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Comparative Effects of Low and High Doses of ACE Inhibitors in Heart Failure
Background on ACE Inhibitors and Heart Failure
Angiotensin-converting enzyme (ACE) inhibitors are commonly used to manage heart failure by reducing morbidity and mortality. However, the optimal dosing of these inhibitors remains a topic of investigation. A study involving 3164 patients with chronic heart failure compared the effects of low doses (2.5 to 5.0 mg daily) and high doses (32.5 to 35 mg daily) of the ACE inhibitor lisinopril over a period of 39 to 58 months. The findings indicated that high doses significantly reduced the risk of death or hospitalization and decreased hospitalizations for heart failure, although they also increased the incidence of dizziness and renal insufficiency.
Role of Tissue-Bound ACE in Blood Pressure Regulation
Research using genetically modified mice has highlighted the critical role of tissue-bound ACE in maintaining blood pressure. Mice expressing a modified form of ACE that is secreted rather than tissue-bound exhibited low blood pressure, renal vascular thickening, and urine concentrating defects. These findings underscore the importance of tissue-bound ACE in blood pressure control and kidney function.
ACE Inhibitory Peptides from Chicken Collagen
Studies have identified ACE-inhibitory peptides derived from chicken collagen hydrolysate. These peptides demonstrated significant ACE-inhibitory activity and effectively reduced blood pressure in hypertensive rats. This suggests potential therapeutic applications for these peptides in managing hypertension.
Gene-Environment Interaction in ACE Inhibition
The response to ACE inhibitors can be influenced by genetic factors and environmental conditions such as sodium intake. In a study involving healthy volunteers, the ACE-DD genotype was associated with a blunted response to ACE inhibition under high sodium conditions. However, this resistance was mitigated under low sodium conditions, indicating a gene-environment interaction that could inform personalized treatment strategies.
ACE2-Independent Actions of Presumed ACE2 Activators
Compounds like XNT and diminazene, previously thought to activate ACE2, were found to exert blood pressure-lowering effects independent of ACE2 activity. This suggests that their beneficial effects in hypertension may be mediated through other mechanisms.
Antiatherosclerotic Effects of ACE Inhibitors
The ACE inhibitor fosinopril has been shown to reduce atherosclerosis in apolipoprotein E deficient mice. This effect was attributed not only to blood pressure reduction but also to the inhibition of LDL oxidation, highlighting the multifaceted benefits of ACE inhibitors in cardiovascular protection.
Screening for ACE Inhibitors Using HPLC-ESI-QqQ-MS
A high-performance liquid chromatography-electrospray ionization triple quadrupole mass spectrometry (HPLC-ESI-QqQ-MS) method has been developed for identifying ACE inhibitors. This method allows for rapid and sensitive detection of ACE inhibitory activity, facilitating the discovery of new therapeutic agents.
Conversion of Angiotensin II to Angiotensin-(1-7)
The conversion of Angiotensin II to Angiotensin-(1-7) in the circulation is primarily dependent on prolyloligopeptidase (POP) rather than ACE2. This finding has implications for understanding the enzymatic pathways involved in the renin-angiotensin system and their roles in blood pressure regulation.
Urinary ACE in Hypertensive Patients
Analysis of ACE activity in the urine of hypertensive patients revealed the presence of ACE forms resembling the N-terminal fragment of the enzyme. These forms may play a role in the development of hypertension and could serve as biomarkers for the condition.
Renal ACE and Hypertension
The presence of ACE in renal tissue is essential for the development of hypertension induced by nitric oxide synthesis inhibition. Mice lacking renal ACE did not develop hypertension under these conditions, highlighting the importance of renal ACE in sodium retention and blood pressure regulation.
Conclusion
The research underscores the complexity of ACE inhibitor therapy, highlighting the importance of dosing, genetic factors, and tissue-specific actions. These insights can guide more effective and personalized approaches to managing hypertension and heart failure.
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