Hemodynamic response to intrathecal sildenafil Bombarda G et al. CLINICS 2011;66(8):1407-1411 Figure 2 - Time course of the mean arterial pressure (D MAP) and heart rate (D HR) following the intrathecal administration of different doses of the cGMP analog 8-bromo-cGMP or the vehicle (DMSO). of sildenafil require a longer time to achieve the effective concentration required for the activation of SPNs located deep inside the spinal cord. In fact, an increase in sympathetic activity has been observed in humans after only a single dose of sildenafil.20,21 In addition, a study recently conducted in our laboratory1 has indicated that the intracerebroventricular administration of sildenafil in rats causes a noticeable increase in lumbar sympathetic activity without an accompanying change in the MAP. To fully understand the implications for human health, the hemodynamic effects caused by the intrathecal admin- istration of sildenafil in conscious rats observed in this study necessitate comparison with similar studies in humans. In a study by Philips et al.20 in which healthy males received oral sildenafil, sildenafil had no effect on the MAP and HR but did elicit a significant increase in muscle sympathetic nerve activity. Despite the absence of hemodynamic changes (arterial pressure and heart rate), the findings of the previous researchers20 demonstrate that sildenafil was able to promote sympathetic activation. However, a study recently conducted by our laboratory1 demonstrated that intracerebroventricular administration of sildenafil (100 mg/ 5 mL) results in a noticeable increase in lumbar sympathetic activity without an accompanying change in the MAP. This contrasts with the significant tachycardia observed in the aforementioned Philips study.20 In the current study, the MAP and HR were unaffected by the intrathecal administration of increasing doses of 8- bromo-cGMP. Conversely, Malik et al.16 performed intrathe- cal administration of 8-bromo-cGMP in anesthetized rats, with the same doses used in the present study, and observed a dose-dependent increase in the MAP. However, it should be noted that the results of the current study were obtained using conscious rats, without the use of anesthesia and its associated detrimental effects. One possible explanation for the absence of any cardiovascular effects following the 8-bromo-cGMP injection is that this compound can act directly on high conductance potassium channels in the cell membrane, thereby promoting hyper- polarization of the cell and decreasing their excitability.22 Therefore, the possible excitatory effect of 8-bromo-cGMP could be antagonized by its direct action on potassium channels, masking any possible activation of SPNs and blunting the hemodynamic response. Finally, it is reason- able to hypothesize that the increase in the MAP and HR caused by the intrathecal administration of sildenafil are not mediated by cGMP. There is evidence that sildenafil can interfere with cAMP activity and inhibit the activity of other PDEs.12-15 It is well known that drug selectivity, dose and route of administration, distribution, pharmacokinetics and the extent of activation of the NO-cGMP pathway are important mechanisms determining the functional role of sildenafil.23 Bischoff12 observed that sildenafil has different inhibitory activity against the 11 families of PDEs. It is possible that the dose of sildenafil used in the present study inhibited not only PDE5 but also other PDEs, including those PDEs that preferentially degrade cGMP, cAMP, or both. Therefore, the additional treatments used in the current study aimed to verify a possible role of cAMP in the hemodynamic response promoted by sildenafil. To accomplish this, the rats were intrathecally injected with a direct activator of adenylate cyclase (forskolin) or a membrane-permeable analogue of cAMP (dibutyryl- cAMP). The intrathecally injected forskolin had no effect on the MAP but increased the HR. However, the intrathe- cally injected dibutyryl-cAMP increased the MAP and the HR, an effect similar to sildenafil, suggesting that cAMP may be involved in the mechanism underlying the Figure 3 - Time course of the mean arterial pressure (D MAP) and heart rate (D HR) following the intrathecal administration of an adenylate cyclase agonist (forskolin), a cAMP analog (dibutyryl-cAMP) or the vehicle (DMSO). *p,0.05 compared to DMSO. 1410