Modulation of haemodynamics, endogeneous antioxidant enzymes, and pathophysiological changes by selective inhibition of angiotensin II type 1 receptors in pressureoverload rats.

BACKGROUND: Constriction of the thoracic or abdominal aorta provides an experimental model of pressure-overload cardiac hypertrophy. Blockade of AT1 receptors is beneficial in preventing target-organ damage in hypertension. OBJECTIVE: To examine the effect of angiotensin II receptor antagonists on blood pressure, endogenous antioxidant enzyme and histopathological changes in pressure-overload rats. METHODS: Pressure overload was produced by abdominal aortic banding (AAB) using a blunt 22-guage needle in male rats as a model of cardiac hypertrophy. After surgery, the AAB-induced hypertension (AABIH) rats were treated with losartan 40 mg/kg/day, candesartan 10 mg/kg/day, irbesartan 10 mg/kg/day per os for 16 weeks. At 16 weeks of surgery, the rats were observed for general characteristics and mortality, and we determined non-invasive blood pressure (NIBP), endogenous antioxidant enzyme catalase and superoxide dismutase (SOD) activities, and histology of the target organs. RESULTS: In the AABIH group, significant increase in systolic blood pressure was observed from weeks 3 to 16 compared with the control group, along with reduced serum catalase and SOD activities. The treated groups showed significant reduction in systolic BP and increase in serum SOD and catalase activities. The histological changes induced in the target organs, namely heart, liver, kidneys and thoracic aorta in the AABIH rats were attenuated in the treated rats. CONCLUSION: Blockade of the AT1 receptor caused an improvement in the myocardial antioxidant reserve and decreased oxidative stress in the hypertensive rats, which was evidenced by the protection observed in the treatment groups.

Modulation of hemodynamics, endogenous antioxidant enzymes, and pathophysiological changes by Angiotensin-converting enzyme inhibitors in pressure-overload rats.

INTRODUCTION: We sought to assess the role of angiotensin-converting enzyme (ACE) inhibitors on systolic blood pressure (BP), endogenous antioxidant enzymes and histopathological changes in pressure-overload rats. METHODS: Pressure overload was produced in male rats by abdominal aortic banding (AAB) using a blunt 22-gauge needle, as a model of cardiac hypertrophy. After surgery, AAB-induced hypertensive (AABIH) groups were treated with captopril 4 mg and ramipril 10 mg/kg per day p.o. for 16 weeks. At 16 weeks, rats were observed for general characteristics and mortality, non-invasive blood pressure (NIBP) and endogenous antioxidant enzyme catalase and superoxide dismutase (SOD) activity and histological evaluation of target organs. RESULTS: In the AABIH group a significant increase in systolic BP was observed in week 3 (149.3 ± 0.821) and persisted until week 16, along with lower levels of serum catalase (144.7 ± 2.204) and SOD (12.92 ± 0.4601) activity compared to the control group. Captopril and ramipril treated groups showed a significantly smaller increase in systolic BP (25.47 ± 3.685, 20.21 ± 3.306) and greater serum SOD (27.33 ± 2.338, 28.95 ± 1.143) and catalase (181.7 ± 8.407, 187.9 ± 8.497) activity, respectively, than the hypertensive rats. The histological changes induced in target organs (heart, liver, kidneys and thoracic aorta) in AABIH rats were attenuated in treated rats. CONCLUSIONS: ACE-inhibition causes an improvement in myocardial antioxidant reserve, reduces oxidative stress, and prevents pathophysiological alterations, while showing a trend for potential target organ protection in hypertensive rats.

Therapeutic class-specific signal detection of bradycardia associated with propranolol hydrochloride.

BACKGROUND: Propranolol hydrochloride, one of the most widely used beta-blocker in the treatment of hypertension since 1960s, shows a number of serious and non-serious adverse events. OBJECTIVE: Major objectives of this study were to extract the Canadian Adverse Drug Reaction Monitoring Program (CADRMP) database for possible toxic signal detection (SD) of propranolol hydrochloride, evaluate the frequency of the bradycardia associated with it in different stratified groups for a putative signal, and generate awareness in healthcare professionals regarding usefulness of SD. MATERIALS AND METHODS: Appropriate statistical methods were used for adverse drug reaction (ADR) signal detection such as, proportional reporting ratio (PRR); reporting odds ratio (ROR); the Chi-square (chi(2)) statistic method; the 95% confidence interval (CI); the observed to expected ratio (O/E); and Du Mouchel method were used to calculate the possible signals. Significance of chi(2) and other calculated statistics, e.g., PRR and ROR, was based on a composite criterion of regulatory guidelines and not on any particular statistical level of significance. RESULTS: Calculated statistics by different methods were compared with the regulatory criteria of a statistic value >/=4.0 for chi(2), and >/=3.0 for the rest for SD to be declared significant. The PRR statistic was found to be 2.5054; by the ROR method it was 2.5820; the chi(2) statistic was 3.2598, whereas the lower and upper limits of 95% CI of PRR were found to be 0.0778 and 1.9104, respectively, by the O/E ratio was found to be 2.3978, and PRR with the help of Du Mouchel was found to be 2.3979. Thus, the bradycardia-propranolol signals calculated in this study were not significant. CONCLUSIONS: The therapeutic class specific signal of bradycardia associated with propranolol hydrochloride was not found potent enough to cause bradycardia. However, since the calculated statistics were very high albeit not significant, the possibility of bradycardia-propranolol pairing should still be analyzed from larger databases.