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Angiotensin converting enzyme inhibitors and endothelial dysfunction
EDITORIAL
AJH 1995; 8:425-445
Angiotensin Converting Enzyme Inhibitors and Endothelial Dysfunction Oscar A. Carretaro
A
sion, diabetes, or hyperlipidemia, imbalance of these systems may result in endothelial dysfunction and could have serious consequences, including vasospasm of coronary and cerebral arteries, peripheral artery disease, thrombosis, atherosclerosis, more severe hypertension, and cardiac dysfunction. For a 5 more detailed review, see Flavahan and Vanhoutte. ACE inhibitors act in part by inhibiting kinin hydrolysis by the endothelium. In tum, kinins stimulate the release of prostaglandins, NO, EDHF, and tPA. The release of these intermediaries may vary in different vascular beds, since there are morphological and functional variations in the endothelium lining different vessels as well as in different species. In this symposium, Mombouli et al6 review the role of EDHF in human and canine coronary vasodilation caused by bradykinin. Although it is known that EDHF causes hyperpolarization and relaxation of some arteries and arterioles in various species via activating K+ -channels, the exact nature of EDHF remains elusive. Desta et af present data suggesting that in canine coronary arteries exposed to bradykinin and then washed extensively, perindoprilat by itself causes ~e laxation that is blocked by either a kinin antagomst (Hoe 140) or an inhibitor of NO synthase (NOS), nitro-L-arginine. On the other hand, the effect of bradykinin on the dog coronary artery is only minim~lly blocked by NO inhibition, as shown by Mombouli ~t al. 6 Thus, in arteries previously exposed to brad~ki nin, ACE inhibitors, acting via kinins, primarily stimulate the presence of NO and not EDHF ~r prostaglandins. At present it is difficult to explam these differences; however, they could be related to synergy between low kinin concentrations and a dir~ct effect of perindoprilat. It is known that vascular tisFrom the Hypertension and Vascular Research Division, Heart sue can synthesize the4 various components of the and Vascular Institute and Department of Medicine, Henry Ford kallikrein-kinin system ; Desta's data also suggest Health Sciences Center, Detroit, Michigan. that the vascular wall may bind kinins and thus ~ct as Address correspondence and reprint requests to Oscar A. a storage site for these peptides. This may explam the Carretero, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI recent results of Campbell et al, 8 who have shown 48202.
ngiotensin converting enzyme (ACE) inhibitors have become an important therapeutic tool, not only as an antihypertensive drug, but also in the treatment of congestive heart failure. Clinical trials in patients with heart failure and experimental studies in animals suggest that ACE inhibitors may have beneficial effects that go beyond their antihypertensive action by preventing endothelial dysfunction. This symposium on the ACE inhibitor perindopril addresses the mechanisms by which ACE inhibitors may act on the endothelium. In addition to preventing conversion of angiotensin I to 11/ ACE inhibitors have other effects, among them inhibiting the hydrolysis of peptides such as bradykinin/ 1 substance P, and many others. 2 Though most ACE inhibitor effects are mediated by inhibition of ACE, inhibition of other enzymes3 as well as direct effects cannot be completely excluded (Figure 1). The endothelium contains receptors for some peptides known to be hydrolyzed by ACE inhibitors. These receptors activate intracellular signals that in turn cause the formation or release of key autacoids, such as nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), superoxide anions, eicosanoids, cell ad-hesion molecules, von Willebrand factor, tissue plasminogen activator (tPA), endothelial growth-promoting and -inhibiting factors, antioxidant enzymes, and mucopolysaccharides. 4 Through these systems the endothelium controls vascular resistance and structure and the fluidity of the blood, regulates adhesion and migration of inflammatory cells, and also helps regulate organ function. As the result of pathological processes, such as hyperten-
~ 1995
by the American Journal of Hypertension, Ltd.
0895-70611951$9.50 0895-7061(95)OO139-G
A]H-MAY1995-VOL. 8, NO.5, PART 2
EDITORIAL 435
Hypothetical mechanisms by which ACE inhibitors lower blood pressure and decrease cardiovascular morbidity and mortality: 1) inhibiting the conversion of angiotensin I to II, thereby diminishing both its direct effects and those mediated by various hormones and autacoids; 2) inhibiting kinin hydrolysis in various tissues and thereby increasing local kinin concentrations. Kinins have both direct effects and effects that are mediated by various autacoids, such as prostaglandins, NO, and endotheliumderived hyperpolarizing factor (EDHF). They increase glucose UP"' take and release tissue plasminogen -Oirec;t oOpiold ~pt. activator (tPA); 3) increasing an-Direct -PGIL oKlnlna -Substance P -Aldosterone giotensin I-derived fragments such -NO -!!Q oNeurOCIanaln -S~ ActIVity as angiotensin 1-7, which have bio-§QtiE oEOHF oChImot. -TxA./PGH. -Glucose upt. logical activity. Their effects have -2!!!!.!! -LHRHoete -Growth Fac:un -tPA been postulated to be mediated by kinins, prostaglandins, and nitric oxide (NO); 4) inhibiting the hydrolysis of other peptide substrates for ACE. Their role in the effects of ACE inhibitors is not well established; 5) ACE inhibitors may have a direct effect, especially those with the SH group. They may act as scavengers of free radicals and thereby increase NO. Some ACE inhibitors also reverse the tachyphylaxis which occurs in response to repeated administration of nitrates (ND-TNG).
HYPOTHETICALMECHANISMSOFACTION OF ANGIOTENSIN-CONYERTING ENZYME INHIBITORS
that the concentration of kinins in cardiovascular tissue is much higher than in plasma. In hypertension, endothelium-dependent vasodilation is altered, and this appears to be secondary to the increase in blood pressure since it is present in various models of secondary hypertension and is reversed along with the hypertension. 9 In this symposium Nitenberg et al10 show that a cold pressor test induces increased flow velocity and vasodilation in the epicardial coronary arteries. Conversely, in patients with essential hypertension whose coronary arteries were normal on angiographic examination and had no other coronary risk factors, this flowdependent vasodilation was converted to vasoconstriction. The coronary response to an endotheliumindependent vasodilator was preserved in hypertensive patients. Ito et al have also found that endothelium-dependent relaxation was impaired in the renal afferent arterioles of spontaneously hypertensive rats (SHR); however, the defect did not involve EORF but rather was due to increased release of an endothelium-dependent constricting factor (EOCF), in this case endoperoxide/thromboxane. l l Recently it was also reported that EOHF is altered in the mesenteric circulation of SHR. 12 Thus at present it is difficult to say that in essential hypertension without vascular lesions there is a decrease in EORF or EOHF or an increase in EOCF; however, it is certain
FIGURE 1.
that the balance between vasoconstrictors and vasodilators is altered in favor of the former. Thuillez et al13 show that in rats with left ventricular dysfunction, endothelium-dependent relaxation is impaired in small arterioles but preserved in large conduit arteries. However, the vasoconstrictor response to blockade of NO synthesis was unaffected. These data could be interpreted as an indication that in this model there is a decrease in EOHF or an increase in EDCF. The ACE inhibitor perindopril reversed some of the hemodynamic changes as well as the altered endothelial dysfunction. The role of kinins and NO in the effect of ACE inhibitors is not limited to vasodilation. We have shown that kinins and NO mediate the suppression of neointima formation by ACE inhibitors. 14 This suggests that these autacoids are also involved in the regulation of cell growth and proliferation or migration. ACE inhibitors decrease myocardial infarct size due to ischemia and reperfusion, and this effect also appears to be mediated by kinins via the release of prostaglandins and NO. IS This may be due to a scavenger effect of NO on superoxides. Whether EOHF participates in these protective effects of ACE inhibitors needs to be studied further. However, it is becoming very clear that ACE inhibitors do more than just block the conversion of angiotensin I to II, and that their influence on the endothelium via autacoids,
44S EDITORIAL
AJH-MAY 1995-VOL. 8, NO.5, PART 2
such as kinins, prostaglandins, NO, and EDHF, is part of their therapeutic effect.
8.
REFERENCES
9.
1.
Carretero OA, Scicli AG, Maitra SR: Role of kinins in t~e.phar~acologi~aleffects of converting enzyme inhibitors, In Horovitz ZP (ed): Angiotensin Converting Enzyme Inhibitors. Mechanisms of Action and Clinical Implications. Baltimore, Urban & Schwarzenberg, 1981, pp 105-121. 2. Erdos EG: Angiotensin I converting enzyme and the changes in our concepts through the years. Lewis K. Dahl memorial lecture. Hypertension 1990;16:363-370. 3. Hooper NM, Hryszko J, Oppong SY, et al: Inhibition by converting enzyme inhibitors of pig kidney aminopeptidase P. Hypertension 1992;19:281-285. 4. Carretero OA, Scicli AG: The kallikrein-kinin system as a regulator of cardiovascular and renal function, in Laragh JH, Brenner BM (eds): Hypertension: Physiology, Diagnosis, and Management, 2nd Ed. New York, Raven Press, 1995, pp 983-999. 5. ~avahan NA, Va~houtte PM: Endothelial cell signal109 and endothelIal dysfunction. Am J Hypertens 1995;8:00~OO.
6.
7.
Mombouli J-V, Vanhoutte PM: Endothelium-derived hrPerpolarizing factor(s) and the potentiation of kinms by converting-enzyme inhibitors. Am J Hypertens 1995;8:00~00. Desta B, Vanhoutte PM, Boulanger CM: Inhibition of the angiotensin converting enzyme by perindoprilat ~~~ase of nitric oxide. Am J Hypertens 1995;8:
10.
11.
12.
13.
Campbell DJ, Kladis A, Duncan AM: Bradykinin peptides in kidney, blood, and other tissues of the rat. Hypertension 1993;21:155-165. Lockette W, Otsuka Y, Carretero OA: The loss of endothelium-dependent vascular relaxation in hypertension. Hypertension 1986;8(suppl 11):11-61-11-66. Nitenberg A, Antony I, Aptecar E, et al: Impairment of flow-dependent coronary dilation in hypertensive patients. Demonstration by cold pressor test-induced flow velocity increase. Am J Hypertens 1995;8:0~ 000. Ito S, Juncos LA, Carretero OA: Pressure-induced constriction of the afferent arteriole of spontaneously hypertensive rats. Hypertension 1992;19(suppl 11):11164-11-167. Li J, Bian K, Bukoski RD: A non-cyclo-oxygenase, non-nitric oxide relaxing factor is present in resistance arteries of normotensive but not spontaneously hypertensive rats. Am J Med Sci 1994;307:7-14. Thuillez C, Mulder P, Elfertak L, et al: Prevention of endothelial dysfunction in small and large arteries in a model of chronic heart failure. Effect of angiotensin converting enzyme inhibition. Am J Hypertens 1995; 8:00~00.
Farhy RD, Carretero OA, Ho K-L, et al: Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res 1993;72:1202-1210. 15. Liu Y-H, Yang X-P, Sharov VG, et al: Paracrine systems in the cardioprotective effect of angiotensinconverting enzyme inhibitors on myocardial ischemia! reperfusion injury in rats. Hypertension (submitted).
14.
AJH 1995; 8:425-445
Angiotensin Converting Enzyme Inhibitors and Endothelial Dysfunction Oscar A. Carretaro
A
sion, diabetes, or hyperlipidemia, imbalance of these systems may result in endothelial dysfunction and could have serious consequences, including vasospasm of coronary and cerebral arteries, peripheral artery disease, thrombosis, atherosclerosis, more severe hypertension, and cardiac dysfunction. For a 5 more detailed review, see Flavahan and Vanhoutte. ACE inhibitors act in part by inhibiting kinin hydrolysis by the endothelium. In tum, kinins stimulate the release of prostaglandins, NO, EDHF, and tPA. The release of these intermediaries may vary in different vascular beds, since there are morphological and functional variations in the endothelium lining different vessels as well as in different species. In this symposium, Mombouli et al6 review the role of EDHF in human and canine coronary vasodilation caused by bradykinin. Although it is known that EDHF causes hyperpolarization and relaxation of some arteries and arterioles in various species via activating K+ -channels, the exact nature of EDHF remains elusive. Desta et af present data suggesting that in canine coronary arteries exposed to bradykinin and then washed extensively, perindoprilat by itself causes ~e laxation that is blocked by either a kinin antagomst (Hoe 140) or an inhibitor of NO synthase (NOS), nitro-L-arginine. On the other hand, the effect of bradykinin on the dog coronary artery is only minim~lly blocked by NO inhibition, as shown by Mombouli ~t al. 6 Thus, in arteries previously exposed to brad~ki nin, ACE inhibitors, acting via kinins, primarily stimulate the presence of NO and not EDHF ~r prostaglandins. At present it is difficult to explam these differences; however, they could be related to synergy between low kinin concentrations and a dir~ct effect of perindoprilat. It is known that vascular tisFrom the Hypertension and Vascular Research Division, Heart sue can synthesize the4 various components of the and Vascular Institute and Department of Medicine, Henry Ford kallikrein-kinin system ; Desta's data also suggest Health Sciences Center, Detroit, Michigan. that the vascular wall may bind kinins and thus ~ct as Address correspondence and reprint requests to Oscar A. a storage site for these peptides. This may explam the Carretero, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI recent results of Campbell et al, 8 who have shown 48202.
ngiotensin converting enzyme (ACE) inhibitors have become an important therapeutic tool, not only as an antihypertensive drug, but also in the treatment of congestive heart failure. Clinical trials in patients with heart failure and experimental studies in animals suggest that ACE inhibitors may have beneficial effects that go beyond their antihypertensive action by preventing endothelial dysfunction. This symposium on the ACE inhibitor perindopril addresses the mechanisms by which ACE inhibitors may act on the endothelium. In addition to preventing conversion of angiotensin I to 11/ ACE inhibitors have other effects, among them inhibiting the hydrolysis of peptides such as bradykinin/ 1 substance P, and many others. 2 Though most ACE inhibitor effects are mediated by inhibition of ACE, inhibition of other enzymes3 as well as direct effects cannot be completely excluded (Figure 1). The endothelium contains receptors for some peptides known to be hydrolyzed by ACE inhibitors. These receptors activate intracellular signals that in turn cause the formation or release of key autacoids, such as nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), superoxide anions, eicosanoids, cell ad-hesion molecules, von Willebrand factor, tissue plasminogen activator (tPA), endothelial growth-promoting and -inhibiting factors, antioxidant enzymes, and mucopolysaccharides. 4 Through these systems the endothelium controls vascular resistance and structure and the fluidity of the blood, regulates adhesion and migration of inflammatory cells, and also helps regulate organ function. As the result of pathological processes, such as hyperten-
~ 1995
by the American Journal of Hypertension, Ltd.
0895-70611951$9.50 0895-7061(95)OO139-G
A]H-MAY1995-VOL. 8, NO.5, PART 2
EDITORIAL 435
Hypothetical mechanisms by which ACE inhibitors lower blood pressure and decrease cardiovascular morbidity and mortality: 1) inhibiting the conversion of angiotensin I to II, thereby diminishing both its direct effects and those mediated by various hormones and autacoids; 2) inhibiting kinin hydrolysis in various tissues and thereby increasing local kinin concentrations. Kinins have both direct effects and effects that are mediated by various autacoids, such as prostaglandins, NO, and endotheliumderived hyperpolarizing factor (EDHF). They increase glucose UP"' take and release tissue plasminogen -Oirec;t oOpiold ~pt. activator (tPA); 3) increasing an-Direct -PGIL oKlnlna -Substance P -Aldosterone giotensin I-derived fragments such -NO -!!Q oNeurOCIanaln -S~ ActIVity as angiotensin 1-7, which have bio-§QtiE oEOHF oChImot. -TxA./PGH. -Glucose upt. logical activity. Their effects have -2!!!!.!! -LHRHoete -Growth Fac:un -tPA been postulated to be mediated by kinins, prostaglandins, and nitric oxide (NO); 4) inhibiting the hydrolysis of other peptide substrates for ACE. Their role in the effects of ACE inhibitors is not well established; 5) ACE inhibitors may have a direct effect, especially those with the SH group. They may act as scavengers of free radicals and thereby increase NO. Some ACE inhibitors also reverse the tachyphylaxis which occurs in response to repeated administration of nitrates (ND-TNG).
HYPOTHETICALMECHANISMSOFACTION OF ANGIOTENSIN-CONYERTING ENZYME INHIBITORS
that the concentration of kinins in cardiovascular tissue is much higher than in plasma. In hypertension, endothelium-dependent vasodilation is altered, and this appears to be secondary to the increase in blood pressure since it is present in various models of secondary hypertension and is reversed along with the hypertension. 9 In this symposium Nitenberg et al10 show that a cold pressor test induces increased flow velocity and vasodilation in the epicardial coronary arteries. Conversely, in patients with essential hypertension whose coronary arteries were normal on angiographic examination and had no other coronary risk factors, this flowdependent vasodilation was converted to vasoconstriction. The coronary response to an endotheliumindependent vasodilator was preserved in hypertensive patients. Ito et al have also found that endothelium-dependent relaxation was impaired in the renal afferent arterioles of spontaneously hypertensive rats (SHR); however, the defect did not involve EORF but rather was due to increased release of an endothelium-dependent constricting factor (EOCF), in this case endoperoxide/thromboxane. l l Recently it was also reported that EOHF is altered in the mesenteric circulation of SHR. 12 Thus at present it is difficult to say that in essential hypertension without vascular lesions there is a decrease in EORF or EOHF or an increase in EOCF; however, it is certain
FIGURE 1.
that the balance between vasoconstrictors and vasodilators is altered in favor of the former. Thuillez et al13 show that in rats with left ventricular dysfunction, endothelium-dependent relaxation is impaired in small arterioles but preserved in large conduit arteries. However, the vasoconstrictor response to blockade of NO synthesis was unaffected. These data could be interpreted as an indication that in this model there is a decrease in EOHF or an increase in EDCF. The ACE inhibitor perindopril reversed some of the hemodynamic changes as well as the altered endothelial dysfunction. The role of kinins and NO in the effect of ACE inhibitors is not limited to vasodilation. We have shown that kinins and NO mediate the suppression of neointima formation by ACE inhibitors. 14 This suggests that these autacoids are also involved in the regulation of cell growth and proliferation or migration. ACE inhibitors decrease myocardial infarct size due to ischemia and reperfusion, and this effect also appears to be mediated by kinins via the release of prostaglandins and NO. IS This may be due to a scavenger effect of NO on superoxides. Whether EOHF participates in these protective effects of ACE inhibitors needs to be studied further. However, it is becoming very clear that ACE inhibitors do more than just block the conversion of angiotensin I to II, and that their influence on the endothelium via autacoids,
44S EDITORIAL
AJH-MAY 1995-VOL. 8, NO.5, PART 2
such as kinins, prostaglandins, NO, and EDHF, is part of their therapeutic effect.
8.
REFERENCES
9.
1.
Carretero OA, Scicli AG, Maitra SR: Role of kinins in t~e.phar~acologi~aleffects of converting enzyme inhibitors, In Horovitz ZP (ed): Angiotensin Converting Enzyme Inhibitors. Mechanisms of Action and Clinical Implications. Baltimore, Urban & Schwarzenberg, 1981, pp 105-121. 2. Erdos EG: Angiotensin I converting enzyme and the changes in our concepts through the years. Lewis K. Dahl memorial lecture. Hypertension 1990;16:363-370. 3. Hooper NM, Hryszko J, Oppong SY, et al: Inhibition by converting enzyme inhibitors of pig kidney aminopeptidase P. Hypertension 1992;19:281-285. 4. Carretero OA, Scicli AG: The kallikrein-kinin system as a regulator of cardiovascular and renal function, in Laragh JH, Brenner BM (eds): Hypertension: Physiology, Diagnosis, and Management, 2nd Ed. New York, Raven Press, 1995, pp 983-999. 5. ~avahan NA, Va~houtte PM: Endothelial cell signal109 and endothelIal dysfunction. Am J Hypertens 1995;8:00~OO.
6.
7.
Mombouli J-V, Vanhoutte PM: Endothelium-derived hrPerpolarizing factor(s) and the potentiation of kinms by converting-enzyme inhibitors. Am J Hypertens 1995;8:00~00. Desta B, Vanhoutte PM, Boulanger CM: Inhibition of the angiotensin converting enzyme by perindoprilat ~~~ase of nitric oxide. Am J Hypertens 1995;8:
10.
11.
12.
13.
Campbell DJ, Kladis A, Duncan AM: Bradykinin peptides in kidney, blood, and other tissues of the rat. Hypertension 1993;21:155-165. Lockette W, Otsuka Y, Carretero OA: The loss of endothelium-dependent vascular relaxation in hypertension. Hypertension 1986;8(suppl 11):11-61-11-66. Nitenberg A, Antony I, Aptecar E, et al: Impairment of flow-dependent coronary dilation in hypertensive patients. Demonstration by cold pressor test-induced flow velocity increase. Am J Hypertens 1995;8:0~ 000. Ito S, Juncos LA, Carretero OA: Pressure-induced constriction of the afferent arteriole of spontaneously hypertensive rats. Hypertension 1992;19(suppl 11):11164-11-167. Li J, Bian K, Bukoski RD: A non-cyclo-oxygenase, non-nitric oxide relaxing factor is present in resistance arteries of normotensive but not spontaneously hypertensive rats. Am J Med Sci 1994;307:7-14. Thuillez C, Mulder P, Elfertak L, et al: Prevention of endothelial dysfunction in small and large arteries in a model of chronic heart failure. Effect of angiotensin converting enzyme inhibition. Am J Hypertens 1995; 8:00~00.
Farhy RD, Carretero OA, Ho K-L, et al: Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res 1993;72:1202-1210. 15. Liu Y-H, Yang X-P, Sharov VG, et al: Paracrine systems in the cardioprotective effect of angiotensinconverting enzyme inhibitors on myocardial ischemia! reperfusion injury in rats. Hypertension (submitted).
14.