Renin Angiotensin System Drugs ACE Inhibitors

The renin-angiotensin system (RAS) has an important role in cardiovascular health and disease, and polymorphisms of the ACE, AGT, angiotensin-II type 1 receptor (AGTR1), and CYP11B2 genes have been targeted for pharmacological research owing to the genetic variation they manifest (refer to previous section). The possibility that variation in these genes may alter drug response is therefore of considerable interest. ACE inhibitors and AT1R blockers have proved efficacious in managing CVDs, such as heart failure, myocardial infarction, hypertension, vascular disease, and nephropathy.

As mentioned earlier, the ACE D allele has been associated with higher circulating and tissue-activity levels and greater AGTR1 expression than the I allele (9,148-150). Similarly, hypertensive patients on ACE inhibitors and carrying the DD genotype showed significant reductions in blood pressure and plasma angiotensin II levels (151,152). Left ventricular hypertrophy and endothelial function also improved in individuals bearing the DD genotype, in comparison with those with the II genotype (29,153). By contrast, other reports showing the pharmacogenetic basis of ACE inhibitors and ACE genotypes were inconsistent (18,150). This suggests that genetic mechanisms are not always disease-specific. Disparities in results may be due to differences in the therapeutic agents used, the duration of drug exposure, or the dose administered. In addition, differences in the study populations may also have influenced the results, particularly because the RAS polymorphisms are known to differ in frequency between racial groups. The other possible explanation for these conflicting data is that other genetic variants in the RAS, including AGT and AGTR1 polymorphisms, interact with the ACE I/D polymorphism to influence drug response (Fig. 1).

The AGT gene Met235Thr polymorphism also affects RAS activity and drug responses. The 235Thr allele has been found to be associated with higher AGT levels and enhanced blood pressure response to ACE inhibitors (14,18,154). In the Schunkert et al. (154) study, the systolic and diastolic blood pressures were higher, and the likelihood of using two or more antihypertensive medications was 2.1 times higher, with the 235Thr allele.

The vascular AGTR1 mediates many detrimental effects of angiotensin II, including vasoconstriction, cardiac remodeling, and aldosterone secretion. The 1166C allele of the gene encoding AGTR1 A1166C polymorphism has also been associated with increased arterial responsiveness to angiotensin II in ischemic heart disease and increased arterial stiffness in hypertensives (155-158). Benetos et al. (157) showed that the 1166C allele was associated with a greater response to ACE inhibitor therapy. The carriers of the C allele manifested a threefold reduction in carotid to femoral PWV (a measure of aortic stiffness) when given perindopril as compared with the AA homozygotes. The AGTR1 gene was also found to be predictive of the blood pressure response to a single dose of losartan, with significantly greater reductions in mean arterial pressure in the 1166C allele carriers than in the 1166A homozygotes (159). However, a study of hypertensives did not reveal any association between this polymorphism and blood pressure responses to ACE inhibition (18).

The aldosterone synthase (CYP11B2) gene polymorphism C-344T has also been associated with responsiveness to ACE inhibition (160). Following treatment, the left ventricular ejection fraction improved in patients who harbored the 344C allele to a greater extent than those with the 344T allele.

RASpolymorphisms associated with adverse reactions to ACE inhibitors: In general, ACE inhibitors are well tolerated in young and older adults and improve a variety of cardiovascular functions. However, the RAS polymorphisms have been associated with adverse reactions, such as the "ACE inhibitor-related cough" and other effects (e.g., angioedema). The II genotype has been associated with increased susceptibility to the development of cough during the treatment period (161). After 4 weeks of therapy, the threshold of cough was significantly reduced for individuals bearing the II genotype but not in individuals bearing the DD genotype. The reported incidence of dry cough is variable, and the reason why ACE inhibitors cause coughing in only certain individuals is still unclear. However, the appearance of this cough in association with ACE inhibitors is thought to be related to the activity of the bradykinin B2 (BDKRB2) receptor gene (162), because treatment with these agents increases the concentration of bradykinin. This in turn may lead to the activation of proinflammatory peptides (e.g., prostaglandins) and to the local release of histamine in airways, which is responsible for the adverse reaction, such as cough, in some patients. It has also been speculated that these adverse effects are genetically predetermined: in particular, involving variants of the genes encoding ACE, chymase and bradykinin B2 receptor (BDKRB2). Interestingly, a recent study supports this view; a significant association has been observed between the TT genotype and T allele of the -38C/T polymorphism in the bradykinin B2 (BDKRB2) gene and ACE inhibitor-related cough in patients with a history of cough, compared with cough-free subjects receiving ACE inhibitors.

Much of the data on RAS polymorphisms and drug response indicates that a geno-typic test may predict the therapeutic efficacy of ACE inhibitors. However, inconsistencies in the reported data means that the situation remains unclear at present. These discordant results are not surprising in view of the complex signaling pathway of RAS as shown in Figure 1.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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