(Circulation. 1997;95:176-182.)
© 1997 American Heart Association, Inc.
Articles |
ACE Inhibitors Promote Nitric Oxide Accumulation to Modulate Myocardial Oxygen Consumption
the Departments of Physiology and Pharmacology (A.N.), New York Medical College, Valhalla.
Correspondence to Thomas H. Hintze, PhD, Professor, Department of Physiology, New York Medical College, Valhalla, NY 10595.
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Abstract |
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Background ACE inhibitors potentiate kinin–nitric oxide (NO)–dependent coronary vascular dilation, and NO can modulate myocardial oxygen consumption. Whether ACE inhibitors also affect myocardial O2 consumption has not been established.
Methods and Results Production of nitrite, a metabolite of NO in aqueous solution, in coronary microvessels and O2 consumption in myocardium were quantified with the use of in vitro tissue preparations, the Greiss reaction, and a Clark-type O2 electrode. In coronary microvessels, kininogen (the precursor of kinin; 10 µg/mL) and three ACE inhibitors (captopril, enalaprilat, or ramiprilat; 10-8 mol/L) increased nitrite production from 76±6 to 173±15, 123±12, 125±12, and 153±12 pmol/mg, respectively (all P<.05). In myocardium, kininogen (10 µg/mL) and captopril, enalaprilat, or ramiprilat (10-4 mol/L) reduced cardiac O2 consumption by 41±2%, 19±3%, 25±2%, and 35±2%, respectively. The changes in both nitrite release and O2 consumption in vitro were blocked by N
-nitro-L-arginine methyl ester or N-nitro-L-arginine, inhibitors of endogenous NO formation. The effects were also blocked by HOE 140, which blocks the bradykinin B2-kinin receptor, and serine protease inhibitors, which inhibit local kinin formation.
Conclusions Our data indicate that stimulation of local kinin formation by use of a precursor for kinin formation or inhibition of kinin degradation by use of ACE inhibitors increases NO formation and is important in the control of cardiac O2 consumption. Vasodilation and control of myocardial O2 consumption by NO may contribute importantly to the therapeutic actions of ACE inhibitors in cardiac disease states.
Key Words: endothelium-derived factors • oxygen • enzymes
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Introduction |
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The endothelium controls vascular smooth muscle tone by producing relaxing and contracting factors.1 Together with shear stress, vasoactive substances that are generated locally by the vasculature, such as kinins, regulate the release of endothelial mediators. The equilibrium between the rate of kinin production in blood vessels and its degradation by kininases may determine the extent of the contribution of these peptides in regulating vascular tone. Kinins are potent vasoactive peptides formed by the enzymatic action of kininogenases on kininogen.2 Because blood vessels contain kinin-generating enzymes and kininogen, endothelial cells are capable of producing kinins from an endogenous source.2 3
It is believed that kinins act as vasoactive substances to cause arterial vessel dilation through the release of NO from endothelium after the activation of B2-kinin receptors.1 2 3 4 5 6 7 8 9 10 Endothelium-derived NO is formed during the metabolism of L-arginine by NO synthase, and NO causes vascular smooth muscle relaxation generally through cGMP-dependent mechanisms.11 12 NO is also produced in cytotoxic activated macrophages, in which it is thought to inhibit mitochondrial respiration of target cells.13 Cytotoxic activated macrophages have been shown to induce intracellular iron loss and inhibition of enzymes such as aconitate hydratase and complex I and complex II of the mitochondrial electron transport chain.14 All of these enzymes have catalytically active nonheme iron coordinated to sulfur, which could be the site of interaction of NO with these enzymes. The inhibitory effects of NO or reactive oxygen species derived from NO are believed to be caused by degradation of the iron-sulfur centers, resulting in the release of Fe ions as iron-nitrosyl complexes. Thus, mammalian mitochondria are sensitive targets for the cytotoxic effect of NO.15 16
Interestingly, a recent study by Shen et al17 has shown that a NO synthase inhibitor can significantly increase whole-body O2 consumption in conscious dogs, suggesting that basal NO release may contribute to the regulation of normal tissue O2 use. King et al18 also suggested a role of endothelium-derived NO in the regulation of skeletal muscle blood flow and suggested that this must be considered in conjunction with its associated effects on O2 demand. In particular, more recent studies from our laboratory19 indicate that endogenous and exogenous NO production can significantly inhibit tissue O2 consumption in dog skeletal muscle slices. From these studies, we reasoned that constitutive NO production from the endothelium of blood vessels can regulate mitochondrial function in the parenchymal cells of peripheral tissue. However, no data are now available concerning the effect of kinin generation on the control of tissue cellular respiration. Because NO production can be stimulated by kinins and it has been shown that there is a local kinin-forming system in canine coronary blood vessels,20 21 22 we hypothesized accordingly that endogenous kinin formation in canine coronary microvessels can modulate local vascular endothelial NO production, which may subsequently inhibit myocardial mitochondrial O2 consumption.
Our present study was carried out to determine (1) whether stimulation of local kinin formation with kininogen and inhibition of kinin degradation with ACE inhibitors can increase NO production in isolated coronary microvessels and (2) whether this kinin-induced NO generation also controls cardiac myocyte O2 consumption in isolated segments of cardiac tissue containing both blood vessels and myocytes.
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Methods |
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Twelve male mongrel dogs (body weight, 21 to 29 kg) were used. Hearts were obtained immediately from pentobarbital-anesthetized dogs and kept in ice-cold PBS containing 0.1% bovine serum albumin at pH 7.4. All of the studies in dogs were approved by the Institutional Animal Care and Use Committee of New York Medical College and conform to current NIH and American Physiological Society guidelines for the use and care of laboratory animals.
Isolation of Coronary Microvessels
The isolation of coronary microvessels from the left ventricle of dog heart was performed by use of the method developed by Gerritsen and Printz23 with minor changes.21
Incubation of Coronary Microvessels
Microvessels were placed in a small package of 80-µm nylon mesh, transferred into a tissue bath containing PBS, and oxygenated with 95% O2 and 5% CO2 for 30 minutes. Approximately 20 mg (wet weight) of tissue was placed in 5-mL plastic tubes that contained 500 µL PBS as control or 450 µL PBS and 50 µL of drugs used to stimulate (eg, ramiprilat and kininogen) or inhibit (eg, L-NAME) NO formation by the coronary microvessels. At the end of the incubation period, the tubes were removed from the bath, the microvessels were removed from the tubes, and sulfanilamide (450 µL of 1%) and NEDA (50 µL of 0.2%) were added to each tube for diazotization of sulfanilic acid by NO. After 5 to 10 minutes' incubation at room temperature, the supernatant was removed from each tube. NO was measured as nitrite, the major metabolite of NO in aqueous solution, by use of a spectrophotometer (Uvikon 930 spectrophotometer, Kontron Instruments Inc) to determine the increase in absorbance at 540 nm in relation to a standard curve generated by known concentrations of nitrite.21
To construct a standard curve for nitrite, a stock solution of NaNO2 (10-5 mol/L) and two sets of tubes that contained 500 µL of 0, 1, 2.5, 5, 7.5, and 10 µmol/L of NaNO2 were prepared. Sulfanilamide (450 µL of 1%) and NEDA (50 µL of 0.2%) were added to each tube and mixed well. The tubes were allowed to stand at room temperature for 5 to 10 minutes for full color (pink) development, and absorbance of nitrite was measured at 540 nm. Absorbance was computed and converted to a straight line by use of linear regression analysis (y=a+bx, R>.99).
Effects of ACE Inhibitors on NO Production by Coronary Microvessels
Coronary microvessels (20 mg) were placed in each tube containing 500 µL PBS as control or 450 µL PBS and 50 µL of 10-10 to 10-1 mol/L of captopril, enalaprilat, or ramiprilat, and nitrite was measured. To assess the role of kinins in the effects of ACE inhibitors, 50 µL of 10-5 mol/L HOE 140 (a specific B2-bradykinin receptor antagonist) was preincubated (all preincubations were for 20 minutes) with tissues before addition of the highest dose of captopril, enalaprilat, or ramiprilat. To determine if nitrite production reflects NO production, the highest dose of captopril, enalaprilat, or ramiprilat was incubated with tissue in the presence of 10-4 mol/L L-NAME, an NO synthase inhibitor. Nitrite was measured. To determine the role of kinin-forming enzymes, the highest dose of captopril, enalaprilat, or ramiprilat was incubated with tissue in the presence of three serine protease inhibitors: TI 100 µg/mL, DCIC 10-5 mol/L, or aprotinin 500 KIU/mL. Nitrite was measured.
Effects of Kininogen on Production of NO by Coronary Microvessels
Increasing amounts of kininogen (0.5 to 10 µg/mL; 50 µL) were added to 450 µL PBS that contained 20 mg of coronary microvessels, and nitrite was measured. HOE 140 (10-5 mol/L), L-NAME (10-4 mol/L), TI (100 µg/mL), DCIC (10-5 mol/L), and aprotinin (500 KIU/mL) were also incubated with tissue 20 minutes before addition of 10 µg/mL kininogen, and nitrite production was measured.
Preparation of Muscle Slices and Determination of O2 Consumption
Myocardial muscle isolated from the left ventricular free wall was freed of epicardium, endocardium, connective tissue, fat, and large arteries and was cut into 30- to 50-mg segments. Before studies of tissue respiration were conducted, these muscle segments were bathed at 37°C for 2 hours in Krebs' solution in which 21% O2/5% CO2/74% N2 was bubbled continuously. Oxygen uptake by muscle slices was measured polarographically with a Yellow Springs Instrument Co apparatus consisting of a YSI model 5300 biological O2 monitor and a Clark-type O2 electrode (YSI 5331). Oxygen consumption studies were performed at 37°C in a stirred 1- to 10-mL bath (YSI 5301) containing 3 mL air-saturated Krebs' solution buffered with 10 mmol/L HEPES (pH 7.4). Tissue respiration was calculated as the rate of decrease in O2 concentration after the addition of muscle slices, assuming an initial O2 concentration of 224 nmol/mL, and was expressed as nanomoles of O2 consumed per minute per gram of tissue. Oxygen uptake by muscle slices was only monitored during the first one third of O2 consumed. The typical observation time for each dose of agent was 5 minutes, and new muscle segments were used for each drug examined. Sodium cyanide (1 mmol/L) was added at the end of each respiration measurement to confirm that the change in O2 consumption was from mitochondrial sources.
Effects of ACE Inhibitors and Kininogen on Cardiac Muscle O2 Consumption
Captopril, enalaprilat, ramiprilat (each 10-7 to 10-4 mol/L), or kininogen (0.5 to 10 µg/mL) was added to the tissue bath in a cumulative concentration-dependent manner, and the effects on muscle O2 consumption were recorded. The effects of captopril, enalaprilat, ramiprilat, and kininogen were determined in the presence and absence of 10-4 mol/L L-NNA, a specific NO synthase inhibitor, or HOE 140. The effect of L-NNA or HOE 140 alone on tissue respiration was also examined. The change in O2 consumption was reported.
Drugs and Chemicals
Drugs and chemicals were purchased from Sigma Chemical Co. Ramiprilat and HOE 140 were generously supplied by Hoechst-Roussel Inc (Somerville, NJ). Bovine kininogen was purchased from Seikagaku Kogyo Co Ltd. L-NNA was purchased from Aldrich.
Statistical Analysis
Data are expressed as mean±SEM. Differences of nitrite production from control were determined by use of ANOVA. Differences of O2 consumption in the mean values were analyzed by use of a Student's t test. A value of P<.05 was considered statistically significant. Statistical analysis and graphs were produced on a 486 computer (Everex) with the use of commercially available software (Lotus 1-2-3; GB-Stat; and Slide Write).
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Effects of ACE Inhibitors on NO Production by Coronary Microvessels
The production of nitrite in response to all three ACE inhibitors was increased in a concentration-related manner in these coronary microvessels. The actual changes in nitrite production are shown in Fig 1
. Compared with control, captopril (10-8 to 10-6 mol/L), enalaprilat (10-10 to 10-7 mol/L), and ramiprilat (10-10 to 10-1 mol/L) substantially increased nitrite production by 66±13%, 83±10%, and 97±10%, respectively (P<.01). Nitrite production during stimulation by the highest concentration of these drugs was significantly decreased by L-NAME, HOE 140, TI, DCIC, and aprotinin (Fig 2).
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Effects of Kininogen on Production of NO by Coronary Microvessels
Kininogen markedly increased nitrite production by coronary microvessels in a concentration-dependent manner (Fig 3). Compared with control, 0.5 to 10 mg/mL of kininogen increased nitrite production by a maximum of 129±11% (P<.01). Nitrite production with the highest concentration of kininogen was decreased significantly by L-NAME, HOE 140, TI, DCIC, and aprotinin (Fig 4) (all P<.01).
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Effects of ACE Inhibitors and Kininogen on Cardiac Muscle O2 Consumption
The ACE inhibitors captopril, enalaprilat, and ramiprilat (each 10-7 to 10-4 mol/L) significantly inhibited O2 consumption in canine myocardial muscle slices in a dose-related manner. The highest doses of captopril, enalaprilat, and ramiprilat reduced O2 consumption by 19±3%, 25±2%, and 35±2%, respectively. Pretreatment with L-NNA (10-4 mol/L) or HOE 140 (10-5 mol/L) abolished the reduction of tissue respiration elicited by these ACE inhibitors at all doses studied (Fig 5). L-NNA or HOE 140 alone had no effect on cardiac muscle O2 consumption. Kininogen (0.5 to 10 µg/mL) reduced myocardial muscle slice O2 consumption by 12±2% to 41±2%. This effect was completely reversed by pretreatment with L-NNA (10-4 mol/L) or HOE 140 (10-5 mol/L), as shown in Fig 6.
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Discussion |
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The most significant finding of the current study is that ACE inhibitors and kininogen can significantly increase nitrite production in isolated coronary microvessels from the dog heart and reduce O2 consumption in cardiac muscle slices. Because both of these effects were blocked by the bradykinin B2 receptor antagonist HOE 140 and by an inhibitor of NO synthesis, our findings suggest a functional linkage among vascular kinins, endothelium-derived NO, and myocardial O2 consumption. More specifically, our study suggests that mitochondrial respiration in cardiac myocytes is subject to regulation by locally formed kinins via an NO-mediated mechanism.
ACE inhibitors have both an antihypertensive and cardioprotective action and are commonly used in the treatment of hypertension and most forms of heart failure.8 The beneficial effects of ACE inhibitors were thought to be primarily due to the inhibition of angiotensin II formation. However, a number of clinical and experimental studies indicate that an additional mechanism linked to the inhibition of bradykinin degradation is also important.7 ACE is a major kininase that inactivates kinins by removing the COOH-terminal Phe-Arg. ACE is located mainly on the plasma membrane of endothelium facing the lumen. During a single passage of kinin through the blood vessels, ACE degrades kinins into inactive fragments.2 Therefore, kinins have a very short biological half-life1 because of proteolytic inactivation. ACE inhibitors can efficiently inhibit the enzymatic activity of ACE and consequently lead to the accumulation of kinin at the surface of the endothelium, with an attendant increase in NO production. In the present study, all of the ACE inhibitors (captopril, enalaprilat, and ramiprilat) significantly increased nitrite production from isolated coronary microvessels. That both L-NAME, a potent inhibitor of endothelial NO synthase,24 and HOE 140 markedly reduced the effect of ACE inhibitors suggests that ACE inhibitors most likely allow the accumulation of endothelium-derived kinins, which in turn stimulates NO production by activating the B2-kinin receptor.
An increasing number of studies3 4 5 6 7 8 9 20 25 26 27 have demonstrated that ACE inhibitors induced endothelium-dependent vasodilation in vivo and vascular ring relaxation in vitro via mechanisms involving local kinins. Schwelk et al,8 Vanhoutte et al,5 and Desta et al9 20 reported that ACE inhibitors potentiate the bradykinin-induced release of endothelium-derived NO in large arterial vessels, yet ACE inhibitors did not elicit endothelium-dependent vascular relaxation by themselves.
Our data indicated that the ACE inhibitors captopril, enalaprilat, and ramiprilat alone caused 66% to 97% increases in NO production, which were abolished by HOE 140. Consistent with our findings, Hecker et al3 7 also found that ramiprilat markedly relaxed precontracted, isolated, endothelium-intact bovine coronary artery with no previous exposure to bradykinin. The fact that ACE inhibitors by themselves increase NO production illustrates that there is an endogenous kinin-forming system in the coronary blood vessels. Our findings imply that the enzyme that forms kinins is tonically active and that kininogen is present in concentrations sufficient to account for the kinin-dependent effects of the ACE inhibitor. In the present study, three serine protease inhibitors (TI, DCIC, and aprotinin) dramatically reduced nitrite production caused by ACE inhibitors, strongly supporting the contention that there is a local kinin-forming system.
Several studies indicate that there is now strong evidence to support the existence of a local kinin-forming system in mammalian vascular tissues.28 29 30 Plasma and tissue kallikreins are the main enzymes involved in the formation of kinin from kininogen.31 Kininogens can be synthesized and stored by endothelial cells in blood vessels. Kallikreins constituting a family of genetically related serine proteases are continuously and constitutively synthesized in endothelium.1 2 Previous studies demonstrated that exogenous tissue kallikrein can elicit relaxation of isolated canine coronary artery rings with endothelium20 and increase kinin formation in cultured human endothelial cells.32 Rodrigo et al33 used Phoneutria nigriventer venom to activate endogenous tissue kallikrein in rabbit tissues, causing NO release and corpus cavernosum smooth muscle relaxation. Kininogen can be synthesized and stored by vascular endothelial cells. Endothelial cells express binding sites for HK.2 Nishikawa et al34 also found that human HK can bind to freshly obtained HUVECs, and exogenous plasma kallikrein can cleave the endothelium-bound HK and liberate bradykinin. No kinin release occurred in either the absence of exogenous kallikrein or the absence of exogenous HK. It seems as if neither endogenous HK nor plasma kallikrein interacts with exogenous plasma kallikrein and HK in HUVECs. In the present study, a purified kininogen markedly increased nitrite production from isolated coronary microvessels in a concentration-dependent manner. L-NAME and HOE 140 dramatically attenuated nitrite production evoked by kininogen, indicating a functionally active endogenous kallikrein. Elevated kinin formation subsequently activated the B2-kinin receptor and stimulated NO production from endothelial cells. Both TI and aprotinin can block kininogen-activated NO production, indicating that cleavage of kininogen by kallikrein in these blood vessels is a necessary step in kininogen-induced NO synthesis.
We17 have recently shown that NO is an inhibitor of tissue O2 consumption. Whether stimulation of vascular endothelial NO production by local kinins can also modulate tissue O2 consumption has not been addressed previously. In the present study, we found that both ACE inhibitors and kininogen can significantly suppress myocardial O2 consumption. This effect could be completely abolished by L-NNA and HOE 140, indicating that the modulation of tissue respiration caused by ACE inhibitors and kininogen was dependent on an NO release mechanism and involved the activation of the B2-kinin receptor. These data link the effects of ACE inhibitors and kininogen on O2 consumption to local kinins and NO synthesis. These data suggest that local kinin formation in blood vessels can modulate adjacent parenchymal cell mitochondrial respiration via an intermediary mechanism mediated by NO production in the endothelium.
Tissue O2 consumption can be reduced by inducible NO derived from different cells types13 14 16 35 in vitro. The role of endothelium-derived NO in the modulation of mitochondrial respiration was not known until recently, when King et al18 and Shen et al17 demonstrated that NO plays an important role in the regulation of both vasodilation and tissue O2 consumption in vivo. King et al18 showed in the hindlimb of anesthetized dogs that inhibition of NO synthesis resulted in a 40% increase in O2 consumption. They also investigated the role of NO in the control of O2 extraction during progressive ischemia in dog hindlimb skeletal muscle and found that NO was essential for the regulation of tissue oxygenation.36 Shen et al17 showed that inhibition of NO synthase by L-NNA in conscious dogs resulted in an immediate 25% increase in whole-body total O2 consumption and a 2°F increase in body temperature, supporting the suggestion that endothelial NO tonically inhibits tissue respiration. In isolated dog hindlimb skeletal muscle19 and myocardial muscle,37 bradykinin inhibited tissue respiration, which was completely reversed by the inhibition of NO synthase. The myocardium contains abundant microvessels in close proximity to myocytes, the distance from the nearest capillary being no greater than 8 µm.38 Each cardiac myocyte is in close proximity to three coronary capillaries. In fact, the diffusion distance from capillary endothelium to myocytes is generally less than the diffusion distance needed for endothelium-derived NO–mediated relaxation of smooth muscle to occur in large epicardial coronary vessels or the aorta. In addition, the surface area of endothelial cells in capillaries is very large. Thus, NO production from blood vessels in the myocardium is likely to serve as a tremendous source of NO for myocytes. A recent study has shown that there are high-affinity B2-kinin receptors on adult dog cardiomyocytes,39 and the endothelial isoform of NO synthase is expressed in rat cardiomyocytes.40 Whether these receptors and enzymes function in myocytes to regulate O2 consumption is still open to question.
Collectively, our present findings lead us to conclude that ACE inhibitor–induced and kininogen-induced inhibition of myocardial O2 consumption are most likely secondary to stimulation of vascular endothelial NO production by kinins. It has also been shown that NO reduces the contractile state of cardiomyocytes in vitro,38 41 42 indicating that endothelium-derived NO has an important effect on myocardial contractility. These data also strongly support our conclusion, because a suppression of myocyte O2 consumption could reduce ATP availability and myocyte shortening.
A number of previous investigations have shown that NO can affect tissue O2 consumption. Granger and Lehninger35 showed that activated macrophages release an undefined substance to suppress cellular respiration in bacteria and various types of mammalian cells in culture. Lancaster and Hibbs14 subsequently demonstrated that the inhibitory effect of activated macrophages on cellular O2 consumption was associated with inducible NO production. The mechanism by which NO inhibits tissue O2 consumption was considered to be through the degradation of the iron-sulfur center of enzymes and formation of a nitrosyl complex to reduce the activity of several mitochondrial enzymes, including aconitate hydratase, NADH-ubiquinone oxidoreductase, and succinate-ubiquinone oxidoreductase in the mitochondrial electron transport chain.35 Because cytochrome C oxidase is the terminal complex of the mitochondrial electron transport chain, it is responsible for virtually all the O2 consumption of tissue. Increasing evidence recently suggests that NO may regulate mitochondrial respiration and tissue O2 consumption mainly through its inhibition of cytochrome oxidase.43 44 The inhibitory effect of NO on cytochrome oxidase is due to a competition with O2 for its binding site. NO binds with high affinity to the O2 binding site of cytochrome oxidase when this site is reduced44 and directly suppresses mitochondrial energy metabolism and cellular ATP production. Our present study indicated that endothelium-derived NO may inhibit parenchymal cell O2 consumption by a similar mechanism.
Interestingly, in the present study, we also found that ramiprilat has a more potent effect on stimulating NO production from coronary microvessels and suppressing O2 consumption in myocardium than enalaprilat or captopril. Ramiprilat (10-8 mol/L) caused a 1.2x and 1.4x greater change in NO production than 10-8 mol/L enalaprilat or captopril, respectively (Fig 1
). The inhibitory effect on myocardial O2 consumption of 10-4 mol/L ramiprilat was also 1.4x and 1.9x more potent than 10-4 mol/L enalaprilat or captopril (Fig 5). Possibly these differences in potency between ramiprilat and enalaprilat or captopril can be explained by their physicochemical and enzyme-binding kinetic properties, because ramiprilat is much more lipophilic than enalaprilat (23x) or captopril (100x). Also, the affinity of ramiprilat for ACE is 7x higher than enalaprilat and 47x higher than captopril in vitro.45 Therefore, the concentration of ramiprilat in cardiac and vascular tissue is thought to be higher than the tissue concentration of either enalaprilat or captopril. Better tissue penetration and a more potent local ACE inhibition in target organs may result in the pronounced pharmacological action that we have found. This may also account for the lowering of nitrite production at the highest dose of ramiprilat, an effect not seen with other ACE inhibitors.
There is increasing evidence that NO produced by NO synthase, either the constitutive or inducible isoform, in myocytes may cause a negative inotropic effect.40 41 42 46 47 48 These actions may be mediated by the accumulation of cGMP or, we would propose, by a direct action of NO on mitochondrial electron transport.17 19 37 If NO production by myocytes is increased in the failing heart, then the control by NO of O2 consumption may also be increased. If this is mediated in part by the accumulation of locally generated angiotensin, then ACE inhibitors should reduce myocyte O2 consumption by reducing locally produced angiotensin II. Although this is only speculation, it would explain the enhanced effects of ramiprilat on O2 consumption in the present study, because ramiprilat is the most lipid-soluble, membrane-permeable ACE inhibitor. However, this would not explain the inhibitory actions of HOE 140 or the serine protease inhibitors in the present study.
In summary, ACE inhibitors and kininogen markedly increase nitrite production by isolated coronary microvessels. This was blocked by L-NAME, HOE 140, and serine protease inhibitors. These results suggest that there is an active, local, kinin-forming system in coronary microvessels that regulates endogenous NO production. ACE inhibitors stimulate NO production, most likely by increasing local kinin levels as a result of the decreased degradation of kinins by ACE. Kininogen and ACE inhibitors dramatically reduced myocardial O2 consumption in isolated myocardial muscle slices, which was completely abolished by L-NNA and HOE 140, again indicating that local kinin formation in coronary microvessels modulates myocardial O2 consumption through an endothelium-derived NO–dependent mechanism. Thus, ACE inhibitors have a new and novel therapeutic effect that may contribute to the cardiac protective effect of these agents. Captopril, enalaprilat, and ramiprilat may provide cardioprotection by (1) promoting tissue vasodilation, (2) reducing angiotensin II and enhancing NO production, and (3) modulating parenchymal myocyte O2 consumption to play an important role in matching O2 supply to tissue O2 demand during various cardiovascular stresses.
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Acknowledgments |
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This study was supported by PO-1-43023 and RO-1 HL-50142, HL-53053, HL-31069, and HL-18579 from the National Heart, Lung, and Blood Institutes.
Received May 5, 1996; revision received September 20, 1996; accepted September 24, 1996.
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