RESUMO
The autonomic innervation of the canine heart develops with considerable regional asymmetry during the early neonatal period. To examine the development of the peptidergic component of the innervation, 28 mongrel puppies 1-6 weeks of age from five litters were studied at weekly intervals. Four of the mothers were also studied as adult and breed controls. Tissue neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) concentrations were determined by radioimmunoassay in myocardial specimens obtained from several specific sites of the cardiac chambers and from the proximal coronary arteries. Data were analysed according to age, cardiac chamber/vessel, gender and individual litter. In general, NPY concentrations in pg/mg protein were six- to eight-fold higher than those of VIP. Also concentrations for both peptides were about two-fold higher in the coronary arteries than the myocardium and differed among chambers, being higher and similar in the atria and lower in the ventricles, particularly for NPY. No gender differences were identified. Concentrations varied among litters, but the developmental pattern was similar with the highest peptide concentrations identified in the first and fourth week. Whereas the differences among chambers may also reflect differing rates of developmental increase of myocardial mass, the pattern corresponds only in part to previously identified functional changes in sympathetic innervation since, in contrast to previous findings, high NPY concentrations in the first 2 weeks suggest anatomically advanced innervation.
Assuntos
Coração/crescimento & desenvolvimento , Coração/inervação , Peptídeos/fisiologia , Fatores Etários , Animais , Cães , Eletrofisiologia , Átrios do Coração/metabolismo , Ventrículos do Coração/metabolismo , Neuropeptídeo Y/fisiologia , Peptídeos/metabolismo , Fatores Sexuais , Distribuição Tecidual , Peptídeo Intestinal Vasoativo/fisiologiaAssuntos
Tumor Carcinoide/diagnóstico , Tumor Carcinoide/secundário , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/secundário , Neoplasias Intestinais/patologia , Tumor Carcinoide/complicações , Tumor Carcinoide/patologia , Diagnóstico Diferencial , Ecocardiografia , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pericárdico/etiologia , Derrame Pleural Maligno/etiologiaRESUMO
Coronary venous hypertension induced by partial coronary sinus obstruction (CSO) in the dog, prevents or delays the predictable ventricular fibrillation (VF) of the early phase of acute ischemia. Also, CSO acting presumably through enhanced myocardial hydration, normalizes the inhomogenous extracellular potassium ([K+]o) accumulation, a major factor in producing the electrophysiological disparities, characteristic of arrhythmogenic substrate. To further clarify the mechanism of early ischemic VF prevention in dogs, radioactive microspheres were used to evaluate regional perfusion changes, resulting from CSO sufficient to raise the coronary sinus pressure to 40 mmHg, before and during ischemia induced by double coronary artery occlusion (CAO) (n=5). Also, global or regional unipolar electrogram mapping was used to assess changes of epicardial ventricular activation times (AT) and sequence and activation recovery intervals (ARI) during CSO, CAO and combined CSO and CAO, induced in random order (n=8). CSO did not affect regional perfusion nor improved collateral blood flow during ischemia. With CSO, AT shortened modestly over time (0.41+/-1.1 ms/min, r=0.85, P<0. 05) and ARI transiently decreased by up to 5.5%. With CAO, AT became variably delayed and isochrone map distortions were indicative of localized conduction delays or blocks, consistent with elevated [K+]o. In contrast, when CAO was preceded by CSO, AT delays were homogenous and normal activation sequence was preserved. Also, whereas with CAO, ARI shortened unequally over the ischemic region by as much as 43% at individual sites (average of 38.3+/-6.8 ms, P<0. 001), with combined CSO and CAO, ARI shortening was less pronounced and more homogenous (26.1+/-5.6 ms, P<0.05), not exceeding 29% at any site. Thus, in accordance with previous findings of enhanced [K+]o homogeneity, coronary venous hypertension reduces the disparities of activation and refractoriness of ischemia attributable, at least in part, to disparate [K+]o accumulation. Since no collateral blood flow improvement could be identified, the salutary electrophysiological effects of CSO may reflect a more homogenous extracellular environment, due to preservation of normal microvascular pressure (Pmv) and sustained filtration and lymph flow.
Assuntos
Vasos Coronários/fisiopatologia , Hipertensão/fisiopatologia , Isquemia Miocárdica/complicações , Isquemia Miocárdica/fisiopatologia , Fibrilação Ventricular/prevenção & controle , Doença Aguda , Animais , Água Corporal/metabolismo , Constrição , Cães , Eletrofisiologia , Espaço Extracelular/metabolismo , Potássio/metabolismo , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/fisiopatologiaRESUMO
Ventricular fibrillation (VF) in mature large mammals is usually a terminal event. It constitutes the most common mode of exitus and the main cause of sudden cardiac death in humans. In neonates, VF is of particular interest because it often reverse spontaneously and promptly to potentially become a non-lethal event. Accordingly, the study of VF and spontaneous defibrillation (SDF) in the neonate is key for the understanding of the developmental anatomical and functional characteristics enabling mammalian myocardium to initiate and sustain this lethal arrhythmia. Such characteristics may include age-related changes of myocardial tissue properties, mass and geometry, autonomic cardiac innervation and myocardial perfusion/hydration. In the human neonate, VF/SDF could provide a plausible framework for explaining and directing the search for the elusive evidence underlying the mechanism and age distribution of the sudden infant death syndrome.
Assuntos
Fibrilação Ventricular/fisiopatologia , Animais , Humanos , Recém-Nascido , Miocárdio/patologia , Tamanho do Órgão , Perfusão , Remissão Espontânea , Fibrilação Ventricular/patologiaRESUMO
Neuropeptide Y (NPY) exerts coronary vasomotor and inotropic effects on the canine heart. To test whether NPY also exerts regional myocardial electrophysiological effects, dose-response and time course changes resulting from intravenous and regional intracoronary infusions of NPY were obtained in 14 alpha-chloralose-anesthetized dogs. Under constant ventricular pacing, activation (A), recovery (R), and A-R interval (ARI) maps were constructed from multiplexed unipolar surface electrograms recorded simultaneously from 64 sites within a 1.6 x 1.6-cm left ventricular region. Effects were compared with those of vasoactive intestinal peptide (VIP) infusions and supramaximal left ansae subclaviae sympathetic nerve stimulation (SNS). The main finding was a uniform shortening of ARI, which reached a maximum of 8.7 +/- 1.2 ms, or 7% of control (P < 0.001), at about three times the baseline NPY plasma concentration (21.6 +/- 1.9 pg/ml). This effect decayed slowly (> 15 min) along with NPY plasma levels. The effect of similar VIP infusions and of SNS was 11%. Thus, compared with the previously identified maximal effect of adenylate cyclase activation (20%), exogenous NPY exerts a moderate but markedly sustained ventricular myocardial electrophysiological effect, which reaches maximum in relatively low plasma concentrations.
Assuntos
Coração/fisiologia , Neuropeptídeo Y/farmacologia , Animais , Cães , Estimulação Elétrica , Eletrofisiologia/métodos , Coração/efeitos dos fármacos , Coração/inervação , Frequência Cardíaca/efeitos dos fármacos , Infusões Intravenosas , Neuropeptídeo Y/administração & dosagem , Neuropeptídeo Y/sangue , Sistema Nervoso Simpático/fisiologia , Fatores de Tempo , Peptídeo Intestinal Vasoativo/administração & dosagem , Peptídeo Intestinal Vasoativo/sangue , Peptídeo Intestinal Vasoativo/farmacologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
The relationship between vagal-induced tachycardia (VT) and release of vasoactive intestinal peptide (VIP) and peptide HI (PHI) into cardiac lymph and coronary sinus blood was studied in 23 alpha-chloralose-anesthetized open-chest dogs that were autonomically decentralized and pretreated with atropine and propranolol. After simultaneous right and left cervical vagal stimulation at 5 V, 20 Hz for 3 min mean +/- SE, increase in heart rate was 38 +/- 6 beats/min, and increase in lymph VIP output from control was 0.308 +/- 0.093 pg/min (P = 0.004). The decrease in VIP arterial minus coronary sinus concentration was not significant. The increase in heart rate did not significantly correlate with increase in lymph VIP output (R2 = 0.141) or decrease in VIP arterial minus coronary sinus concentration (R2 = 0.059). The increases in heart rate and lymph VIP output were blocked by hexamethonium. Increase in lymph PHI output from control during VT (5 dogs) was 0.797 +/- 0.658 pg/min. Arterial-coronary sinus PHI concentration difference did not change in these dogs. These data indicate that VT is associated but not significantly correlated with VIP and PHI release into cardiac lymph. Cholinoceptive nicotinic receptors may mediate VIP release and VT in anesthetized dogs.
Assuntos
Frequência Cardíaca/fisiologia , Peptídeo PHI/metabolismo , Taquicardia/fisiopatologia , Nervo Vago/fisiologia , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Pressão Sanguínea , Cães , Estimulação Elétrica , Eletrocardiografia , Sistema Linfático/fisiologia , Sistema Linfático/fisiopatologia , Peptídeo PHI/sangue , Peptídeo Intestinal Vasoativo/sangueRESUMO
Partial coronary sinus obstruction (CSO) in the dog prevents or delays the predictable ventricular fibrillation (VF) of the early phase of acute ischemia, by normalizing regional electrophysiological disparities which presumably reflect inhomogeneous extracellular potassium ([K+]o) accumulation. To clarify whether CSO indeed affects [K+]o inhomogeneity, we determined in 12 chloralose anesthetized dogs the dynamic [K+]o changes occurring early during reversible coronary artery occlusion (CAO) involving the mid-left anterior descending branch. These changes were compared to those observed during CAO preceded by CSO sufficient to increase the coronary sinus pressure to 40 mmHg. [K+]o was determined using valinomycin coated electrodes implanted within the ischemic (IZ) and the normal (NZ) zones, as well as immediately inside (BZi) and outside (BZo) the visible border. [K+]o increased rapidly within the IZ and the BZi reaching plateau 5 min after CAO, at about three-fold control (11.89 +/- 1.12 mEq/l). Unexpectedly, [K+]o also increased initially outside the border (BZo) but declined after 3 min to a lower level (7.00 +/- 0.40 mEq/l), thus creating a steep gradient of up to 5.54 +/- 0.20 mEq/l, P < 0.001) across the visible border. In four trials, the gradient coincided with VF. With CSO preceding CAO, the development of this border zone gradient was entirely prevented. Moreover, [K+]o reached a significantly lower and similar level in the IZ, BZi and BZo (9.5 +/- 0.89 mEq/l, P < 0.001) and no VF was observed. Thus the beneficial electrophysiologic and antiarrhythmic effects of CSO in acute ischemia may be explained by [K+]o equalization.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Água Corporal/fisiologia , Doença das Coronárias/metabolismo , Potássio/metabolismo , Fibrilação Ventricular/prevenção & controle , Potenciais de Ação , Animais , Transporte Biológico , Hipóxia Celular , Doença das Coronárias/complicações , Doença das Coronárias/patologia , Cães , Espaço Extracelular/metabolismo , Hemodinâmica , Fibrilação Ventricular/metabolismoRESUMO
The effects of right cervical vagal and left sympathetic stimulation on release of immunoreactive vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) into cardiac venous and lymphatic effluent was tested in 11 anesthetized adult mongrel dogs. After stimulation of the right cervical vagus (1 ms, 20 Hz, 5 V) for 3 min, VIP output in lymphatic effluent was significantly increased at 1.90 +/- 0.56 pg/min compared with control of 0.90 +/- 0.42 pg/min. NPY output in lymphatic effluent and VIP and NPY release into coronary venous effluent, as measured by the arterial-coronary sinus concentration difference, were not changed. After stimulation of the ansae of the left sympathetic ganglion (1 ms, 10 Hz, 5 V) for 3 min, NPY output in lymphatic effluent was significantly increased at 4.72 +/- 1.58 pg/min compared with a control of 0.73 +/- 0.66 pg/min. VIP output in lymphatic effluent was not changed. VIP arterial-coronary sinus concentration difference decreased slightly but significantly, and NPY arterial-coronary sinus concentration difference decreased markedly after left sympathetic stimulation. In three additional dogs in which coronary sinus blood flow was measured, NPY overflow during left sympathetic stimulation increased from 28.2 +/- 23.5 to 129.6 +/- 212.7 pg/min. Thus VIP and NPY release from the canine heart can be evoked by right cervical vagal and left sympathetic stimulation, respectively. VIP and NPY may play a role as cardiac noncholinergic-nonadrenergic neurotransmitters.
Assuntos
Miocárdio/metabolismo , Neuropeptídeo Y/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Artérias , Vasos Coronários , Cães , Estimulação Elétrica , Hemodinâmica , Linfa/metabolismo , Neuropeptídeo Y/sangue , Concentração Osmolar , Nervo Vago/fisiologia , Peptídeo Intestinal Vasoativo/sangueRESUMO
The hypotheses that vasoactive intestinal peptide (VIP) is evenly distributed throughout atrial and ventricular myocardium and is present in postganglionic parasympathetic neurons in the regions of the sinoatrial and atrioventricular nodes were tested in three groups of dogs. Neuropeptide Y (NPY) tissue concentrations were determined in each group. In six sham dogs VIP and NPY concentrations were evenly distributed and were higher in atria compared with ventricles. In nine parasympathectomized dogs, VIP concentrations in sample sites from regions of the sinoatrial and atrioventricular nodes were comparable to those in sham-operated controls. In nine denervated dogs VIP concentrations were significantly decreased in three adjacent sample sites along the atrioventricular groove. In these dogs NPY concentrations were not detectable or were significantly decreased at all sample sites of both atria and ventricles. These data suggest that VIP neurons are evenly distributed in atrial and ventricular myocardium but do not originate in parasympathetic ganglia supplying the sinoatrial and atrioventricular nodes. The data also demonstrate the possible presence of extrinsic VIP neurons in the canine right ventricle and indicate that NPY may be a useful marker of myocardial adrenergic innervation.
Assuntos
Miocárdio/metabolismo , Neuropeptídeo Y/metabolismo , Sistema Nervoso Parassimpático/fisiologia , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Denervação , Cães , Feminino , Masculino , Concentração Osmolar , Distribuição TecidualRESUMO
We examined whether partial coronary sinus obstruction affects the latency of the early ventricular fibrillation (VF) of acute ischemia. During baseline trials 15 of 19 open-chest dogs fibrillated repeatedly and predictably within 2 to 5 minutes (251.6 +/- 64 seconds) after reversible, double coronary artery occlusion without developing profound hemodynamic deterioration. The effect of partial coronary sinus obstruction sufficient to increase coronary sinus pressure to 40 mm Hg could be adequately tested in 11 dogs. Coronary sinus obstruction consistently prevented VF in five dogs, significantly prolonged the VF latency in three (p < 0.01 to p < 0.001), and had no clear effect in another three. The overall effect was significant at the p < 0.01 level. VF latency prolongation/prevention was also positively correlated to the residual coronary sinus pressure at the time of VF (r = 0.76; p < 0.008), as well as the baseline VF latency (r = 0.75; (p < 0.008). The protective effect of coronary venous hypertension most likely reflects preservation of adequate extracellular fluid in the ischemic region after the perfusion arrest. This extracellular fluid may constitute a key component in the prevention of early ischemic arrhythmias by preserving interstitial hydraulic continuity and tissue homogeneity through enhanced dilution and diffusion of solutes.
Assuntos
Doença das Coronárias/complicações , Vasos Coronários , Fibrilação Ventricular/etiologia , Animais , Doença das Coronárias/fisiopatologia , Cães , Coração/fisiopatologia , Frequência Cardíaca , Hemodinâmica , Ligadura , Traumatismo por Reperfusão Miocárdica , Pressão , Tempo de Reação , Reprodutibilidade dos TestesRESUMO
In the course of studying developmental changes of induction and maintenance of ventricular fibrillation in canine pups, we have documented that at about the third week of age, hearts reach a critical point where ventricular fibrillation may become both inducible and sustainable, thus forming the basis for cardiac arrhythmic death. Since age-related variations of cardiac mass may account for these findings, this study was conducted to systematically investigate the role of changing heart mass on the induction and maintenance of ventricular fibrillation in the canine heart, during the early postnatal development. Repetitive determinations of ventricular fibrillation threshold and individual incidence of spontaneous defibrillation were obtained in 87 puppies 1-6 weeks old, from litters of varied body size breeds, studied at weekly intervals. Overall, ventricular fibrillation threshold correlated positively with ventricular weight (VFTmA = 3.30 + 1.27 Vwtg, r = 0.71). However the slopes were steeper and correlations were stronger for the first, second and sixth week and nonsignificant in the fourth and fifth weeks. The ventricular fibrillation to ventricular weight ratio also varied with age (P < 0.01). Spontaneous defibrillation occurred at least once in 68 of the puppies (78%). In general, spontaneous defibrillation was more likely to occur in hearts weighing less than 9 grams (P < 0.01), but the overall correlation of the decreasing defibrillation incidence to increasing weight was weak (SDF % = 48.6-0.90 Vwtg, r = 0.106). Spontaneous defibrillation was not observed at any age or weight in two litters, totaling 9 puppies.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Ventrículos do Coração/anatomia & histologia , Fibrilação Ventricular/fisiopatologia , Envelhecimento , Animais , Animais Recém-Nascidos , Peso Corporal , Cães , Tamanho do Órgão , Distribuição AleatóriaRESUMO
OBJECTIVE: The aim was (1) to test the hypothesis that the prevention of haemodynamic deterioration decreases arrhythmia formation in the infarcting heart and augments the antiarrhythmic effects of beta blockade; and (2) to assess the ventricular fibrillation threshold as an index of innate arrhythmogenic propensity. METHODS: Changes in ventricular fibrillation threshold as an index of innate arrhythmogenic propensity. METHODS: Changes in ventricular fibrillation threshold were determined for 50 min after anterior descending coronary artery occlusion in open chest pigs (group 1, n = 5). In group 2 (n = 9), ventricular fibrillation threshold was studied in the same way but cardiac output was maintained at 100 ml.min-1.kg-1 body weight and mean aortic pressure at 60(SEM 3) mm Hg by means of right heart and arterio-arterial bypass. In both groups intravenous propranolol 1.2 mg.kg-1 was injected 35-40 min after coronary artery occlusion. In group 3 (n = 6) spontaneous arrhythmias following coronary artery occlusion were recorded to test how well the ventricular fibrillation threshold reflected the incidence and time course of these arrhythmias. RESULTS: In group 1, there was a deep trough in ventricular fibrillation threshold--from 11.3(0.3) mA to 6.0(0.3) mA--within 10 min of coronary artery occlusion (47% decrease, p < 0.001). There was a shallower trough between 10 and 30 min. In group 2, preocclusion ventricular fibrillation threshold increased from 13.9(1.2) mA to 32.1(5.6) mA (p < 0.05) because of stabilised haemodynamics. After coronary occlusion, fibrillation threshold remained high throughout, being 22.7(1.3) mA and 20.4(1.1) mA at the times of the expected troughs (p < 0.005 v group 1 for both values). Propranolol increased ventricular fibrillation threshold by 24(7)% in group 1 (p < 0.05) and by 53(8)% in group 2 (p < 0.0005). In group 3 spontaneous arrhythmias followed a biphasic pattern, similar to group 1. There was a positive correlation between ventricular fibrillation threshold and arrhythmia score (r = 0.84). CONCLUSIONS: (1) Haemodynamic stabilisation increased ventricular fibrillation threshold during ischaemia and enhanced the antiarrhythmic effects of beta blockade. (2) The ventricular fibrillation threshold accurately reflects the incidence and time course of spontaneous arrhythmias in this model.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Hemodinâmica/fisiologia , Isquemia Miocárdica/complicações , Fibrilação Ventricular/prevenção & controle , Animais , Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Propranolol/uso terapêutico , Suínos , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
This study was conducted to systematically investigate whether induction and maintenance of ventricular fibrillation in the canine heart, change with age during the early postnatal development. Forty-eight mongrel puppies from seven litters, were randomly selected for size and studied at weekly intervals from 1-6 weeks for determination of ventricular fibrillation threshold and incidence of spontaneous defibrillation. Another fourteen mongrel puppies 8-11 weeks old and 10 adult dogs were similarly studied. Ventricular fibrillation threshold increased progressively with age up to the eighth week (VFTmA = 8.38 + 2.67 wk-0.134.wk2, r = 0.995) and thereafter reached a plateau, which was not significantly different from the ventricular fibrillation threshold of adult dogs (26.5 +/- 2.2 mA). In contrast, the high incidence of spontaneous defibrillation at early age decreased rapidly between second and fourth week and became rare thereafter, (%SDF = 281.e-0.60wk, r = 0.94. This rapid drop could not be explained by the increase in mean body weight, which did not change significantly during this early period (BWkg = 0.59.e0.23wk, r = 0.97). Our findings suggest first, that the vulnerability of the neonatal dog heart to electrical induction of ventricular fibrillation decreases progressively during early age. Second, that spontaneous defibrillation decreases precipitously between the second and fourth week of age, a change not sufficiently explained by the modest body weight gain during that time. Thus, it appears that about the third week of age ventricular vulnerability to fibrillation and ability to defibrillation reach a critical point, where lethal arrhythmias may become both inducible and sustainable, to result in death.
Assuntos
Envelhecimento/fisiologia , Fibrilação Ventricular/etiologia , Animais , Animais Recém-Nascidos , Peso Corporal , Estimulação Cardíaca Artificial , Limiar Diferencial , Cães , Remissão Espontânea , Fibrilação Ventricular/fisiopatologiaRESUMO
The effect of total cardiac denervation on the distribution of cardiac immunoreactive vasoactive intestinal peptide (IR-VIP) was determined in four groups of dogs. Denervated dogs killed at either 7 days (group 1) or 30 days (group 3) were compared with sham-operated dogs killed at either 7 days (group 2) or 30 days (group 4). The highest concentrations of IR-VIP were found in the left atrium and proximal left anterior descending and circumflex coronary arteries and were not affected by denervation. Concentrations of IR-VIP in the left ventricle were barely detectable. Only right ventricular IR-VIP concentrations were significantly lower in denervated compared with sham-operated dogs in both groups. Thus these data provide evidence of intrinsic VIP innervation of the atria and epicardial coronary arteries and localized extrinsic VIP innervation of the right ventricle of the canine heart.
Assuntos
Sistema de Condução Cardíaco/fisiologia , Miocárdio/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Denervação , Cães , Feminino , Técnicas Imunoenzimáticas , Masculino , Concentração Osmolar , RadioimunoensaioRESUMO
The purpose of this study was to investigate the relationship between dopamine (DA) exposure and myocardial catecholamine and neuropeptide Y (NPY) concentrations in patients with severe congestive heart failure due to idiopathic dilated cardiomyopathy (IDC). Both nonfailing (NF) and failing (F) hearts were obtained in collaboration with the Utah Cardiac Transplantation Program and the Intermountain Organ Recovery System. The patients were stratified into five groups according to their preoperative exposure to dobutamine (DBT) and/or DA. Compared to 12 untreated, NF control hearts, norepinephrine (NE) concentrations were significantly decreased in 30 untreated F hearts obtained from patients with IDC. Norepinephrine concentrations were also significantly decreased in DA-treated NF hearts and in DA-treated F hearts compared to untreated NF and untreated or DBT-treated failing hearts, respectively. NPY concentrations were significantly decreased in untreated F hearts and were further decreased in dopamine-treated NF and DA-treated F hearts compared to untreated NF and untreated or DBT-treated F hearts. Thus, NE and NPY depletion related to DA administration was evident in both NF and F myocardium and was specific for DA in that it was not evident in patients who received the direct-acting beta-agonist inotrope DBT. These data suggest that the major inotropic mechanism of action of DA is through cardiac adrenergic neurotransmitter release. The data also provide further support for the concept that indirect acting inotropes such as DA may have limited inotropic potential in F hearts where neuronal NE has been depleted.
Assuntos
Cardiomiopatia Dilatada/metabolismo , Catecolaminas/metabolismo , Dopamina/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Miocárdio/metabolismo , Neuropeptídeo Y/metabolismo , Adulto , Dobutamina/farmacologia , Eletrocardiografia , Feminino , Coração/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Adrenérgicos beta/análiseRESUMO
Vasoactive intestinal peptide (VIP) is a potent inotrope and coronary vasodilator. To test whether VIP also exerts regional myocardial electrophysiological (EP) effects, dose-response and time-course effects of intracoronary injections (10(-10)-10(-4) M) were obtained in 4 intact hearts and 12 in situ normoperfused right ventricular flap preparations in chloralose-anesthetized dogs. Under constant rate, activation (A), recovery (R), and A-R interval (ARI) maps were constructed from multiplexed unipolar surface electrograms recorded simultaneously from 32 sites. Effects were compared with those of isoproterenol (Iso) and forskolin (For). The main finding with all agonists was the uniform shortening of ARIs in a dose-response fashion with a maximum of 30 +/- 4 ms or 20% from control. Although the maximal EP changes were similar for all agonists, they occurred at different molecular concentrations (10(-6) Iso, 10(-5) VIP, and 10(-4) For). Also, whereas the duration of EP effect did not exceed 5 min for Iso and For, it was markedly sustained for VIP, outlasting its contractile but paralleling its vasodilatory effect. The physiological endoepicardial differences in ARI and the recovery sequence were preserved for all agonists. Thus VIP, in addition to coronary vasodilation and myocardial inotropy, exerts a strong balanced global myocardial EP effect, similar to, but more sustained than, the adrenergic effect. The difference in duration of inotropic and EP effects may point to different mediating mechanisms.
Assuntos
Coração/efeitos dos fármacos , Peptídeo Intestinal Vasoativo/farmacologia , Animais , Cães , Eletrofisiologia , Coração/fisiologia , Sistema de Condução Cardíaco/fisiologia , Técnicas In Vitro , Fatores de TempoRESUMO
The effects of intracoronary injections of vasoactive intestinal peptide (VIP) on left ventricular (LV) dp/dt, coronary blood flow (CBF), and myocardial oxygen consumption (MVO2) were compared with isoproterenol (ISO) and forskolin in 18 dogs using a preparation in which cardiac output, mean systemic arterial pressure, and heart rate were fixed. In eight dogs in which the effects of VIP and ISO were compared using doses ranging from 2 x 10(-12) to 2 x 10(-8) mol, both agents significantly increased LV dp/dt at doses greater than or equal to 6.6 x 10(-10) mol. At maximal doses (2 x 10(-9) to 2 x 10(-8) mol) the effect of ISO was significantly greater than VIP. Both VIP and ISO significantly increased CBF at all doses, but at maximal doses the effect of VIP on CBF was significantly greater than ISO. The increase in CBF relative to the increase in MVO2, an index of direct coronary vasodilation, was significantly greater for VIP compared with ISO. In 10 additional dogs the effects of VIP and ISO were compared with forskolin given in doses ranging from 2 x 10(-9) to 2 x 10(-7) mol. At maximal doses (2 x 10(-7) mol) the increase in LV dp/dt was similar to VIP but significantly less than ISO, whereas the increase in CBF was similar to ISO but significantly less than VIP. The increase in CBF relative to the increase in MVO2 was significantly greater for forskolin compared with ISO, indicating a direct vasodilator effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Colforsina/farmacologia , Circulação Coronária/efeitos dos fármacos , Isoproterenol/farmacologia , Contração Miocárdica/efeitos dos fármacos , Peptídeo Intestinal Vasoativo/farmacologia , Animais , Vasos Coronários/efeitos dos fármacos , Cães , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Miocárdio/metabolismo , Consumo de Oxigênio/efeitos dos fármacosRESUMO
Desensitization to the hemodynamic effects of vasoactive intestinal polypeptide (VIP) was examined in 12 anesthetized, open-chest dogs in which cardiac output, systemic arterial resistance, and heart rate were fixed. VIP was administered by intracoronary infusion, and the effects were compared with isoproterenol and forskolin. Measurements of left ventricular maximum rate of pressure development (dP/dt), coronary blood flow, and myocardial oxygen consumption were made before and after a 90-min infusion of either isoproterenol (6 dogs) or VIP (6 dogs). After isoproterenol infusion, there was a significant decrease in the effect of isoproterenol on left ventricular dP/dt and coronary blood flow. The effects of VIP and forskolin were not changed. After VIP infusion, there was a significant decrease in the effect of VIP on left ventricular dP/dt with no change in the effects of isoproterenol and forskolin. In this group, a significant increase in coronary blood flow with minimal change in myocardial oxygen could still be elicited by VIP injection after VIP infusion. The agonist infusion time to achieve a decrease in inotropic effect was less for VIP when compared with isoproterenol. Thus these data demonstrate acute homologous desensitization of myocardial VIP and beta-adrenergic receptors in canine myocardium with no development of heterologous desensitization, desensitization involving the catalytic subunit of adenylate cyclase, or desensitization of the VIP-mediated primary coronary vasodilator response.
Assuntos
Circulação Coronária/efeitos dos fármacos , Coração/fisiologia , Isoproterenol/farmacologia , Receptores dos Hormônios Gastrointestinais/fisiologia , Peptídeo Intestinal Vasoativo/farmacologia , Animais , Colforsina/farmacologia , Cães , Relação Dose-Resposta a Droga , Coração/efeitos dos fármacos , Oxigênio/sangue , Consumo de Oxigênio/efeitos dos fármacos , Receptores dos Hormônios Gastrointestinais/efeitos dos fármacos , Receptores de Peptídeo Intestinal Vasoativo , Valores de Referência , Peptídeo Intestinal Vasoativo/fisiologiaRESUMO
We determined the ventricular fibrillation threshold (VFT) changes in response to graded coronary sinus (CS) obstruction in 13 chloralose-anesthetized dogs with fixed heart rate (150 min-1, mean systemic arterial pressure (80 mm Hg), and cardiac index (100 ml/min.kg-1 body weight). VFT in milliamperes (VFTmA) increased linearily with CS pressure (CSP) increases up to 41.2 +/- 1.4 mm Hg (VFTmA = 6.5 + 0.14 CSP mm Hg, p less than 0.01). Total coronary venous effluent (CBF) did not change significantly, suggesting compensatory coronary vasodilation. Myocardial O2 consumption also remained unchanged. At higher CSP, both CBF and VFT declined precipitously (VFTmA = 20.9 - 0.27 CSP mm Hg, p less than 0.02). With simultaneous increases of systemic arterial along with CSP, VFT increased again along with the CSP-induced reduction of gradient until it reached 42.8 +/- 3.2 mm Hg. We conclude that with coronary venous obstruction, despite coronary perfusion gradient reduction to about 40 mm Hg, CBF remains constant. This constant flow vasodilation is associated with substantial (82%) VFT increase. The mechanism may involve enhanced homogeneity of CBF distribution and increased extracellular fluid.
Assuntos
Vasos Coronários/fisiologia , Fibrilação Ventricular/etiologia , Animais , Débito Cardíaco , Constrição , Circulação Coronária , Cães , Frequência Cardíaca , Pressão Venosa , Fibrilação Ventricular/fisiopatologiaRESUMO
The relationship between the antifibrillatory and hemodynamic effects of propranolol and timolol was tested in 32 dogs divided into three groups. In closed-chest animals (group 1), the maximal increase of the ventricular fibrillation threshold (VFT) from the control state was 67.3 +/- 22.6% (n = 5, p less than 0.01) for propranolol and 95.8 +/- 18.8% (n = 9, p less than 0.005) for timolol. These effects were paralleled by a decrease in the cardiac index of 34.7 +/- 10.2% (p less than 0.05) and 32.5 +/- 9.4% (p less than 0.02) for propranolol and timolol, respectively. The mean systemic arterial pressure (SAP) also decreased by 25.0 +/- 8.8% (p less than 0.05) and 19.2 +/- 5.1% (p less than 0.01). In open-chest animals (group 2), timolol increased the VFT by 86.6 +/- 27% (n = 5, p less than 0.05) and decreased the cardiac index by 57.3 +/- 6.3% (p less than 0.005) and the mean SAP by 28.5 +/- 2.9% (p less than 0.02). In open-chest animals with stabilized peripheral hemodynamics (group 3), VFT increased by 354 +/- 130% (p less than 0.05) and 437 +/- 144% (p less than 0.05) after the maximal administered doses of propranolol (n = 6) and timolol (n = 7), respectively. These results suggest that the electrophysiologic and hemodynamic effects of beta blockade are parallel and interdependent, with the hemodynamic deterioration markedly blunting the beneficial electrophysiologic effects.