**2.3. Renin-angiotensin system inhibitors**

Numerous genes from the renin-angiotensin system (RAS) pathway have been shown to play a key role in the regulation of blood pressure and influence the cardiovascular sys‐ tem. Several pharmacogenetic studies of the RAS were conducted. However, due to the complexity of RAS, associations between drug efficiency and polymorphisms are not consistent [42-45].

Angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to angiotensin II in plasma and tissue and prevent the degradation of bradykinin. Clinically, ACE inhibitors reduce peripheral vascular resistance and pulmonary capillary wedge pres‐ sure and increase cardiac output and renal blood flow. Treatment with ACE inhibitors in hypertension has been associated with improvements in vascular compliance, regression of left ventricular hypertrophy, improved systolic and diastolic function, and improvements in insulin sensitivity [46]. One study showed that ACE DD polymorphism is associated with poor collateral circulation (PCC). PCC in patients carrying the D allele may be associated with endothelial dysfunction and elevated blood ACE levels in these patients [47].

The insertion/deletion (I/D) in the angiotensin I-converting enzyme (ACE) gene is one of the candidates for studies. The D allele has been associated with more improvement in coronary endothelial dysfunction with ACE inhibitor therapy than the I allele [48]. Reductions in sys‐ tolic and diastolic blood pressures were significantly greater for patients with the D/D geno‐ type than for patients with the I/D and I/I genotypes [49].

Diastolic blood pressure tended to decrease more for the ACE I/I genotype than for other ACE genotypes and the I/I genotype was also predictive of greater diastolic blood pressure decline [50]. Decline in renal function during ACE inhibitor treatment tended to be greater in heart failure patients with the ACE I/I genotype [51]. The I/I genotype has also been asso‐ ciated with increased susceptibility to the development of cough during ACE inhibitor ther‐ apy. After four weeks of therapy with an ACE inhibitor in healthy volunteers, the threshold for cough was significantly reduced for the I/I genotype but not the D/D genotype [52].

Another gene of interest is the angiotensinogen (AGT) gene. It was reported that the angio‐ tensinogen 235Met/Thr polymorphism is also associated with RAS activity and drug re‐ sponses. In subjects on ACE inhibitor monotherapy with 235Thr allele the response is higher than in the control group. Systolic and diastolic blood pressures were higher and the likeli‐ hood of using two or more antihypertensive medications was 2.1 times higher with the 235Thr polymorphism [53].

An association with polymorphisms in the angiotensin AT1 receptor (AGT1R) gene and ACE inhibitors' efficiency are found in some studies. The AGT1R mediates some negative effects of angiotensin II, such as vasoconstriction, cardiac remodelling, and aldosterone se‐ cretion. Angiotensin II blockers bind to angiotensin II receptors, thereby antagonizing the ef‐ fect of angiotensin II, a potent vasoconstrictor [54]. The 1166C allele of AGT1R has been associated with increased arterial responsiveness to angiotensin II in ischemic heart disease and increased aortic stiffness in hypertension. During ACE inhibitor treatment, reductions in aortic stiffness were reported to be three times greater in carriers of the 1166C allele than in 1166A homozygotes [55, 56]. AGTR1 (C573T) and ACE (ID) association between ACE in‐ hibitor therapy and increased MI risk for carriers of the AGTR1 C573 allele were reported; however, no significant interaction between ACE inhibitor treatment and ACE (ID) alleles for either stroke or MI were found [28]. One research group found no associations between BP response and ACE (ID), AGTR1 (A1166C), CYP11B2 (-344 C/T), AGT (-6 A/G) [57].

After 12 weeks of treatment with irbesartan (Angiotensin II Blocker), plasma concentration of the drug was related to change in systolic BP in TT homozygotes of AGTR1 (C5245T) but not for other genotypes [58].
