CLINICS 2011;66(8):1407-1411 BASIC RESEARCH DOI:10.1590/S1807-59322011000800017 Role of cGMP and cAMP in the hemodynamic response to intrathecal sildenafil administration Gabriela Bombarda,I Joa˜ o Paulo J. Sabino,I Carlos Alberto A. da Silva,I Rubens Fazan Jr.,I Maria Cristina O. Salgado,II Helio C. SalgadoI I Department of Physiology, School of Medicine of Ribeir a˜o Preto, University of S a˜o Paulo, Sa˜ o Paulo, SP, Brazil. II Pharmacology, School of Medicine of Ribeira˜ o Preto, University of S a˜o Paulo, S a˜o Paulo, SP, Brazil. Ribeir a˜o Preto, SP, Brazil. INTRODUCTION: Results from our laboratory have demonstrated that intracerebroventricular administration of sildenafil to conscious rats promoted a noticeable increase in both lumbar sympathetic activity and heart rate, with no change in the mean arterial pressure. The intracerebroventricular administration of sildenafil may have produced the hemodynamic effects by activating sympathetic preganglionic neurons in the supraspinal regions and spinal cord. It is well documented that sildenafil increases intracellular cGMP levels by inhibiting phosphodiesterase type 5 and increases cAMP levels by inhibiting other phosphodiesterases. OBJECTIVE: To examine and compare, in conscious rats, the hemodynamic response following the intrathecal administration of sildenafil, 8-bromo-cGMP (an analog of cGMP), forskolin (an activator of adenylate cyclase), or dibutyryl-cAMP (an analog of cAMP) in order to elucidate the possible role of the sympathetic preganglionic neurons in the observed hemodynamic response. RESULTS: The hemodynamic responses observed following intrathecal administration of the studied drugs demonstrated the following: 1) sildenafil increased the mean arterial pressure and heart rate in a dose-dependent manner, 2) increasing doses of 8-bromo-cGMP did not alter the mean arterial pressure and heart rate, 3) forskolin did not affect the mean arterial pressure but did increase the heart rate and 4) dibutyryl-cAMP increased the mean arterial pressure and heart rate, similar to the effect observed following the intrathecal injection of the highest dose of sildenafil. CONCLUSION: Overall, the findings of the current study suggest that the cardiovascular response following the intrathecal administration of sildenafil to conscious rats involves the inhibition of phosphodiesterases other than phosphodiesterase type 5 that increase the cAMP level and the activation of sympathetic preganglionic neurons. KEYWORDS: Sympathetic preganglionic neurons; Lumbar sympathetic activity; Forskolin; Phosphodiesterase 5; Spinal cord. Bombarda G, Sabino JPJ, Silva CAA, Fazan R Jr, Salgado MCO, Salgado HC. Role of cGMP and cAMP in the hemodynamic response to intrathecal sildenafil administration. Clinics. 2011;66(8):1407-1411. Received for publication on April 1, 2011; First review completed on April 20, 2011; Accepted for publication on April 20, 2011 E-mail: hcsalgado@fmrp.usp.br Tel.: 55 16 3602-3201 INTRODUCTION Previous results from our laboratory have demonstrated that the administration of sildenafil into the left lateral ventricle of conscious rats elicited a marked increase in the lumbar sympathetic activity associated with tachycardia but no change in the arterial pressure.1 The intracerebroven- tricular administration of sildenafil may have produced sympathetic overactivity in the spinal cord, thereby activat- ing sympathetic preganglionic neurons (SPNs) in addition to supraspinal areas, such as the rostral ventrola- teral medulla, circumventricular organs (subfornical organ, Copyright 2011 CLINICS – This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non- commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. organum vasculosum lamina terminalis, and area postrema) and hypothalamic sites controlling the sympathetic drive.2-5 Thus, the increase in lumbar sympathetic activity and tachycardia observed in conscious rats following the administration of sildenafil into the left lateral ventricle may be explained by an effect in the spinal cord that is probably mediated by SPN activation.1 Therefore, in order to test the hypothesis that sildenafil is able to directly activate the SPNs and cause a hemodynamic response, the first goal of the present study was to examine, in conscious rats, the effects of sildenafil on the mean arterial pressure (MAP) and heart rate (HR) following intrathecal adminis- tration. Sildenafil increases intracellular cGMP levels via inhibition of phosphodiesterase type 5 (PDE5).6-11 Moreover, sildenafil can inhibit other phosphodiesterases, including those that preferentially degrade cGMP, cAMP, or both depending on the dose. The inhibition of phosphodiesterases leads to an 1407