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Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting
1Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Insights
Hypertension causes endothelial dysfunction and monocyte macrophage infiltration in rats. Angiotensin converting enzyme inhibitors like cilazapril effectively reduce both, suggesting a shared mechanism of action for these drugs.
Area of Science:
- Cardiovascular Research
- Pharmacology
Background:
- Hypertension is linked to impaired endothelium-dependent relaxation.
- Angiotensin converting enzyme inhibitors (ACE inhibitors) can prevent endothelial dysfunction.
Purpose of the Study:
- To investigate the association between endothelial dysfunction and subendothelial monocyte macrophage infiltration in spontaneously hypertensive rats.
- To determine if cilazapril treatment affects both conditions.
Main Methods:
- Quantified monocyte macrophage infiltration using morphometry.
- Assessed endothelial function via serotonin ratio in isolated arterial rings.
- Examined regional distribution of dysfunction and infiltration across arteries.
Main Results:
- Endothelial dysfunction and monocyte macrophage infiltration showed similar regional patterns, peaking in the carotid artery and absent in the renal artery.
- Two-week cilazapril treatment significantly reduced endothelial dysfunction (32% decrease in serotonin ratio) and aortic monocyte macrophage infiltration (38% decrease).
Conclusions:
- Endothelial dysfunction and subendothelial monocyte macrophage infiltration are associated in spontaneously hypertensive rats.
- Cilazapril effectively reduces both endothelial dysfunction and monocyte macrophage infiltration, indicating a potential shared pathway targeted by ACE inhibitors.
Abstract:
Hypertension is associated with an impairment of endothelium-dependent relaxation. The angiotensin converting enzyme inhibitors captopril and cilazapril can prevent this endothelial dysfunction. We recently observed that long-term treatment with cilazapril could also prevent subendothelial infiltration by mononuclear cells in spontaneously hypertensive rats. This prompted us to examine whether, in spontaneously hypertensive rats, endothelial dysfunction and subendothelial infiltration by mononuclear cells are associated. These cells were characterized as monocyte macrophages. Infiltration by monocyte macrophages was quantified by morphometry. Endothelial function was estimated by calculating serotonin ratio (maximal contraction to serotonin on isolated arterial rings with endothelium over maximal contraction on paired rings without endothelium). The regional distribution of endothelial dysfunction and subendothelial monocyte macrophages was similar. Both were maximal in the carotid artery, less in the aorta, and nonexistent in the renal artery. A 2-week treatment with cilazapril decreased both endothelial dysfunction (serotonin ratio decreased by 32%) and the number of subendothelial monocyte macrophages in the aorta, which decreased by 38%. We conclude that in spontaneously hypertensive rats, endothelial dysfunction and subendothelial monocyte macrophage infiltration are associated and that cilazapril can decrease both. The observation that angiotensin converting enzyme inhibitors affect subendothelial accumulation of monocyte macrophage may lead to a better understanding of the mechanism of action of this class of drugs.