Efecto inotrópico y cronotrópico del propranolol sobre aurículas extraídas de ratas con insulina-resistencia inducida por fructosa / Inotropic and chronotropic effects of propranolol in isolated atrium of rats with fructose-induced insulin-resistance

La insulina-resistencia (IR) es una deficiencia metabólica asociada princi palmente con diabetes tipo 2 y comúnmente relacionada a la etiopatogenia de enfermedades cardiovasculares, siendo el factor determinante del síndrome metabólico. La investigación pretende conocer los efectos cronotrópico e inotrópico del propranolol sobre aurículas de ratas IR. Para ello, 16 ejemplares Sprague-Dawley, fueron divididos en Grupo control, alimentado ad libitum con alimento para perros Perrarina® y Grupo experimental, alimentado con Perrarina®-manteca vegetal, y suministro de agua con fructosa (20%)-sacarosa (20%) durante ocho meses. Al finalizar este periodo, se verificó la insulina-resistencia y las aurículas extraídas se mantuvieron en solución Krebs (37ºC, pH 7,4; 95% O2 - 5% CO2), en baño de órganos aislados marca Letica®, conectado a un polígrafo Grass®, registrándose la frecuencia de los latidos y evaluando las diferencias a través de la prueba t de Student (grado de significancia p<0,05). Se establecieron curvas dosis-respuesta acumulativas con isoproterenol y previa incubación de 15 minutos con propranolol (1x10 -6 M), registrándose un efecto cronotrópico negativo en el grupo control mas no así en las ratas IR, estableciéndose diferencias significativas entre el porcentaje de incremento de los latidos/seg en ambos grupos (Control 58,81±4,08; IR 68,84±4,16; p<0,001). La máxima fuerza de contracción auricular alcanzada por el grupo IR con propranolol (278,47±11,22), generó diferencias significativas (p<0,001), en comparación con el grupo control (42,60±3,13), evidenciándose que el propranolol no generó bloqueo sobre los receptores beta-adrenérgicos auriculares de las ratas insulina-resistentes.

Insulin resistance (IR) is a metabolic deficiency associated with type 2 diabe tes and commonly related to the pathogenesis of cardiovascular diseases, being the determining factor of the metabolic syndrome. This research aims to understand the chronotropic and inotropic effects of Propranolol in isolated atrium of rats with fructose-induced insulin-resistance. For this reason, 16 male Sprague-Dawley rats were assigned to two groups and given ad libitum access to one of the following diets: Perrarina® dog chow or Perrarina® dog chow supplemen ted with vegetable shortening and with fructose (20%) and sucrose (20%) added to the water supply. Both groups were maintained on their respective dietary regimens for eight months. At the end of this period insulin resistance was verified by routine blood test. The rat hearts were rapidly removed, and the atria were dissected and kept in Krebs solutions (37ºC, pH 7.4; 95% O2 - 5% CO2) in an isolated organ bath Letica®, connected to a polygraph Grass®, registering atria frequency. The Student ́s t-test was used to evaluate statistical differences between the two groups (p<0.05). Cumulative dose-response curves with isoproterenol were established in basal condition, and after fifteen minutes of pre-incubation with propranolol (1x10 -6 M). A significant positive chronotropic effect was observed in IR rats (8.84±4.16 vs 58.81±4.08 beats/sec of control; p<0.001). The maximum force of atrial contraction after pre-incubation with propranolol was significantly higher in the IR group (278.47±11.22 atrial contraction percentage; p<0.001). These findings suggest that a blunted response of atrial β-adrenoceptor to propranolol exists in rats with fructose-induced insulin-resistance.

Effects of eugenol on resting tension of rat atria

In cardiac and skeletal muscle, eugenol (μM range) blocks excitation-contraction coupling. In skeletal muscle, however, larger doses of eugenol (mM range) induce calcium release from the sarcoplasmic reticulum. The effects of eugenol are therefore dependent on its concentration. In this study, we evaluated the effects of eugenol on the contractility of isolated, quiescent atrial trabeculae from male Wistar rats (250-300 g; n=131) and measured atrial ATP content. Eugenol (1, 3, 5, 7, and 10 mM) increased resting tension in a dose-dependent manner. Ryanodine [100 µM; a specific ryanodine receptor (RyR) blocker] and procaine (30 mM; a nonspecific RyR blocker) did not block the increased resting tension induced by eugenol regardless of whether extracellular calcium was present. The myosin-specific inhibitor 2,3-butanedione monoxime (BDM), however, reversed the increase in resting tension induced by eugenol. In Triton-skinned atrial trabeculae, in which all membranes were solubilized, eugenol did not change resting tension, maximum force produced, or the force vs pCa relationship (pCa=-log [Ca2+]). Given that eugenol reduced ATP concentration, the increase in resting tension observed in this study may have resulted from cooperative activation of cardiac thin filaments by strongly attached cross-bridges (rigor state).

effect of paroxetine on ouabain-induced toxicity in isolated guinea pig atria

It has been reported that selective serotonin reuptake inhibitors [SSRIs] possess some cardiac effects. In the present study we have investigated the effect of paroxetine [PX], a potent SSRI agent, on spontaneously as well as ouabain-induced arrhythmia beating isolated guinea-pig atria. The Guinea-pig heart was rapidly removed; the auricles were dissected out in oxygenated modified Krebs solution. The rate and force of spontaneous contractions were recorded isometrically with a photosensitive transducer. PX [1-16 micro g/ml] caused a dose-dependent decrease in the rate of contractions [14-70%] and contractile force [8-16%]. Ouabain alone [1.2 micro g/ml] produced arrhythmia at 7.2 +/- 1.5 min and asystole at 20.1 +/- 3.1 min. Pretreatment with PX [4 micro g/ml] significantly increased the time of arrhythmia onset to 19.8 min. In addition, PX prolonged the duration of action beating from 20.1 +/- 3.1 min to 43.1 +/- 2.6 and delayed the occurrence of asystole. The pattern of contractile force by PX + ouabain treatment was more regular than that observed after administration of ouabain alone. The above findings may the probably be due to the inhibition of cardiac Na[+] and Ca[2+] channels or autonomic nervous system. Results also suggest that PX may reduce the membrane conductance through inhibition of ionic channels to prevent ouabain-induced arrhythmia

Ptychodiscus brevis toxin decreases the spontaneous activity of rat right atria involving muscarinic receptors and potassium channels.

Marine dinoflagellate Ptychodiscus brevis toxin (PbTx), is known to produce toxic effects on cardiovascular system. The present experiments were conducted to evaluate the effect of synthetic phosphorus containing Ptychodiscus brevis toxin on spontaneously beating right atrium in vitro. The PbTx (0.84-84 microM) decreased the rate and force of right atrial contractions in a concentration-dependent manner. Ethanol, a vehicle present in highest concentration of PbTx, had no effect on atrial rate or force of contraction. Pretreatment with atropine blocked the PbTx-induced decrease in atrial rate and force of contraction. The tetraethylammonium, a potassium channel blocker, blocked the PbTx-induced decrease in atrial rate and force, where as, L-type of calcium channel blocker, nifedipine blocked the PbTx-induced force of contraction but not the rate changes. The results indicate that the PbTx decreased the atrial rate and force of contraction via cholinergic receptors involving K+ channel.

Bradycardia induced by Mesobuthus tamulus scorpion venom involves muscarinic receptor-G-protein-coupled cell signaling pathways.

Indian red scorpion (Mesobuthus tamulus; MBT) envenomation produces various cardio-respiratory abnormalities including cardiac dysrhythmias. The underlying cell signaling pathways for the cardiac dysrhythmias produced by MBT venom are not known. The present study was therefore conducted to delineate the second messenger signaling pathways involved in MBT venom-induced atrial rhythm changes. The effects of venom and various antagonists were examined on spontaneously beating rat right atrial preparations in vitro. The MBT-venom produced an increase (35%), a decrease (45%) and again an increase (50%) in rate at 0.03, 0.3 and 3.0 microg/ml of venom, respectively. On the other hand, force of contraction exhibited a concentration-dependent rise (up to 40%) at all concentrations of venom. Pretreatment with atropine (0.3 microM) blocked the decrease in atrial rate at 0.3 microg/ml concentration of venom while no such blockade was seen in force of contraction. Submaximal concentration of ACh (0.1 nM) decreased the atrial rate by 25%. In the presence of MBT venom (0.3 microg/ml), ACh-induced fall in atrial rate was enhanced. The venom-induced fall in atrial rate and augmentation of ACh response were blocked by pertussis toxin (PTx; a Gi-inhibitor) or methylene blue (a G-cyclase inhibitor). The results indicate that the decrease in atrial rate produced by venom is mediated muscarinic by receptors via Gi-guanylyl cyclase mediated cell signaling pathways.

Effects of 4-[2-Alkylthio-1-benzyl-5-imidazolyl]-dihydropyridines on the isolated rat colon and right atrium contractility

In order to provide a pharmacological profile for some newly synthesized dihydropyridines, we investigated their effects on the isolated rat colon segments and the isolated rat atrium contractility. The tested compounds include alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 2-alkylthio-1-benzyl-5-imidazolyl substituent, and nifedipine as a positive control substance. Isolated rat colon and atrial tissues were prepared. Rat colon was contracted with 80 mM KC1, and maximum response was recorded [100%]. After washing tissue with Krebs solution it was preincubated with different concentrations of test compounds and again KC1 was added and percent change in contraction was calculated. Spontaneous contractions and its frequency for colon and atrium before and after addition of test compounds were also recorded and percent change was calculated. Nifedipine [10[-8]-10[-5] M] was used as positive control at all experiments. The compounds showed similar effects to that of nifedipine on the isolated rat colon. The potency of these analogues with concentration range 10[-5] to 10[-4] M was compared to potency of nifedipine which was effective at 10[-8] to 10[-5] M [P<0.01]. However, unlike nifedipine, the test compounds exerted significant positive inotropic effect on the isolated rat atrium [P < 0.01]. Our observations suggest that these analogues of nifedipine selectively enhance contractility of heart muscle while causing relaxation of intestinal smooth muscle. These compounds may serve as valuable probes to develop novel dihydropyridines with dual smooth muscle relaxant effect and positive inotropic action

Effect of Allium sativum L. aqueous extract on contraction power of isolated atrium from rats following administration of adrenaline

Synthetic drugs, although very effective, have their own side effects. Recently, herbal plants have received more attention to avoid the unpleasant effects of synthetic agents. To investigate the effects of garlic aqueous extract on contraction power of isolated atrium from male rats following administration of adrenalin. Male rats [Spirague Dawley, Albino, 200-250 gr] were divided into 7 groups as follows: Control, adrenalin, garlic extract [10 mg/kg, 20 mg/kg, and 40mg/kg], Propranolol and Propranolol plus garlic extract at a single concentration of 40 mg/kg. Later the contraction power was recorded using a physiograph set. Garlic extract at all three concentrations used in our study caused a reduction of atrial contraction power in adrenalin group. When the degree of contraction power reduction was compared between garlic extract [40mg/kg] and garlic extract plus Propranolol groups, no statistically significant difference found. Atrial contraction power decreased in presence of garlic aqueous extract and the degree of reduction was significant in both low and high doses, statistically

Negative inotropic and chronotropic effects on the guinea pig atrium of extracts obtained from Averrhoa carambola L. leaves

It has been reported that star fruit can lead to a fatal outcome in uremic patients. The intoxication syndrome consists of hiccups, mental confusion, dizziness, and vomiting. On the other hand, folk medicine uses teas and infusions of carambola leaves to treat headache, vomiting, cough, insomnia, and diabetes. This motivated us to determine if Averrhoa carambola can act on the contractility and automaticity of the guinea pig heart. We measured the atrial isometric force in stimulated left atria and determined the chronotropic changes in spontaneously beating right atria. The carambola leaf extracts (1.5 mg/ml) abolished the contractile force in a concentration-dependent manner. Among the crude, methanolic, ethanolic, aqueous, and acetic extracts, the aqueous one was the most potent (EC50 = 520 ± 94 æg/ml; flavonoids and tannins are the main constituents; Na+ and K+ contents in 1.0 mg/ml of aqueous extract were 0.12 ± 0.016 and 1.19 ± 0.15 mM, respectively). The aqueous extract abolished the positive Bowditch staircase phenomenon and reduced the inotropic response to CaCl2 (0.17-8.22 mM), events that are dependent on the cellular Ca2+ inward current. The adrenergic, muscarinic or opioid membrane receptors do not seem to participate in the mechanism of action of the cardioactive substance(s). In spontaneously beating atria, the aqueous extract promoted a negative chronotropic effect that was antagonized by 0.1 æM isoproterenol bitartrate. With this agonist, the EC50 of the aqueous extract increased from 133 ± 58 to 650 ± 100 æg/ml. These data regarding the effect of A. carambola on guinea pig atrial contractility and automaticity indicate an L-type Ca2+ channel blockade.

Inotropic effect of Citrus sinensis ( L. ) Osbeck leaf extracts on the guinea pig atrium

The objective of the present investigation was to determine the contractile effect of crude and acetone leaf extracts of Citrus sinensis (L.) Osb. on mammalian myocardium. Crude leaf extracts have been used in folk medicine to treat neurological disorders. Some flavonoids isolated from this plant presented a positive inotropic effect on myocardium. This motivated us to test the extracts on the atria of guinea pigs of both sexes (300-500 g) and surprisingly we observed inotropic depression instead of an increase in force. The maximum effect of the crude extract was 79.4 ± 8.1 percent of the control force amplitude (N = 5 hearts, 10 trials, 27 ± 0.1°C, stimulus: 2 Hz, 400 V, 0.5 ms). The EC50 for crude, ethanol, acetic, aqueous, and acetone extracts was 300, 300, 600, 1000, and 140 æg/ml, respectively, with a Hill constant of 1.8, 2.0, 2.5, 2.0, and 1.4, respectively. Blockade of cholinergic, beta-adrenergic, or opioid membrane receptors with 1.5 æM atropine sulfate, 1 æM propranolol, and 10 æM naloxone, respectively, did not change the effect of the crude extract. The acetone extract abolished the Bowditch positive staircase phenomenon (N = 5 hearts, 10 trials, 27 ± 0.1°C), suggesting a possible reduction of the calcium inward current, and also promoted the so-called Woodworth phenomenon. The effect was concentration-dependent and indicated the existence of another inhibitory contractile mechanism such as the simultaneous activation of some of the membrane potassium channels reducing the myocardial action potential duration and further decreasing the cellular calcium entry.

Sildenafil citrate [viagra] induced enhancement of right atrial contractility in isolated rat heart in vitro

The present study deals with the chronotropic effects of Sildenafil citrate [Viagra] on right atrial contracctility of mammalian isolated heart muscle. Effects of Sildenafil citrate on rat isolated heart in-vitro using right atrial samples, in comparison with nor-adrenaline, revealed that Sildenafil at 10[-7] M and above produced dose related increases in contractility. The maximum observed increase at 10[-4] M represented a 126% +/- 31% increase above control amplitude. Nor-adrenaline produced similar dose-related increases in contractility and was appoximately three times more potent than Sildenafil citrate. Dimaprit also produced similar responses to the Sildenafil but was less potent. These results indicated that rat responds to Sildenafil citrate, which increases contracility and enhances atrial automaticity, with sensitivity comparable to that for nor-adrenaline. The selective antagonism of the Sildenafil contractility response by cimetidine indicated that this response is mediated via histamine H [2]-receptors and not H [1] noradrenergic beta receptors. The involvement of histamine H [2]- receptors is confirmed by the similarity of the response to dimaprit. The production of spontaneous contractions by dimaprit further suggests that Sildenafil citrate-induced enhancement of atrial automaticity is mediated via modified histamine H [2]-receptors

O íon magnésio no tratamento de acidentes causados pelos escorpiöes Tityus serrulatus, T. bahiensis e Centruroides sculpturatus: estudo experimental / Magnesium in the treatment of accidents caused by the scorpions Tityus serrulatus, T. bahiensis and Centruroides sculpturatus: an experimental study

Os efeitos produzidos pelas peçonhas escorpiônicas säo consequentes, em sua maioria, à liberaçäo de acetilcolina (ACh) e catecolaminas. A verificaçäo de que o magnésio (Mg2+) inibe a liberaçäo de ACh em razäo de bloquear o influxo de cálcio nas terminaçöes nervosas, levou-nos a investigar a açäo deste cátion sobre os distúrbios produzidos pelas peçonhas escorpiônicas. Relatamos na presente comunicaçäo a açäo do Mg2+ sobre os efeitos induzidos pelas peçonhas dos escorpiöes Tityus serrulatus, T. bahiensis e Centruroides sculpturatus nas preparaçöes isoladas nervo frênico-diafragma, íleo, canal deferente e átrios de rato e in vivo, em ratos anestesiados com registro da pressäo arterial e do eletrocardiograma. Os efeitos da peçonha dos escorpiöes nas preparaçöes isoladas foram abolidos ou muito atenuados pelo Mg2+. O Mg2+, no entanto, somente antagonizou os efeitos da peçonha de C. sculpturatus no íleo de rato. Em ratos anestesiados, a hipertensäo e arritmias provocadas pela peçonha de T. serrulatus foram revertidas com exclusäo de bradicardia pela injeçäo do Mg2+. A peçonha de C. sculpturatus na maioria das experiências causou hipotensäo e arritmias de pequena gravidade. O Mg2+ reverteu as arritmias, mas causou quedas acentuadas da pressäo arterial. Os resultados da pesquisa sugerem o emprego do Mg2+ em acidentes graves na ausência de hipotensäo e bradicardia, produzidos por T. serrulatus e T. bahiensis. Parece contra-indicado nos acidentes causados por C. sculpturatus em vista de seu efeito acima referido na pressäo arterial.

Indian red scorpion venom modulates spontaneous activity of rat right atria through the involvement of cholinergic and adrenergic systems.

The effect of Indian red scorpion (Mesobuthus tamulus concanesis, Pocock; MBT) venom was investigated on isolated rat right atrial preparations. MBT venom (0.001-3.0 micrograms/ml) exhibited a peculiar concentration-response pattern with respect to rate. The venom concentrations between 0.001-0.01 microgram/ml increased the atrial rate (phase I), followed by a relative decrease with 0.03-0.3 microgram/ml (phase II), and then an abrupt increase with 0.6-3.0 micrograms/ml (phase III). On the other hand, the force was unaltered by venom at phases I and II, while an increase was seen at phase III (3.0 micrograms/ml). Propranolol (0.1 microM) completely blocked the cardiostimulant action of venom at phase III. Further, this stimulant action of venom was absent in atria obtained from reserpinized animals. Pretreatment with atropine (0.3 microM), produced tachycardia at concentrations 0.1-0.3 microgram/ml of venom. But, hexamethonium (30 microM) had no influence on the venom (0.1 microgram/ml)-induced alterations in rate. However, MBT venom increased the acetylcholinesterase (AChE) activity (2-3 fold) in a concentration-dependent manner. Tetrodotoxin (2 microM), did not block the increase in rate produced by 0.01 microgram/ml of venom. Results suggest that, MBT venom-induced alterations of cardiac rhythmicity are mediated through cholinergic as well as adrenergic mechanisms depending upon the concentrations. The modulation of atrial rate at very low concentrations may be due to the direct action of venom on the atrium.

Differential effects of isoproterenol on the activity of angiotensin-converting enzyme in the rat heart and aorta

The excessive stimulation of beta-adrenergic receptors in the heart induces myocardial hypertrophy. There are several experimental data suggesting that this hypertrophy may also depend, at least partially, on the increase of local production of angiotensin II secondary to the activation of the cardiac renin-angiotensin system. In this study we investigated the effects of isoproterenol on the activity of angiotensin-converting enzyme (ACE) in the heart and also in the aorta and plasma. Male Wistar rats weighing 250 to 305 g were treated with a dose of (ñ)-isoproterenol (0.3 mg kg-1 day-1, N = 8) sufficient to produce cardiac hypertrophy without deleterious effects on the pumping capacity of the heart. Control rats (N = 7) were treated with vehicle (corn oil). The animals were killed one week later. ACE activity was determined in vitro in the four cardiac chambers, aorta and plasma by a fluorimetric assay. A significant hypertrophy was observed in both ventricular chambers. ACE activity in the atria remained constant after isoproterenol treatment. There was a significant increase (P<0.05) of ACE activity in the right ventricle (6.9 = 0.9 to 8.2 = 0.6 nmol His-Leu g-1 min-1) and in the left ventricle (6.4 ñ 1.1 to 8.9 ñ 0.8 nmol His-Leu g-1 min-1). In the aorta, however, ACE activity decreased (P<0.01) after isoproterenol (41 = 3 to 27 = 2 nmol His-Leu g-1 min-1) while it remained unchanged in the plasma. These data suggest that ACE expression in the heart can be increased by stimulation of beta-adrenoceptors. However, this effect is not observed on other local renin-angiotensin systems, such as the aorta. Our data also suggest that the increased sympathetic discharge and the elevated plasma concentration of catecholamines may contribute to the upregulation of ACE expression in the heart after myocardial infarction and heart failure

Efecto de la amilorida y su derivado diclorobenzamil sobre la auricula aislada del acure (Cavia porcellus): interaccion con otras maniobras inotropicas / Effect of amiloride and dichlorobenzamil derivative in the guinea pig atria: interaction with other inotropic mechanisms

Se estudiaron los efectos cronotrópico e inotrópico de la Amilorida (AMI) y la dicloro-benzamil-Amilorida (DCB-AMI) sobre las aurículas aislada del acure, así como la interacción de estas drogas con la beta-metil-digoxina (BM_DIGO), la epinefrina y la disminución del potasio extracelular (de 4 a 1 mM). La AMI (1 mM) causa un efecto inotrópico positivo y cronotrópico negativo, independientes del sistema autonómico. La DCB-AMI causa um efecto bimodal sobre la fuerza de contracción: la aumenta a bajas dosis pero la disminuye a concentraciones mayores de 10(-6) M. También disminuye levemente la frecuencia sinusal. El efecto de la AMI sobre el automatismo sinusal no es alterado por la BM-DIGO. En cambio, la AMI ((10(-3 M) disminuye el efecto inotrópico positivo de la BM-DIGO e incrementa la dosis tóxica en preparaciones aisladas. La curva dosis-respuesta a la epinefrina no varía en presencia de AMI. Resultados similares se obtuvieron con DCB-AMI (2 x 10(-7 M). El incremento de contractilidad que se observa al disminuir la concentración extracelular de potasio a 1 mM no se altera en presencia de AMI. La actividad de la Na+/K+ ATPasa dependiente de Mg++ de la fracción microsomal obtenida del corazón del acure disminuye en 10 por ciento aproximadamente en presencia de AMI (1nM). Por otra parte, el efecto inhibitorio sobre la enzima obtenido con ouabaína no varía con esta droga. En conclusión, nuestros resultados sugieren múltiples efectos de la AMI y DCB-AMI sobre el corazón del acure. La inhibición del intercambiador Na+/Ca++ explica solo parte de ellos; el bloqueo de los canales lentos parece fundamental para explicar nuestras observaciones.

Modulatory effects of diltiazem on inotropic responses to amrinone on rabbit isolated atria.

The effect of pretreatment with graded concentration of diltiazem on the inotropic responses to amrinone were studied on isolated atria of rabbit. The responses to amrinone were modified by diltiazem in a biphasic manner; initial potentiation followed by inhibition. The potentiation is proposed to be due to synergistic rise in cytosolic calcium ion concentration by diltiazem and amrinone. The inhibition by diltiazem in higher concentration may be due to blockade of calcium ion influx and depletion of intracellular calcium ion from storage sites.

Effects of trypan blue on the action of adrenergic agonists in the guinea-pig isolated atrium.

It has been reported that trypan blue, a diazo dye with polyamphipathic structure, can inhibit the coupling of receptors to G-proteins. The present study was carried out to investigate the effect of trypan blue on the actions of adrenoceptor agonists in the guinea-pig atrium. Trypan blue (10 and 100 microM) antagonized the positive inotropic effects of isoprenaline and dobutamine by shifting their concentration-response curves to the right. With the selective beta 2-adrenoceptor agonist, salbutamol, there was a reduction of response in the presence of trypan blue. Therefore, we concluded that trypan blue diminish the response to beta-adrenoceptor agonists possibly via decoupling receptors from Gs. Trypan blue and similar agents, due to their unique mode of action, can be used as tools for the investigation of the mechanism of receptor-G protein coupling in the whole tissue preparation.

Chronotropic, inotropic and lusitropic effects of capsaicin on isolated rat Atria

This work includes results on chronotropic, inotropic and lusitropic changes induced by capsaicin on isolated rat atria. As regards spontaneous frequency, it was stimulated from 10(-9) M up to 7 x 10(-7) M of capsaicin. A simultaneous depression in developed force (F) showed a signigicant correlation with this positive chronotropic effect up to 7 X 10(-8) M of capsaicin, which is the result of the negative staircase phenomenon in the rat heart. The correlation was lost at 2 and 7 x 10(-7) M of capsaicin since in spite of the sustained increase in atrial rate the decrease in F was reversed and then depressed again at 2 and 7x 10(-6) M of capsaicin without changes in frequency. A concentration of capsaicin that overcome the negative staircase phenomenon, 5 x 10(-7) M, was tested as unique dose resulting in stimulation of the chronotropic, inotropic and lusitropic states of the atria. Percentual differences with respect to control values were maximal after 1-3 minutes for frequency (10+3 per cent), F (29+4 per cent), maximal velocity of force development (+F=50+12 per cent) (in all cases +F and -F,bold indicates +F and -F, respectively) and maximal velocity of relaxation (-F=64+13 per cent); a positive lusitropic effect was significant after 8-10 minutes (+F/-F=-17+7 per cent). Capsaicin did not affect the rat atria in the presence of 10(-6) M of ruthenium red, a blocker of capsaicin activation of sensory nerves, indicating that the stimulatory effects were entirely mediated by the release of neurotransmitters and that this concentration of capsaicin was not deleterous "per se". Capsaicin elicited similar inotropic responses in electrically driven isolated atria (+F=41+9 per cent) but the positive lusitropic effect was lost suggesting that capsaicin-induced increases in -F are limited at a frequency higher than the spontaneous frequency (11+6 vs. 32+4 per cent, respectively). 10(-6) M of CGRP8(-37), an antagonist of CGRP1 receptors, suppress the stimulatory effects of capsaicin on atrial contraction. In summary, atrial rate as compared to atrial contraction is more sensitive to the neurotransmitter released by capsaicin, which results in mechanical effects expressing the negative staircase phenomenon in the rat at low concentrations of capsaicin. The positive chronotropic, inotropic and lusitropic responses elicited by capsaicin are mediated by the reelease of neurotransmitters from sensory fibbers and no deletereous effects...

Mechanism of cardiotoxicity induced by a marine toxin isolated from Ptychodiscus brevis.

An organophosphate toxin of marine origin isolated from red tide dinoflagellate P. brevis produced a dose-dependent dual effect on rat atria, i.e. positive inotropic effect at low concentrations (2.8 x 10(-8) to 8.4 x 10(-7) M) and negative inotropic and chronotropic responses at an elevated dose (4.8 x 10(-6) to 7.2 x 10(-4) M). The negative chronotropic and inotropic responses of the toxin were potentiated with physostigmine and ouabain whereas antagonized by atropine and hemicholinium-3 pretreatments and those effects remained unaltered by isoproterenol, phenylephrine and ouabain pretreatments. The results indicate that the toxin induced negative inotropic and chronotropic effects are mediated through release of acetylcholine from the nerve endings and consequent activation of muscarinic receptor. In atria exposed to guanethidine, bretylium, propranolol and tyramine tachyphylaxis, the positive inotropic response of the toxin was not modified. However, the response was antagonized by EGTA, nifedipine, ryanodine, calcium-free ringer and potentiated with caffeine and amiloride pretreatments. The results suggest that the positive inotropic effect of the toxin is mediated through Ca2+ influx and impairment of Na+/Ca2+ exchange process.

Negative inotropic effect of chagasic IGG mediated by nitric oxide

In this paper we analyse the interaction of IgG from T. cruzi infected patients with cardiac muscarinic acetycholine receptors (mAChRs). Human chagasic IgG, activating M2 mAChR simulated the agonist actions excerting negative inotropic effect and simulation of nitric oxide synthase (NOS). Inhibitos of phospholipase C, protein Kinase C, calcium/calmodulin, NOS and guanylate cyclase activities prevented the chagasis effects upon contractility and NOS activity.

Negative inotropic effect of carbachol on rat atria mediated by nitric oxide

En este trabajo nosotros mostramos que la aurícula aislada de rata sintetiza óxido nítrico (ON) y este actúa como un mensajero intracelular incrementando la producción de GMPc, que a su vez modula el efecto contráctil inhibitorio ejercido por la activación muscarínica. El carbacol activando al receptor muscrínico M2 estimula el ciclo de los fosfoinosítidos y a la óxido nítrico sintaza con la consiguiente producción de ON. Los inhibidores de fosfolipasa C, proteína quinasa C, calcio/calmodulina, óxido nítrico sintaza y guanilato ciclasa, desvían hacia la derecha la curva dosis-respuesta del carbacol sobre la contractilidad. Más aun, en nitroprusiato de sodio y el 8-bromo GMPc indujeron un efecto inotrópico negativo, similar a las bajas concentraciones de carbacol. Estos reultados sugieren que el carbacol activando a receptores muscarínicos de tipo M2 ejerce un efecto inotrópico negativo asociado a un incremento en la producción de ON. Este mecanismo parece ser secundario a la estimulación del ciclo de los fosfoinosítidos vía la activación de la fosfolipas C; que desencadeando reacciones en cascada llevan a la producción de ON, el cual contribuye al efecto inotrópico negativo ejercido por bajas concentraciones de carbacol