Studies on the angiotensin converting enzyme gene polymorphism and ACE inhibitors

Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, an important step in the control of blood pressure. The gene encoding for ACE is subject to an insertion/deletion (I/D) polymorphism which is associated with different levels of the enzyme in serum. This polymorphism accounts for 47% of the variability in serum ACE concentrations between subjects but its relevance to tissue ACE is unknown. ACE inhibition increases kinin level, for example bradykinin. Kinins have been proposed be involved in the pathogenesis of cough due to ACE inhibitors, a common adverse effect in those prescribed these drugs. A genetic link was proposed to explain the differing susceptibility of subjects to develop cough. Those susceptible may differ in the cough reflexes initially or perhaps have different degrees of tissue ACE activity. In this thesis I examined healthy subjects using substrates and inhibitors of ACE to identify any possible differences in tissue ACE between those of different ACE genotype. I also examined the natural history of ACE inhibitor cough in particular changes in cough reflex and the possible roles of kinins in its aetiology. The frequency of ACE genotype amongst those who developed cough was also examined. a) The pressor response to angiotensin 1 was examined in 16 healthy subjects (DD, n=8; and II, n=8). The R(d)25 was the rate of angiotensin I infusion which caused a 25 mmHg rise in diastolic blood pressure. The geometric mean rate of infusion of angiotensin I required to achieve the R(d)25 was 2.53pg/min in II subjects and 2.67pg/min in DD subjects (ratio of doses (II:DD) = 0.95; 95% CI 0.44 to 2.02, p>0.05). b) The hypotensive response and serum ACE responses to an ACE inhibitor drug were examined in 27 healthy subjects grouped according to ACE genotype. Although changes after enalapril paralleled those differences seen between the different genotypes before no differences were seen between the groups when hypotensive responses were examined. c) A prospective controlled study comparing subjects taking ACE inhibitors (n=21) with those taking other anti-hypertensives (n= 12) examined the cough reflex changes that occur during prolonged treatment using capsaicin challenge. A new cough developed in 8 subjects. There were no differences in capsaicin sensitivity between groups at baseline. At one month a significant increase in capsaicin potency from baseline was observed for patients with enalapril cough (relative potency 4.7, 95% CI 1.2-18.5, p<0.025). d) A prospective study examined different subjects (n=8) with cough as the ACE inhibitors were discontinued and confirmed the change in cough sensitivity at day 28, this time to lie in the opposite direction, (relative potency 0.2, 95% CI 0.1-0.7, p<0.05) e) The dermal responses to bradykinin were examined in 105 healthy subjects (DD genotype, n=30; ID genotype, n=51; and II genotype n=24). Using parallel line analysis the potency of bradykinin in subjects of II genotype relative to those of DD genotype was 1.25, with a 95% confidence interval of 0.83 to 1.88. f) The cough response to bradykinin was examined in 27 healthy subjects (DD, n=9; ID, n=9; and II, n=9). Bradykinin produced cough in 74% of subjects but there were no differences in the cough responses between genotypes. g) The distribution of ACE genotypes was examined in 31 patients with cough due to ACE inhibitor. No increase in frequency of one genotvpe over another was identified. (DD, n=12; ID, n=I3; II, n=6) In conclusion the I/D polymorphism in the ACE gene could not predict responses to either substrates of ACE or ACE inhibitor drugs in healthy subjects. The cough due to ACE inhibitors leads to reversible changes in cough reflex sensitivity. Individuals who develop cough do not seem to differ in their initial cough reflexes nor in their genotype in the I/D polymorphism of the ACE gene.