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Effects of ACE inhibition and bradykinin antagonism on cardiovascular changes in uremic rats
K Amann1, P Gassmann, M Buzello
1Departments of Pathology, Heidelberg, Erlangen, Germany. kerstin.amann@patho.imed.uni-erlangen.de
Insights
Bradykinin mediates the cardiovascular benefits of angiotensin-converting enzyme (ACE) inhibitors like Ramipril in uremic rats. Blocking bradykinin receptors negates Ramipril
Area of Science:
- Cardiovascular research
- Renal failure pathophysiology
- Pharmacology
Background:
- Cardiovascular mortality is a significant concern in patients with renal failure.
- Structural heart and vascular abnormalities increase cardiovascular risk in renal failure.
- Angiotensin-converting enzyme (ACE) inhibitors improve cardiovascular outcomes, but the precise mechanisms, including the role of bradykinin versus angiotensin II, remain unclear.
Purpose of the Study:
- To investigate the potential role of bradykinin in mediating the cardiovascular protective effects of ACE inhibitors.
- To determine if bradykinin receptor antagonism affects the structural changes in the heart and vasculature associated with renal failure.
Main Methods:
- Subtotally nephrectomized (SNX) rats were treated with Ramipril (an ACE inhibitor), Hoe140 (a bradykinin B2 receptor antagonist), or a combination.
- Treatment was administered either early (day 3 post-SNX) or late (week 4 post-SNX) to assess prevention and reversal of structural changes.
- Cardiac hypertrophy (left ventricular weight) and aortic wall thickness were assessed using morphometric and stereologic techniques.
Main Results:
- Ramipril significantly reduced cardiac hypertrophy and aortic wall thickening in SNX rats, an effect completely blocked by Hoe140.
- Hoe140 alone exacerbated cardiac structural changes (increased intercapillary distance) in SNX rats.
- Neither Ramipril nor Hoe140 modified the wall-to-lumen ratio of intramyocardial arterioles or intercapillary distance in the heart.
Conclusions:
- Bradykinin plays a crucial role in the beneficial cardiovascular structural effects of Ramipril in uremic hypertensive rats.
- The protective effects of ACE inhibition on cardiac and vascular remodeling in this model are, at least in part, mediated through the bradykinin system.
Background:
Cardiovascular death continues to be a major problem in renal failure. Structural abnormalities of the heart and the vasculature contribute to the increased cardiovascular risk. They are ameliorated by angiotensin-converting enzyme (ACE) inhibitors, but because of the nonspecifity of ACE inhibition, it is uncertain whether the beneficial effect is mediated by interfering with angiotensin II (Ang II) or by modulating other effector systems, for example, bradykinin.
Methods:
To assess a potential role of bradykinin, subtotally nephrectomized Sprague-Dawley rats (SNX) received either the ACE inhibitor Ramipril (Rami, 0.2 mg/kg body weight p.o.), the specific B2 bradykinin receptor antagonist Hoe140 (0.2 mg/kg body weight, s.c.), or a combination of both, and were compared to sham-operated controls. To separately assess the effect of Ramipril on development and reversal of structural abnormalities, animals were either treated from the third day after SNX or from the fourth week after SNX onward (0.01 mg/kg body weight, p.o.).
Results:
Heart and aorta were evaluated by morphometric and stereologic techniques. The weight of the perfused left ventricle, as an index of cardiac hypertrophy, was significantly higher in untreated SNX. While it was significantly lower in animals with early and late Ramipril treatment, the beneficial effect was completely antagonized by Hoe140. The wall-to-lumen ratio of intramyocardial arterioles was significantly higher in untreated SNX compared with controls, but failed to be modified by administration of either Ramipril or Hoe140. In the heart, the intercapillary distance was significantly higher in SNX, but it was not lowered by either early or late Ramipril or Hoe140 treatment. Treatment of SNX with Hoe140 alone, however, resulted in a marked further increase in intercapillary distance. The wall thickness of the aorta was significantly higher in SNX than in controls; early and late Ramipril treatment prevented such increase, and this effect was antagonized by Hoe140.
Conclusion:
These findings illustrate that bradykinin plays an important role for the beneficial effect of Ramipril in preventing (and potentially reversing) abnormal cardiovascular structure in uremic hypertensive rats.