Efeitos cardiovasculares de AAL 195, um inibidor de fosfodiesterase 4, em ratos espontaneamente hipertensos

Abstract

Introduction: Hypertension is a disease with high prevalence and represents one of the main risk factors for cardiovascular diseases. Despite the antihypertensive drugs available, many hypertensive patients do not reach ideal blood pressure levels, demonstrating the need to search for more effective pharmacological agents. Phosphodiesterases (PDE), enzymes that hydrolyze the cyclic binding of cAMP and cGMP, are widely distributed in the cardiovascular system. Inhibitors of these enzymes have been shown to be useful in the therapy of diseases of multifactorial origin, such as hypertension. Objective: To evaluate the actions of the PDE4 inhibitor, AAL 195, on the cardiovascular system of hypertensive rats. Methods: Male SHR rats were used for all experiments. The cardiovascular effects induced by AAL 195 were evaluated through direct measurement of blood pressure and superior mesenteric artery preparations. Results: In non-anesthetized SHR rats, i.v. in bolus AAL 195 induced hypotension associated with tachycardia, in a dose-independent manner. After treatment with nifedipine, the hypotensive and tachycardic effects were attenuated, suggesting the participation of L-type Ca2+ channels (Cav-L) in these effects. The treatment with propranolol was not able to change the hypotensive effect, however, the tachycardic effect was attenuated. It is known that PDE4D3 inhibition in cardiomyocytes is capable of activating Cav-L, as well as modulating β2-adrenergic responses. Therefore, it is suggested that the tachycardic effect is mediated by a direct inhibition of cardiac PDE4. The subacute effects of AAL 195 were evaluated after its administration via the orogastric route. Thus, it was observed that the compound promoted antihypertensive activity at the dose of 10 mg/kg. In superior mesenteric artery rings from SHR rats, AAL 195 promoted vasorelaxation in rings pre-contracted with PHE in a concentration-dependent manner. After removal of the endothelium, there was a shift in the concentrationresponse curve to the right, with no change in the maximum effect. In preparations without endothelium, incubated with TEA (5 mM or 1 mM), vasorelaxation was attenuated, revealing the involvement of K+ channels, more precisely BKCa. In rings pre-contracted with 80 mM KCl, AAL 195 promoted a vasorelaxant effect, suggesting inhibition of Ca2+ influx through VOCCs. This hypothesis was confirmed by the attenuation of contractions induced by CaCl2 in depolarizing solution nominally without Ca2+ and by vasorelaxation promoted by AAL 195 in rings pre-contracted with S(-)-Bay K 8644, an activator of Cav-L. AAL 195 attenuated transient contractions induced by PHE in Ca2+ -free medium, indicating inhibition of Ca2+ release through IP3R. In preparations pre-incubated with KT 5720, the vasorelaxation of AAL 195 was also attenuated, revealing a possible activation of PKA by AAL 195. Conclusion: AAL 195 was able to promote hypotensive, vasorelaxant and antihypertensive effects in SHR rats. However, it also promoted a tachycardic effect, probably due to PDE4 inhibition in cardiomyocytes. Studies with AAL 195 reveal significant cardiovascular effects, characterizing a molecule with great potential as an antihypertensive drug, as well as a potent pharmacological tool.