Role of cGMP and cAMP in the hemodynamic response to intrathecal sildenafil administration

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.

Aspectos farmacológicos dos inibidores da ECA e dos receptores de angiotensina II / Pharmacological aspects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers

Drogas que interferem com o sistema renina-angiotensina, como inibidores da enzima conversora de angiotensina (ECA), estão disponíveis por mais de 20 anos. Estas drogas são atualmente reconhecidas como muito efetivas no tratamento de pacientes com hipertensão, insuficiência cardíaca, nefropatia diabética ou pacientes com alto risco cardiovascular. O recente desenvolvimento de antagonistas seletivos para os receptores de angiotensina II (Ang II) levou a uma melhora significativa na tolerabilidade deste grupo de drogas, embora mantenha alta eficácia clinica. Nesta revisão, trataremos de destacar os mecanismos de ação e os principais efeitos farmacológicos dos inibidores da ECA e dos antagonistas de receptor de Ang II