RESUMEN
Methylxanthines, such as theophylline, have been used to treat cardiorespiratory disorders, whereas caffeine is the most widely consumed psychoactive agent in various soft drinks. Because of the worldwide use of these drugs and the recently synthesized xanthine derivatives, an intensive research on the cardiac actions of these substances is under progress. This review focuses on the molecular mechanisms involved in the actions of xanthine derivatives with special reference to their adenosine receptor antagonistic properties. The main basic and human studies on the action of xanthines on impulse initiation and conduction, as well as the electrophysiological and mechanical activity of the working myocardium will be overviewed. The potential beneficial and harmful actions of the methylxanthines will be discussed in light of the recent experimental and clinical findings. The pharmacological features and clinical observations with adenosine receptor subtype-specific xanthine antagonists are also the subject of this paper. Based on the adenosine receptor-antagonistic activity of these compounds, it can be raised that xanthine derivatives might inhibit the cardioprotective action of endogenous adenosine on various subtypes (A(1), A(2A), A(2B) and A(3)) of adenosine receptors. Adenosine is an important endogenous substance with crucial role in the regulation of cardiac function under physiological and pathological conditions (preconditioning, postconditioning, ischemia/reperfusion injury). Recent clinical studies show that acute administration of caffeine or theophylline can inhibit various types of preconditioning in human subjects. There are no human studies, however, for the cardiovascular actions of long-term administration of these drugs. Upregulation of adenosine receptors and increased effectiveness of adenosine receptor-related cardiovascular functions have been observed after long-lasting treatment with methylxanthines. In addition, there are data indicating that blood adenosine level increases after long-term caffeine administration. Since the salutary actions (and also the adverse reactions) of a number of xanthine derivatives are repeatedly shown, the main goal is the development of novel structures that mimic the actions of the conventional methylxanthines as lead compounds, but their adenosine receptor subtype-specificity is higher, their water solubility is optimal, and the unwanted reactions are minimized.
Asunto(s)
Fármacos Cardiovasculares/química , Xantinas/química , Potenciales de Acción/efectos de los fármacos , Animales , Cafeína/farmacología , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/uso terapéutico , Ensayos Clínicos como Asunto , Cardiopatías/tratamiento farmacológico , Humanos , Antagonistas de Receptores Purinérgicos P1/química , Antagonistas de Receptores Purinérgicos P1/farmacología , Antagonistas de Receptores Purinérgicos P1/uso terapéutico , Receptores Purinérgicos P1/química , Receptores Purinérgicos P1/metabolismo , Xantinas/efectos adversos , Xantinas/uso terapéuticoRESUMEN
This review focuses on the potential role of site- and event-selective adenosinergic drugs in the treatment of cardiovascular diseases. Adenosine is released from the myocardium and vessels in response to various forms of stress and acts on four receptor subtypes (A1, A2A, A2B and A3). Adenosine is an important endogenous substance with important homeostatic activity in the regulation of cardiac function and circulation. Adenosine receptors are also involved in the modulation of various cellular events playing crucial role in physiological and pathological processes of the cardiovascular system. These actions are associated to activation of distinct adenosine receptor subtypes, therefore drugs targeting specific adenosine receptors might be promising therapeutic tools in treatment of several disorders including various forms of cardiac arrhythmia, myocardial ischemia-reperfusion injury, angina pectoris, chronic heart failure, etc. Recently, in addition to subtype-specific adenosine receptor agonists and antagonists, a number of substances that enhance adenosine receptor activation locally at the site where the release of endogenous adenosine is the most intensive have been developed. Thus global actions of adenosine receptor agonists and antagonists, as well as desensitization or down-regulation following chronic administration of these orthosteric compounds can possibly be avoided. We discuss the chemical, pharmacological and clinical features of these compounds: (1) inhibitors of membrane adenosine transporters (NBTI, dipyridamole), (2) inhibitors of adenosine deaminase (coformycin, EHNA), (3) inhibitors of adenosine kinase (tubercidin, aristeromycin), (4) inhibitors of AMP deaminase (GP3269), (5) activators of 5'-nucleotidase (methotrexate), (6) adenosine regulators (acadesine) and (7) allosteric adenosine receptor modulators (PD81723, LUF6000). The development of this type of substances might offer a novel therapeutic approach for treating cardiovascular diseases in the near future.
Asunto(s)
Adenosina/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Adenosina/análogos & derivados , Adenosina/química , Animales , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Humanos , Receptores Purinérgicos P1/metabolismo , Relación Estructura-ActividadRESUMEN
The significance of PDE2 on the atrial inotropy was studied in eu- and hyperthyroidism. The contractile force was measured and negative inotropic capacity of N6-cyclopentyladenosine (CPA) was determined on left atria isolated from 8-day thyroxine- or solvent-treated guinea pigs, in the presence or absence of EHNA (adenosine deaminase and PDE2 inhibitor) or NBTI (nucleoside transporter inhibitor). EHNA was administered to inhibit PDE2, while NBTI was used to model the accumulation of endogenous adenosine. The reduction of the contractile force caused by EHNA was smaller in the thyroxine-treated atria than in the solvent-treated samples. Contrary, NBTI induced a decrease in the contractile force without significant difference between the two groups. In addition, EHNA enhanced the efficiency of CPA in thyroxine-treated atria and did not affect it in solvent-treated samples, while the response to CPA was decreased by NBTI in all atria, especially in hyperthyroidism. On the basis of greater retention of the contractile force and sustained/enhanced responsiveness to CPA in the presence of EHNA we conclude that PDE2's inhibition has a significant positive inotropic effect in guinea pig atria and this effect is proven to be augmented in hyperthyroidism.
Asunto(s)
Adenina/análogos & derivados , Adenosina/análogos & derivados , Cardiotónicos/farmacología , GMP Cíclico/farmacología , Atrios Cardíacos/metabolismo , Hipertiroidismo/metabolismo , Contracción Miocárdica/efectos de los fármacos , Hidrolasas Diéster Fosfóricas/metabolismo , Tioinosina/análogos & derivados , Adenina/farmacología , Adenosina/farmacología , Animales , Técnicas de Cultivo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2 , Cobayas , Atrios Cardíacos/efectos de los fármacos , Masculino , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Tioinosina/farmacologíaRESUMEN
The effects of a 10-day i.p. treatment of rats with diazepam on responses to subtype selective adenosine receptor agonists were studied 3 h, 2 and 8 days after termination of diazepam treatment in isolated cardiovascular tissues possessing distinct adenosine receptors. After long-lasting diazepam exposure, the relaxation elicited by the specific A2A receptor agonist CGS 21680 was enhanced in rat main pulmonary arteries (a tissue containing A2A adenosine receptors). The increased sensitivity of A2A receptors observed 3 h and 2 days after withdrawal of diazepam was completely restored by the 8th day of the wash-out period. N6-cyclopentyladenosine (CPA)-induced suppression in mechanical activity of electrically stimulated rat atrial myocardium (a tissue containing A1 adenosine receptors) was not altered following diazepam treatment. In order to reveal the possible role of inhibition of membrane adenosine transport in the effects of diazepam (a moderate inhibitor of membrane adenosine transport), the action of a 10-day treatment with dipyridamole or S-(p-nitrobenzyl)-6-thioinosine (NBTI; prototypic adenosine uptake inhibitors) was also studied. Dipyridamole or NBTI treatment, like diazepam, increased the responsiveness of rat pulmonary artery to CGS 21680, but did not influence the cardiodepressive effect of CPA in electrically driven left atrial myocardium. The CGS 21680-induced relaxations were significantly antagonized by 10 nM ZM 241385 (a selective A2A adenosine receptor antagonist) in vessels of diazepam-treated rats. The relaxation responses to verapamil were unaltered in pulmonary arteries obtained from animals chronically treated with diazepam, dipyridamole or NBTI. These results suggest that chronic diazepam treatment is able to enhance the A2A adenosine receptor-mediated vascular functions, but does not modify the responses mediated via A1 receptors of rat myocardium, where nucleoside transport inhibitory sites of membrane are of a very low density. It is possible that sensitization of A2A adenosine receptor-mediated vasorelaxation is due to a long-lasting inhibition of membrane adenosine transporter during diazepam treatment.
Asunto(s)
Diazepam/farmacología , Relajación Muscular/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Receptores Purinérgicos P1/fisiología , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Animales , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/fisiología , Diazepam/farmacocinética , Fosfatos de Dinucleósidos/farmacología , Dipiridamol/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Corazón/efectos de los fármacos , Corazón/fisiología , Atrios Cardíacos/efectos de los fármacos , Fenetilaminas/farmacología , Arteria Pulmonar/fisiología , Agonistas del Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Ratas , Ratas Wistar , Receptor de Adenosina A2A , Tioinosina/análogos & derivados , Tioinosina/farmacología , Triazinas/farmacología , Triazoles/farmacología , Verapamilo/farmacologíaRESUMEN
In electrically driven myocardial preparations obtained from chronically methylxanthine-[aminophylline (APH) and 8-phenyltheophylline (8-PT)] or solvent(DMSO)-treated guinea pigs no differences were found in alteration of mechanical activity under hypoxia and reoxygenation. The vasoconstrictor effects observed after in vitro exposure of pulmonary arterial preparations (excised from either methylxanthine- or solvent-treated guinea pigs) to both noradrenaline and PGF2 alpha were also similar. In methylxanthine-treated vascular tissues, however, nitroglycerin and NO exerted more pronounced vasorelaxant effect than in specimens prepared from solvent-treated guinea pigs.
Asunto(s)
Hipoxia/fisiopatología , Músculo Liso Vascular/efectos de los fármacos , Antagonistas de Receptores Purinérgicos P1 , Aminofilina/farmacología , Animales , Función Atrial/efectos de los fármacos , Cardiotónicos/farmacología , Dinoprost/farmacología , Femenino , Cobayas , Técnicas In Vitro , Óxido Nítrico/farmacología , Norepinefrina/farmacología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Teofilina/análogos & derivados , Teofilina/farmacología , Factores de Tiempo , VasoconstricciónRESUMEN
In isolated guinea pig pulmonary arteries (precontracted with 1 microM noradrenaline) N6-cyclopentyladenosine (CPA), a selective A1 adenosine receptor agonist, exerted a concentration-dependent contraction, whereas 5'-N-ethylcarboxamidoadenosine (NECA), a non-selective A1/A2 receptor agonist, in the presence of DPCPX (a highly selective A1 receptor antagonist), produced a concentration-related rapid relaxation. Pulmonary arteries obtained from guinea pigs treated with aminophylline (APH) or 8-phenyltheophylline (8-PT) for 10 consecutive days, displayed more pronounced contraction in response to CPA compared to those of solvent-treated animals. Relaxant action of NECA was, however, attenuated in arteries prepared from methylxanthine-treated guinea pigs. Opposite changes were found in vascular tissues excised from chronically dipyridamole(DP)-treated guinea pigs.
Asunto(s)
Arteria Pulmonar/metabolismo , Receptores Purinérgicos/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina-5'-(N-etilcarboxamida) , Animales , Femenino , Cobayas , Arteria Pulmonar/efectos de los fármacos , Agonistas del Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Vasoconstricción , Vasodilatación , Xantinas/farmacologíaRESUMEN
The concentration-related sensitization of guinea pig left atrium to adenosine in the presence of diazepam is well established. It was found in our experiments that the cardiodepressive action of hypoxia is significantly enhanced by diazepam in the left atrial myocardium. In atrial preparations obtained from guinea pigs treated with diazepam for 10 days, the hypoxia-induced depression of myocardial contractility was not altered. These results indicate that diazepam-treatment does not impaire the hypoxic tolerance of myocardium.
Asunto(s)
Cardiomiopatías/fisiopatología , Diazepam/farmacología , Corazón/efectos de los fármacos , Corazón/fisiopatología , Hipoxia/fisiopatología , Animales , Femenino , Cobayas , Contracción Miocárdica/efectos de los fármacos , Factores de TiempoRESUMEN
In guinea pig main pulmonary artery precontracted with noradrenaline, adenosine exerted an initial phasic contraction followed by a tonic contraction and a slow relaxation. After selective blockade by 1,3-dipropyl-8-cyclopentylxanthine (DPCPX: 10 nM) of A1 receptors, adenosine only elicited a rapid relaxation. This initial response was characterized by use of adenosine (AR) and its analogues N6-cyclopentyl-adenosine (CPA), R-N6-phenylisopropyladenosine (R-PIA), 2-chloroadenosine (CADO), 5'-N-ethyl-carboxamidoadenosine(NECA), N6-2-(4-aminophenyl) ethyl adenosine (APNEA) and 2-p-((carboxyethyl)-phenethylamino)-5'-carboxamidoadenosine (CGS 21 680). The order of potency of the adenosine analogues for purine-induced phasic contraction was CPA > R-PIA > NECA = APNEA > AR > CGS 21 680 suggesting the involvement of activation of A1 type adenosine receptors in the contraction phase. DPCPX antagonized the CPA-induced contraction with a pA2 = 9.27 +/- 0.26, but the Schild plot slope parameter was significantly lower than unity (0.58 +/- 0.09). In contrast, in electrically driven guinea pig atrial myocardium (a tissue reported to possess A1 receptors), the DPCPX-CPA antagonism was purely competitive (pA2 = 8.95 +/- 0.06; slope = 0.93 +/- 0.06). In the presence of 300 nM DPCPX, the rank order of potency for the purine-induced fast relaxation was NECA > CADO = AR > CGS 21 680 = R-PIA > CPA. The NECA- and adenosine-induced relaxation was influenced neither by 300 nM CP 66713 (an antagonist at A2a receptors), nor by endothelial removal and inhibition of nitric oxide synthase (100 microM NG-nitro-L-arginine: L-NOARG).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Adenosina/farmacología , Músculo Liso Vascular/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Receptores Purinérgicos P1/fisiología , Adenosina/análogos & derivados , Aminoácido Oxidorreductasas/antagonistas & inhibidores , Animales , Cobayas , Técnicas In Vitro , Contracción Isométrica/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/enzimología , Contracción Miocárdica/efectos de los fármacos , Óxido Nítrico Sintasa , Arteria Pulmonar/enzimología , Antagonistas de Receptores Purinérgicos P1 , Purinas/farmacología , Receptores Purinérgicos P1/efectos de los fármacosAsunto(s)
Arritmias Cardíacas/inducido químicamente , Canales de Calcio/metabolismo , Cardiotónicos , Digoxina , Corazón/efectos de los fármacos , Miocardio/metabolismo , Canales de Potasio/metabolismo , Animales , Arritmias Cardíacas/fisiopatología , Canales de Calcio/efectos de los fármacos , Cobayas , Canales de Potasio/efectos de los fármacosAsunto(s)
4-Aminopiridina/farmacología , Adenosina/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Músculo Liso Vascular/efectos de los fármacos , Nodo Sinoatrial/efectos de los fármacos , Adenosina/antagonistas & inhibidores , Animales , Perros , Técnicas In Vitro , Contracción Isométrica , Relajación Muscular/efectos de los fármacos , ConejosRESUMEN
The action of adenosine on the fibrillation threshold, effective refractory period, electric diastolic threshold and mechanical activity of the atrial and ventricular myocardium was studied in vivo and in vitro. In anaesthetized, open-chest cats, the atrial fibrillation threshold significantly decreased under adenosine-infusion (1 mumols/kg/min). In electrically stimulated atrial myocardium of cats, adenosine (10 mumols/l-1 mmol/l) was capable of evoking a concentration-dependent decrease in electric diastolic threshold and shortening the functional refractory period. Adenosine decreased also the contractile force. The shortening on the functional refractory period was more prominent in electrically driven guinea-pig left atrial myocardium. This action could be antagonized by aminophylline, a competitive antagonist on P1 purinoceptors. In ventricular myocardium, adenosine did not influence the fibrillation threshold, the electric diastolic threshold, the functional refractory period or contractile force. On the basis of these observations it can be assumed that the above changes in the extracellular electrophysiological parameters may play a role in the pathomechanism of atrial fibrillation occasionally manifested during treatment with adenosine in patients as well as in dogs.
Asunto(s)
Adenosina/farmacología , Fibrilación Atrial/fisiopatología , Corazón/fisiopatología , Aminofilina/farmacología , Animales , Gatos , Electrofisiología , Femenino , Técnicas In Vitro , Masculino , Contracción Miocárdica/efectos de los fármacos , Periodo Refractario Electrofisiológico/efectos de los fármacosRESUMEN
The action of almitrine bismesylate, a potent ventilatory stimulant drug, was studied on the contractile responses to some putative transmitters of carotid body (dopamine, noradrenaline, PGF2 alpha, adenosine) in segments of guinea pig pulmonary arteries. Almitrine (10 mumol/l) was capable of mitigating the contractions evoked by dopamine (0.3 mmol/l), noradrenaline (1 mumol/l) and PGF2 alpha (10 mumol/l) as well. In vessels precontracted with noradrenaline, almitrine (added to the nutrient solution of vessels before applying noradrenaline) potentiated the adenosine-induced initial contractile response without influencing the methylxanthine-sensitive relaxing effect of this purine nucleoside. In contrast, almitrine antagonized the adenosine-induced contraction when applied under precontracted state of arteries. It is supposed that the results presented here could provide some explanation for the variable action of almitrine on pulmonary circulation. On the other hand, these results could serve as a pharmacological basis for further studies of the almitrine action on isolated carotid bodies.
Asunto(s)
Piperazinas/farmacología , Arteria Pulmonar/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Adenosina/farmacología , Almitrina , Animales , Cuerpo Carotídeo/efectos de los fármacos , Cuerpo Carotídeo/fisiología , Catecolaminas/farmacología , Células Quimiorreceptoras/efectos de los fármacos , Células Quimiorreceptoras/fisiología , Dinoprost , Femenino , Cobayas , Técnicas In Vitro , Masculino , Prostaglandinas F/farmacologíaRESUMEN
Myocardial contractility and Ca2+-pump function of sarcoplasmic reticulum (SR) were studied on hearts of untreated, thyroidectomized and thyroxine-treated rats. In hypothyroid rats the contractile force, the maximum velocity of tension development and relaxation significantly decreased (by 73.2%, 68.2%; and 67.8%, respectively), while the time to peak tension was prolonged (by 25.9%) as compared with the control group. In hyperthyroidism opposite changes were found. Since the transport of calcium opposite changes were found. Since the transport of calcium by SR plays an important role in controlling contraction and, first of all, relaxation of muscle, function of the sarcoplasmic reticulum was also investigated under the above experimental conditions. In thyroidectomized rats the rate of Ca2+-uptake and Ca2+-activated ATPase activity of SR significantly decreased (by 31.7% and 61.0%, respectively), while Ca2+-binding remained unchanged. After thyroxine treatment both the Ca2+-uptake and binding capacity of SR were even decreased (by 25.6% and 12.9%, respectively), in spite of an increase in Ca2+-activated ATPase activity (by 67.3%). These changes in Ca2+ transport function of cardiac SR may only partially be responsible for the abnormalities in contraction and relaxation observed in hearts from hypo- and hyperthyroid rats.
Asunto(s)
Calcio/metabolismo , Hipertiroidismo/fisiopatología , Hipotiroidismo/fisiopatología , Contracción Miocárdica , Retículo Sarcoplasmático/fisiopatología , Animales , ATPasas Transportadoras de Calcio/metabolismo , Masculino , Miocardio/metabolismo , Ratas , Retículo Sarcoplasmático/metabolismo , Tiroxina/fisiologíaRESUMEN
The effect of moderate and severe hypoxia on the electrical and mechanical activity of isolated left atria of guinea-pigs was compared in the presence and absence of coformycin, a highly specific and tight-binding inhibitor of adenosine deaminase. The myocardial actions of hypoxia (reduction in the duration of intracellularly recorded action potentials and decrease in isometric tension, maximum velocity of contraction and relaxation as well as in time to peak tension) were significantly enhanced by coformycin, when applied in a concentration of 7 mumol/l producing nearly complete inhibition of adenosine deaminase in atrial muscle. These effects of coformycin were moderate during early hypoxia (0-5 min) and became pronounced during the late phase of oxygen deprivation (5-16 min). The results are in favour of the previous assumption that under hypoxic conditions the increased tissue level of adenosine might contribute to the functional impairment of the guinea-pig myocardium.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Coformicina/farmacología , Miocardio/metabolismo , Nucleósido Desaminasas/antagonistas & inhibidores , Oxígeno/fisiología , Ribonucleósidos/farmacología , Potenciales de Acción/efectos de los fármacos , Adenosina/metabolismo , Animales , Femenino , Cobayas , Técnicas In Vitro , Masculino , Potenciales de la Membrana/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Factores de TiempoRESUMEN
The effects of coformycin, a highly potent and specific inhibitor of the intracellular enzyme adenosine deaminase and the influence of dipyridamole, an inhibitor of the cellular adenosine uptake mechanism, were studied on the adenosine-induced changes in the electrical and mechanical activity of isolated electrically driven left atria of guinea-pig hearts. Adenosine (0.1 mumol/l-1 mmol/l) by itself elicited a concentration-dependent decrease in the action potential duration and contractile force of atrial preparations. Coformycin, when applied in a concentration inducing a nearly complete inhibition of adenosine deaminase activity in intact atrial myocardium (7 mumol/l), enhanced the adenosine-induced reduction both in the duration of the intracellularly recorded action potential and in the contractile force of the atria, preferentially at higher concentrations of adenosine (10 mumol/l-1 mmol/l). The calculated half recovery time during wash-out (t1/2) was found to be about 6 times longer than that of controls (317.5 +/- 47 and 51.3 +/- 4.3 sec, respectively). In contrast with adenosine, the action of 2-chloroadenosine (an adenosine deaminase resistant purine derivative) on the atrial contractile force was not affected in the presence of coformycin. Dipyridamole (0.3 mumol/l) was capable of significantly potentiating the adenosine-induced depression of atrial mechanical activity, mainly at lower concentrations of adenosine (0.1-10 mumol/l). Preincubation of atrial preparations with a combination of coformycin and dipyridamole produced a strong enhancement in the adenosine-induced decrease of mechanical activity at all concentrations of adenosine. It is suggested that adenosine might exert its myocardial actions not only through the known extracellular, but also via possible intracellular purinoceptors.