Human Vascular Reactivity and Polymorphisms of the Angiotensin-Converting Enzyme and the Angiotensin Type 1 Receptor Genes

Abstract

The D allele of the insertion (I)/deletion (D) polymorphism in the angiotensin-converting enzyme (ACE) gene and the C allele of the A1166-C polymorphism in the angiotensin II type 1 receptor (AGT1R) gene have been associated with altered vascular structure and with an increased risk of myocardial infarction. The aim of this study was to determine whether differences in vascular function could be demonstrated to link the previously described changes in structure and the disease outcome. 70 subjects were recruited at random from patients undergoing colonic resection, resistance arteries were excised and were mounted in a small vessel wire myograph. Vasomotor responses to potassium chloride, noradrenaline, prostaglandin F_2α, angiotensin I, angiotensin II, acetylcholine and substance P were performed in 30 subjects. Genotype was established in a blinded fashion after completion of myography. To exclude the possibility of masking of genetic influence by non-ACE conversion of angiotensin I, vasomotor responses were then performed to proline¹⁰-angiotensin I in a further 30 subjects and to angiotensin I in the presence of chymostatin in a further 10 subjects. No significant effect of the I/D polymorphism of the ACE gene was seen on vasomotor function. The C allele of the AGT1R gene was associated with an increase in sensitivity to prostaglandin F_2α but not with alteration to the other vasoactive agents studied. The I/D ACE and A1166-C AGT1 receptor polymorphism do not appear to result in differences in vasomotor function in isolated human mesenteric resistance arterioles in subjects without evidence of underlying hypertensive or cardiovascular disease.

Angiotensinogen and angiotensin-converting enzyme gene copy number and angiotensin and bradykinin peptide levels in mice

“…Surprisingly, the I/D polymorphism is reported to have no effect on Ang II/Ang I ratio, despite 40-60% higher plasma ACE activity in DD than II subjects [34,39,42,43]. The I/D polymorphism is reported to have no measurable effect on conversion of Ang I to Ang II in vivo, or the aldosterone response to Ang I administration [34,39,41,43,45], although there are conflicting reports concerning the effect of the I/D polymorphism on the pressor and vasoconstrictor responses to Ang I [39][40][41][45][46][47]. There are also conflicting reports of the effects of the I/D polymorphism on bradykinin metabolism.…”

Angiotensin II receptor polymorphisms in hypertension. Pharmacogenomic considerations

“…injection of methylergonovine maleate, a potent vasoconstrictor whose effects have been explored in CAD [40]. Other studies did not find differences in vasomotor function in isolated human mesenteric resistance arterioles but an increase was seen in sensitivity to prostaglandin F2α in REVIEW arterioles from patients with C allele in AG 1 TR gene [41] and after Ang II infusion to assess familial resemblance in hypertensive patients [42]. Thus, taken alone the A1166C polymorphism in the AGT 1 R gene neither represents a risk factor for adverse events complicating coronary interventions nor seems to have significant impact on further long-term processes such as development and severity of CAD [43][44][45].…”

Age-related increase of pulse pressure and gene polymorphisms in essential hypertension: a preliminary study

“…12 The balance between NO and angiotensin II (Ang II) is crucial for vascular homeostasis.There is evidence, in humans, that the Ang II AT 1 -receptor gene and the eNOS G 298 T gene are specifically implicated in this balance. On four different human conduit arteries, [13][14][15][16] the presence of the C mutant allele of the AT 1 -receptor gene was shown to be associated (using in vivo and in vitro experiments) with enhancement of the contractile response of large arterial vessels, particularly under phenylephrine and angiotensin. Regarding the eNOS G 298 T gene, it has been reported that the coronary vasoconstrictive response to phenylephrine is enhanced in 894T carriers when compared to the GG group, resulting in increased coronary vascular reactivity and CV risk.…”