Enhanced angiotensin-converting enzyme activity and impaired endothelium-dependent vasodilation in aortae from hypertensive rats: evidence for a causal link

Endothelial vasomotor function is im pal red in a variety of disorders repr esenting both early and late stages of atherosclerosis. There is experiment al evidence for enhanced vascular angiotensin-converting enzyme (ACE) activ ity in these disorders. We explored whether enhanced vascular ACE activity accounts for endothelial dysfunction in experimental hypertension. Hyperten sion was induced in rats by coarctation of the aorta. At 2 weeks post-opera tion, the animals were randomly divided into groups receiving the ACE inhib itor quinapril (2.0 mg.kg(-1).day(-1)), the angiotensin type-I receptor ant agonist losartan (3.0 mg.kg(-1).day(-1)), the B-2 kinin receptor antagonist icatibant (0.4 mg.kg(-1).day(-1)), quinapril plus icatibant, losartan plus icatibant, or no drug. Analyses were performed 4 weeks post-operation. Non e of the drug treatments had any significant effect on blood pressure. ACE activity was nearly doubled in aortae from untreated hypertensive rats as c ompared with sham-operated rats. Quinapril reduced ACE activity in aortae f rom hypertensive rats by 75%, losartan caused a 40% decrease, and icatibant had no effect. Endothelium-dependent, nitric oxide-mediated vasodilator re sponses studied in vitro were impaired by 40% in aortae from untreated hype rtensive rats as compared with sham-operated rats. Both quinapril and losar tan restored endothelial vasomotor function in aortae from hypertensive rat s. Co-applied icatibant negated the effects of quinapril, but not those of losartan. The level of endothelial NO synthase (eNOS) mRNA determined by co mpetitive RNA PCR was decreased by half in aortae from untreated hypertensi ve rats as compared with sham-operated rats. Quinapril induced an increase in the eNOS mRNA level of 350% in aortae from hypertensive rats, which was negated by co-applied icatibant. Losartan restored eNOS mRNA expression in aortae from hypertensive rats to normal levels, and this effect was not mod ified by co-applied icatibant. These findings suggest that enhanced vascula r ACE activity accounts for endothelial vasomotor dysfunction by impairing the bioavailability of endothelium-derived NO. Both enhanced formation of a ngiotensin II and enhanced metabolism of bradykinin might account for a vas cular deficiency of bioactive NO.