RESUMEN
Myocardial relaxation and stiffness are influenced by fibrillar collagen content. Cyclic nucleotide signaling regulators have been investigated targeting more effective modulation of collagen deposition during myocardial healing process. To assess the effects of phosphodiesterase type 3 and phosphodiesterase type 5 inhibitors on cardiac function and left ventricular myocardial fibrosis in catecholamine-induced myocardial injury, sildenafil and pimobendan were administered to male Wistar rats 24 hours after isoproterenol injection. Echocardiography and electrocardiogram were performed to assess kinetic and rhythm changes during 45 days of drug administration. At the end of study, type I and type III collagen were measured through immunohistochemistry analysis, and left ventricular pressure was assessed through invasive method. Echocardiography assessment showed increased relative wall thickness at 45 days in pimobendan group with significant diastolic dysfunction and increased collagen I deposition compared with nontreated positive group (3.03 ± 0.31 vs. 2.73 ± 0.28%, P < 0.05). Diastolic pressure correlated positively with type I collagen (r = 0.54, P < 0.05). Type III collagen analysis did not demonstrate difference among the groups. Sildenafil administration attenuated type I collagen deposition (2.15 ± 0.51 vs. positive group, P < 0.05) and suggested to be related to arrhythmic events. Arrhythmic events were not related to the quantity of fibrillar collagen deposition. Although negative modulation of collagen synthesis through cyclic nucleotides signaling have shown promising results, in this study, pimobendan postconditioning resulted in increased collagen type I formation and severe diastolic dysfunction while sildenafil postconditioning reduced collagen type I deposition and attenuated diastolic dysfunction.
Asunto(s)
Isoproterenol , Miocardio/enzimología , Inhibidores de Fosfodiesterasa 3/toxicidad , Inhibidores de Fosfodiesterasa 5/farmacología , Piridazinas/toxicidad , Citrato de Sildenafil/farmacología , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/enzimología , Arritmias Cardíacas/fisiopatología , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Masculino , Miocardio/patología , Ratas Wistar , Medición de Riesgo , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/enzimología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial ß1- and ß2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE1 elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE1 (1 µM). Bay 60-7550 (1 µM), but not EHNA (10 µM), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 µM), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 µM) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE1 was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE1, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal.
Asunto(s)
Alprostadil , Arritmia Sinusal/inducido químicamente , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Frecuencia Cardíaca/efectos de los fármacos , Norepinefrina , Inhibidores de Fosfodiesterasa 3/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Taquicardia Supraventricular/inducido químicamente , Animales , Arritmia Sinusal/enzimología , Arritmia Sinusal/fisiopatología , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Modelos Animales de Enfermedad , Hidrólisis , Preparación de Corazón Aislado , Masculino , Ratones , Inhibidores de Fosfodiesterasa 3/toxicidad , Inhibidores de Fosfodiesterasa 4/toxicidad , Receptores Adrenérgicos beta 1/metabolismo , Receptores de Prostaglandina E/metabolismo , Sistemas de Mensajero Secundario/efectos de los fármacos , Taquicardia Supraventricular/enzimología , Taquicardia Supraventricular/fisiopatología , Factores de TiempoRESUMEN
The calcium sensitizer and PDEIII inhibitor EMD82571 caused exencephaly, micrognathia, agnathia and facial cleft in 58% of fetuses. In pursue of mechanisms and to define adverse outcome pathways pregnant Wistar rats were dosed daily with either EMD82571 (50 or 150mg/kg/day) or retinoic acid (12mg/kg/day) on gestational days 6-11 and 6-17, respectively. Hypothesis driven and whole genome microarray experiments were performed with whole embryo, maternal liver, embryonic liver and malformed bone at gestational days 12 and 20. This revealed regulation of genes critically involved in osteogenesis, odontogenesis, differentiation and development and extracellular matrix. Importantly, repression of osteocalcin and members of TGF-ß/BMP signaling hampered osteo- and odontogenesis. Furthermore, EMD82571 impaired neurulation by inhibiting mid hinge point formation to cause neural tube defects. Taken collectively, a molecular rationale for the observed teratogenicity induced by EMD82571 is presented that links molecular initiating events with AOPs.
Asunto(s)
Inhibidores de Fosfodiesterasa 3/toxicidad , Quinolinas/toxicidad , Teratógenos/toxicidad , Tiadiazinas/toxicidad , Animales , Ácidos y Sales Biliares/metabolismo , Huesos/metabolismo , Calcio/metabolismo , Anomalías Craneofaciales/inducido químicamente , Femenino , Perfilación de la Expresión Génica , Hígado/efectos de los fármacos , Hígado/patología , Defectos del Tubo Neural/inducido químicamente , Neurulación/efectos de los fármacos , Análisis de Secuencia por Matrices de Oligonucleótidos , Tamaño de los Órganos/efectos de los fármacos , Osteogénesis , Embarazo , Ratas Wistar , ToxicogenéticaRESUMEN
Analogues with the scaffolds of 3-cyano-4-alkoxyphenyl-6-bromoaryl-2-pyridone and 2-amino-3-cyano-4-alkoxyphenyl-6-bromoarylpyridine were synthesized. Cyclization of the 2-amino derivatives with formic acid and formamide gave the corresponding pyrido[2,3-d]pyrimidin-4(3H)-one and the pyrido[2,3-d]-pyrimidin-4-amine derivatives, respectively. Active phosphodiesterase 3 (PDE3) inhibitors were identified from each of the four aforementioned scaffolds. This is the first report that pyrido[2,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4-amine derivatives can inhibit PDE3. The analogues with the pyridone and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds inhibited both cAMP and cyclic guanosine monophosphate (cGMP) hydrolysis by PDE3, while the amine containing scaffolds were more selective for cGMP hydrolysis. This observation may set the base for substrate-selective pharmacological modulation of this important class of drug targets and with less side effects, particularly tachcardia. The dual inhibitors of PDE3 were more potent inhibitor towards the growth of HT-29 cancer cell lines.