Name: ANTONIO MARCOS BIROCALE

Publication date: 19/11/2019
Advisor:

Name	Role
NAZARE SOUZA BISSOLI	Advisor *

Examining board:

Name	Role
ALESSANDRA SIMAO PADILHA	Internal Examiner *
BRENO VALENTIM NOGUEIRA	External Examiner *
CARMEM LUIZA SARTORIO	Internal Examiner *
NAZARE SOUZA BISSOLI	Advisor *

Summary: Telmisartan is a type I angiotensin receptor blocker and a partial PPARγ agonist that have been used to treat hypertension. PPARγ activation is known to act inducing boné loss. The aim of the present study was to evaluate two distinct interventions: use of telmisartan or treadmill running, under bone mineral density, bone microarchitecture, and the mechanical properties in the femur of spontaneously hypertensive rats. Three-month-old rats were ovariectomized (OVX) or SHAM operated were distributed into 06 groups: 1) sedentary SHAM (SS); 2) SHAM using telmisartana (ST); 3) SHAM exercised (SE); 4) sedentary castrated (CS); 5) OVX using telmisartana (CT) and; 6) OVX exercised (EC). Treatment with telmisartan or vehicle substance were performed by oral gavage for 8 weeks. Blood pressure measures were taken and, after euthanasia, bones (femur and a fifth lumbar vertebra) were analyzed by dual energy X-ray and/or computed microtomography. Protein expression levels of PPARγ were measured in the femur by western blotting. Results showed that blood pressure was reduced in both groups of animals using telmisartan, with a greater reduction in values in the CT group compared to the ST group. Final body weight, heart weight, and ratio of heart weight to tibial length were also reduced by 8-week drug use when compared to their respective controls. Regarding biometric and biomechanical parameters there were reduction in femur size, reduction in maximum load, stiffness and reduction in resilience and fracture load. Bone mineral density decreased in both total femur and fifth lumbar vertebra in animals treated with telmisartan. Bone parameters related to the integrity of trabecular microarchitecture by microtomography also deteriorated by the use of telmisartan in OVX rats groups. Protein expression levels of PPARγ were increased by ovariectomy alone and by treatment with telmisartana. Considering the effects of exercise practice, main results indicated a reduction in blood pressure in both groups of exercised animals. Final body weight was increased while uterus weight was reduced by ovariectomy per se, and exercise did not have influenced this result. Heart weight, tibial length and ratio heart weight were increased by physical activity. As for biometric and biomechanical modifications, there was an increase in maximum strength, and a reduction in stiffness and resilience. There was also an increase in femur size in castrated and exercised rats when compared to SHAM rats. Few changes in physical parameters of femur and tibia were affected by exercise. Regarding mineral
density on femur and fifth lumbar vertebra, exercise was able to restore losses caused by castration itself. Microarchitectural parameters in general were also improved by physical activity. Results showed that the use of telmisartan in ovariectomized rats negatively impairs microarchitecture due to a reduction in bone mass and deterioration of trabecular structure. The treadmill physical activity had a positive impact to modify the organization of the evaluated bones. Thus, our findings suggested caution in the possible therapeutic applications of telmisartan in clinical practice, in order to protect bone health under hypertensive conditions. Moreover, running-type physical exercise seems to be an effective way to stimulate the maintenance of bone health. Further studies are needed to clarify the mechanisms by which telmisartan favors bone loss in these models.

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