Efeito do citrato de sildenafil sobre o controle autonômico cardiovascular em ratos normotensos.

Vanessa Capuano

Sildenafil citrate (Viagra) is a broadly used agent to treat erectile dysfunction. Several clinical trials, however, have demonstrated that in heart diseased patients in use of organic nitrates, the association with sildenafil could significantly enhance cardiac events risk. The possible mechanisms implicated in this increased risk are not completely understood, but an eventual reflex sympathetic over-activation due to the vasodilation and light hypotension caused by sildenafil may not be ruled out. However, there are only a few reports in literature concerning to this issue. Therefore, the aim of the present study was to evaluate if sildenafil, acutely administrated, is able to provoke autonomic imbalance by means of spectral analysis of heart rate and arterial pressure variabilities, associated to evaluation of the spontaneous and induced baroreflex control of heart rate and to measurements of the cardiac tonic autonomic control by means of pharmacological blockade. Thirty one normotensive male Wistar rats, weighing 250-350 gr. were studied. Twenty four hours before direct measurements of hemodynamic parameters, the animals were anesthetized with sodium pentobarbital (40 mg/kg, i.p.) e had their femoral vessels catheterized for direct arterial blood pressure recordings and drug administration. In the following day, after fifteen minutes of baseline arterial pressure (AP) recordings, a group of animals (Sil, n=18) has received a bolus injection (1mg/Kg. i.v.) followed by continuous administration (1mg/Kg/hour, i.v.) of sildenafil. A second group of animals (Con, n=13) has received a bolus injection (1mL/Kg) and a continuous infusion (1mL/Kg/hora) of physiological saline solution (vehicle). Arterial blood pressure was continuously recorded during thirty minutes after to start the treatment and it was analyzed by means of spectral analysis of heart rate (pulse interval-PI) and systolic (SAP) arterial pressure variabilities, which were extracted from direct pulsatile arterial blood pressure signal. Mean values of PI and SAP as well as its respective values of variance and low (LF) and high frequencies (HF) spectral components were quantified. In addition, PI and SAP time series were used to estimate the alfa-index (square root of ratio between LF-PI and LF-SAP), an index that measures the spontaneous cardiac barereflex sensitivity. Following, alternate bolus injections of phenylephrine and sodium nitroprusside were administrated in order to induce changes in arterial pressure and to evaluate barorreflex-mediated heart rate responses, which permit to calculate an index of pharmacologically induced baroreflex sensitivity. At the end of the experimental protocol, sequential pharmacological blockade of autonomic nervous system using atropine or propranolol was performed in order to estimate the sympathetic and parasympathetic cardiac tonic control, the pacemaker intrinsic heart rate (IHR) and the sympathovagal index (ratio between basal HR and IHR). Sildenafil caused a significant tachycardia (from 3258bpm in baseline to 3559bpm after treatment, p<0,001)and arterial hypotension (PAS from 1303mmHg in baseline to 1253mmHg, p<0,05), while saline (vehicle) infusion did not provoke any change in the hemodynamic parameters. Spectral components of PI and SAP variability as well as spontaneous and pharmacologically induced barorreflex sensitivities and IHR were not modified after treatment for both sildenafil and vehicle. Regarding to heart rate tonic control, sildenafil induced a significant reduction of parasympathetic vagal effect on the heart associated to an increase in SVI and a trend towards increased sympathetic effect on heart rate. In conclusion, although sildenafil, acutely administrated, causes a light arterial hypotension associated to probably reflex tachycardia, due to vagal parasympathetic inhibition, these changes were not associated to alterations in heart rate and arterial pressure variabilites and cardiac baroreflex sensitivity.

Efeito do citrato de sildenafil sobre o controle autonômico cardiovascular em ratos normotensos.

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