Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart

This study examined whether increased superoxide (O(2)(-).) production contributes to coronary endothelial dysfunction and decreased coronary blood flow (CBF) in congestive heart failure (CHF). To test this hypothesis, the effects of the low-molecular-weight SOD mimetic M40401 on CBF and myocardial oxygen consumption (MVo(2)) were examined in dogs during normal conditions and after CHF was produced by 4 wk of rapid ventricular pacing. The development of CHF was associated with decreases of left ventricular (LV) systolic pressure, maximum first derivative of LV pressure, MVo(2), and CBF at rest and during treadmill exercise as well as endothelial dysfunction with impaired vasodilation in response to intracoronary acetylcholine. M40401 increased CBF (18 +/- 5%, P < 0.01) and MVo(2) (14 +/- 6%, P < 0.01) in CHF dogs and almost totally reversed the impaired CBF response to acetylcholine. M40401 had no effect on acetylcholine-induced coronary vasodilation, CBF, or MVo(2) in normal dogs. Western blot analysis demonstrated that extracellular SOD (EC-SOD) was significantly decreased in CHF hearts, whereas mitochondrial Mn-containing SOD was increased. Cytosolic Cu/Zn-containing SOD was unchanged. Both increased O(2)(-). production and decreased vascular O(2)(-). scavenging ability by EC-SOD could have contributed to endothelial dysfunction in the failing hearts.     

Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure

Inhibition of phosphodiesterase type 5 (PDE5) can relax systemic and coronary vessels by causing accumulation of cGMP. Both the endothelial dysfunction with decreased nitric oxide production and increased natriuretic peptide levels in congestive heart failure (CHF) have the potential to alter cGMP production, thereby influencing the response to PDE5 inhibition. Consequently, this study examined the effects of PDE5 inhibition with sildenafil in dogs with CHF produced by rapid ventricular pacing. CHF resulted in decreases of left ventricular (LV) systolic pressure, coronary blood flow, and the maximal first time derivative of LV pressure (LV dP/dt(max)) at rest and during treadmill exercise compared with normal, whereas resting LV end-diastolic pressure increased from 10 +/- 1.4 to 23 +/- 1.4 mmHg. Sildenafil (2 and 10 mg/kg per os) caused a 5- to 6-mmHg decrease of aortic pressure (P < 0.05), with no change of heart rate, LV systolic pressure, or LV dP/dt(max). Sildenafil caused no change in coronary flow or myocardial oxygen consumption in animals with CHF at rest or during exercise. In contrast to findings in normal animals, sildenafil did not augment endothelium-dependent coronary vasodilation in response to acetylcholine in animals with CHF. Furthermore, Western blotting showed decreased PDE5 protein expression in myocardium from failing hearts. These findings demonstrate that PDE5 contributes little to regulation of coronary hemodynamics in CHF.     

Volume expansion potentiates cardiac sympathetic afferent reflex in dogs

Our previous study (27) showed that the cardiac sympathetic afferent reflex (CSAR) was enhanced in dogs with congestive heart failure. The aim of this study was to test whether blood volume expansion, which is one characteristic of congestive heart failure, potentiates the CSAR in normal dogs. Ten dogs were studied with sino-aortic denervation and bilateral cervical vagotomy. Arterial pressure, left ventricular pressure, left ventricular epicardial diameter, heart rate, and renal sympathetic nerve activity were measured. Coronary blood flow was also measured and, depending on the experimental procedure, controlled. Blood volume expansion was carried out by infusion of isosmotic dextran into a femoral vein at 40 ml/kg at a rate of 50 ml/min. CSAR was elicited by application of bradykinin (5 and 50 microg) and capsaicin (10 and 100 microg) to the epicardial surface of the left ventricle. Volume expansion increased arterial pressure, left ventricular pressure, left ventricular diameter, and coronary blood flow. Volume expansion without controlled coronary blood flow only enhanced the RSNA response to the high dose (50 microg) of epicardial bradykinin (17. 3 +/- 1.9 vs. 10.6 +/- 4.8%, P < 0.05). However, volume expansion significantly enhanced the RSNA responses to all doses of bradykinin and capsaicin when coronary blood flow was held at the prevolume expansion level. The RSNA responses to bradykinin (16. 9 +/- 4.1 vs. 5.0 +/- 1.3% for 5 microg, P < 0.05, and 28.9 +/- 3.7 vs. 10.6 +/- 4.8% for 50 microg, P < 0.05) and capsaicin (29.8 +/- 6.0 vs. 9.3 +/- 3.1% for 10 microg, P < 0.05, and 34.2 +/- 2.7 vs. 15.1 +/- 2.7% for 100 microg, P < 0.05) were significantly augmented. These results indicate that acute volume expansion potentiated the CSAR. These data suggest that enhancement of the CSAR in congestive heart failure may be mediated by the concomitant cardiac dilation, which accompanies this disease state.     

Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts

Congestive heart failure (CHF) is associated with impaired endothelium-dependent nitric oxide (NO)-mediated vasodilation (endothelial dysfunction). We hypothesized that coronary endothelial dysfunction in CHF may be due in part to decreased dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades endogenous inhibitors of NO synthase (NOS), including asymmetric dimethylarginine. Coronary blood flow and the endothelium-dependent vasodilator response to acetylcholine were studied in dogs in which CHF was produced by rapid ventricular pacing for 4 wk. Coronary flow and myocardial O2 consumption at rest and during treadmill exercise were decreased after development of CHF, and the vasodilator response to intracoronary acetylcholine (75 microg/min) was decreased by 39 +/- 5%. DDAH activity and DDAH isoform 2 (DDAH-2) protein content were decreased by 53 +/- 13% and 58 +/- 14%, respectively, in hearts with CHF, whereas endothelial NOS and DDAH isoform 1 (DDAH-1) were increased. Caveolin-1 and protein arginine N-methyltransferase 1, the enzyme that produces asymmetric dimethylarginine, were unchanged. Immunohistochemical staining showed DDAH-1 strongly expressed in coronary endothelium and smooth muscle and in the sarcolemma of cardiac myocytes. In cultured human endothelial cells, DDAH-1 was uniformly distributed in the cytosol and nucleus, whereas DDAH-2 was found only in the cytosol. Decreased DDAH activity and DDAH-2 protein expression may cause accumulation of endogenous inhibitors of endothelial NOS, thereby contributing to endothelial dysfunction in the failing heart.     

Effect of coronary vasodilators and pacing upon regional oxygen balance of the ischaemic myocardium

In anaesthetized open-chest dogs, regional contractile force, epicardial tissue blood flow, and local NADH redox levels were recorded during graded ventricular pacing in the range 150-285 bpm. These parameters were measured before, and 30 min following LAD coronary artery occlusion. It was found that during pacing, blood supply to the untreated ischaemic region was reduced by 65.4 +/- 11% of control values at a rate of 150 bpm, and fell to -105 +/- 40.2% at a rate of 225 bpm. Hypopneic respiration prevented this pacing induced flow reduction. Pacing in the presence of nitroglycerin resulted in a marked increase in regional flow. Similarly, the vasodilator treatments prevented the marked elevation in NADH levels (77.5 +/- 15.6%) produced by pacing in the untreated ischaemic myocardium. The reduction in regional contractile force in the ischaemic region produced following pacing (-30.5%) was reversed during both vasodilator treatments (+47.2% during nitroglycerin and +23.4% during hypopnea). It was concluded that vasodilation improves regional ischaemic myocardial oxygen balance, thus expanding the functional reserve of the ischaemic muscle. Nitroglycerin is more active.     

Effect of sildenafil on coronary active and reactive hyperemia

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.     

Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure

Coronary blood flow (CBF) and myocardial oxygen consumption (MVO(2)) are reduced in dogs with pacing-induced congestive heart failure (CHF), which suggests that energy metabolism is downregulated. Because nitric oxide (NO) can inhibit mitochondrial respiration, we examined the effects of NO inhibition on CBF and MVO(2) in dogs with CHF. CBF and MVO(2) were measured at rest and during treadmill exercise in 10 dogs with CHF produced by rapid ventricular pacing before and after inhibition of NO production with N(G)-nitro-L-arginine (L-NNA, 10 mg/kg iv). The development of CHF was accompanied by decreases in aortic and left ventricular (LV) systolic pressure and an increase in LV end-diastolic pressure (25 +/- 2 mmHg). L-NNA increased MVO(2) at rest (from 3.07 +/- 0.61 to 4.15 +/- 0.80 ml/min) and during exercise; this was accompanied by an increase in CBF at rest (from 31 +/- 2 to 40 +/- 4 ml/min) and during exercise (both P < 0.05). Although L-NNA significantly increased LV systolic pressure, similar increases in pressure produced by phenylephrine did not increase MVO(2). The findings suggest that NO exerts tonic inhibition on respiration in the failing heart.     

Redistribution in left ventricular regional flow following acute right ventricular pressure overload

The left ventricular dysfunction following acute pulmowary hypertension remains unexplained. We wondered if acute pulmonary hypertension could alter the transmural flow distribution within the left ventricular myocardium, independent of coronary flow and perfusion pressure. We used a canine preparation in which the left coronary system was perfused at constant flow and induced a two- to three-fold increase in pulmonary artery pressure by banding the pulmonary artery. Regional myocardial blood flow of the left coronary system was measured using radioactive microspheres, injected into the left coronary system before and after 10-30 min of banding of the pulmonary artery. The left ventricular subendocardial:epicardial ratio fell by 12 and 31% (p less than 0.05) of control value, 10 and 30 min, respectively, after banding of the pulmonary artery, the total flow to the left coronary system being kept constant. Left atrial mean pressure increased from 2.9 +/- 2.4 to 3.6 +/- 1.9 and 6.0 +/- 2.1 (p less than 0.05) following banding. The mechanism of the redistribution of coronary flow may relate to inappropriate vasodilation of the right septal myocardium with consequent relative left ventricular subendocardial hypoperfusion which might aggravate left ventricular ischemia in the presence of hypotension and hypoxia.     

Shear stress-induced vasodilation in porcine coronary conduit arteries is independent of nitric oxide release

The present study was performed to determine the importance of nitric oxide in eliciting epicardial coronary artery dilation during sustained increases in shear stress in the absence of pulsatile flow. Isolated first-order porcine epicardial coronary conduit arteries (approximately 500 microm) were preconstricted (U-46619) and subjected to steady-state changes in flow in vitro. Nonpulsatile flow (shear stress range from 0 to approximately 100 dyn/cm2) produced a graded dilation of epicardial arteries. Inhibiting nitric oxide synthase with 10(-5) M N(omega)-nitro-L-arginine methyl ester (L-NAME) blocked bradykinin-induced vasodilation but did not affect the flow-diameter relation or the maximum change in diameter from static conditions (67 +/- 10 microm in control vs. 71 +/- 8 microm after L-NAME, P = not significant). The addition of indomethacin (10(-5) M) had no effect on flow-mediated vasodilation. Depolarizing vascular smooth muscle with KCl (60 mM) or removing the endothelium blocked bradykinin vasodilation and completely abolished flow-mediated responses. The K+ channel blocker tetraethylammonium chloride (TEA; 10(-4)M) attenuated flow-mediated vasodilation (maximum diameter change was 110 +/- 18 microm under control conditions vs. 58 +/- 10 microm after TEA, P < 0.001). These data indicate that epicardial coronary arteries dilate to steady-state changes in nonpulsatile flow via a mechanism that is independent of nitric oxide production. The ability to completely block this with KCl and attenuate it with TEA supports the hypothesis that epicardial coronary arteries dilate to steady levels of shear stress through hyperpolarization of vascular smooth muscle. This may be secondary to the release of an endothelium-dependent hyperpolarizing factor.     

Role of pertussis toxin-sensitive G protein in metabolic vasodilation of coronary microcirculation

We have previously demonstrated that pertussis toxin (PTX)-sensitive G protein (G(PTX)) plays a major role in coronary microvascular vasomotion during hypoperfusion. We aimed to elucidate the role of G(PTX) during increasing metabolic demand. In 18 mongrel dogs, coronary arteriolar diameters were measured by fluorescence microangiography using a floating objective. Myocardial oxygen consumption (MVO(2)) was increased by rapid left atrial pacing. In six dogs, PTX (300 ng/ml) was superfused onto the heart surface for 2 h to locally block G(PTX). In eight dogs, the vehicle (Krebs solution) was superfused in the same way. Before and after each treatment, the diameters were measured during control (130 beats/min) and rapid pacing (260 beats/min) in each group. Metabolic stimulation before and after the vehicle treatment caused 8.6 +/- 1. 8 and 16.1 +/- 3.6% dilation of coronary arterioles <100 microm in diameter (57 +/- 8 microm at control, n = 10), respectively. PTX treatment clearly abolished the dilation of arterioles (12.8 +/- 2. 5% before and 0.9 +/- 1.6% after the treatment, P < 0.001 vs. vehicle; 66 +/- 8 microm at control, n = 11) in response to metabolic stimulation. The increases in MVO(2) and coronary flow velocity were comparable between the vehicle and PTX groups. In four dogs, 8-phenyltheophylline (10 microM, superfusion for 30 min) did not affect the metabolic dilation of arterioles (15.3 +/- 2.0% before and 16.4 +/- 3.8% after treatment; 84.3 +/- 11.0 microm at control, n = 8). Thus we conclude that G(PTX) plays a major role in regulating the coronary microvascular tone during active hyperemia, and adenosine does not contribute to metabolic vasodilation via G(PTX) activation.     

Importance of antioxidant and antiapoptotic effects of beta-receptor blockers in heart failure therapy

The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) are mediated via its beta-adrenergic blocking, antioxidant, and/or alpha-adrenergic blocking action. Rabbits with heart failure induced by rapid cardiac pacing were randomized to receive subcutaneous carvedilol, metoprolol, propranolol plus doxazosin, or placebo pellets for 8 wk and compared with sham-operated rabbits without pacing. We found rapid cardiac pacing produced clinical heart failure, left ventricular dilation, and decline of left ventricular fractional shortening. This was associated with an increase in left ventricular end-diastolic pressure, decrease in left ventricular first derivative of left ventricular pressure, and myocyte hypertrophy. Tissue oxidative stress measured by GSH/GSSG was increased in the heart with increased oxidation product of mitochondrial DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine, increase of Bax, decrease of Bcl-2, and increase of apoptotic myocytes as measured by anti-single-stranded DNA monoclonal antibody. Administration of carvedilol and metoprolol, which had no effect in sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which has less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, GSH/GSSG correlated significantly with changes of left ventricular end-diastolic dimension (r = -0.678, P < 0.0001), fractional shortening (r = 0.706, P < 0.0001), and apoptotic myocytes (r = -0.473, P = 0.0001). Thus our findings suggest antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of clinical beneficial effects of beta-receptors in the treatment of CHF.     

Endothelin-1 promotes vascular structural remodeling during the progression of heart failure prevention of vascular remodeling using a specific endothelin-converting enzyme inhibitor.

To evaluate the effects of endothelin (ET)-converting enzyme (ECE) inhibitor on vascular remodeling in dogs with congestive heart failure (CHF), we chronically administered an ECE inhibitor, FR901533 (FR, iv. 0.3mg/kg/hr, n=6), to dogs with CHF induced by rapid ventricular pacing. Vehicle CHF dogs were given saline (n=7). In the vehicle CHF group after 3 weeks of pacing, the ET system was activated in the plasma and vasculature (3 and 5 times higher than normal, respectively). Inward remodeling occurred in the femoral artery; medial thickness (MT, 225+/-5 vs 193+/-4 microm, P<0.05) and deposition of collagen (DC, 22+/-2 vs 17+/-1%, P<0.01) significantly increased, while lumen diameter (LD, 1173+/-39 vs 1481+/-44 microm, P<0.05) decreased in the femoral artery with CHF compared with the normal femoral artery. There were significant correlations between the number of ET-1 positive cells and MT, DC, LD and systemic vascular resistance. FR significantly suppressed the changes in these vascular parameters compared with the changes in the vehicle CHF group despite the lack of an effect on blood pressure, and moreover FR caused decreases in ET-1 levels in both the plasma and femoral artery (reduced to 43% and 54%, respectively, of the levels in the vehicle CHF group, P<0.05). In conclusion, ET-1 plays a critical role in the structural deterioration of the vasculature during the progression of CHF, and ECE inhibitors can prevent the development of vascular remodeling.     

Muscle metaboreflex-induced increases in cardiac sympathetic activity vasoconstrict the coronary vasculature.

Ischemia of active skeletal muscle evokes a powerful blood pressure-raising reflex termed the muscle metaboreflex (MMR). MMR activation increases cardiac sympathetic nerve activity, which increases heart rate, ventricular contractility, and cardiac output (CO). However, despite the marked increase in ventricular work, no coronary vasodilation occurs. Using conscious, chronically instrumented dogs, we observed MMR-induced changes in arterial pressure, CO, left circumflex coronary blood flow (CBF), and coronary vascular conductance (CVC) before and after alpha1-receptor blockade (prazosin, 100 microg/kg iv). MMR was activated during mild treadmill exercise by partially reducing hindlimb blood flow. In control experiments, MMR activation caused a substantial pressor response-mediated via increases in CO. Although CBF increased (+28.1 +/- 3.7 ml/min; P < 0.05), CVC did not change (0.45 +/- 0.05 vs. 0.47 +/- 0.06 ml x min(-1) x mmHg(-1), exercise vs. exercise with MMR activation, respectively; P > 0.05). Thus all of the increase in CBF was due to the increase in arterial pressure. In contrast, after prazosin, MMR activation caused a greater increase in CBF (+55.9 +/- 17.1 ml/min; P < 0.05 vs. control) and CVC rose significantly (0.59 +/- 0.08 vs. 0.81 +/- 0.17 ml x min(-1) x mmHg(-1), exercise vs. exercise with MMR activation, respectively; P < 0.05). A greater increase in CO also occurred (+2.01 +/- 0.1 vs. +3.27 +/- 1.1 l/min, control vs. prazosin, respectively; P < 0.05). We conclude that the MMR-induced increases in sympathetic activity to the heart functionally restrain coronary vasodilation, which may limit increases in ventricular function.     

Reactive oxygen species mediate arachidonic acid-induced dilation in porcine coronary microvessels

Reactive oxygen species (ROS) have been proposed to mediate vasodilation in the microcirculation. We investigated the role of ROS in arachidonic acid (AA)-induced coronary microvascular dilation. Porcine epicardial coronary arterioles (110 +/- 4 microm diameter) were mounted onto pipettes in oxygenated Krebs buffer. Vessels were incubated with vehicle or 1 mM Tiron (a nonselective ROS scavenger), 250 U/ml polyethylene-glycolated (PEG)-superoxide dismutase (SOD; an O2- scavenger), 250 U/ml PEG-catalase (a H2O2 scavenger), or the cyclooxygenase (COX) inhibitors indomethacin (10 microM) or diclofenac (10 microM) for 30 min. After endothelin constriction (30-60% of resting diameter), cumulative concentrations of AA (10(-10)-10(-5)M) were added and internal diameters measured by video microscopy. AA (10-7 M) produced 37 +/- 6% dilation, which was eliminated by the administration of indomethacin (4 +/- 7%, P < 0.05) or diclofenac (-8 +/- 8%, P < 0.05), as well as by Tiron (-4 +/- 5%, P < 0.05), PEG-SOD (-10 +/- 6%, P < 0.05), or PEG-catalase (1 +/- 4%, P < 0.05). Incubation of small coronary arteries with [3H]AA resulted in the formation of prostaglandins, which was blocked by indomethacin. In separate studies in microvessels, AA induced concentration-dependent increases in fluorescence of the oxidant-sensitive probe dichlorodihydrofluorescein diacetate, which was inhibited by pretreatment with indomethacin or by SOD + catalase. We conclude that in porcine coronary microvessels, COX-derived ROS contribute to AA-induced vasodilation.     

Cardiac response to submaximal exercise in dogs susceptible to sudden cardiac death

The hemodynamic response to submaximal exercise was investigated in 38 mongrel dogs with healed anterior wall myocardial infarctions. The dogs were chronically instrumented to measure heart rate (HR), left ventricular pressure (LVP), LVP rate of change, and coronary blood flow. A 2 min coronary occlusion was initiated during the last minute of an exercise stress test and continued for 1 min after cessation of exercise. Nineteen dogs had ventricular fibrillation (susceptible) while 19 animals did not (resistant) during this test. The cardiac response to submaximal exercise was markedly different between the two groups. The susceptible dogs exhibited a significantly higher HR and left ventricular end-diastolic pressure (LVEDP) but a significantly lower left ventricular systolic pressure (LVSP) in response to exercise than did the resistant animals. (For example, response to 6.4 kph at 8% grade; HR, susceptible 201.4 +/- 5.1 beats/min vs. resistant 176.2 +/- 5.6 beats/min; LVEDP, susceptible 19.4 +/- 1.1 mmHg vs. resistant 12.3 +/- 1.7 mmHg; LVSP, susceptible 136.9 +/- 7.9 mmHg vs. resistant 154.6 +/- 9.8 mmHg.) beta-Adrenergic receptor blockade with propranolol reduced the difference noted in the HR response but exacerbated the LVP differences (response to 6.4 kph at 8% grade; HR, susceptible 163.4 +/- 4.7 mmHg vs. resistant 150.3 +/- 6.4 mmHg; LVEDP susceptible 28.4 +/- 2.1 mmHg vs. resistant 19.6 +/- 3.0 mmHg; LVSP, susceptible 122.2 +/- 8.1 mmHg vs. resistant 142.8 +/- 10.7 mmHg). These data indicate that the animals particularly vulnerable to ventricular fibrillation also exhibit a greater degree of left ventricular dysfunction and an increased sympathetic efferent activity.     

Effects of exercise training on coronary transport capacity

Coronary transport capacity was estimated in eight sedentary control and eight exercise-trained anesthetized dogs by determining the differences between base line and the highest coronary blood flow and permeability-surface area product (PS) obtained during maximal adenosine vasodilation with coronary perfusion pressure constant. The anterior descending branch of the left coronary artery was cannulated and pump-perfused under constant-pressure conditions (approximately equal to 100 Torr) while aortic, central venous, and coronary perfusion pressures, heart rate, electrocardiogram, and coronary flow were monitored. Myocardial extraction and PS of 51Cr-labeled ethylenediaminetetraacetic acid were determined with the single-injection indicator-diffusion method. The efficacy of the 16 +/- 1 wk exercise training program was shown by significant increases in the succinate dehydrogenase activities of the gastrocnemius, gluteus medialis, and long head of triceps brachii muscles. There were no differences between control and trained dogs for either resting coronary blood flow or PS. During maximal vasodilation with adenosine, the trained dogs had significantly lower perfusion pressures with constant flow and, with constant-pressure vasodilation, greater coronary blood flow and PS. It is concluded that exercise training in dogs induces an increased coronary transport capacity that includes increases in coronary blood flow capacity (26% of control) and capillary diffusion capacity (82% of control).     

Beta-adrenergic receptor blockade impairs NO-dependent dilation of large coronary arteries during exercise

Shear stress-dependent nitric oxide (NO) formation prevents immoderate vascular constriction. We examined whether shear stress-dependent NO formation limits exercise-induced coronary artery constriction after beta-adrenergic receptor blockade in dogs. Control exercise led to increases (P < 0.01) in coronary blood flow (CBF) by 38 +/- 5 ml/min from 41 +/- 5 ml/min and in the external diameter of epicardial coronary arteries (CD) by 0.24 +/- 0.03 mm from 3.33 +/- 0.20 mm. CD and shear stress were linearly related. After propranolol, CD fell (P < 0.01) during exercise (0.08 +/- 0.03 from 3.23 +/- 0.19 mm), and the slope of the relationship between CD and shear stress was reduced (P < 0.01). This slope was not further altered by the additional blockade of NO formation. In propranolol-treated resting dogs, flow-dependent effects of intracoronary adenosine to mimic exercise-induced increases in shear stress (after propranolol) led to increases (P < 0.01) in CD (0.09 +/- 0.02 from 3.68 +/- 0.27 mm). Thus both shear stress-dependent NO formation and beta-adrenergic receptor activation are required to cause CD dilation during exercise. Suppression of beta-adrenergic receptor activation leads to impaired shear stress-dependent NO formation and allows alpha-adrenergic constriction to become dominant.     

Preservation of myocardial oxygen balance and functional reserve by coronary vasodilators

Reduced myocardial function at very high heart rates may be due to limited coronary blood supply. The effects of the vasodilators nitroglycerin (10 micrograms kg-1 min-1) and elevated CO2 upon regional function during tachycardia were studied. In open-chest anaesthetized dogs, regional contractile force, epicardial tissue blood flow and local NADH redox level were recorded during graded ventricular pacing. It was found that the vasodilating action of nitroglycerin in the unpaced heart was much lower than produced by CO2 (23.6 +/- 5.8% vs. 137.6 +/- 33.5%). Maximal pacing at 275 bpm caused only a moderate flow elevation in control (20 +/- 6.8%) and CO2 conditions (20.3 +/- 4.03%), but marked vasodilation during nitroglycerin infusion (85.2 +/- 14.6%). Regional function during tachycardia was improved similarly by both vasodilators. NADH levels increased with heart rates under all experimental conditions, but the absolute NADH levels were consistently lower following vasodilator treatments. The lowest NADH levels were observed during nitroglycerin treatment at all heart rates. It is suggested that nitroglycerin augments myocardial functional reserve by preserving oxygen balance more than predicted by its vasodilatory effect alone.     

结扎冠状动脉后快速起搏方法建立急性心功能不全动物模型

目的探讨建立急性心功能不全动物模型的可行性。方法完全结扎犬前降支,进行快速右室起搏,使心输出量(CCO)较基础状态稳定地下降50%,分别测定基础及心输出量下降状态下的血压(AP)、血氧(SaO2)、平均右房压(mRAP)、平均肺毛压(mPCWP)、系统血管阻力(SVR)、心腔大小、左室射血分数(LVEF)、血浆肾素活性(PRA)、内皮素(ET)、尿量(UO)、血肌酐(Scr)、肌酐清除率(Ccr)。结果结扎LAD和快速右室起搏后,CCO较基础状态均稳定地下降50%,CCO降低后,AP、SaO2显著下降,mRAP、mPCWP、SVR显著升高;心脏各腔室明显扩大,LVEF显著降低;PRA、ET、Scr明显升高,UO、Ccr明显下降。结论结扎冠状动脉前降支及快速右心室起搏可成功制作急性心功能不全的动物模型。