(Hypertension. 2000;35:717.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Angiotensin II Type 1 Receptor A1166C Gene Polymorphism Is Associated With an Increased Response to Angiotensin II in Human Arteries
From the Departments of Clinical Pharmacology (P.P. van G., Y.M.P., A.A.V., H.B., N.O., W. van G.) and Cardiology (P.P. van G., Y.M.P., A.A.V., M.O., H.J.G.M.C.), University Hospital Groningen, Groningen, the Netherlands; and Department of Cardiology (A.A.V.), St Antonius Hospital Nieuwegein, Nieuwegein, the Netherlands.
Correspondence to Dr Peter Paul van Geel, Department of Clinical Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail P.P.Geel{at}MED.RUG.NL
Abstract—An adenine/cytosine (A/C) base substitution at position 1166 in the angiotensin II type 1 receptor (AT1R) 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 AT1R 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 AT1R 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 µmol/L) and KCl (60 mmol/L) in organ bath experiments. Patients homozygous for the C allele (n=17) had significantly greater angiotensin II responses (percentage of this maximal KCl-induced response) than did patients genotyped with AA+AC (n=95, P<0.05). Although ACE inhibition increased the response to angiotensin II, the difference in the response to angiotensin II, between CC and AA+AC 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.
Key Words: angiotensin II • receptors, angiotensin II • arteries • genetics • risk factors • polymorphism
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