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.

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1 Angiotensin converting enzyme (ACE) is thought to be the main enzyme to convert antiotensin I to the vasoactive angiotensin II. Recently, in the human heart, it was found that the majority of angiotensin II formation was due to another enzyme, identi®ed as human heart chymase. In the human vasculature however, the predominance of either ACE or non-ACE conversion of angiotensin I remains unclear. 2 To study the e ects of ACE-and chymase-inhibition on angiotensin II formation in human arteries, segments of internal mammary arteries were obtained from 37 patients who underwent coronary bypass surgery. 3 Organ bath experiments showed that 100 mM captopril inhibited slightly the response to angiotensin I (pD 2 from 7.09+0.11 ± 6.79+0.10, P50.001), while 100 mM captopril nearly abolished the response to [pro 10 ] angiotensin I, a selective substrate for ACE, and the maximum contraction was reduced from 83+19% ± 23+17% of the control response (P=0.01). A signi®cant decrease of the pD 2 of angiotensin I similar to captopril was observed in the presence of 50 mM chymostatin (pD 2 from 7.36+0.13 ± 6.99+0.15, P50.039), without in¯uencing the maximum response. In the presence of both inhibitors, e ects were much more pronounced than either inhibitor alone, and a 300 times higher dose was needed to yield a signi®cant contraction response to angiotensin I. 4 These results indicate the presence of an ACE and a non-ACE angiontensin II forming pathway in human internal mammary arteries.

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