Increase In Coronary Blood Flow Research Articles

The insertion/deletion polymorphism of the angiotensin-converting enzyme gene determines coronary vascular tone and nitric oxide activity

OBJECTIVESWe investigated whether the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene modulates vasomotor tone and endothelial function.BACKGROUNDThe deletion allele of the ACE I/D polymorphism has been associated with increased incidence of cardiovascular pathology. The risk is synergistically increased in patients who also possess the C allele at position 1,166 of the angiotensin type I (AT1) receptor gene.METHODSIn 177 patients with coronary atherosclerosis or its risk factors, we investigated endothelial function with intracoronary acetylcholine (ACH), endothelium-independent smooth muscle function with sodium nitroprusside (SNP) and basal nitric oxide activity with L-NG monomethyl arginine.RESULTSCompared with ACE II genotype, patients with the ACE DD genotype had lower coronary microvascular and epicardial responses with SNP (coronary blood flow increase 196 ± 26% vs. 121 ± 11%, p = 0.003, and diameter increase 21.9 ± 2% vs. 17 ± 1%, p = 0.03, ACE II vs. DD, respectively). L-NG monomethyl arginine induced greater constriction in patients with the ACE DD compared with ACE II genotype (coronary blood flow −10 ± 4% vs. 11 ± 5%, p = 0.003, ACE DD vs. II and diameter constriction −6.3 ± 1.2% vs. −1.9 ± 1.2%, p = 0.01, respectively, in patients with atherosclerosis). No difference in ACH-mediated vasomotion was detected between the three ACE genotypes. The AT1 receptor polymorphism did not influence responses to either SNP or ACH.CONCLUSIONSPatients possessing the D allele of the ACE gene have increased vascular smooth muscle tone. The enhanced tone appears to be counterbalanced by an increase in basal nitric oxide activity in patients with atherosclerosis.

Interaction of isoflurane and cromakalim, a KATP channel opener, on coronary and systemic haemodynamics in chronically instrumented dogs.

Although isoflurane has been shown to cause coronary and systemic vasodilation through KATP channel activation, the interaction of KATP channel openers and isoflurane has not been fully investigated. The present study was carried out to determine the haemodynamic actions of cromakalim, a KATP channel opener, under the conscious state and during isoflurane anaesthesia in chronically instrumented dogs. Fourteen dogs were chronically instrumented to measure systemic and coronary haemodynamics. Each dog was randomly assigned to receive doses of either cromakalim, 4 and 10 microg x kg(-1) i.v., or isoflurane, 2.1% end-tidal (1.5 MAC), plus cromakalim, 4 and 10 microg x kg(-1) i.v. Cromakalim dose-relatedly decreased mean arterial pressure and systemic vascular resistance and increased coronary blood flow in both conscious and anaesthetized states. With isoflurane, the duration of effects of cromakalim were prolonged. Isoflurane exerted an additive effect on the increase in coronary blood flow induced by a low-dose cromakalim, whereas it did not influence the effect of a high-dose cromakalim. The maximum rate of increase in left ventricular pressure and segment shortening were increased by cromakalim in the conscious state but unchanged during isoflurane anaesthesia. The results suggest that the coronary vasodilating effects of isoflurane and cromakalim are basically additive until cromakalim exerts the maximal effect, and that the action of cromakalim on the coronary vasculature is prolonged by isoflurane.

ANALYTICAL METHODS TO DETECT THE AUTOOXIDATION OF ADRENOLUTIN AS A STEP IN CATECHOLAMINE METABOLISM

The acute hemodynamic effects of organophosphate (OP) intoxication include positive chronotropic and inotropic changes along with increases in intraventricular pressure and coronary blood flow. These observations are consistent with an enhanced sympathetic tone that correlates neurogenic cardiomyopathy to adrenergic overactivity and subsequent, focal catecholamine (CA) release and cellular oxidative stress. Several mechanisms have been proposed to explain the cardiotoxicity associated with elevated CA concentrations. However, it is suggested that the oxidative metabolites of CA's, rather than (or in addition to) the parent CA's per se, may initiate or be in part responsible for the cardiotoxicity. The chromatographic profile of adrenochrome (1) and adrenolutin (2) (Figure 1) are described in this study in an isocratic, reverse phase HPLC method using UV/VIS and electrochemical (EC) detection. The aqueous adrenochrome standard shows a retention time of 1.9 minutes under employed conditions. Furthermore, us...

Cholesterol Lowering With Pravastatin Improves Resistance Artery Endothelial Function: Report of Six Subjects With Normal Coronary Arteriograms

Improvement in coronary artery endothelial function has been demonstrated after cholesterol lowering in hypercholesterolemic patients with significant atherosclerosis. However, to our knowledge, no previous study has shown improvement in resistance artery function in subjects with normal coronary arteries after cholesterol lowering. The purpose of our study was to investigate the effect of cholesterol lowering with pravastatin on coronary resistance artery endothelial function in the setting of angiographically normal coronary arteries. Invasive testing of coronary endothelial and vasomotor function was performed at baseline and after 6 months of pravastatin treatment in six patients with normal coronary arteriograms. After 6 months of pravastatin treatment, low-density lipoprotein cholesterol level dropped from 157+/-11 to 117+/-8 mg/dL (p = 0.02) and percent increase in coronary blood flow after acetylcholine improved from 97+/-13% to 160+/-16% (p = 0.01). There was a trend (p = 0.17) toward enhanced epicardial dilation in response to acetylcholine after pravastatin treatment when compared with the baseline study. Our study demonstrates significant improvement in coronary resistance artery endothelial function after 6 months of cholesterol lowering with pravastatin in six subjects presenting with chest pain who were found to have normal coronary arteriograms. A trend toward improved epicardial vasomotion was also observed.

Role of K(ATP)(+) channels and adenosine in the control of coronary blood flow during exercise.

The present study was designed to examine the role of ATP-sensitive potassium (K(ATP)(+)) channels during exercise and to test the hypothesis that adenosine increases to compensate for the loss of K(ATP)(+) channel function and adenosine inhibition produced by glibenclamide. Graded treadmill exercise was used to increase myocardial O(2) consumption in dogs before and during K(ATP)(+) channel blockade with glibenclamide (1 mg/kg iv), which also blocks adenosine mediated coronary vasodilation. Cardiac interstitial adenosine concentration was estimated from arterial and coronary venous values by using a previously tested mathematical model (Kroll K and Stepp DW. Am J Physiol Heart Circ Physiol 270: H1469-H1483, 1996). Coronary venous O(2) tension was used as an index of the balance between O(2) delivery and myocardial O(2) consumption. During control exercise, myocardial O(2) consumption increased approximately 4-fold, and coronary venous O(2) tension fell from 19 to 14 Torr. After K(ATP)(+) channel blockade, coronary venous O(2) tension was decreased below control vehicle values at rest and during exercise. However, during exercise with glibenclamide, the slope of the line of coronary venous O(2) tension vs. myocardial O(2) consumption was the same as during control exercise. Estimated interstitial adenosine concentration with glibenclamide was not different from control vehicle and was well below the level necessary to overcome the 10-fold shift in the adenosine dose-response curve due to glibenclamide. In conclusion, K(ATP)(+) channel blockade decreases the balance between resting coronary O(2) delivery and myocardial O(2) consumption, but K(ATP)(+) channels are not required for the increase in coronary blood flow during exercise. Furthermore, interstitial adenosine concentration does not increase to compensate for the loss of K(ATP)(+) channel function.

The influence of left ventricular geometry on coronary vasomotion in patients with essential hypertension

The objective of this study was to assess the influence of left ventricular (LV) geometric pattern on coronary vasomotion in patients with essential hypertension. We studied 34 hypertensive patients, who had never been treated, with angiographically normal coronary arteries. Patients were classified into four LV geometric patterns by echocardiography: normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. The responses of coronary vasomotion in left anterior descending artery to vasoactive agents (acetylcholine, isosorbide dinitrate, adenosine triphosphate) were examined using a Doppler guidewire and quantitative coronary angiography. The percent increase in coronary blood flow evoked with acetylcholine (endothelium-dependent vasomotion) showed lowest in concentric hypertrophy, followed by eccentric hypertrophy, concentric remodeling, and normal geometry. The significant linear relationship between acetylcholine-induced coronary blood flow and LV mass was noted. There was no difference in the percent increase in coronary blood flow evoked with isosorbide dinitrate (endothelium-independent vasomotion of conduit vessel) among the four groups. The percent increase in coronary blood flow evoked with adenosine triphosphate (endothelium-independent vasomotion of resistant vessel) was significantly lower in patients with concentric hypertrophy than in the other three groups. The results in this study suggest that coronary vasomotion may be associated with LV geometry in patients with hypertension. The endothelium-dependent vasodilation is impaired progressively as LV hypertrophy advances. The endothelium-independent vasodilation of microvessels is impaired only in concentric hypertrophy. This advanced abnormality of coronary vasomotion may contribute to the high cardiovascular morbidity and mortality in patients with concentric hypertrophy.

Premarin-induced increases in coronary and uterine blood flow in nonpregnant sheep*1

Objective: Menopause is associated with an increased incidence of cardiovascular disease among women, and estrogen replacement therapy is thought to reduce the risk of coronary artery disease. The mechanism by which this occurs is unclear, but coronary arterial endothelial and vascular smooth muscle cells have been shown to contain estrogen receptors, and their stimulation appears to increase nitric oxide synthesis. One conjugated estrogen preparation (Premarin) is widely used in postmenopausal hormone replacement therapy, but little is known about its effects on cardiovascular hemodynamics. Study Design: This study was designed to determine whether Premarin, like 17β-estradiol, has significant effects on cardiac output and coronary and uterine blood flows at doses used clinically (0.625, 1.25, and 2.5 mg). Nonpregnant oophorectomized sheep were implanted with instruments to measure cardiac output, left coronary (circumflex) artery blood flow, uterine blood flow, heart rate, and systemic arterial blood pressure. After recovery from surgery, the animals received intravenous bolus injections of either 17β-estradiol (1.0 μg/kg), Premarin (0.625, 1.25, or 2.5 mg), or vehicle on different days. Results: The 1.0-μg/kg dose of 17β-estradiol significantly increased coronary blood flow by 15% ± 2% from baseline (mean ± SEM). Premarin also increased coronary blood flow significantly at the 1.25- and 2.5-mg dose levels by 12% ± 3% and 14% ± 4%, respectively. As expected 17β-estradiol increased uterine blood flow from a baseline of 15 ± 3 mL/min to 169 ± 19 mL/min. Premarin treatment was associated with a significant increase in uterine blood flow, which increased from an average baseline of 14 ± 4 mL/min to 46 ± 10 mL/min, 95 ± 18 mL/min, and 135 ± 20 mL/min at the three doses tested (0.625, 1.25, and 2.5 mg, respectively). 17β-Estradiol also increased cardiac output by 12% ± 3%. Premarin increased cardiac output 2% ± 3%, 9% ± 4%, and 11% ± 3%, with only the highest dose producing a significant change. 17β-Estradiol also increased heart rate by 12% ± 1%, whereas Premarin at doses of 0.625, 1.25, and 2.5 mg increased it by 4% ± 3%, 7% ± 4%, and 10% ± 2%, respectively (increase significant only at the highest dose). Neither 17β-estradiol nor Premarin altered either stroke volume or systemic arterial pressure. Conclusion: Premarin, like 17β-estradiol, has significant systemic, coronary, and uterine vascular effects. These vascular effects may help to explain in part why these compounds are cardioprotective. (Am J Obstet Gynecol 2000;183:12-7.)

Premarin-induced increases in coronary and uterine blood flow in nonpregnant sheep

Objective: Menopause is associated with an increased incidence of cardiovascular disease among women, and estrogen replacement therapy is thought to reduce the risk of coronary artery disease. The mechanism by which this occurs is unclear, but coronary arterial endothelial and vascular smooth muscle cells have been shown to contain estrogen receptors, and their stimulation appears to increase nitric oxide synthesis. One conjugated estrogen preparation (Premarin) is widely used in postmenopausal hormone replacement therapy, but little is known about its effects on cardiovascular hemodynamics. Study Design: This study was designed to determine whether Premarin, like 17β-estradiol, has significant effects on cardiac output and coronary and uterine blood flows at doses used clinically (0.625, 1.25, and 2.5 mg). Nonpregnant oophorectomized sheep were implanted with instruments to measure cardiac output, left coronary (circumflex) artery blood flow, uterine blood flow, heart rate, and systemic arterial blood pressure. After recovery from surgery, the animals received intravenous bolus injections of either 17β-estradiol (1.0 μg/kg), Premarin (0.625, 1.25, or 2.5 mg), or vehicle on different days. Results: The 1.0-μg/kg dose of 17β-estradiol significantly increased coronary blood flow by 15% ± 2% from baseline (mean ± SEM). Premarin also increased coronary blood flow significantly at the 1.25- and 2.5-mg dose levels by 12% ± 3% and 14% ± 4%, respectively. As expected 17β-estradiol increased uterine blood flow from a baseline of 15 ± 3 mL/min to 169 ± 19 mL/min. Premarin treatment was associated with a significant increase in uterine blood flow, which increased from an average baseline of 14 ± 4 mL/min to 46 ± 10 mL/min, 95 ± 18 mL/min, and 135 ± 20 mL/min at the three doses tested (0.625, 1.25, and 2.5 mg, respectively). 17β-Estradiol also increased cardiac output by 12% ± 3%. Premarin increased cardiac output 2% ± 3%, 9% ± 4%, and 11% ± 3%, with only the highest dose producing a significant change. 17β-Estradiol also increased heart rate by 12% ± 1%, whereas Premarin at doses of 0.625, 1.25, and 2.5 mg increased it by 4% ± 3%, 7% ± 4%, and 10% ± 2%, respectively (increase significant only at the highest dose). Neither 17β-estradiol nor Premarin altered either stroke volume or systemic arterial pressure. Conclusion: Premarin, like 17β-estradiol, has significant systemic, coronary, and uterine vascular effects. These vascular effects may help to explain in part why these compounds are cardioprotective. (Am J Obstet Gynecol 2000;183:12-7.)

Effect of ligation of spleen vessels on left ventricular function and coronary blood flow in dogs injected with scorpion venom.

Scorpion sting may cause myocardial dysfunction in human victims, probably by increased O2 demand and decreased O2 supply. In dog, scorpion venom (SV) causes no myocardial dysfunction. Myocardium is probably protected by "autotransfusion" of blood from the spleen to the circulation, increasing coronary blood flow (CBF) and O2 delivery. We hypothesized that ligation of spleen vessels prior to injection of SV in dogs would prevent the autotransfusion of blood, thereby causing myocardial ischemia due to decreased CBF, simulating the hemodynamic pattern of human envenomation. We studied cardiac output (CO), CBF, left ventricular (LV) O2 delivery and contractility in 11 dogs injected with 0.07 mg/kg of SV (Leiurus quinquestriatus). Ligation of spleen vessels was performed on 6 of the 11 dogs prior to SV injection. 15 min after SV injection CO had increased by 186% in control dogs, while ligation of spleen vessels completely prevented CO elevation (p<0.001). In both groups, however, LV dp/dt increased by 400% and dp/dt/p by 170% (p<0.001). CBF increased by 350% and 550% in the spleen and control groups (p<0.001) respectively. This was associated with elevation of diastolic blood pressure and a decrease in coronary vascular resistance. LV O2 delivery increased (p<0.05) in both groups. At 60 minutes there was a decrease in CO, stroke work, and LV end systolic pressure in both groups, while LV contractility remained above baseline. Scorpion venom injection in dogs causes an initial increase in CO by auto-transfusion of blood from the spleen. Prevention of the autotransfusion does not preclude increases in CBF, O2 delivery and LV contractility.

Coronary nitric oxide production in response to exercise and endothelium-dependent agonists.

Endothelium-derived nitric oxide (NO) contributes to epicardial coronary artery vasodilation during exercise. However, blockade of NO production does not impair the increase in coronary blood flow (CBF) during exercise, suggesting that NO is not obligatory for exercise-induced coronary resistance vessel dilation. In contrast, the increases in CBF produced by endothelium-dependent agonists are decreased after NO blockade. Consequently, this study was performed to determine whether the increase in coronary NO production in response to agonists is greater than that which occurs during exercise. We measured the oxidation products of NO (nitrate+nitrite=NO(x)) in aortic and coronary sinus plasma using chemiluminescence to assess NO(x) production across the coronary circulation in chronically instrumented dogs during a 3-stage treadmill exercise protocol and in response to intracoronary administration of the endothelium-dependent agonists acetylcholine (37.5 microg/min) and bradykinin (3.0 microg/min). No coronary NO(x) production could be detected at rest or during the first 2 stages of exercise; only at the highest level of exercise was a small increase in coronary NO(x) production measured. In contrast, coronary production of NO(x) was significantly increased in response to endothelium-dependent agonists. Coronary NO production in response to endothelium-dependent agonists is greater than in response to the increase in shear stress associated with exercise. These findings support previous studies suggesting that NO is not required for the coronary vasodilation that occurs in the normal heart during exercise.

Effects of bradykinin on coronary blood flow and vasomotion in transplant patients

OBJECTIVESTo evaluate the effects of exogenous bradykinin on coronary epicardial and microcirculatory tone in transplant patients (HTXs), and to compare them with the effects of acetylcholine.BACKGROUNDCoronary endothelial dysfunction has been reported to occur early after heart transplantation, most notably when acetylcholine was the endothelium-function marker used. The effects of bradykinin on coronary vasomotion are unknown in HTXs.METHODSSixteen HTXs were compared 3.6 ± 1.7 months after transplantation to seven control subjects. Coronary flow velocity was measured using guide-wire Doppler. Diameters (D) of three segments of the left coronary artery and coronary blood flow (CBF) were assessed at baseline, after 3-min infusions of increasing bradykinin doses (50, 150 and 250 ng/min) then of increasing acetylcholine doses (estimated blood concentrations of 10-8, 10-7 and 10-6 M).RESULTSBradykinin induced similar dose-dependent increases in D and CBF in both groups: D was 11 ± 12%, 19 ± 14% and 22 ± 16% (all p < 0.0001), and CBF was 50 ± 40%, 130 ± 68% and 186 ± 77% (all p < 0.0001). Acetylcholine induced significant epicardial vasodilation in control subjects and vasoconstriction in HTX, as well as a marked increase in CBF in both groups. Acute allograft rejection, present in 8 of the 16 HTXs, did not modify responses to bradykinin, but was associated with a smaller CBF increase in response to acetylcholine (p < 0.05).CONCLUSIONSThe coronary vasodilating effects of bradykinin are preserved early after heart transplantation, even in the presence of acute allograft rejection. Although there is an abnormal vasoconstricting response to acetylcholine reflecting endothelium dysfunction, the endothelium remains a functionally active organ in heart transplant recipients.

Direct coronary vasomotor effects of sevoflurane and desflurane in in situ canine hearts.

An extracorporeal system was used to investigate the direct coronary vasomotor effects of sevoflurane and desflurane in vivo. The role of the adenosine triphosphate-sensitive potassium channels (KATP channels) in these effects was evaluated. Twenty-one open-chest, anesthetized (fentanyl-midazolam) dogs were studied. The left anterior descending coronary artery was perfused at controlled pressure (80 mmHg) with normal arterial blood or arterial blood equilibrated with either sevoflurane or desflurane. Series 1 (n = 16) was divided into two groups of equal size on the basis of whether sevoflurane (1.2, 2.4, and 4.8%) or desflurane (3.6, 7.2, and 14.4%) was studied. The concentrations for the anesthetics corresponded to 0.5, 1.0, and 2.0 minimum alveolar concentration (MAC), respectively. Coronary blood flow (CBF) was measured with an ultrasonic, transit-time transducer. Local coronary venous samples were obtained and used to evaluate changes in myocardial oxygen extraction (EO2). In series 2 (n = 5), changes in CBF by 1 MAC sevoflurane and desflurane were assessed before and during intracoronary infusion of the KATP channel inhibitor glibenclamide (100 microg/min). Intracoronary sevoflurane and desflurane caused concentration-dependent increases in CBF (and decreases in EO2) that were comparable. Glibenclamide blunted significantly the anesthetic-induced increases in CBF. Sevoflurane and desflurane have comparable coronary vasodilative effects in in situ canine hearts. The KATP channels play a prominent role in these effects. When compared with data obtained previously in the same model, the coronary vasodilative effects of sevoflurane and desflurane are similar to those of enflurane and halothane but considerably smaller than that of isoflurane.

Coronary and uterine vascular responses to raloxifene in the sheep

Objective:We sought to determine whether raloAfene increases coronary and uterine blood flow in ovariectomized ewes. Study Design:Twelve ewes were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, coronary blood flow, and uterine blood flow. Sheep received 17ß-estradiol, Estrace, raloxifene, or KY Jelly vehicle on separate days. Results:17ß-Estradiol increased uterine blood flow from 21 ± 3 to 254 ± 36 mpl/min and coronary blood flow by 21% ± 2% within 2 hours. Estrace increased uterine blood flow from 30 ± 7 to 260 ± 62 ml/min and coronary blood flow by 8% ± 4% within 3 hours. Raloxifene increased uterine blood flow from 20 ± 3 ml/min to 220 ± 53 mUmin by 6 hours and coronary blood flow by 22% ± 5% within 24 hours. To determine whether hemodynamic responses were mediated by nitric oxide, l-nitroarginine methyl ester was administered and produced an approximate 50% decrease in uterine blood flow for all 3 compounds. l-Nitroarginine methyl ester attenuated increases in coronary blood flow induced by I7ß-estradiol, Estrace, and raloxifene. Conclusions:Raloxifene has significant coronary and uterine vascular effects in the ovariectomized ewe. The coronary and uterine responses are partially mediated by nitric oxide.

Consequences of Inspired Oxygen Fraction Manipulation on Myocardial Oxygen Pressure, Adenosine and Lactate Concentrations: A Combined Myocardial Microdialysis and Sensitive Oxygen Electrode Study in Pigs

Adenosine is a potent vasodilator whose concentration has been shown to increase in cardiac tissue in response to hypoxia. However, the time-dependent relationship between the levels of myocardial interstitial adenosine and tissue oxygenation has not yet been completely established. Therefore, the purpose of this study was to investigate the complex relationship between tissue myocardial oxygen tension (PtiO2) and interstitial myocardial adenosine and lactate concentrations by developing a new technique which combines a cardiac microdialysis probe and a Clark-type PO2 electrode. The combined and the single microdialysis probes were implanted in the left ventricular myocardium of anesthetized pigs. The consequences of the combined use of microdialysis and P O2probes on myocardial PtiO2and microdialysis performances against glucose were evaluated. A moderate but significant reduction in the relative recovery against glucose of the combined probe was observed when compared to that of the single microdialysis probe (42±2v 32±1%, mean±S.E.M.n=5 P<0.05), at 2μl/min microdialysis probe perfusion flow. Similarly, myocardial oxygen enrichment, measured by the P O2electrode, was negligible when microdialysis probe perfusion flow was 2μl/min. Systemic hypoxia (FiO2=0.08) resulted in a significant decrease in PtiO2from 30±4 to 11±2 mmHg, limited increase in coronary blood flow (CBF), and a significant increase in myocardial adenosine and lactate concentrations from 0.34±0.05 to 0.98±0.06μmol/l and from 0.45±0.05 to 0.97±0.06 mmol/l respectively (P<0.05). Increasing the FiO2to 0.3 restored the PtiO2and hemodynamic parameters to baseline values with no changes in interstitial adenosine and lactate concentrations. Nevertheless, myocardial interstitial adenosine remained significantly higher than baseline values. In conclusion, this study demonstrates the ability of a combined probe to measure simultaneously regional myocardial PtiO2and metabolite concentration during hypoxia. The hypoxia-induced increase in myocardial adenosine persists after correction of hypoxia. The physiological significance of this observation requires further studies.

Beneficial effects of the T- and L-type calcium channel antagonist, mibefradil, against exercise-induced myocardial stunning in dogs.

Abnormalities in calcium homeostasis such as calcium overload have been shown to participate in the pathogenesis of myocardial stunning. The goal of this study was to investigate the effects of mibefradil, a mixed T- and L-type calcium channels antagonist on exercise-induced ischemia (i.e., high-flow ischemia). Nine dogs were permanently instrumented to measure left ventricular wall thickening (Wth) and coronary blood flow (Doppler). Infusion of saline or mibefradil (30 and 40 microg/kg/min, i.v., for 20 min) was started 10 min before exercise (10 min, 14 km/h; slope, 13%) and stopped at its end. Circumflex coronary artery stenosis (pneumatic occluders) was set up 5 min before exercise to suppress exercise-induced increase in mean coronary blood flow without simultaneously affecting Wth at rest. Mibefradil (30 microg/kg/min) was also administered at the beginning of the recovery period in a subset of four dogs. During exercise with saline, Wth was dramatically reduced (-77 +/- 7%; p < 0.05) and recovered only after 24 h. Mibefradil at both doses significantly limited tachycardia during exercise (211 +/- 7 and 210 +/- 5 beats/min vs. 240 +/- 8 beats/min for mibefradil, 30 microg/kg/min, mibefradil, 40 microg/kg/min, and saline, respectively) but exerted no negative inotropic effects. Mibefradil at both doses significantly reduced the intensity of myocardial stunning and the time to recovery in Wth (3 h). Administration of mibefradil at the beginning of the recovery period did not protect against myocardial stunning. Administration of a mixed T- and L-type calcium channel antagonists before ischemia confers cardioprotection against exercise-induced myocardial stunning. This may potentially be related to the limitation of exercise-induced tachycardia and/or the prevention of calcium overload.

Nifedipine-induced coronary vasodilation in ischemic hearts is attributable to bradykinin- and NO-dependent mechanisms in dogs.

Dihydropyridine calcium channel blockers protect endothelial cells against ischemia and reperfusion injury, suggesting that nifedipine may increase the in vivo cardiac NO level and thus coronary blood flow (CBF) in ischemic hearts. We tested this hypothesis. In open-chest dogs, coronary perfusion pressure (CPP) was reduced in the left anterior descending coronary artery so that CBF decreased to one third of the control level, and thereafter CPP was maintained constant (103+/-8 to 43+/-3 mm Hg, n=9). We obtained fractional shortening (FS) and lactate extraction ratio (LER) as indices of regional myocardial contraction and metabolism. Both FS (26.4+/-2.1% to 6.7+/-2.0%, n=9, P<0.001) and LER (32+/-6% to -37+/-5%, n=9, P<0.001) showed a decrease when CPP was reduced. After intracoronary infusion of nifedipine (4 microgram. kg(-1). min(-1)), CBF increased from 30+/-1 to 48+/-4 mL. 100 g(-1). min(-1) (P<0.01) without a change of CPP (n=9). Both FS (14.0+/-1.9%, n=9) and LER (-9+/-7%, n=9) also increased (P<0.01). Nifedipine increased the difference in the level of metabolites of NO (nitrate+nitrite; 9+/-3 to 25+/-5 nmol/mL, n=9, P<0.01) and bradykinin (22+/-5 to 58+/-4 pmol/mL, n=9, P<0.01) between coronary venous and arterial blood. L-NAME (an NO synthase inhibitor) or HOE-140 (a bradykinin receptor antagonist) attenuated (P<0.05) the increase in CBF (29+/-3 and 35+/-2 mL. 100 g(-1). min(-1), n=5 each), FS (4.8+/-0.6% and 6.9+/-1.7%, n=5 each), LER (-47+/-8% and -35+/-9%, n=5 each), and nitrate+nitrite (3+/-2 and 8+/-4 nmol/mL, n=5 each) due to nifedipine infusion. These results indicate that the calcium channel blocker nifedipine mediates coronary vasodilation and improves myocardial ischemia through both bradykinin/NO-dependent and -independent mechanisms.

Effects of Intracoronary Calcium Chloride and Epinephrine on Coronary Blood Flow, Oxidative Metabolism, and Mechanical Function in Canine Normal and Stunned Myocardium

Background : The effects of calcium chloride (CaCI2) on regional mechanical function, coronary blood flow (CBF) and myocardial oxygen consumption (MVO2) were examined in normal and stunned myocardium in an open-chest canine model. The effects were compared with those of epinephrine. Methods : Thirty-one dogs were acutely instrumented under enflurane anesthesia to measure aortic and left ventricular pressure, pulmonary and left anterior descending (LAD) coronary flow, and subendocardial segment length the in LAD region. CaCl2 (0.1, 0.25, 0.5, 0.75 mg/ml of LAD flow, n=16) or epinephrine (4, 10, 20, 30 ng/ml of LAD flow, n=15) was directly infused into the LAD before (normal) and after 15 min of its occlusion and reperfusion (shunned). Simultaneous measurements of arterial and coronary venous contents of oxygen and lactate were made to calculate oxygen (EO2) and lactate (E1ac ) extraction ratio during CaCl2 or epinephrine infusion. Results : Both CaCl2 and epinephrine infusions in normal myocardium resulted in dose-dependent increases in mechanical functions and MVO2. These changes were accompanied by parallel increases in CBF, resulting in no changes of EO2 with CaCl2, while CBF increased more than MVO2 with epinephrine, resulting in a decrease in EOz. After ischemia and reperfusion, mechanical functions and E were significantly depressed, but similar mechanical responses to both agents with resultant unaltered EO2 were observed. E1ac was decreased further during epinephrine, while it remained unaltered during CaCl infusion in stunned myocardium. Conclusions : CaCl2, similar to epinephrine, exerts positive inotropic and lusittopic effects in normal and stunned myocardium in dogs. In addition, CaCl2 has no duect effect on coronary vascular tone in either normal or stunned myocardium, while epinephrine causes direct vasodilation in normal but not in stunned myocardium. (Korean J Anesthesiol 2000; 39: S23-S34)

Comparison of cardiotropic drug effects on haemodynamic and myocardial energetics in patients with heart failure: a computer simulation

The purpose of our study is to compare haemodynamic responses and the ischaemic potential of commonly used inotropes (dopamine, dobutamine and milrinone) using a computer model of the cardiovascular system. Cardiotropic drugs interact with the model by changing ventricular elastance and resistance of the individual circulation. All three drugs increase cardiac index in a dose-dependent manner. Dopamine at medium and high infusion rates increases heart rate, systemic vascular resistance and arterial blood pressure. The associated increase in coronary blood flow, however, is not sufficient to account for increased oxygen demand. Both dobutamine and milrinone decrease vascular resistance and increase coronary blood flow. The more pronounced increase in heart rate associated with dobutamine, however, results in a higher ischaemic potential for this drug. Our simulation demonstrates that although all the drugs studied improve cardiac function in simulated patients with heart failure, milrinone accomplishes this at a lower energy cost. The computer simulation developed can be used to assess the complex effect of cardiotropic drugs and possibly suggest optimal drug therapy in specific clinical situations.

Atrial natriuretic peptide reduces the severe consequences of coronary artery occlusion in anaesthetized dogs.

The aim of the present study was to examine the effects of atrial natriuretic peptide (ANP) on the responses to coronary artery occlusion. In chloralose-urethane anaesthetised mongrel dogs either saline (controls) or human synthetic ANP was infused intravenously (10 microg kg(-1) + 0.1 microg kg(-1) min(-1)), starting 30 min before and continuing 10 min during a 25 min occlusion of the left anterior descending coronary artery (LAD). ANP infusion resulted in a fall in mean arterial blood pressure (by 17 +/- 2 mmHg, p < 0.05), a transient (max. at 5 min) increase in coronary blood flow (by 24 +/- 5 ml min(-1), p < 0.05), and a reduction in coronary vascular resistance (by 0.27 +/- 0.05 mmHg ml(-1), p < 0.05). When the LAD coronary artery was occluded, there was a less marked elevation in left ventricular end-diastolic pressure (LVEDP) in the ANP-treated dogs than in the controls (9.0 +/- 0.9 versus 12.2 +/- 0.8 mmHg, p < 0.05). Compared to the controls, ANP reduced the number of ventricular premature beats (VPBs, 26 +/- 12 versus 416 +/- 87, p < 0.05), the number of episodes of ventricular tachycardia per dogs (VT, 0.7 +/- 0.3 versus 12.4 +/- 4.2, p < 0.05), and the incidences of VT (45% versus 100%, p < 0.05) and ventricular fibrillation (VF 18% versus 57%, p < 0.05) during occlusion. Reperfusion of the ischaemic myocardium at the end of the occlusion period led to VF in all the control dogs (survival from the combined ischaemia-reperfusion insult was therefore 0%), but VF following reperfusion was much less in the dogs given ANP (survival 64%; p < 0.05). The severity of myocardial ischaemia, as assessed from changes in the epicardial ST-segment and the degree of inhomogeneity, was significantly less marked in dogs given ANP. We conclude that ANP protects the myocardium from the consequences of myocardial ischaemia resulting from acute coronary artery occlusion and reperfusion in anaesthetized dogs.

Efecto de la inhibición de la ciclooxigenasa en la adaptación del flujo coronario a la taquicardia

The role of different endothelium-derived vasoactive substances in the regulation of coronary circulation during tachycardia is not well defined. In order to elucidate the contribution of prostacyclin to the adaptation of coronary blood flow to tachycardia, the effect of meclofenamate, a cyclooxygenase inhibitor on the coronary blood flow response to rapid atrial pacing was analyzed in a porcine model. A group of seventeen pigs were instrumented for coronary blood flow, aortic pressure and atrial pacing. Heart rate was increased by 20 beats every 5 minutes. Coronary blood flow and aortic pressure were measured, and coronary resistance calculated, basally and at each pacing interval, before and after saline serum (n = 6), meclofenamate 5 mg/kg, i.v. (n = 7) or meclofenamate 35 mg/kg, i.v. (n = 4). Neither saline nor meclofenamate modified the normal increase of coronary blood flow provoked by rapid atrial pacing (163 +/- 28% increase before versus 172 +/- 29% after saline; 159 +/- 21% increase before versus 161 +/- 22% after meclofenamate low doses and 201 +/- 39% before vs 172 +/- 36 after meclofenamate high doses). There were no differences in the response of coronary vascular resistance to tachycardia before and after meclofenamate (44% reduction vs 40% respectively). Cyclooxygenase blockade does not modify the response of coronary circulation to rapid atrial pacing, suggesting that prostacyclin does not play a limiting role in the regulation of coronary blood flow during tachycardia in this model.