M Oosterga

Angiotensin II Type 1 Receptor A1166C Gene Polymorphism Is Associated With an Increased Response to Angiotensin II in Human Arteries

An adenine/cytosine (A/C) base substitution at position 1166 in the angiotensin II type 1 receptor (AT(1)R) 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 AT(1)R 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 AT(1)R 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 micromol/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.

Dual pathway for angiotensin II formation in human internal mammary arteries

1 Angiotensin converting enzyme (ACE) is thought to be the main enzyme to convert antiotensin I to the vasoactive angiotensin II. Recently, in the human heart, it was found that the majority of angiotensin II formation was due to another enzyme, identified as human heart chymase. In the human vasculature however, the predominance of either ACE or non‐ACE conversion of angiotensin I remains unclear. 2 To study the effects of ACE‐ and chymase‐inhibition on angiotensin II formation in human arteries, segments of internal mammary arteries were obtained from 37 patients who underwent coronary bypass surgery. 3 Organ bath experiments showed that 100 μM captopril inhibited slightly the response to angiotensin I (pD2 from 7.09±0.11–6.79±0.10, P<0.001), while 100 μM captopril nearly abolished the response to [pro10] angiotensin I, a selective substrate for ACE, and the maximum contraction was reduced from 83±19%–23±17% of the control response (P=0.01). A significant decrease of the pD2 of angiotensin I similar to captopril was observed in the presence of 50 μM chymostatin (pD2 from 7.36±0.13–6.99±0.15, P<0.039), without influencing the maximum response. In the presence of both inhibitors, effects were much more pronounced than either inhibitor alone, and a 300 times higher dose was needed to yield a significant contraction response to angiotensin I. 4 These results indicate the presence of an ACE and a non‐ACE angiontensin II forming pathway in human internal mammary arteries.

Effects of Aspirin on Angiotensin-Converting Enzyme Inhibition and Left Ventricular Dilation One Year After Acute Myocardial Infarction

There are conflicting reports on the interaction of aspirin with angiotensin-converting enzyme inhibitors in heart failure and systemic hypertension. A post hoc analysis of the Captopril and Thrombolysis Study (CATS) study was conducted. At randomization, 94 patients (31.5%) took aspirin. In patients who took aspirin, the cumulative alpha-hydroxy butyrate dehydrogenase release was 1,151 +/- 132 IU/L in patients randomized to captopril compared with 1,401 +/- 136 IU/L in patients randomized to placebo (difference -250 +/- 189 [95% confidence interval (CI) -620 to 120]). This difference was comparable to the difference in patients who did not use aspirin (-199 +/- 147 [95% CI -488 to 897]). One year after acute myocardial infarction, an increase in left ventricular end-diastolic volume index of 2.2 +/- 3.0 ml/m2 in captopril-treated and 1.9 +/- 2.9 ml/m2 in placebo-treated patients was observed in patients who took aspirin (difference 0.4 +/- 4.2 [95% CI -8.2 to 8.9]). This difference was also comparable to the difference in patients who did not take aspirin (2.2 +/- 3.8 [95% CI -5.2 to 9.7]). One year after acute myocardial infarction, patients who did take aspirin had a mean change in LV end-diastolic volume index of 2.1 +/- 2.1 ml/m2 compared with 8.4 +/- 1.9 ml/m2 in patients who did not use aspirin (p = 0.02). Thus, aspirin does not attenuate the acute and long-term effects of angiotensin-converting enzyme inhibition after acute myocardial infarction, but independently reduces LV dilation after myocardial infarction.

Plasma Angiotensin-Converting Enzyme Activity and Left Ventricular Dilation After Myocardial Infarction

BACKGROUND Left ventricular dilation after acute myocardial infarction (MI) is mainly determined by infarct size. In addition, this detrimental structural adaptation seems to be augmented in patients with the ACE DD genotype. The ACE DD genotype is associated with increased ACE activity. The aim of the present study was to evaluate whether ACE activity per se may carry prognostic significance for subsequent left ventricular dilation as assessed by echocardiography during 1-year follow-up after acute MI. METHODS AND RESULTS Left ventricular end-systolic and end-diastolic volume indexes were assessed by two-dimensional echocardiography. In 102 consecutive patients, plasma ACE activity was determined 3.7 +/- 0.1 hours after the onset of MI. In 64 of these patients, left ventricular volume indexes obtained at baseline and 1 year after MI were used for the present analysis. Patients were divided ino a group having low ACE activity (< or = IU/L, n = 15) and a group having high ACE activity (> 12 IU/L, n = 49). Infarct size was a significant predictor of the increase in left ventricular volume indexes (P = .0001) in these patients. Multivariate regression analysis, after correction for infarct size, demonstrated that elevated plasma ACE activity is a significant predictor of the increase in left ventricular end-diastolic and end-systolic volume indexes (P = .0006 and P = .02, respectively) 1 year after MI. CONCLUSIONS Elevated plasma ACE activity determined soon after the onset of MI may be a significant predictor of the development of left ventricular dilation and may identify patients at risk.

Angiotensin II formation in human vasculature after chronic ACE inhibition: A prospective, randomized, placebo-controlled study

The QUO VADIS (the effects of QUinapril On Vascular Ace and Determinants of ISchemia) study was a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of long-term angiotensin-converting enzyme (ACE) inhibition on angiotensin II formation in human vasculature. Patients (n < 187) scheduled for coronary artery bypass surgery used study medication 27 ± 1 days before surgery. Segments of internal mammary arteries were exposed to increasing doses (0.1 nM-1 µM) of angiotensin I and II in organ baths. The rate of local angiotensin II formation is a function of the reciprocal of the difference between the pEC50s of the dose response curves to angiotensin I and II (−log/mol) and of the area between the curves (units). Quinapril (40 mg) and captopril (3×50 mg) similarly and significantly reduced mean blood pressure compared with placebo (p = 0.04). Difference between pEC50s was 0.90 ± 0.08 in quinapril patients compared with 0.60 ± 0.08 for placebo (p <5 0.01); the area between curves was 91 ± 8 for quinapril patients compared with 67 ± 8 for placebo (p = 0.03). Angiotensin II formation was decreased to a lesser extent with captopril and was not statistically different from placebo (p = 0.3); the difference between pEC50s was 0.83 ± 0.15; the area between curves was 84 ± 12. This is the first randomized study to demonstrate that long-term oral treatment with an ACE inhibitor reduces vascular angiotensin II formation in humans.

Vascular effects of quinapril completely depend on ACE insertion/deletion polymorphism

Introduction The angiotensin-converting enzyme (ACE) DD-genotype is associated with increased plasma and myocardial ACE-activity. The influence of the ACE insertion/deletion (I/D) polymorphism on the effects of ACE-inhibition on vascular responses has not been previously described. Materials and methods In the randomised, double-blind QUinapril On Vascular ACE and Determinants of Ischemia Study (QUO VADIS), 149 patients undergoing coronary bypass surgery were randomised to receive either the ACE inhibitor, quinapril, or placebo. In 82 patients, we obtained ACE-genotype, and measured vascular responses to angiotensin II (Ang II) in left internal mammary arteries. Results In the placebo group, the mean maximal vasoconstriction to Ang II was significantly lower in patients with the DD-genotype than in those with the ID/II genotype (36.2±5.11% [n=13] vs. 55.6±4.57% [n=25]; p=0.01). In the quinapril group, the mean maximal vasoconstriction to Ang II was similar [n=8] vs. 57.7±4.07% [n=35]; p=0.85). between DD- and ID/II-genotype (59.6±9.19% Conclusions DD-genotype patients showed decreased vascular responses to Ang II but treatment with quinapril completely restored the decreased vascular response in DD-genotype patients to the same level as II/ID-genotype patients, while no effect of quinapril was demonstrated in the II/ID-genotype patients.

Dyslipidemia and endothelium-dependent relaxation in internal mammary arteries used for coronary bypass surgery

OBJECTIVE Impairment of endothelium-dependent relaxation is related to dyslipidemia and may be an early marker for atherosclerosis in angiographically smooth arteries. The aim of the present study was to relate preoperative serum lipids to endothelium-dependent relaxation in internal mammary arteries of patients undergoing coronary bypass surgery. METHODS The study group consisted of 37 patients, from whom segments of the internal mammary artery were obtained during surgery. Measurements of endothelium-dependent relaxation were performed in organ baths by adding methacholine (10 nM-10 microM). RESULTS All internal mammary arteries dilated in response to methacholine, ranging from 4 to 112% of the precontraction to 10 mumol phenylephrine. In a multiple regression model, increased total serum cholesterol appeared to be the best predictor for impaired endothelium-dependent relaxation. A 1 mmol increase of total cholesterol was associated with a 11.2% decrease of endothelium-dependent relaxation (P = 0.006). When total cholesterol was omitted from the model, LDL-cholesterol became the best predictor of endothelium-dependent relaxation (regression coefficient 10.3%/mmol; P = 0.02). No other variable was significantly associated with endothelium-dependent relaxation, and none of the preoperative variables was associated with endothelium-independent relaxation, expressed as the response to sodium nitrite (10 mM). CONCLUSION Our study showed that endothelium-dependent relaxation in apparently non-diseased internal mammary arteries used for coronary bypass surgery was independently related to preoperative (LDL)-cholesterol levels.

Differences between angiotensin-converting enzyme inhibition and angiotensin II-AT1 antagonism on angiotensin-mediated responses in human internal mammary arteries

The current study aimed to demonstrate differences between angiotensin (Ang)-converting enzyme (ACE) inhibition and Ang II–AT1 receptor antagonism on full concentration-contraction responses to Ang I. Contraction responses to increasing concentrations of Ang I (1 n M–1 &mgr;M) were evaluated in organ baths in the presence of captopril (10 &mgr;M–1 m M) with or without a chymase inhibitor (1 &mgr;M soybean trypsin inhibitor), or irbesartan (0.1 n M–&mgr;M), in internal mammary arteries from 25 patients undergoing coronary bypass surgery. Responses were expressed as a percentage of the control response to 10 &mgr;M phenylephrine. Captopril did not change the maximum response to Ang I (control: 46.3 ± 6.3%, captopril: 43.0 ± 4.6%). In contrast, 0.1 &mgr;M irbesartan completely blocked the maximum response to Ang I (from 45.8 ± 6.7% to 1.9 ± 1.9%, p < 0.001). However, addition of soybean trypsin inhibitor to captopril more effectively shifted −log pD2 than captopril alone (0.47 ± 0.06 vs 0.95 ± 0.14 log units, p = 0.007). Ang I–mediated effects are much more effectively inhibited by Ang II antagonism than by ACE inhibition. The incomplete effects of captopril on the inhibition of Ang II formation might be caused by alternative Ang II forming enzyme(s), as was demonstrated by the additive effects of soybean trypsin inhibitor added to captopril.