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Vascular renin-angiotensin-system, endothelial function and atherosclerosis?
Insights
Sustained activation of the renin-angiotensin system increases heart attack risk. Blocking this system, particularly with angiotensin converting enzyme inhibitors, may protect against heart attacks and atherosclerosis.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Biochemistry
Background:
- The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulation.
- Sustained RAS activation is linked to an increased risk of myocardial infarction (MI).
- Nitric oxide (NO) has protective antiatherogenic effects on the vasculature.
Purpose of the Study:
- To investigate the proatherogenic effects of activated RAS.
- To explore the role of nitric oxide (NO) downregulation in RAS-mediated atherogenesis.
- To evaluate the potential of RAS blockade in preventing atherosclerosis and MI.
Main Methods:
- Review of clinical observations linking RAS activation to MI risk.
- Analysis of experimental evidence on RAS, NO, and atherosclerosis.
- Examination of the effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor type-1 (AT1) antagonists.
Main Results:
- Activated RAS, particularly via angiotensin II, downregulates endothelial nitric oxide (NO) releasability.
- Hypertension-induced arterial distension upregulates local RAS, further reducing NO.
- RAS blockade (ACE inhibitors, AT1 antagonists) normalizes NO releasability and attenuates experimental atherosclerosis.
Conclusions:
- Activated RAS contributes to atheroma development by reducing NO bioavailability.
- Chronic RAS blockade demonstrates antiatherogenic potential by restoring NO function.
- Further studies are needed to confirm the antiatherogenic benefits of RAS blockade in humans.
Abstract:
Clinical observations demonstrate an enhanced risk for myocardial infarction in patients with sustained activation of the local and/or systemic renin-angiotensin system, such as a high renin-sodium profile or a heritably enhanced expression of angiotensin converting enzyme. Chronic renin-angiotensin system blockade by angiotensin converting enzyme inhibition in patients with moderate heart failure reduces the rate of myocardial infarction and reinfarction. Preliminary experimental evidence suggests that these clinical observations may be partially explained by a proatherogenic effect of an activated renin-angiotensin system, which can downregulate the endothelial releasability of nitric oxide. Nitric oxide exerts many potentially antiatherogenic effects on endothelium, platelets and low density lipoproteins and indirectly on monocytes and leukocytes. Hypertension-induced chronic distension of elastic arteries upregulates the local renin-angiotensin system in these arteries and thereby downregulates nitric oxide releasability. Enhanced local synthesis of the trophic factor angiotensin-II and reduced releasability of the antitrophic factor nitric oxide appear to cooperate in the trophic adaptation of the distended vessel wall to the enhanced load, but with the disadvantage of enhanced susceptibility for atheroma development due to reduced releasability of nitric oxide. Chronic blockade of the renin angiotensin system by angiotensin converting enzyme inhibitors or by angiotensin receptor type-1 antagonists normalizes a reduced endothelial releasability of nitric oxide in several models, partially by a bradykinin-dependent mechanism. This endothelial protection proved to attenuate the progression of atherosclerosis in experimental models. The antiatherogenic potential of renin angiotensin system blockade in humans is presently under study.