Banca de QUALIFICAÇÃO: JESSYKA CAROLINA GALVÃO DA SILVA
Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.STUDENT : JESSYKA CAROLINA GALVÃO DA SILVA
DATE: 25/11/2021
TIME: 15:00
LOCAL: On line (meet)
TITLE:
CARDIOVASCULAR EFFECTS OF AAL 195, AN INHIBITOR OF PHOSPHODIESTERASE 4 IN SPONTANEOUSLY HYPERTENSIVE RATS
KEY WORDS:
AAL 195. Hypertension. Phosphodiesterase 4 Inhibitors. Spontaneously Hypertensive Rats. Vasodilation.
PAGES: 106
BIG AREA: Ciências Biológicas
AREA: Farmacologia
SUBÁREA: Farmacologia Cardiorenal
SUMMARY:
Hypertension is a disease with high prevalence and represents one of the main risk factors for cardiovascular disease. 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. Phosphodiestarases (PDE), enzymes that hydrolyze 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. Therefore, the objective of this work is to evaluate the actions of the PDE4 inhibitor, AAL 195, on the cardiovascular system of hypertensive rats. For this purpose, male spontaneously hypertensive rats (SHR) were used for all experiments, under CEUA-UFAL approval. Cardiovascular effects induced by AAL 195 were assessed by direct measurement of blood pressure and superior mesenteric artery preparations. Thus, in non-anesthetized SHR rats, AAL 195 (0.1; 0.5, 1 and 5 mg/kg, iv) induced hypotension (-24.6±1.7; -28.5±2.1; -28.9±4.6; -40.9±3.8%, respectively) associated with tachycardia (7.8±2.5; 13.4±3.7; 10.9±3.3; 12.1±3.8%, respectively), in a dose-independent manner. The hypotensive (-44.7±3.5 %) and tachycardic (34.5±5.7%) effects were also observed after administration of the ED50 of AAL 195 (1.48 mg/Kg, i.v.). In rats treated with atropine (2 mg/kg, i.v.), the hypotensive effect was not altered. However, there was a significant attenuation of tachycardia (5.2 ± 0.7%). This suggests that the hypotensive and tachycardic effects are independent. Treatment with L-NAME (20 mg/kg, iv) or indomethacin (3 mg/kg, iv) did not alter the hypotensive or tachycardic response. However, in rats treated with nifedipine (1 mg/kg, iv), the hypotensive (-27.0±3.5 %) and tachycardic (7.6±3.8 %) effects were significantly attenuated, suggesting the participation of L-type voltage-sensitive Ca2+ channels in these effects. In superior mesenteric artery rings of SHR rats, AAL 195 (10-9 – 3x10-5 M) promoted vasorelaxation in rings pre-contracted with phenylephrine (10 µM) (Emax = 100.0 ± 5.15%, pD2 = 6 .65 ± 0.08 M) in a concentration-dependent manner. After removal of the endothelium, the AAL 195 concentration-response curve was shifted to the right (pD2 = 6.25±0.05 M), without changing the maximum effect (Emax = 95.50±1.54%). In preparations without endothelium, incubated with 5mM of TEA, the vasorelaxation was attenuated (Emax = 81.05±4.91 %), indicating a possible participation of K+ channels in this effect. In preparations pre-incubated with GLIB (10 µM) or with 4-AP (1 mM), the vasorelaxant effect was potentiated, and the presence of apamine (0.1 µM) did not alter this effect. However, in the presence of 1 mM TEA, vasorelaxation was attenuated (Emax = 85.71±3.73 %), probably there is a participation of BKCa in this effect. AAL 195 (3x10-8 – 10-3 M) was also able to promote vasorelaxation in rings pre-contracted with 80 mM of KCl, which demonstrates a nonspecific effect of the compound. Therefore, AAL 195 was able to promote hypotensive and vasorelaxant effects in SHR. However, it also promoted a tachycardic effect, probably due to the inhibition of PDE4 in cardiomyocytes.
BANKING MEMBERS:
Presidente - 1547952 - EURICA ADELIA NOGUEIRA RIBEIRO
Interno - 1974414 - OLAGIDE WAGNER DE CASTRO
Externo ao Programa - 1811274 - HUGO JUAREZ VIEIRA PEREIRA
Externa ao Programa - 3509820 - MARIA ALINE BARROS FIDELIS DE MOURA