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Possible protective effects of kinins and converting enzyme inhibitors in cardiovascular tissues
H Nolly1, R Miatello, M T Damiani
1Laboratory of Experimental Hypertension and Vasoactive Substances, School of Medicine and National Council of Research, Mendoza, Argentina.
Insights
The isolated rat heart continuously releases kallikrein-kinin system components. ACE inhibitor ramipril enhances bradykinin release and may normalize endothelial function in cardiac hypertrophy.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Biochemistry
Background:
- The kallikrein-kinin system (KKS) plays a crucial role in regulating blood pressure and vascular function.
- Dysregulation of the KKS is implicated in various cardiovascular diseases, including cardiac hypertrophy.
- ACE inhibitors are known to modulate the KKS, but their direct effects on cardiac KKS components require further investigation.
Purpose of the Study:
- To investigate the release of KKS components from isolated perfused rat hearts.
- To assess the impact of the ACE inhibitor ramipril on kinin release and breakdown.
- To examine the alterations in cardiac KKS activity in models of cardiac hypertrophy.
Main Methods:
- Isolated perfused rat heart model to measure KKS components in venous effluent.
- Radioimmunoassay (RIA) for quantifying cardiac kallikrein (CKK), kininogen, and kinins.
- Induction of cardiac hypertrophy via aortic banding and aortocaval shunt.
- Administration of ramiprilat and protein synthesis inhibitor puromycin.
Main Results:
- Isolated rat hearts continuously released CKK, kininogen, and kinins.
- Puromycin pretreatment significantly reduced CKK and kininogen release.
- Ramiprilat significantly increased kinin release, indicating reduced bradykinin breakdown.
- Cardiac hypertrophy models showed increased CKK levels, which were further elevated in ramipril-treated animals.
Conclusions:
- The isolated rat heart actively synthesizes and releases KKS components.
- Ramipril enhances bradykinin availability by inhibiting its degradation, suggesting a cardioprotective mechanism.
- Cardiac hypertrophy stimulates KKS activity, and ACE inhibitors may potentiate kinin's effects, potentially normalizing endothelial function.
Abstract:
The main objective of this study was to determine if the components of the kallikrein-kinin system are released into the venous effluent from isolated perfused rat hearts. To assess the contribution of kinins and the vascular and cardioprotective effects of the ACE inhibitor ramipril, we determined the status of cardiac kallikrein (CKK), potent kinin-generating enzyme, in rats with right ventricular hypertrophy induced by chronic volume overload and left ventricular hypertrophy by aortic banding. CKK was measured as previously described (Nolly, H.L., Carbini, L., Carretero, O.A., Scicli, A.G., 1994). Kininogen by a modification of the technique of Dinitz and Carvalho (1963) and kinins were extracted with a Sep-Pak C18 cartridge and measured by RIA. CKK (169 +/- 9 pg Bk/30 min), kininogen (670 +/- 45 pg Bk/30 min) and immunoreactive kinins (62 +/- 10 pg Bk/30 min) were released into the perfusate. The release was almost constant over a 120 min period. Pretreatment with the protein synthesis inhibitor puromycin (10 mg i.p.) lowered the release of kallikrein (42 +/- 12 pg Bk/30 min, p < 0.001) and kininogen (128 +/- 56 pg Bk/30 min, p < 0.001). Addition of ramiprilat (10 micrograms/ml) increased kinin release from 54 +/- 18 to 204 +/- 76 pg Bk/30 min (p < 0.001). Aortic banding of rats increased their blood pressure (BP) (p < 0.001), relative heart weight (RHW) (p < 0.001) and CKK (p < 0.001). Ramipril treatment induced a reduction in BP (p < 0.05) and RHW (p < 0.005) while CKK remained elevated. Aortocaval shunts increased their ANF plasma levels (p < 0.05), RHW (p < 0.001) and CKK (p < 0.01). Ramipril treatment induced a reduction in RHW (p < 0.05), while CKK and ANF increased significantly (p < 0.05). The present data show that the components of the kallikrein-kinin system are continuously formed in the isolated rat heart and that ramipril reduces bradykinin breakdown with subsequent increase in bradykinin outflow. The experiments with aorta caval shunt and aortic banding show that cardiac tissues increase their kinin-generating activity and this was even higher in ramipril-treated animals. This may suggest that the actual level of kinins is finely tuned to the local metabolic demands. In this experimental model of cardiac hypertrophy. ACE inhibitors potentiate the actions of kinins and probably try to normalise endothelial cell function.