The cardiopulmonary reflexes of spontaneously hypertensive rats are normalized after regression of left ventricular hypertrophy and hypertension

Cardiopulmonary reflexes are activated via changes in cardiac filling pressure (volume-sensitive reflex) and chemical stimulation (chemosensitive reflex). The sensitivity of the cardiopulmonary reflexes to these stimuli is impaired in the spontaneously hypertensive rat (SHR) and other models of hypertension and is thought to be associated with cardiac hypertrophy. The present study investigated whether the sensitivity of the cardiopulmonary reflexes in SHR is restored when cardiac hypertrophy and hypertension are reduced by enalapril treatment. Untreated SHR and WKY rats were fed a normal diet. Another groups of rats were treated with enalapril (10 mg kg-1 day-1, mixed in the diet; SHRE or WKYE) for one month. After treatment, the volume-sensitive reflex was evaluated in each group by determining the decrease in magnitude of the efferent renal sympathetic nerve activity (RSNA) produced by acute isotonic saline volume expansion. Chemoreflex sensitivity was evaluated by examining the bradycardia response elicited by phenyldiguanide administration. Cardiac hypertrophy was determined from the left ventricular/body weight (LV/BW) ratio. Volume expansion produced an attenuated renal sympathoinhibitory response in SHR as compared to WKY rats. As compared to the levels observed in normotensive WKY rats, however, enalapril treatment restored the volume expansion-induced decrease in RSNA in SHRE. SHR with established hypertension had a higher LV/BW ratio (45 percent) as compared to normotensive WKY rats. With enalapril treatment, the LV/BW ratio was reduced to 19 percent in SHRE. Finally, the reflex-induced bradycardia response produced by phenyldiguanide was significantly attenuated in SHR compared to WKY rats. Unlike the effects on the volume reflex, the sensitivity of the cardiac chemosensitive reflex to phenyldiguanide was not restored by enalapril treatment in SHRE. Taken together, these results indicate that the impairment of the volume-sensitive, but not the chemosensitive, reflex can be restored by treatment of SHR with enalapril. It is possible that by augmenting the gain of the volume-sensitive reflex control of RSNA, enalapril contributed to the reversal of cardiac hypertrophy and normalization of arterial blood pressure in SHR.

Evaluación de la toxicidad del indorrenato sobre la reproducción / The toxicity evaluation of indorenate on the reproductive system

Se estudiaron los efectos del indorrenato, un nuevo fármaco antihipertensivo, sobre la fertilidad, desarrollo peri-postnatal y embrionario en rata, a dosis de 0, 10, 20, 40 y 60 mg/kg/día, administrados oralmente. Durante el estudio de fertilidad, con excepción de la dosis de 60 mg/kg, ningún tratamiento afectó el peso de los progenitores, la fertilidad, el peso fetal o la sobrevivencia. Tampoco las dosis bajas dieron lugar a retardo en aparición del reflejo de enderezamiento, despliegue de pabellón auricular y respuesta al ruido. Las dosis de 40 y 60 mg/kg, por su parte, disminuyeron significativamente el número de fetos vivos y aumentó el de reabsorciones embrionarias. En el estudio peri-postnatal, 40 y 60 mg/kg aumentaron el número de fetos muertos al nacer, y la segunda, afectó también su sobrevivencia, el aumento ponderal y el reflejo de caída. La capacidad reproductiva de la generación F1 no fue modificada. El fármaco no provocó embriotoxicidad ni teratogenicidad, administrado durante el período de organogénesis, en contraste con la serotonina, de la cual es análogo estructural. Se concluye que el indorrenato hasta la dosis de 20 mg/kg, que representa aproximadamente 1200 veces la que se pretende utilizar en pacientes hipertensos, no ejerce efecto toxico aparente sobre la reproducción, desarrollo embrionario y fetal en rata