Impaired vasodilation of peripheral response to acetylcholine in human with abdominal aortic aneurysm

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Impaired vasodilation of peripheral response to acetylcholine in human with abdominal aortic aneurysm arteries beings in Kimihiro Komori, MD, PhD, Kyoutaro Mawatari, MD, Hiroyuki Itoh, MD, and Keizo

1 Impaired vasodilation of peripheral response to acetylcholine in human with abdominal aortic aneurysm arteries beings in Kimihiro Komori, MD, PhD, Kyoutaro Mawatari, MD, Hiroyuki Itoh, MD, and Keizo Sugimachi, MD, PhD, Fukuoka, Japan Purpose: Most aneurysms are generally presumed to be atherosclerotic in origin. Endothelium-dependent dilations were impaired in the cases of atherosclerosis. It is not clear whether the endothelial function of the peripheral arteries in humans with abdominal aortic aneurysm is impaired. The purpose of this study is to characterize endotheliumdependent relaxations in patients with abdominal aortic aneurysm. Methods: Responses of external iliac artery blood flow to acetylcholine (30 wg/min: an endothelium-dependent vasodilator) and sodium nitroprusside (10 wg/min: a direct dilator of smooth muscle) were examined by electromagnetic blood flow meter in a group of 13 patients consisting of six patients with abdominal aortic aneurysm, six patients with colorectal cancer, and one patient with abdominal aortic aneurysm and rectal cancer. Results: The mean blood flow before administration of drugs was comparable between the two groups. In the patients with abdominal aortic aneurysm, infusion of acetylcholine did not significantly increase the mean blood flow, whereas in the patients with colorectal cancer, acetylcholine increased the blood flow significantly. The increases of blood flow by an infusion of sodium nitroprusside were comparable between the two groups. In one patient with abdominal aortic aneurysm and rectal cancer, acetylcholine did not alter the blood flow, and sodium nitroprusside increased the blood flow, which was similar to what the patient with abdominal aortic aneurysm experienced. Conclusions: These results suggest that in patients with abdominal aortic aneurysm, the endothelium-dependent vasodilations of the peripheral artery were impaired without changing the smooth muscle property. (J VASC SURG 1994;20:803-7.) It has been recognized that vascular endothelium plays a pivotal role in regulating vascular smooth muscle tone. 1-3 Studies in animals demonstrated that a variety of pathologic settings such as hypercholesterolemia, hypertension, and atherosclerosis impair endothelium-dependent vasorelaxations. 4-8 Recent studies in human beings have demonstrated that angiographically normal coronary arteries dilate and that arteries with atherosclerotic lesions constrict with acetylcholine infusion. 9,1 Provided they are not associated with cystic medial necrosis (Marfan's syndrome) or hypertensive From The Second Department of Surgery, Faculty of Medicine, Kyushu University, Fukuoka. Supported in part by a grant-in-aid for general scientific research from the Ministry of Education, Science and Culture of Japan. Reprint requests: Kimihiro Komori, MD, The Second Department of Surgery, Faculty of Medicine, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812, Japan. Copyright 1994 by The Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter /94/$ /1/58383 dissection, most aneurysms are generally presumed to be atherosclerotic in origin, n However, no studies have determined whether the endothelial function of the peripheral arteries in human beings with abdominal aortic aneurysm () was altered. The purpose of this study is to characterize endothelium-dependent relaxations in patients with. For this purpose responses of blood flow in the left external iliac artery to intraarterial infusions of acetylcholine (an endothelium-dependent vasodilator) and to sodium nitroprusside (an endotheliumindependent vasodilator) were examined with an electromagnetic blood flow meter. MATERIAL AND METHODS The study was conducted on a group of 13 patients, consisting of six patients with, six patients with colorectal cancer, and one patient with and rectal cancer. The average age of patients with was years, with a range of 64 to 72 years. The average age of patients with colo- 803

804 Komori et al November 1994 k,. / x. /,. / J /" /'~ ~/~Drug External Ililc~ "~'~, Artery }-!t ~ Electromagnetic ~ ~ w Meter Fig. 1. Left common, external, and internal iliac arteries were exposed and controlled with ligatures.

2 804 Komori et al November 1994 k,. / x. /,. / J /" /'~ ~/~Drug External Ililc~ "~'~, Artery }-!t ~ Electromagnetic ~ ~ w Meter Fig. 1. Left common, external, and internal iliac arteries were exposed and controlled with ligatures. Drug was infused below bifurcation of iliac artery with infusion pump. Blood flow was measured at about 3 cm distal external iliac artery with electromagnetic blood flow meter. rectal cancer was years, with a range of 64 to 73 years. No significant difference in age existed between the two groups. The pulsations of posterior and anterior tibial arteries were palpable in all patients. Angiography performed on all the patients with did not demonstrate any significant stenosis of peripheral arteries. No patients had ischemic symptoms such as intermittent claudication or rest pain of the lower extremities. Written informed consent was obtained from each patient. Measurement of blood flow. During the operation left common, external, and internal iliac arteries were exposed. The drug was infused below the bifurcation of the iliac artery with an infusion pump before the repair of aneurysm. The blood flow was measured at about 3 cm distal external iliac artery with an electromagnetic blood flow meter (Nihon Koden MF-27, Tokyo, Japan) (Fig. 1). The measurements of iliac artery blood flow were performed during continuous infusion of acetylcholine at a dose of 30 ~g/min for i minute. After the blood flow was restored to the baseline within 10 minutes, sodium nitroprusside (SNP) at a dose of 10 ~g/min for 1 minute was infused. 12,13 Statistical analysis. The results are expressed as mean SEM. Statistical evaluation of the data was observed with Student's t test for paired or unpaired observations. A p value of less than 0.05 was considered to have statistical significance. RESULTS The average serum cholesterol and tryglyceride in patients with were _ 16.1 mg/dl and 87.7 _ mg/dl, respectively. The average serum cholesterol and tryglyceride in the patients with colorectal cancer were mg/dl and mg/dl, respectively. No significant difference existed between the two groups (Table I). Hemodynamic response. Before the infusion of drugs the mean blood pressure was mm Hg in the group and _+ 5.6 mm Hg in the patients with colorectal cancer, respectively. No significant difference existed between the two groups. Intraarterial infusion of acetylcholine and SNP did not alter mean systemic arterial pressure or heart rate in any of the patients. Before the application of drugs the mean blood flow of the left iliad artery was similar for both groups (: _ ml/min, colorectal cancer: _ ml/min). Infusion of acetylcholine (30 ~g/min) increased the mean blood flow significantly in the patients with colorectal cancer, whereas in the patients with it did not significantly increase the blood flow (Figs. 2 and 3). The percent increase in blood flow induced by acetylcholine in the patients with colorectal cancer was 43% _+ 4%, whereas in the patients with it was 8% +_ 3%. Infusion of SNP at a dose of 10 ~g/min increased the mean blood flow significantly in both groups (Figs. 2 and 4). The percent increases in blood flow induced by SNP were 81% _+ 16% in the group and 103% _+ 12% in the patients with colorectal cancer, respectively. In the patients with and rectal cancer, acetylcholine increased the mean blood flow slightly from 180 ml/min to 182 ml/min, whereas SNP increased the mean blood flow from 180 ml/min to 440 ml/min (Fig. 2). DISCUSSION The major finding of this study is that in patients with, infusion of acetylcholine did not significantly increase the mean blood flow, whereas in patients with colorectal cancer, acetylcholine increased the blood flow significantly. The increases of the blood flow by the infusion of SNP were similar for both groups. These results suggest that in patients

3 IOURNAL OF VASCULAR SURGERY Volume 20, Number 5 Komori et al. 805 colorectal ca. 1` ACh t SNP t rectal ca. t 1' ~,,,~eo~,~,0 ~'~'#~#~ 1` f I 100m~/min L 30see J Fig. 2. Actual recording of effect of ace@choline (30 ~g/min) and sodium nitroprusside (10 ixg/min) on mean blood flow in patient with abdominal aortic aneurysm, colorectal cancer, and abdominal aortic aneurysm and rectal cancer. Both drugs were applied at arrow. Ca., cancer. Table I. Clinical characteristics of patients Sex Age (yr) Hypertension Smoking Chol (mg/dl) TG (mg/dl) Colorectal cancer I M 66 2 M 64 3 M 67 4 M 64 5 M 69 6 F 73 1 M 64 2 M 72 3 M 67 4 M 71 5 M 72 6 M 66 AA_A + rectal cancer 1 M Cbol, serum cholesterol; TG, serum triglyceride;.m, male; F, female. with, the endothelium-dependent vasodilations of the peripheral artery were impaired. The measurement in blood flow of iliac artery may reflect the responses of the peripheral vessel bed distal to iliac artery. In the patients with colorectal cancer, acetylcholine or SNP increased the mean blood flow of the iliac artery, whereas acetylcholine or SNP did not alter mcan systemic arterial pressure. Therefore vascular resistance distal to the iliac artery by infusion of acetylcholine or SNP may be decreased, thus inducing increase in the blood flow of the iliac artery. On the other hand in the patients with, acetylcholine did not significantly increase the mean blood flow. This may be due to the fact that endothelium-dependent responses to ace@choline in the peripheral artery distal to lilac artery were impaired. The impairment of endothelium-dependent responses in patients with may not be due to changes in responsiveness of vascular smooth-muscle cells, because the relaxations to sodium nitroprusside, which induces relaxations by activation of guanylate cyclase as does endothelium-derived relaxing factor, 14,15 were not altered. The production or release of endothelium-derived relaxing factor may be depressed, because the peripheral arteries of patients with usually have an atherosclerotic change. Provided they are not associated with cystic medial

806 Komori et al. November i994.a (%) 0 50-0.1 r~ 25- ct~ < r..) Z ~. 0 8-+-3 T I P < 0.05 43 4 --l-- iniiiiiiiiniin i{!!i! i!!i!i! il i!i!i!i!i!n i!i!!ii!iiiiiiiiiiiii!ii iiiiiii iiiiiii i i!

4 806 Komori et al. November i994.a (%) r~ 25- ct~ < r..) Z ~ T I P < l-- iniiiiiiiiniin i{!!i! i!!i!i! il i!i!i!i!i!n i!i!!ii!iiiiiiiiiiiii!ii iiiiiii iiiiiii i i! iiiii i;iiiiiiiiiiiiiiiiiiiiiiiiiiliiiii;i!i!iliiiiii! Colorectal Ca. Fig. 3. Effect of acetylcholine on mean blood flow. Infusion of acetylcholine (30 txg/min) increased mean blood flow significantly in patients with colorectal cancer, whereas in patient with abdominal aortic aneurysm it did not significantly increase blood flow. Data are mean + SE (n = 6 observations). Ca., Cancer. necrosis (Marfan's syndrome) or hypertensive dissection, most aneurysms are generally presumed to be atherosclerotic in origin, n Impaired endotheliumdependent relaxations to acetylcholine in hypercholesterolemia or atherosclerosis have been reported in the porcine iliac artery, s monkey iliac artery, 8 and human coronary artery. 9,1 Reduction in the response to acetylcholine in the endothelial ceils of patients with may be due to loss of acetylcholine receptors, loss of coupling mechanisms, or loss of production of nitric oxide. The endothelium modulates the underlying vascular smooth muscle by releasing the potent vasodilator, endothelium-derived relaxing factor, 1,2 and other factors such as endothelium derived hyperpolarizing factor ~6 or endothelium-derived contracting factor. 17 Endothelium-derived relaxing factor not only relaxes vascular smooth muscle but also reduces platelet adhesion 18 and is in itself a potent antiaggregatory substance.1921 One characteristic of a diseased vascular wall is impairment of the endotheliumdependent relaxations. This characteristic has been demonstrated repeatedly in hypertensive animals and in those with atherosclerosis, a8,gz In human beings atherosclerotic arteries do not relax when infused in situ with acetylcholine; instead a paradoxical vasoconstriction occurs. 9,m In addition it has been clinically observed that aortic aneurysm and peripheral 0 M ct~ < ~a z (%) ,...~ i!iiiiii!!i!in!ni!i!ii!i!iil iiiiiiii!!!ii!iiiiiiiiiiiiiiiiiii!i!iiiiiiiiiiiiiiiiii ::::::::::%:::::::::::::::::::::::::::::::::::::::: ::::::::::::::::::::::::::::::::::5:::::::::::::::::: ::::::: 50- iiiiiiiiiiimii!ii!iiiiiiiiiii!iiiiimiiiii!iiii iiiiiiiiiiiiiiiiiiiiiiiiiiii!iiiiiiiiiiiiiii iiiiii!iii!i!iiiii!iiiiiii!i!iiiiiiiiiililiiiiiiiiiiii!i i! i! i! i!i!ili! i!i! i :.:.:.:.:.:+:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:+:.:.:. ~!i!ii~!~ii!i!i!i!i!;iiiii~ii!~!i!~!i!~!~ii!i!i!i!i!~i~! iiiiiiiiiiiiiiiiiiiii!iiiiiiiiiiiiiiiiiiiiiiiiiiiiii!iiii iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii!iiii iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii I 103±12 Colorectal Ca. Fig. 4. Effect of sodium nitroprusside on mean blood flow. Infusion of sodium nitroprusside (10 txg/min) increased mean blood flow significantly in patients with abdominal aortic aneurysm and colorectal cancer. No significant difference existed between two groups. Data are mean -+ SE (n = 6 observations). Ca., Cancer. occlusive disease occur simultaneously. We obtained clear evidence that endothelium-dependent relaxations in response to acetylcholine are impaired in patients with. This impairment in the endothelium may accelerate peripheral arterial dysfunction in patients with. The authors are grateful to Mr. Timothy D. Keeley for reading the manuscript. REFERENCES 1. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth musde by acetylcholine. Nature 1980;288: Furchgott RF. Role of endothelium in response of vascular smooth muscle. Circ Res 1983;53: Vanhoutte PM. The endothelium: modulation of vascular smooth muscle tone. N Engl J Med 1988;319: Verbeuren T], Jordaens RH, Zonnekeyn LL, Van Hove CE. Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ Res 1986;58: Komori K, Shimokawa H, Vanhoutte PM. Hypercholesterolemia impairs endothelium-dependent relaxations to aggre-

Volume 20, Number 5 I(olftOri et al. 807 gating platelets in porcine iliac arteries. J VASC SURG 1989; 10:318-25. 6. Bossaler C, Hbib GB, Yamamoto H, Williams C, Wells S, Henry PD.

5 Volume 20, Number 5 I(olftOri et al. 807 gating platelets in porcine iliac arteries. J VASC SURG 1989; 10: Bossaler C, Hbib GB, Yamamoto H, Williams C, Wells S, Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest 1987;79: Luscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 1986;8: Frieman RC, Mitchell GG, Heistad DD, Armstrong ML, Harrison DG. Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylchollne and thrombin in primates. Circ Res 1986;58: Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986;315: Werns SW, Walton JA, Hsia HH, Nabel EG, 8anz ML, Pitt B. Evidence of endothelial dysfimction in angiographically normal coronary arteries of patients with atherosclerotic coronary. Circulation 1989;79: Hertzer NR. Abdominal aortic and lilac aneurysms. In: Haimovici H, ed. Vascular surgery. 3rd ed. Norwalk, Conn.: Appleton & Lange, 1989: Liao JK, Bettmann MA, Sandor T, Tucker JI, Coleman SM, Creager MA. Differential impairment of vasodilator responsiveness of peripheral resistance and conduit vessels in htunans with atherosclerosis. Circ Res 1991;68:I Egashira K, Inou T, Hirooka Y, Yamada A, Maruoka Y, Kai H, Sugimachi M, Suzuki S, Takeshita A. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993;91: I(appaport RM, Murad F. Agonist-induced endotheliumdependent relaxations in rat thoracic aorta may be mediated through C-GMP. Circ Res 1983;52: Ignarro LJ, Kadowitz PJ. The pharmacological and physiological role of cyclic GMP in vascular smooth muscle relaxation. Ann Rev Pharmacol Toxicol 1985;25: Komori K, Vanhoutte PM. Endothelium-derived hyperpolarizing factor. Blood Vessels 1990;27: Vanhoutte PM, Katusic ZS. Endothelium-derived contracting factor: endothelin and/or superoxide anion? Trends Pharmacol Sci 1988;9: Sneddon JM, Vane JR. Endothelium-derived relaxing factor reduces platelet adhesion to bovine endothelial cells. Proc Natl Acad Sci U S A 1988;85: Azuma H, Ishikawa M, Sekizaki S. Endothelimxl-dependent inhibition of platelet aggregation. Br l Pharmacol 1!)86;88: Radomski MW, Palmer RMJ, Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br }" Pharmacol I987;92: I. Furlong B, Henderson AH, Lews MJ, Smith JA. Endothelium-derived relaxing factor inhibits in vitro platelet aggregation. Br J Pharmacol 1987;90: Jayakody L, Senarme M, Thompson M, Kappagoda T. Endothelium-dependent relaxation in experimental atherosclerosis in the rabbit. Circ Res 1987;60: Submitted Jan. 19, 1994; accepted June 13, i994.

PCTH 400. Endothelial dysfunction and cardiovascular diseases. Blood vessel LAST LECTURE. Endothelium. High blood pressure

PCTH 400. Endothelial dysfunction and cardiovascular diseases. Blood vessel LAST LECTURE. Endothelium. High blood pressure PCTH 400 LAST LECTURE Endothelial dysfunction and cardiovascular diseases. Classic Vascular pharmacology -chronic -systemic Local Vascular pharmacology -acute -targeted High blood pressure Blood pressure