Efeitos do losartan e espironolactona sobre a estrutura e função do coração de ratos espontaneamente hipertensos

Sérgio Lamêgo Rodrigues

Background: The clinical syndrome of heart failure is the final pathway for myriad diseases that affect the heart, mainly ischemic heart disease and hypertension. Left ventricular hypertrophy is accompanied by a structural remodeling that includes myocyte hypertrophy and interstitial fibrosis. These structural abnormalities related to fibrosis lead to increased diastolic stiffness. It has been reported that renin-angiotensin-aldosterone system has an important regulatory role in this condition. Study purpose: To evaluate weather SHRs treated with losartan (AT1 receptor blocker) and spironolactone (mineralocorticoid receptor blocker) reverse left ventricular hypertrophy and/or stiffness. Methods: 12 weeks old male Wistar-Kyoto and SHRs, were studied. The SHRs were divided in 5 groups: S-Con = control group. S-Los = treated with losartan (8 mg/Kg/day); S-E20 = treated with spironolactone (20 mg/Kg/day); S-Los+E20 = treated with losartan plus spironolactone (8 mg/Kg e 20 mg/Kg/day) respectively; S-E80 = treated with spironolactone (80 mg/Kg/day). Transthoracic echo Doppler studies were performed after six weeks treatment with a commercially available echocardiograph equipped with a 10 MHz transducer (Esaote). Animals from groups S-Con, S-Los, S-E20 e S-E80 were anesthetized with intraperitoneal injection of Ketamine HCl (50 mg/Kg) plus xylazine (5,0 mg/Kg). Awaken rats from these groups had their blood pressure and heart rate recorded thru a catheter put in abdominal aorta via femoral artery cannulation. Hemodynamic studies were performed in all rats, after been anesthetized with intraperitoneal injection of chloral hydrate (40 mg/kg), during spontaneous respiration. After data collection, the heart was arrested in diastole with potassium chloride. The heart was exposed and, in situ, the passive pressure-volume characteristics of left ventricle were recorded. Afterwards, the ventricles and lungs were excised, dried and weighed. Results: In awaken animals, we didnt find differences in mean blood pressure, except for a tendency to a lesser value in the S-Los and S-E80 when compared to S-Con (159 4 e 1615 vs 177 6 mmHg) respectively. Nevertheless, the systolic blood pressure were significantly reduced in S-Los and S-E80 when compared to S-Con e S-E20 (197 6; 200 5 vs 228 5 e 210 7 mmHg) respectively; P <0,05. Echocardiography Doppler measurements in S-Los compared to S-Con showed a significantly reduced internal diameter of left atrium (3,36 0,16 vs 4,34 0,05 mm) respectively P <0,05 and also a decreased final left ventricle diastolic and systolic diameters (7,40 0,31 vs 8,88 0,41 mm and 3,68 0,36 vs 4,58 0,092 ) respectively, P <0,05. Echocardiographic estimates of left ventricular mass had a fair correlation with pathologic measurements (r= 0,73). Left ventricular mass in S-Los was decreased when compared to other groups, but significantly to S-Con. Mitral E/A ratio and IVRT (isovolumic relaxation time) were significantly increased in S-E80 when compared to S-Con e S-E20. The E/A ratio was (2,44 0,07 vs 2,00 0,15 e 2,020,08 respectively), P <0,05. The IVRT was (40,80 1,89 vs 27,80 2,34; 34,60 2,02; 36,00 3,90), respectively P<0,05. In the losartan treated groups (S-Los and S-Los+E20), the left ventricle/body weight ratio was significantly lower when compared to S-Con (2,5 0,05 e 2,6 0,06 vs 3,0 0,1 mg/g) respectively, P<0,05. The modifications in myocardial rigidity are easily detected, observing the shifts in the pressure-volume curve (P/V). Compared to WKY, there is a remarkable shift in the curve to the left in group S-Con. The stiffness constant (K) in S-Con is significantly increased when compared to WKY (K= 6,28 1,6 vs 3,4 2,1 mmHg/μL) respectively P <0,05. Treatment with losartan (S-Los) promotes a rightward shift in the curve and a lower stiffness constant when compared to S-Con (K=4,28 1,7 vs 6,28 1,6 mmHg/μL) albeit, not significantly. Nevertheless, these effects were incremented and became significant (compared to S-Con), when spironolactone (20 mg/Kg/day) was added to losartan (SLos+E20), (K= 3,63 0,87 vs 6,28 1,6 mmHg/μL) respectively, P <0,05. Treatment with spironolactone (80 mg/Kg/day) shifts the curve to the right as far as the curve of the WKY group. The S-E80 and WKY stiffness constant are practically similar (3,53 1,7 and 3,4 2,1 mmHg/μL) respectively. But, when compared to S-Con, the stiffness constant of S-E80 and WKY were significantly lower, (K= 6,28 1,6 vs 3,53 1,7 and 3,4 2,1 mmHg/μL) respectively, P <0,05. Conclusion: In SHRs, treatment with spironolactone monotherapy- (80 mg/Kg/day) and/or (20 mg/Kg/day) associated with losartan, induces a better left ventricular compliance, regardless of changes in hemodinamics or left ventricular mass. Therefore these results suggest a possible effect of aldosterone in myocardial stiffness. Furthermore, aldosterone antagonist associated with AT1 blockers in treatment of heart failure, hypertension or other cardiovascular disorder taxed by increased myocardial fibrosis, could be beneficial

Efeitos do losartan e espironolactona sobre a estrutura e função do coração de ratos espontaneamente hipertensos

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