Hypoxia-induced vasodilation in the right coronary circulation of conscious dogs: role of adrenergic activation.

The role of adrenergic activation in the right coronary (RC) flow response to hypoxia has not been previously delineated, and limited information from left coronary studies is inconsistent. Seven dogs were instrumented with catheters implanted in the aorta and in the right ventricle to measure aortic pressure and right ventricular (RV) pressure, respectively. A flow transducer was placed around the RC artery to measure RC flow. After recovery from surgery, the dogs were exposed to systemic hypoxia in a Plexiglas chamber ventilated with N(2). Percent O(2) in the chamber was monitored, and blood samples and hemodynamic data were collected as chamber O(2) was progressively reduced to approximately 6%. The chamber was then opened, and the dog breathed room air. Phentolamine, 1 mg/kg, and propranolol, 2 mg/kg, were then administered via the RV catheter to achieve adrenergic blockade, and the hypoxia protocol was repeated. During hypoxia, arterial PO(2) progressively fell from 87+/-3 to 25+/-1 mmHg during untreated control condition and from 90+/-4 to 23+/-1 mmHg during adrenergic blockade. In the unblocked condition, hypoxia caused increases in aortic pressure, heart rate, RV pressure, and RV dP/dt(max). After adrenergic blockade, normoxic aortic pressure was reduced; heart rate and RV dP/dt(max) tended to be lower. Aortic pressure rose during hypoxia, but to lesser values than before blockade. Heart rate and RV dP/dt(max) also increased, but only at more severe hypoxia, and these values were less than before blockade. Normoxic flow and hypoxia-induced increases in RC flow and conductance were not altered by blockade. The relationship between RC conductance and RV triple product, an index of RV O(2) demand, was steeper after blockade. These findings indicate that in the normal, unblocked condition, RC flow during hypoxia is restrained by an adrenergic-mediated increase in RC vasomotor tone.

Coronary arteriolar vasoconstriction to angiotensin II is augmented in prediabetic metabolic syndrome via activation of AT1 receptors.

The metabolic syndrome is associated with activation of the renin-angiotensin system. However, whether the coronary vascular response to ANG II is altered under this condition is unknown. Experiments were conducted in control and chronically high-fat-fed dogs with the prediabetic metabolic syndrome both in vitro (isolated coronary arterioles, 60-110 microm) and in vivo (anesthetized and conscious). We found that plasma renin activity and ANG II levels are elevated in high-fat-fed dogs and that this increase in ANG II is associated with a significant increase in ANG II-mediated coronary vasoconstriction in isolated coronary arterioles and in anesthetized open-chest dogs. The vasoconstriction to ANG II is abolished by ANG II type 1 (AT1) receptor blockade. In conscious chronically instrumented dogs, AT1 receptor blockade with telmisartan improved the balance between coronary blood flow and myocardial oxygen consumption in the high-fat-fed dogs but not in normal control dogs, i.e., the relationship between coronary venous Po2 and myocardial oxygen consumption was shifted upward, toward normal control values. Quantitative assessment of coronary arteriolar AT1 and ANG II type 2 (AT2) receptor mRNA levels by real-time PCR revealed no significant difference between normal control and high-fat-fed dogs; however, Western blot analysis showed a significant increase in AT1 receptor protein level with no change in AT2 receptor protein density. These findings indicate that AT1 receptor-mediated coronary constriction is augmented in the prediabetic metabolic syndrome and contributes to impaired control of coronary blood flow via increases in circulating ANG II and/or coronary arteriolar AT1 receptor density.

Nitric oxide contributes to right coronary vasodilation during systemic hypoxia.

As arterial partial pressure of O(2) (Pa(O(2))) is reduced during systemic hypoxia, right ventricular (RV) work and myocardial O(2) consumption (MVo(2)) increase. Mechanisms responsible for maintaining RV O(2) demand/supply balance during hypoxia have not been delineated. To address this problem, right coronary (RC) blood flow and RV O(2) extraction were measured in nine conscious, instrumented dogs exposed to normobaric hypoxia. Catheters were implanted in the right ventricle for measuring pressure, in the ascending aorta for measuring arterial pressure and for sampling arterial blood, and in an RC vein. A flow transducer was placed around the RC artery. After recovery from surgery, dogs were exposed to hypoxia in a chamber ventilated with N(2), and blood samples and hemodynamic data were collected as chamber O(2) was reduced progressively to approximately 8%. After control measurements were made, the chamber was opened and the dog was allowed to recover. N(omega)-nitro-L-arginine (L-NNA) was then administered (35 mg/kg, via RV catheter) to inhibit nitric oxide (NO) production, and the hypoxia protocol was repeated. RC blood flow increased during hypoxia due to coronary vasodilation, because RC conductance increased from 0.65 +/- 0.05 to 1.32 +/- 0.12 ml x min(-1) x 100 g(-1) x L-NNA blunted the hypoxia-induced increase in RC conductance. RV O(2) extraction remained constant at 64 +/- 4% as Pa(O(2)) was decreased, but after L-NNA, extraction increased to 70 +/- 3% during normoxia and then to 78 +/- 3% during hypoxia. RV MVo(2) increased during hypoxia, but after L-NNA, MVo(2) was lower at any respective Pa(O(2)). The relationship between heart rate times RV systolic pressure (rate-pressure product) and RV MVo(2) was not altered by l-NNA. To account for L-NNA-mediated decreases in RV MVo(2), O(2) demand/supply variables were plotted as functions of MVo(2). Slope of the conductance-MVo(2) relationship was depressed by L-NNA (P = 0.03), whereas the slope of the extraction-MVo(2) relationship increased (P = 0.003). In summary, increases in RV MVo(2) during hypoxia are met normally by increasing RC blood flow. When NO synthesis is blocked, the large RV O(2) extraction reserve is mobilized to maintain RV O(2) demand/supply balance. We conclude that NO contributes to RC vasodilation during systemic hypoxia.

Nitric oxide contributes to oxygen demand-supply balance in hypoperfused right ventricle.

OBJECTIVE: The present study examined the role of nitric oxide (NO) in oxygen demand-supply balance in hypoperfused canine right ventricular myocardium. METHODS: The right coronary artery of anesthetized, open-chest dogs was perfused at pressures of 80, 60, and 40 mm Hg, and right ventricular myocardial oxygen consumption, right coronary blood flow and other hemodynamic and cardiac function variables were measured. Right ventricular mechanical function was indexed as the product of heart rate x peak right ventricular systolic pressure x right ventricular dP/dt(max). NO synthesis blocker N(omega)-nitro-L-arginine methyl ester (L-NAME, 150 mug/min) was infused into the right coronary artery to block NO synthesis. RESULTS: Neither hypoperfusion nor L-NAME altered right ventricular function. Right ventricular myocardial oxygen consumption fell with coronary perfusion pressure, but less steeply after L-NAME, and at all perfusion pressures was elevated above control. The increase in myocardial oxygen consumption in the absence of NO was met by increased oxygen extraction and by non-NO dependent vasodilation, but the relationship between flow and oxygen consumption was displaced downward after L-NAME. As right coronary perfusion pressure was reduced, the relationship between right ventricular oxygen consumption and right coronary venous PO(2) became steeper after L-NAME, and right coronary venous PO(2) was significantly reduced. CONCLUSIONS: During right coronary hypoperfusion, right ventricular function is well maintained, but myocardial oxygen consumption falls, reflecting an increase in oxygen utilization efficiency. NO contributes to this adaptation to hypoperfusion by restraining myocardial oxygen consumption, and by promoting coronary vasodilation with less severe reduction in myocardial PO(2). NO has an important role in right ventricular oxygen demand-supply balance when right coronary perfusion pressure is reduced.

Intermittent hypoxic training protects canine myocardium from infarction.

This investigation examined cardiac protective effects of normobaric intermittent hypoxia training. Six dogs underwent intermittent hypoxic training for 20 consecutive days in a normobaric chamber ventilated intermittently with N2 to reduce fraction of inspired oxygen (FiO2) to 9.5%-10%. Hypoxic periods, initially 5 mins and increasing to 10 mins, were followed by 4-min normoxic periods. This hypoxia-normoxia protocol was repeated, initially 5 times and increasing to 8 times. The dogs showed no discomfort during intermittent hypoxic training. After 20 days of hypoxic training, the resistance of ventricular myocardium to infarction was assessed in an acute experiment. The left anterior descending (LAD) coronary artery was occluded for 60 mins and then reperfused for 5 hrs. At 30 mins of LAD occlusion, radioactive microspheres were injected through a left atrial catheter to assess coronary collateral blood flow into the ischemic region. After 5 hrs reperfusion, the heart was dyed to delineate the area at risk (AAR) of infarction and stained with triphenyl tetrazolium chloride to identify infarcted myocardium. During LAD occlusion and reperfusion, systemic hemodynamics and global left ventricular function were stable. Infarction was not detected in 4 hearts and was 1.6% of AAR in the other 2 hearts. In contrast, 6 dogs sham-trained in a chamber ventilated with compressed air and 5 untrained dogs subjected to the same LAD occlusion/reperfusion protocol had infarcts of 36.8% +/- 5.8% and 35.2% +/- 9.5% of the AAR, respectively. The reduction in infarct size of four of the six hypoxia-trained dogs could not be explained by enhanced collateral blood flow to the AAR. Hypoxia-trained dogs had no ventricular tachycardia or ventricular fibrillation. Three sham-trained dogs had ventricular tachycardia and two had ventricular fibrillation. Three untrained dogs had ventricular fibrillation. In conclusion, intermittent hypoxic training protects canine myocardium from infarction and life-threatening arrhythmias during coronary artery occlusion and reperfusion. The mechanism responsible for this potent cardioprotection merits further study.

Alpha-adrenergic vasoconstrictor tone limits right coronary blood flow in exercising dogs.

In exercising dogs, increased myocardial O2 consumption (MVO2) of the left ventricle is met primarily by hyperemia, whereas increased O2 extraction makes a greater contribution to right ventricular (RV) O2 supply. We hypothesized that alpha-adrenergic vasoconstrictor tone limits right coronary (RC) blood flow during exercise, forcing increased O2 extraction. This tone might also contribute to lesser RC vascular conductance at rest. Accordingly, RV O2 balance was examined at rest and during graded treadmill exercise before and during alpha-adrenergic blockade with phentolamine (1 mg/kg, i.v., n=6). The transmural distribution of RC flow was measured with radiolabeled microspheres in 4 additional dogs. At rest, alpha-adrenergic receptor blockade did not significantly increase RC flow or conductance. During exercise, alpha-adrenergic blockade increased RC flow and conductance responses to increased RV MVO2 by 25% and 60%, respectively. The transmural distribution of RC flow was not altered by exercise or by alpha-adrenergic blockade. Before alpha-adrenergic blockade, hyperemia provided 39%-66% of the additional O2 consumed by the right ventricle during graded exercise; after alpha-adrenergic blockade, hyperemia contributed 74%-85%. After alpha-adrenergic blockade, the slope of the relationship between RC venous PO2 and RV MVO2 became less steep, reflecting less O2 extraction due to enhanced hyperemia. Additional experiments were conducted on 5 anesthetized, open-chest dogs with constant RC perfusion pressure and beta-adrenergic blockade. The RC flow response to intracoronary norepinephrine was shifted to the left compared with that measured in the left coronary circulation, consistent with observations in the conscious exercising dogs. In conclusion, alpha-adrenergic vasoconstrictor tone does not restrict resting RC blood flow, but during exercise, this tone transmurally blunts RC hyperemia and forces the right ventricle to mobilize its O2 extraction reserve. This effect is more pronounced than has been reported for the left ventricle.

Alpha-adrenoceptor-mediated coronary vasoconstriction is augmented during exercise in experimental diabetes mellitus.

This study tested whether alpha-adrenoceptor-mediated coronary vasoconstriction is augmented during exercise in diabetes mellitus. Experiments were conducted in dogs instrumented with catheters in the aorta and coronary sinus and with a flow transducer around the circumflex coronary artery. Diabetes was induced with alloxan monohydrate (n = 8, 40 mg/kg i.v.). Arterial plasma glucose concentration increased from 4.7 +/- 0.2 mM in nondiabetic, control dogs (n = 8) to 21.4 +/- 1.9 mM 1 wk after alloxan injection. Coronary blood flow, myocardial oxygen consumption (MVo(2)), aortic pressure, and heart rate were measured at rest and during graded treadmill exercise before and after infusion of the alpha-adrenoceptor antagonist phentolamine (1 mg/kg iv). In untreated diabetic dogs, exercise increased MVo(2) 2.7-fold, coronary blood flow 2.2-fold, and heart rate 2.3-fold. Coronary venous Po(2) fell as MVo(2) increased during exercise. After alpha-adrenoceptor blockade, exercise increased MVo(2) 3.1-fold, coronary blood flow 2.7-fold, and heart rate 2.1-fold. Relative to untreated diabetic dogs, alpha-adrenoceptor blockade significantly decreased the slope of the relationship between coronary venous Po(2) and MVo(2). The difference between the untreated and phentolamine-treated slopes was greater in the diabetic dogs than in the nondiabetic dogs. In addition, the decrease in coronary blood flow to intracoronary norepinephrine infusion was significantly augmented in anesthetized, open-chest, beta-adrenoceptor-blocked diabetic dogs compared with the nondiabetic dogs. These findings demonstrate that alpha-adrenoceptor-mediated coronary vasoconstriction is augmented in alloxan-induced diabetic dogs during physiological increases in MVo(2).

Coronary blood flow regulation in the prediabetic metabolic syndrome.

This study tested whether the pre-diabetic metabolic syndrome impairs coronary blood flow control sufficiently to alter the balance between coronary blood flow and myocardial metabolism. Experiments were conducted in dogs instrumented with catheters in the aorta, coronary sinus, and left ventricle and with flow transducers around the circumflex coronary artery and aorta. Coronary blood flow, myocardial oxygen consumption (MVO(2)), cardiac output, aortic pressure, left ventricular pressure and heart rate were measured at rest and during treadmill exercise in normal, control and high fat fed dogs. High fat feeding for approximately six weeks increased body weight 15%, increased aortic blood pressure 10%, and induced insulin resistance. Fasting plasma insulin levels were increased 2.4-fold while plasma glucose concentration was unchanged relative to controls (5.0 +/- 0.3 mM). The cardiac index increased with exercise but was not altered by high fat feeding. The metabolic syndrome reduced the slope of the relationship between coronary blood flow and MVO(2) ( P < 0.0001) and decreased coronary venous PO(2) at a given level of MVO(2) ( P < 0.05). These findings indicate that the metabolic syndrome impairs the balance between myocardial oxygen delivery and metabolism by tonically vasoconstricting the coronary circulation.

Endogenous nitric oxide regulates right coronary blood flow during acute pulmonary hypertension in conscious dogs.

This study investigated the role of nitric oxide (NO) in the control of right coronary (RC) blood flow at rest and during acute pulmonary hypertension. Experiments were performed in seven chronically instrumented, conscious dogs. NO synthesis was inhibited by systemic administration of N(omega)-nitro-L-arginine (LNA, 35 mg/kg). Inflation of a balloon in the main pulmonary artery raised right ventricular (RV) peak systolic pressure from 34 +/- 2 to 47 +/- 3 mmHg before LNA and from 37 +/- 2 to 47 +/- 3 mmHg after LNA, but did not affect mean systemic arterial pressure. RV O(2) consumption (MVO(2)) increased from 4.4 +/- 0.7 to 6.1 +/- 0.7 ml/min/100 g. 82 % of the elevated RV MVO(2) was provided by RC blood flow, which increased from 46 +/- 7 to 61 +/- 8 ml/min/100 g. After LNA, resting RV MVO(2) and RC flow fell. RC venous PO(2) fell, but RV lactate uptake was not altered. During pulmonary hypertension, the increase in RC blood flow was blunted by LNA, so that only 66 % of the elevated RV MVO(2) was supplied by increased RC flow. Analysis of O(2) supply variables as functions of RV MVO(2) further demonstrated a significant role of NO in regulating RC flow at rest and during moderate pulmonary hypertension. Conclusions NO is required for the RC hyperemic response to acute pulmonary hypertension as well as for normal resting RC blood flow. After blockade of NO synthesis, RV O(2) supply at rest and during pulmonary hypertension was sustained by increased RV O(2) extraction.

Coronary blood flow control is impaired at rest and during exercise in conscious diabetic dogs.

This study tested whether diabetes mellitus impairs coronary blood flow control sufficiently to alter the balance between myocardial oxygen delivery and metabolism. Dogs (n = 7) were instrumented with catheters in the aorta and coronary sinus, and with a flow transducer on the circumflex coronary artery. Coronary blood flow, myocardial oxygen consumption (MVO2), heart rate and aortic pressure were measured at rest and during treadmill exercise before and after induction of diabetes with alloxan monohydrate (40 - 60 mg/kg). Arterial plasma glucose concentration increased from 4.6+/-0.2 mM in non-diabetic, control dogs to 20.2+/-2.3 mM one week after alloxan injection. In non-diabetic control dogs, exercise increased MVO2 3.1-fold, coronary blood flow 2.7-fold, and heart rate 2.4-fold. Coronary venous PO2 decreased from 19.4+/-0.6 mmHg at rest to 14.7+/-0.7 mmHg during exercise. Diabetes significantly attenuated exercise coronary hyperemia and reduced coronary venous PO2 at rest (15.6+/-0.5 mmHg) and during exercise (12.6+/-0.8 mmHg). Diabetes also significantly reduced myocardial oxygen delivery at each level of exercise. Acute hyperglycemia alone did not alter exercise-induced coronary vasodilation or reduce coronary venous PO2. These findings demonstrate that experimental diabetes attenuates functional coronary hyperemia and impairs the balance between coronary blood flow and myocardial metabolism. However, this deleterious effect is not related to acute hyperglycemia but to the chronic disease process of diabetes mellitus.

ATP-dependent K(+) channels contribute to local metabolic coronary vasodilation in experimental diabetes.

This study tested whether ATP-dependent K(+) channels (K(ATP) channels) are an important mechanism of functional coronary hyperemia in conscious, instrument-implanted diabetic dogs. Data were collected at rest and during exercise before and after induction of diabetes with alloxan monohydrate (40-60 mg/kg intravenously). K(ATP) channels were inhibited with glibenclamide (1 mg/kg intravenously). In nondiabetic dogs, arterial plasma glucose concentration increased from 4.8 +/- 0.3 to 21.5 +/- 2.2 mmol/l 1 week after alloxan injection. In nondiabetic dogs, exercise increased myocardial oxygen consumption (MVO(2)) 3.4-fold, myocardial O(2) delivery 3.0-fold, and heart rate 2.4-fold. Coronary venous PO(2) decreased from 19.9 +/- 0.8 mmHg at rest to 14.8 +/- 0.8 mmHg during exercise. Diabetes significantly reduced myocardial O(2) delivery and lowered coronary venous PO(2) from 16.3 +/- 0.6 mmHg at rest to 13.1 +/- 0.9 mmHg during exercise. Glibenclamide did not alter the slope of the coronary venous PO(2) versus MVO(2) relationship in nondiabetic dogs. In diabetic dogs, however, glibenclamide further reduced myocardial O(2) delivery; coronary venous PO(2) fell to 9.0 +/- 1.0 mmHg during exercise, and the slope of the coronary venous PO(2) versus MVO(2) relationship steepened. These findings indicate that K(ATP) channels contribute to local metabolic coronary vasodilation in alloxan-induced diabetic dogs.

Nitric oxide modulates right ventricular flow and oxygen consumption during norepinephrine infusion.

This study was designed to test if nitric oxide (NO) contributes to norepinephrine-induced right coronary vasodilation and if NO blunts the norepinephrine-induced increase in myocardial oxygen consumption (MVO(2)) in the right ventricle. In five anesthetized, open-chest dogs, mean aortic pressure, heart rate, right ventricular rate of pressure development over time (dP/dt), right coronary blood flow, and right ventricular MVO(2) were measured before and during graded intracoronary infusions of norepinephrine in the absence and presence of a NO synthase blocker, N(omega)-nitro-L-arginine methyl ester (L-NAME; 150 microg/min i.c.). During both conditions, right coronary blood flow and right ventricular MVO(2) significantly increased with graded infusions of norepinephrine. L-NAME significantly blunted the coronary hyperemic response to norepinephrine, although L-NAME did not alter the relationship between right ventricular MVO(2) and norepinephrine dose. However, when right ventricular function was indexed by heart rate x right ventricular maximum dP/dt x peak right ventricular systolic pressure, L-NAME significantly increased the oxygen cost of right ventricular function. These results indicate that NO contributes to norepinephrine-induced right coronary vasodilation and improves right ventricular oxygen utilization efficiency.