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Angiotensin-converting enzyme inhibition improves cardiac function. Role of bradykinin
P Gohlke1, W Linz, B A Schölkens
1Department of Pharmacology, Christian Albrechts University of Kiel, Germany.
Insights
Ramipril, an ACE inhibitor, prevents hypertension and heart issues in rats. Its beneficial effects on cardiac function and metabolism are mediated by bradykinin potentiation, not just ACE inhibition.
Area of Science:
- Cardiovascular Pharmacology
- Renal Physiology
Background:
- Hypertension and left ventricular hypertrophy are significant cardiovascular risks.
- Angiotensin-converting enzyme (ACE) inhibitors are widely used to manage hypertension.
- The role of bradykinin potentiation in ACE inhibitor efficacy requires further elucidation.
Purpose of the Study:
- To investigate the effects of ramipril on hypertension and cardiac remodeling in stroke-prone spontaneously hypertensive rats.
- To determine the contribution of bradykinin potentiation to ramipril's actions.
- To assess ramipril's impact on cardiac function and metabolism.
Main Methods:
- Administration of low and high doses of ramipril to rats prenatally and postnatally.
- Co-treatment with a bradykinin B2-receptor antagonist (Hoe 140) to block bradykinin potentiation.
- Assessment of blood pressure, cardiac hypertrophy, cardiac function (left ventricular pressure, dP/dtmax), and cardiac metabolism (enzyme activities, metabolite concentrations).
Main Results:
- High-dose ramipril prevented hypertension and left ventricular hypertrophy.
- Ramipril improved cardiac function and normalized cardiac metabolism, increasing glycogen and ATP levels while decreasing lactate.
- Bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism.
Conclusions:
- Ramipril effectively prevents hypertension and cardiac hypertrophy in a rat model.
- The beneficial cardiovascular and metabolic effects of ramipril are dependent on bradykinin potentiation.
- These findings highlight the importance of the bradykinin system in mediating ACE inhibitor therapy.
Abstract:
The effect of chronic low- and high-dose treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril (0.01 and 1 mg/kg per day) on the development of hypertension and left ventricular hypertrophy as well as on functional and biochemical alterations of the heart was studied in stroke-prone spontaneously hypertensive rats treated prenatally and subsequently up to the age of 20 weeks. The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment of rats with the bradykinin B2-receptor antagonist Hoe 140 (500 micrograms/kg per day SC) from 6 to 20 weeks of age. High- but not low-dose ACE inhibitor treatment prevented the development of hypertension and left ventricular hypertrophy. Chronic bradykinin receptor blockade did not attenuate the antihypertensive and antihypertrophic actions of ramipril. High-dose ramipril treatment improved cardiac function, as demonstrated by an increase in left ventricular pressure (29.9%), dP/dtmax (34.9%), and coronary flow (22.1%), without a change in heart rate. The activities of lactate dehydrogenase and creatine kinase and lactate concentration in the coronary effluent were reduced by 39.3%, 55.5%, and 66.7%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 31.3%, 39.9%, and 73.7%, respectively, whereas lactate was decreased by 20.8%. Chronic low-dose ACE inhibitor treatment led to a pattern of changes in cardiodynamics and cardiac metabolism similar to that observed with the high dose. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by chronic bradykinin receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)