatos , Relación Dosis-Respuesta a Droga , Femenino , Imidazoles/farmacología , Masculino , Fragmentos de Péptidos/farmacología , Piridinas/farmacología , Tetrazoles/farmacología , Resistencia Vascular/efectos de los fármacosRESUMEN
Pulmonary vascular responses to angiotensin (ANG) peptides were investigated in the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. Intralobar injections of ANG I, II, and III caused dose-related increases in lobar arterial pressure, whereas ANG (1-7) and ANG (3-8) (ANG IV) had modest pressor activity. ANG I, II, and III had similar activity and were more potent than norepinephrine and ANG (1-7) and ANG IV but less potent than the thromboxane A2 mimic, U-46619, in increasing lobar arterial pressure. The time course of responses to ANG I, II, and III was similar, and after administration of ANG receptor antagonists, DuP 532 and L-158,809, responses to ANG I, II, and III was reduced, whereas responses to norepinephrine, serotonin, and U-46619 were not altered. After administration of the ANG-converting-enzyme inhibitor, captopril, responses to ANG I were reduced. The converting-enzyme inhibitor enhanced pressor responses to ANG II and III but did not alter responses to norepinephrine, U-46619, or serotonin. Moreover, under elevated-tone conditions, pulmonary vasodilator responses to bradykinin were increased following administration of captopril, whereas vasodilator responses to acetylcholine and nitrovasodilators were not altered. These results demonstrate that ANG I, II, and III have similar pulmonary pressor activity and that responses are mediated by ANG II type 1 receptors. Pressor responses to ANG I are reduced, whereas vasodilator responses to bradykinin are enhanced by captopril.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Angiotensina III/farmacología , Angiotensina II/farmacología , Angiotensina I/farmacología , Presión Sanguínea/efectos de los fármacos , Circulación Pulmonar/efectos de los fármacos , Antagonistas de Receptores de Angiotensina , Animales , Captopril/farmacología , Gatos , Femenino , Imidazoles/farmacología , Masculino , Tetrazoles/farmacologíaRESUMEN
Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K+ATP channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine benzyl ester and N omega-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Bradiquinina/farmacología , Circulación Pulmonar/efectos de los fármacos , 3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Obstrucción de las Vías Aéreas/fisiopatología , Aminoácido Oxidorreductasas/antagonistas & inhibidores , Animales , Bradiquinina/análogos & derivados , Bradiquinina/antagonistas & inhibidores , Bronquios/fisiopatología , Gatos , Azul de Metileno/farmacología , Óxido Nítrico Sintasa , Purinonas/farmacología , Vasodilatación/fisiologíaRESUMEN
The comparative effects of the nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine (L-NNA), N omega-nitro-L-arginine methyl ester (L-NAME), and N omega-nitro-L-arginine benzyl ester (L-NABE) on baseline tone and on vasodilator responses to acetylcholine (ACh), bradykinin (BK), and substance P (SP) were compared in the pulmonary vascular bed of the cat under constant flow conditions. After administration of the NO synthase inhibitors in intravenous doses of 100 mg/kg, the increase in lobar arterial pressure and the attenuation of vasodilator responses to ACh, BK, and SP were similar, whereas responses to adenosine and felodipine, endothelium-independent vasodilator agents, were not altered. In addition to inhibiting responses to ACh, BK, and substance P, the NO synthase inhibitors enhanced vasodilator responses to S-nitroso-N-acetylpenicillamine and NO. Moreover, atropine inhibited pulmonary vasodilator responses to ACh but not to SP or BK, and L-NAME or L-NABE had no effect on the decrease in heart rate in response to efferent vagal stimulation, a muscarinic receptor-mediated response that is independent of NO release. The similar inhibitory effects of L-NNA, L-NAME, and L-NABE on vasodilator responses to ACh, BK, and SP suggest that the L-arginine analogue, L-NNA, as well as the methyl and benzyl esters of L-NNA are useful probes for studying NO-mediated endothelium-dependent responses in the pulmonary vascular bed of the intact-chest cat.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Arginina/análogos & derivados , Circulación Pulmonar/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Acetilcolina/farmacología , Aminoácido Oxidorreductasas/antagonistas & inhibidores , Animales , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Bradiquinina/farmacología , Gatos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintasa , Nitroarginina , Sustancia P/farmacologíaRESUMEN
Pulmonary vascular responses to the newly discovered hypotensive peptide, adrenomedullin, were compared with responses to the structurally related peptides, calcitonin gene-related peptide (CGRP) and amylin, in the intact-chest cat. Under conditions of controlled blood flow, when tone in the pulmonary vascular bed had been raised to a high steady level, intralobar injections of adrenomedullin (0.03-1 nmol), CGRP (0.1-3 nmol), and amylin (0.1 and 0.3 nmol) caused dose-related decreases in lobar arterial pressure without changing left atrial pressure. In terms of relative vasodilator activity in the pulmonary vascular bed, the dose of the peptide that decreased lobar arterial pressure 7.5 mm Hg (ED7.5 mm Hg) was significantly lower for adrenomedullin than for CGRP. The duration of the pulmonary vasodilator responses to CGRP was longer than for adrenomedullin, and both peptides decreased systemic arterial pressure when injected into the perfused lobar artery in the higher doses studied. The present data demonstrate that synthetic human adrenomedullin and CGRP have potent but relatively short-lasting vasodilator activity in the pulmonary vascular bed. These data show also that amylin, a structurally related pancreatic peptide, also has significant pulmonary vasodilator activity.
Asunto(s)
Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/farmacología , Péptidos/farmacología , Vasodilatación/efectos de los fármacos , Adrenomedulina , Amiloide/farmacología , Animales , Gatos , Relación Dosis-Respuesta a Droga , Femenino , Polipéptido Amiloide de los Islotes Pancreáticos , Pulmón/irrigación sanguínea , Masculino , Arteria Pulmonar/efectos de los fármacos , Venas Pulmonares/efectos de los fármacosRESUMEN
Responses to synthetic human adrenomedullin, a novel hypotensive peptide localized in several organ systems, including the lung, and the carboxy terminal 15-52 amino acid fragment of adrenomedullin (ADM15-52) were investigated in the pulmonary vascular bed of the intact-chest cat. Under constant flow conditions when baseline tone in the pulmonary vascular bed was raised to a high steady level, injections of adrenomedullin and ADM15-52 into the perfused lobar artery in doses of 0.1-1 nmol, caused significant dose-related decreases in lobar arterial pressure. Since left atrial pressure was unchanged, the decreases in lobar arterial pressure reflect decreases in pulmonary lobar vascular resistance. Adrenomedullin and ADM15-52 exhibited similar vasodilator activity and were approximately 3-fold more potent than bradykinin in the pulmonary vascular bed of the cat. Pulmonary vasodilator responses to adrenomedullin and ADM15-52 were rapid in onset and lasted for 150-200 sec, depending on the dose of the peptide injected. The present results demonstrate that synthetic human adrenomedullin and ADM15-52 possess potent, short-lasting vasodilator activity in the pulmonary vascular bed of the cat and suggest that amino acids 15-52 in the peptide are important for the expression of vasodilator activity in the pulmonary vascular bed of the cat.
Asunto(s)
Antihipertensivos/farmacología , Péptidos/farmacología , Circulación Pulmonar/efectos de los fármacos , Vasodilatadores/farmacología , Adrenomedulina , Animales , Antihipertensivos/farmacocinética , Presión Sanguínea/efectos de los fármacos , Gatos , Femenino , Masculino , Péptidos/farmacocinéticaRESUMEN
Responses to pituitary adenylate cyclase activating polypeptide (PACAP)-38 were investigated and compared with responses to PACAP-27 and vasoactive intestinal polypeptide (VIP) in the pulmonary vascular bed of the intact-chest cat under constant flow conditions. Under low resting tone baseline conditions, injections of PACAP-38 had little or no effect on lobar arterial pressure; however, when tone in the pulmonary vascular bed was raised to a high steady level (35-40 mm Hg) with U46619, intralobar injections of PACAP-38 caused dose-related decreases in lobar arterial pressure without altering left atrial pressure. The peptide induced biphasic changes in systemic arterial pressure. PACAP-38 was more potent than VIP in decreasing lobar arterial pressure, and both peptides were significantly less potent than PACAP-27 in dilating the pulmonary vascular bed. The present data show that PACAP-38 has significant vasodilator activity in the pulmonary vascular bed of the cat, and that the 27 amino acid form of the peptide is approximately 3-fold more potent than PACAP-38.
Asunto(s)
Neuropéptidos/farmacología , Neurotransmisores/farmacología , Venas Pulmonares/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Gatos , Femenino , Masculino , Perfusión , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
Eighty-one cases of testicular gonadal stromal tumor have been reported in the literature. An additional case is herein reported. The pathologic, immunohistologic, and histogenetic aspects are presented.