Efeitos do tratamento com Composto 21 durante a gestação de ratas hipertensas no sistema cardiovascular da prole

Abstract

Hypertension is the main risk factor for developing other pathologies such as cardiac hypertrophy. Previous studies have shown that the AT2 receptor activation by Compound 21 (C21), an AT2 receptor agonist, promotes beneficial effects on the cardiovascular system. In addition, maternal exposure to beneficial factors proved important in mitigating or preventing the development of diseases in the offspring. Therefore, this study aimed to evaluate whether treatment with C21 during pregnancy in hypertensive rats could attenuate the development of hypertension and promote cardioprotective effects in the offspring. Spontaneously hypertensive rats (SHR) were treated with C21 (0.3 mg/kg/day, osmotic minipump) throughout the gestational period and females in the control group underwent the same surgical procedure but did not receive treatment. The systolic blood pressure was measured weekly by tail plethysmography between the 6th and 16th weeks of age. Cardiac function of the offspring was evaluated by echocardiography and the baroreflex and chemoreflex sensibility were assessed at 16 weeks old. Then, the animals were euthanized for evaluation of left ventricular function after ischemia and coronary reactivity by isolated heart preparation (Langendorff technique) and aortic vascular reactivity in the organ bath system. Samples of the left ventricle were collected for morphological and molecular analyses. Systolic blood pressure of the SHR C21 was lower than the control group from the 6th to the 16th week, without changes in heart rate. The experimental group showed greater baroreflex sensitivity (SHR -0.3530 ± 0.06 vs. SHR C21 -0.6594 ± 0.10 Δbpm/ΔmmHg, P<0.05). Echocardiographic parameters were not different between groups. The time of ischemia-reperfusion arrhythmia in isolated hearts was significantly reduced in the experimental group (SHR, 87.60 ± 34.13 vs. SHR C21, 5.66 ± 4.91 seconds, P<0.05). Coronary vasodilation in response to bradykinin was improved in the treated group (SHR, -2.87 ± 1.25 vs. SHR C21, -12.96 ± 3.28 %, P<0.05). However, aortic vascular reactivity was not different between groups. Maternal treatment with C21 reduced cardiomyocyte area (SHR, 396.9 ± 6.33 vs. SHR C21, 320.5 ± 6.44 μm2, P<0.05), and interstitial (SHR, 15.93 ± 0.85 vs. SHR C21, 8.92 ± 0.49 %, P<0.05) and perivascular fibrosis (SHR, 1.93 ± 0.14 vs. SHR C21, 1.18 ± 0.13 μm2, P <0.05) in left ventricles of offspring. Nuclear factor of activated T-cells (NFAT) total (SHR, 41,65 ± 3,49 vs. SHR C21, 27,01 ± 2,72 a.u., P<0,05) and nuclear (SHR, 3,09 ± 0,23 vs. SHR C21, 1,01 ± 0,13 a.u., P<0,05) expression was lower in the treated group. The expression of proteins involved in pathways related to pathological cardiac remodeling was not different between the groups. The expression of AT1 and AT2 receptor proteins in the heart was also not altered by maternal treatment. These results demonstrate that maternal treatment of spontaneously hypertensive rats during pregnancy with C21 can attenuate the development of hypertension and promote cardioprotective effects in the offspring. These data suggest that AT2 receptor activation during pregnancy may be a potential therapeutic strategy for the prevention of cardiovascular disorders in offspring.