Abstract-The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to angiotensin-(1-5) and can lead to elevation of angiotensin-(1-7) levels in plasma and tissue. In animal models, angiotensin-(1-7) itself causes or enhances vasodilation and inhibits vascular contractions to angiotensin II. The function of angiotensin-(1-5) is unknown. We investigated whether angiotensin-(1-7) and angiotensin-(1-5) inhibit ACE or antagonize angiotensin-induced vasoconstrictions in humans. ACE activity in plasma and atrial tissue was inhibited by angiotensin-(1-7) up to 100%, with an IC 50 of 3.0 and 4.0 mol/L, respectively. In human internal mammary arteries, contractions induced by angiotensin I and II and the non-ACE-specific substrate [Pro 11 ,D-Ala 12 ]-angiotensin I were antagonized by angiotensin-(1-7) (10 Ϫ5 mol/L) in a noncompetitive way, with a 60% inhibition of the maximal response to angiotensin II. Contractions to ACE-specific substrate [Pro 10 ]-angiotensin I were also inhibited, an effect only partly accounted for by antagonism of angiotensin II. Angiotensin-(1-5) inhibited plasma ACE activity with a potency equal to that of angiotensin I but had no effect on arterial contractions. In conclusion, angiotensin-(1-7) blocks angiotensin II-induced vasoconstriction and inhibits ACE in human cardiovascular tissues. Angiotensin-(1-5) only inhibits ACE. These results show that angiotensin-(1-7) may be an important modulator of the human renin-angiotensin system. (Hypertension. 1999;34:296-301.)
Abstract-An adenine/cytosine (A/C) base substitution at position 1166 in the angiotensin II type 1 receptor (AT 1 R) gene is associated with the incidence of essential hypertension and increased coronary artery vasoconstriction. However, it is still unknown whether this polymorphism is associated with a difference in angiotensin II responsiveness. Therefore, we assessed whether the AT 1 R polymorphism is associated with different responses to angiotensin II in isolated human arteries. Furthermore, we evaluated whether inhibition of the renin-angiotensin system modifies the effect of the AT 1 R polymorphism. One hundred twelve patients who were undergoing coronary artery bypass graft surgery were prospectively randomized to receive an ACE inhibitor or a placebo for 1 week before surgery. Excess segments of the internal mammary artery were exposed to angiotensin II (0.1 nmol/L to 1 mol/L) and KCl (60 mmol/L) in organ bath experiments. Patients homozygous for the C allele (nϭ17) had significantly greater angiotensin II responses (percentage of this maximal KCl-induced response) than did patients genotyped with AAϩAC (nϭ95, PϽ0.05). Although ACE inhibition increased the response to angiotensin II, the difference in the response to angiotensin II, between CC and AAϩAC patients remained intact in ACE inhibitor-treated patients. These results indicate increased responses to angiotensin II in patients with the CC genotype. The mechanism is preserved during ACE inhibition, which in itself also increased the response to angiotensin II. This reveals that the A1166C polymorphism may be in linkage disequilibrium with a functional mutation that alters angiotensin II responsiveness, which may explain the described relation between this polymorphism and cardiovascular abnormalities.
The functional studies lost NO capacity in IJV grafts, whereas NO capacity in GEA grafts remained intact. Intimal hyperplasia in IJV grafts was extensive, whereas GEA grafts demonstrated preservation of pre-existent intimal architecture. These results may encourage the application of the human GEA as bypass graft for reconstruction of arteries in the lower limb or foot.
In the present review, we discuss the role of clinical dosing of angiotensin converting enzyme (ACE) inhibitors in the treatment of left ventricular dysfunction. Although the precise mechanism of action of ACE inhibitors is still unresolved, the clinical efficacy of ACE inhibitors in the treatment of left ventricular dysfunction is well established. However, it is unclear whether the doses used in clinical trials translate directly into daily practice. Several reasons may cause differences between clinical practice and controlled trials: (1) clinical trials used higher doses than in normal practice; (2) some patients may be relatively 'resistant' to ACE inhibition; and/or (3) ACE activity increases during ACE inhibitor therapy and may provide escape mechanisms when the drug regimen is not strictly adhered to. Therefore, it is of interest that recent trials suggest that only the higher doses of ACE inhibition are clinically efficacious. In conclusion, it is suggested that optimal benefit from treatment with an ACE inhibitor in patients with left ventricular dysfunction requires sufficient and frequent dosing of the ACE inhibitor, e.g., enalapril 10 mg twice daily or captopril 25 mg three times daily.
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