Biomedical subjects

B D Guth

Publications and source records attributed to B D Guth.

At least 37 records · Page 2Linked to original sources

PubMed1991

No effect of coronary perfusion on regional myocardial function within the autoregulatory range in pigs. Evidence against the Gregg phenomenon.

BACKGROUND: The hypothesis that increases in coronary perfusion increase ventricular performance independently from providing enhanced oxygen supply ("Gregg phenomenon") remains controversial. METHODS AND RESULTS: To study the physiological significance of changes in coronary perfusion on global and regional myocardial function in situ, the left anterior descending coronary artery of isoflurane-anesthetized swine was cannulated, and perfusion was varied. In one group of swine (n = 5), coronary arterial pressure was increased in four steps from 88 +/- 11 to 186 +/- 11 mm Hg by increasing the speed of the pump circuit providing coronary blood flow. No changes in left ventricular end-diastolic pressure, peak pressure, or maximum left ventricular dP/dt were observed. Subendocardial blood flow (by radiolabeled microspheres) increased from 0.96 +/- 0.27 to 2.04 +/- 0.73 ml/min/g without any increase in systolic wall thickening (by sonomicrometry) or myocardial oxygen consumption of the anterior myocardium. In a second group of swine (n = 8), coronary arterial pressure was kept constant and coronary blood flow was increased stepwise by intracoronary adenosine infusion. End-diastolic pressure, peak pressure, and maximum left ventricular dP/dt remained unchanged when coronary blood flow increased from 21.7 +/- 9.8 to 93.8 +/- 34.1 ml/min. Subendocardial blood flow increased from 0.89 +/- 0.26 to 3.28 +/- 1.02 ml/min/g, again without any increase in systolic wall thickening (45.6 +/- 8.6 versus 42.6 +/- 9.8%) and myocardial oxygen consumption (5.75 +/- 1.18 versus 5.87 +/- 1.67 ml/min/100 g). In a third group of swine (n = 10), coronary arterial pressure was lowered by intracoronary adenosine infusion during constant coronary inflow. Left ventricular hemodynamics remained unchanged. With a decrease in coronary arterial pressure from 130 +/- 25 to 71 +/- 14 mm Hg, no decreases in subendocardial blood flow and systolic wall thickening were observed. Only when coronary arterial pressure was further reduced to 57 +/- 13 mm Hg did systolic wall thickening fall to 25.7 +/- 9.9% (control, 31.1 +/- 11.1%), associated with a decrease in subendocardial blood flow from 1.17 +/- 0.39 to 0.87 +/- 0.52 ml/min/g. CONCLUSIONS: Thus, the Gregg phenomenon plays no significant role within or above the autoregulatory pressure-flow range normally seen in anesthetized swine in situ.

Animals↗

PubMed1991

Effect of alpha-adrenergic stimulation on regional contractile function and myocardial blood flow with and without ischemia.

BACKGROUND: The effect of alpha-adrenergic receptor activation on regional contractile function and transmural myocardial blood flow is controversial. Accordingly, the effects of selective alpha 1-(methoxamine) and alpha 2-(BHT 933) receptor stimulation on regional contractile function and transmural myocardial blood flow distribution were studied in 15 anesthetized open-chest dogs. METHODS AND RESULTS: The alpha-adrenergic agonists were separately infused into the cannulated left circumflex coronary artery during control and ischemic conditions in the same animal. Mean coronary perfusion pressure was held constant by a servocontrolled pump in an extracorporeal circuit. Ischemia was created by reducing coronary perfusion pressure to the level at which percent systolic wall thickening (%WT) decreased by 54%. Contractile function during control conditions was unchanged, whereas under ischemic conditions a further significant decrease in %WT of 27% occurred with either alpha 1- or alpha 2-receptor stimulation without any change in the anterior (control) wall function. Both alpha 1- and alpha 2-receptor stimulations during control conditions resulted in a relatively uniform transmural decrease in blood flow with no change in the subendocardial-to-subepicardial blood flow ratio. With alpha 1-stimulation during ischemia (n = 13), there was a tendency toward decreased subepicardial blood flow with no change in subendocardial flow, resulting in an increased subendocardial-to-subepicardial blood flow ratio (0.61 +/- 0.23 to 0.82 +/- 0.40, p less than 0.05). alpha 2-Receptor stimulation during ischemia (n = 12) produced a significant decrease in subepicardial blood flow (0.45 +/- 0.20 to 0.35 +/- 0.12 ml/min/g, p less than 0.01) with no change in subendocardial blood flow, also resulting in an increased subendocardial-to-subepicardial blood flow ratio. CONCLUSIONS: These results indicate the selective vasoconstriction in outer wall layers during ischemia mediated by either alpha 1- or alpha 2-receptors can cause a decrease in regional contractile function despite unchanged subendocardial blood flow and improved subendocardial-to-subepicardial flow ratio. This suggests an adverse effect of alpha-adrenergic vasoconstriction during ischemia in this coronary perfusion pressure-controlled canine model.

Adrenergic alpha-Agonists↗

PubMed1990

Alpha-adrenergic regulation of myocardial performance in the exercising dog: evidence for both presynaptic alpha 1- and alpha 2-adrenoceptors.

New evidence supporting both presynaptic alpha 1- and alpha 2-adrenoceptors playing a role in the regulation of myocardial contractile performance in the exercising dog is reviewed. Studies utilized chronically instrumented dogs having sonomicrometers for the measurement of regional wall thickening and transducers for the measurement of left ventricular and systemic hemodynamics. During steady state exercise, either the selective alpha 1-adrenoceptor blocker prazosin (80 micrograms/kg) or the selective alpha 2-adrenoceptor blocker idazoxan (80 micrograms/kg) was infused into the left atrium while exercise continued. Immediately following the administration of either alpha-adrenoceptor blocking agent, there were substantial increases in heart rate, left ventricular dP/dt and regional contractile function as assessed using sonomicrometers, and norepinephrine release by the myocardium increased substantially. beta-adrenergic blockade prevented the heart rate and contractile effects of either alpha 1- or alpha 2-adrenoceptor blocker whereas norepinephrine release was further enhanced. These effects could not be attributed to baroreceptor unloading. In dogs studied under resting conditions with norepinephrine infusion to produce an increase in dP/dt similar to that observed during treadmill exercise, no sympathetic augmentation was observed following either alpha-blocker. Together, these studies provide evidence that both alpha 1- and alpha 2-adrenoceptors participate in the modulation of sympathetic neuronal norepinephrine release in the canine myocardium.

Adrenergic alpha-Antagonists↗

PubMed1990

Mechanisms of benefit in the ischemic myocardium due to heart rate reduction.

The studies reviewed here examine the role of heart rate reduction in the beneficial effect observed following beta-adrenoceptor blockade during exercise-induced ischemia in conscious dogs. To further study the effects of heart rate reduction on regional blood flow in an ischemic bed without collateral circulation, anesthetized swine with controlled coronary perfusion were also studied. Measurements of regional myocardial blood flow (microspheres) and contractile function (sonomicrometers) during steady state exercise in dogs with chronic coronary artery stenosis indicated the existence of severe regional contractile dysfunction and subendocardial ischemia. The administration of beta-adrenoceptor blockade (1.0 mg/kg atenolol) improved regional contractile function when heart rate was reduced from 220 to 165 beats/min. Atrial pacing during exercise to prevent the bradycardia following beta-adrenoceptor blockade eliminated the improved regional function and blood flow. Thus, the beneficial effect of beta-blockade was only apparent when exercise heart rate was reduced. In anesthetized swine with constant inflow coronary perfusion, two levels of coronary hypoperfusion were examined at heart rates of 91 beats/min or 55 beats/min. Bradycardia was produced using the bradycardic agent UL-FS 49 (0.3 mg/kg). Regional contractile function and subendocardial blood flow were markedly improved at the lower heart rate for either level of reduced coronary perfusion, indicating a redistribution of blood flow towards the subendocardium. The improvement in contractile function was larger than predicted on the basis of the improvement in blood flow per min to the subendocardium. Independent relationships between regional contractile function and the subendocardial blood flow per min were observed for each heart rate. Thus, the studies in conscious exercising dogs indicated that heart rate reduction is an essential mechanism for the improvement of ischemic regional myocardial contractile function during exercise by beta-blockade. This is likely the result of the marked improvement in subendocardial blood flow per beat which accompanies the reduced heart rate; regional myocardial blood flow per beat appears to be a predictor of regional contractile function during ischemia both at rest and during exercise.

Animals↗

PubMed1990

Alpha 2-adrenergic coronary constriction in ischemic myocardium during exercise.

The effect of either selective alpha 1- or alpha 2-adrenoceptor blockade on ischemic myocardial blood flow and function was examined in beta-blocked dogs trained to run on a motor-driven treadmill. The animals were instrumented with sonomicrometers for the assessment of regional systolic wall thickening (%WTh) of the left ventricle. For drug infusion, an intracoronary catheter was implanted in the circumflex coronary artery and a hydraulic cuff was placed proximally around the artery. Following systemic beta-blockade with 0.8 mg/kg propranolol, an acute stenosis of the circumflex coronary artery inflated during exercise induced severe dysfunction in the posterior wall. Intracoronary infusion of 80 micrograms/kg of the selective alpha 2-adrenoceptor blocking agent idazoxan improved posterior wall (PW)-%WTh from 5.1 +/- 1.6 to 10.8 +/- 2.8% (p less than 0.06) and regional myocardial blood flow (radiolabelled microspheres) in the subendocardium of the posterior wall from 0.17 +/- 0.05 to 0.45 +/- 0.30 (ml/min)/g (p less than 0.05). No increases in regional blood flow and regional myocardial function were observed after infusion of the selective alpha 1-adrenoceptor blocking agent prazosin (20 micrograms/kg) under the same experimental conditions. It is concluded that during severe ischemia, significant postjunctional alpha 2-adrenoceptor mediated coronary vasoconstriction exists. Regional alpha 2-adrenoceptor blockade, but not alpha 1-adrenoceptor blockade is effective in reducing regional ischemia and dysfunction by attenuating sympathetic vasoconstriction in the conscious dog.

Adrenergic alpha-Antagonists↗

PubMed1990

Prevention of alpha-adrenergic coronary constriction by calcium-antagonists.

This manuscript reviews the experimental evidence for a functional antagonism of Ca-antagonists against alpha-adrenoceptor-mediated increases in coronary vasomotor tone. In studies on anesthetized dogs, intravenous nifedipine effectively prevented the alpha 1-adrenoceptor-mediated increase in epicardial coronary resistance, as well as the increase in end-diastolic resistance mediated by both alpha 1- and alpha 2-adrenoceptors during cardiac sympathetic nerve stimulation. Both intracoronary and intravenous administration of nifedipine also prevented the alpha 2-adrenoceptor-mediated increase in coronary resistance distal to severe stenoses, as well as the resulting ischemic dysfunction and net lactate production during cardiac sympathetic nerve stimulation. Felodipine was equally effective as nifedipine in preventing an alpha 2-adrenoceptor-mediated increase in coronary resistance and the resulting contractile dysfunction distal to severe coronary stenoses. alpha 1- and alpha 2-Adrenergic coronary constriction also contribute to the severity of myocardial ischemia in conscious dogs during treadmill exercise. Again, nifedipine improved regional myocardial blood flow and attenuated regional contractile dysfunction during exercise-induced ischemia in conscious dogs with a chronic coronary stenosis. This beneficial effect of nifedipine was attributed to a recruitment of coronary dilator reserve and not to a reduction in heart rate or afterload. In conclusion, there is solid experimental evidence for a functional antagonism of Ca-antagonists against alpha-adrenergic coronary constriction and its contribution to myocardial ischemia.

Animals↗

PubMed1990

Minimal alpha 1- and alpha 2-adrenoceptor-mediated coronary vasoconstriction in the anaesthetized swine.

alpha-Adrenoceptor-mediated coronary vasoconstriction contributes to the initiation and aggravation of experimental and clinical myocardial ischaemia. However, the extent of alpha 1- and alpha 2-adrenoceptor-mediated constriction has not been characterized in the porcine coronary circulation despite the frequent use of this experimental model. Fifteen swine were anaesthetized with either alpha-chloralose, enflurane or isoflurane to determine the amount of alpha-adrenoceptor-mediated coronary constriction elicited by either the selective alpha 1-adrenoceptor agonist methoxamine or the selective alpha 2-adrenoceptor agonist azepexole. The left anterior descending coronary artery was cannulated and perfused by an external pump delivering constant blood flow from the carotid artery. Following bilateral cervical vagotomy and beta-adrenoceptor blockade with propranolol (2 mg kg-1), graded dosages of either one of the alpha-adrenoceptor agonists (9-45 micrograms kg-1 min-1) were infused into the coronary perfusion line while coronary arterial pressure (CAP) was measured through a distal side arm of the cannula to detect changes in coronary vascular resistance. Infusion of the alpha-adrenoceptor agonists was terminated when systemic arterial pressure increased. Sonomicrometers were used to measure anterior left ventricular wall thickening for the assessment of regional contractile function. During methoxamine infusion, no increase in vascular resistance was observed during alpha-chloralose, enflurane or isoflurane anaesthesia, whereas the infusion of azepexole increased CAP from 103 +/- 31 mmHg to 120 +/- 35 mmHg (alpha-chloralose), from 101 +/- 16 mmHg to 122 +/- 11 mmHg (enflurane) and from 84 +/- 20 mmHg to 94 +/- 19 mmHg (isoflurane), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1990

Changes of left ventricular diastolic function in exercising dogs without and with ischemia.

Left ventricular (LV) diastolic function in the absence and presence of regional ischemia was examined in eight conscious dogs chronically instrumented with ultrasonic devices for measuring LV wall thickness and volume. During treadmill exercise, ischemia was induced (hydraulic occluder) to produce less than 10% systolic wall thickening in the ischemic zone. LV filling was assessed by the peak filling rate (PFR), mean filling rates in the first and second halves of filling (mFR1 and mFR2), an early filling index from mitral valve opening to minimal diastolic pressure (PDm), and the percentage of atrial filling. Also, LV relaxation (tau) and wall thinning rates during isovolumetric relaxation and the first and second halves of the filling phase were assessed. During control exercise without ischemia, PDm decreased by 2.61 mm Hg (p less than 0.05) to -1.1 mm Hg and there was a downward shift of the entire LV diastolic pressure-volume (P-V) curve. The LV relaxation rate, PFR, mFR1, and mFR2 were enhanced. Early filling was increased by 116%, the percentage of atrial filling by 118%, and overall diastolic filling by 23% despite a 63% decrease in the filling period. During ischemic exercise, systolic function was depressed compared with the resting state, PDm increased by 4.84 mm Hg (p less than 0.005) associated with a pronounced rightward and upward shift of the early portion of the P-V curve. LV relaxation rate, PFR, and mFR1 were reduced, the early filling index fell sharply by 62% but percentage of atrial filling was unchanged, while overall diastolic filling decreased by 30%. The thinning rate of the control wall was enhanced, whereas that of ischemic wall was depressed. Multiple factors contributed to the markedly impaired early and overall diastolic LV filling during ischemia, including impaired systolic function, reduced relaxation rate, nonuniformity of wall motion, an upward shift of the early diastolic P-V curve, and absence of a compensatory increase in late diastolic filling.

Animals↗

PubMed1990

Myocardial lactate release during ischemia in swine. Relation to regional blood flow.

To determine the relation between regional myocardial blood flow, contractile function, and myocardial lactate release during mild-to-moderate regional myocardial ischemia, nine open-chest swine were instrumented for measurement of regional myocardial blood flow (microsphere method), contractile function (sonomicrometry), and hemodynamics. L-[1-14C]Lactate or L-[U-13C]lactate was infused intravenously using a primed continuous infusion technique to quantify regional myocardial lactate release. D-[U-13C]glucose or D-[6-14C]glucose was simultaneously infused to determine the contribution of exogenous glucose to lactate release. Graded coronary ischemia (two to three levels) was created in the left anterior descending coronary arterial distribution by mechanically constricting the artery in five animals or by decreasing flow through a cannulated left anterior descending artery in four animals. In all nine animals, subendocardial blood flow was 0.99 +/- 0.21 (ml/min)/g during control and 0.34 +/- 0.14 (ml/min)/g during the most severe grade of underperfusion (p less than 0.001) in the left anterior descending coronary arterial distribution. Regional myocardial lactate release was 0.15 +/- 0.09 and 1.19 +/- 0.75 mumols/ml, respectively (p less than 0.003). A highly significant inverse correlation was observed between subendocardial blood flow and myocardial lactate release during the graded reductions in blood flow (r = -0.71, p less than 0.001). Results from sonomicrometry showed a significant reduction in contractile ventricular function in the anterior wall during the graded reductions in blood flow. The regional arterial-venous glucose difference increased significantly with underperfusion in the left anterior descending coronary arterial distribution, from 0.14 +/- 0.15 to 0.56 +/- 0.37 mumols/ml (p less than 0.003). The contribution of exogenous glucose to lactate release also increased significantly; 0.04 +/- 0.03 mumols/ml of the lactate came from exogenous glucose during control compared with 0.64 +/- 0.59 mumols/ml during the most severe underperfusion (p less than 0.02). A significant positive correlation exists between lactate release and lactate from exogenous glucose during graded underperfusion (r = 0.96, p less than 0.001). In summary, these data demonstrate a close inverse relation between regional myocardial lactate release and regional subendocardial blood flow during graded ischemia.

Animals↗

PubMed1990

Myocardial effects of selective alpha-adrenoceptor blockade during exercise in dogs.

To study the effect of selective alpha 1- or alpha 2-adrenergic blockade on the myocardial contractile and chronotropic response to exercise, 29 dogs were chronically instrumented with a sonomicrometer for measuring myocardial wall thickness and a micromanometer for measuring left ventricular pressure. During treadmill exercise, either the selective alpha 1-blocker prazosin (80 micrograms/kg, n = 12) or the alpha 2-blocker idazoxan (80 micrograms/kg, n = 8) was infused into the left atrium beginning 2-3 minutes after the onset of exercise. alpha 1-Adrenoceptor blockade, like alpha 2-adrenoceptor blockade, was found to cause significant increases in systolic wall thickening, thickening velocity, heart rate, and left ventricular contractility, indicating an increase in inotropic state that was comparable to that with alpha 2-adrenoceptor blockade. Preventing the decrease in aortic blood pressure after selective alpha 1-blockade by using either systemic angiotensin II infusion (n = 6) or inflation of an intra-aortic balloon (n = 6) did not prevent the observed increases in wall thickening, heart rate, and left ventricular contractility. In four of the dogs treated with prazosin, the norepinephrine concentration in the coronary sinus was found to more than double after alpha 1-blockade. beta-Adrenergic blockade (propranolol, 1.0 mg/kg) prevented the increased contractile and chronotropic state caused by alpha 1- or alpha 2-blockade. Selective alpha-adrenergic blockade during adrenergic activation by intravenous norepinephrine infusion, in contrast to exercise, had no effect on wall thickening, heart rate, or left ventricular contractility. These data indicate that selective alpha 1-adrenergic blockade, like selective alpha 2-adrenergic blockade, causes a significant augmentation of heart rate and left ventricular contractility in the dog during dynamic exercise. These data are consistent with the hypothesis that this occurs through a presynaptic disinhibition of neural norepinephrine release mediated by a prejunctional alpha 1-adrenoceptor.

Adrenergic alpha-Antagonists↗

PubMed1989

Myocardial creatine kinase exchange rates and 31P NMR relaxation rates in intact pigs.

In this study, we used 31P NMR to investigate the relationship between cardiac workload and creatine kinase flux in intact pigs. NMR measurements were performed on anesthetized miniature swine in which a surface coil was surgically implanted on the surface of the left ventricle. Cardiac workload was varied by infusion of norepinephrine. Phosphate exchange between creatine phosphate and ATP was measured by a combined saturation transfer, saturation recovery pulse sequence. Exchange measurements showed that creatine kinase flux and concentrations of PCr and ATP were independent of workload for a 2.5-fold range of cardiac rate-pressure products. It appears that, if creatine kinase flux is coupled to work load, the pig heart operates in a regime where small changes in metabolite concentrations or creatine kinase flux are sufficient to maintain elevated workloads. Exchange and relaxation measurements, at 2.0 and 4.7 T, yielded T1 relaxation times for creatine phosphate and ATP which are longer than most reported values. Analysis of the T1 data indicates that chemical-shift anisotropy is a plausible mechanism for a portion of the spin-lattice relaxation rate at high field strengths.

Animals↗

PubMed1989

Pharmacological mechanisms to attenuate sympathetically induced myocardial ischemia.

Distal to a coronary stenosis, resting myocardial blood flow and function can be maintained by a compensatory dilation of the poststenotic vascular bed and an increased collateral blood flow from adjacent coronary vessels. Under this condition, electrical stimulation of cardiac sympathetic nerves, as well as their activation during sympathoexcitatory reflexes and exercise, induces a poststenotic alpha 2-adrenoceptor-mediated coronary constriction and a beta-adrenoceptor-mediated, tachycardia-related redistribution of blood flow away from the ischemia myocardium. Thus, activation of cardiac sympathetic nerves can precipitate poststenotic myocardial ischemia. In experimental studies in anesthetized, vagotomized dogs, as well as in conscious, chronically instrumented dogs, selective alpha 2-adrenoceptor antagonists and calcium-channel blockade with nifedipine were able to attenuate the sympathetically induced poststenotic myocardial ischemia. Beta-adrenoceptor blockade with atenolol was only proven beneficial as long as there was a heart-rate reduction. Conversely, a specific bradycardic agent (ULFS-49) also exerted beneficial effects. Myocardial ischemia can activate cardiac sympathetic afferents and then, by a spinal reflex, can in turn activate sympathetic efferents and aggravate the severity of myocardial ischemia. This vicious cycle could be interrupted by segmental epidural anesthesia with procaine as well as by blockade of sympathoexcitation at the central nervous level with clonidine in anesthetized dogs.

Animals↗

PubMed1989

Neurogenic regulation of coronary vasomotor tone.

Controversies on acetylcholine-induced increases or decreases in coronary blood flow arise from obvious species differences, the role of endothelium in mediating vascular smooth muscle responses and the marked negative chronotropic and inotropic effects of acetylcholine. In man, there appears to be a predominant dilation of intact epicardial coronary arteries and a constriction of atherosclerotic segments. However, at present there is no evidence for a vagal initiation of myocardial ischaemia. Coronary vascular beta-receptors mediate dilation, but appear to be functionally insignificant during sympathetic activation. The beta-adrenergic mechanisms contributing to myocardial ischaemia are indirect, mediated by a tachycardia-related redistribution of blood flow away from the ischaemic myocardium. alpha-receptors mediating epicardial coronary artery constriction in experimental studies appear not to be responsible for the initiation of ischaemia in patients with angina at rest. However, alpha-adrenergic constriction of coronary resistance vessels resulting in the precipitation of poststenotic myocardial ischaemia was demonstrated in experimental studies and recently confirmed in patients with effort angina.

Animals↗

PubMed1989

Selective thromboxane A2 receptor blockade in experimental exercise-induced myocardial ischaemia in dogs.

Thromboxane A2 receptor stimulation induces blood platelet aggregation and vasoconstriction, both potential causes of impaired perfusion of ischaemic myocardium. To study the potential role of thromboxane A2 receptor blockade in exercise-induced myocardial ischaemia and post-exercise myocardial dysfunction, nine conscious chronically instrumented dogs with single-vessel coronary artery stenosis (ameroid constrictor) were studied before, during and after steady-state treadmill runs which induced regional myocardial ischaemia. Three hours after a control run, the dogs were exercised again after the infusion of a selective thromboxane A2 receptor blocker: BM 13.177 (10 mg kg-1 i.v.). In the control run, systolic wall thickening (WTh, sonomicrometer) in the post-stenotic myocardium decreased from 22.1 +/- 9.1% at rest to 8.8 +/- 5.2% (mean +/- SD). Subendocardial blood flow (microspheres) in the ischaemic area decreased from 0.75 +/- 0.25 to 0.45 +/- 0.27 (ml min-1 g). The WTh in the ischaemic region remained depressed at 20 min after the run. BM 13.177 reduced peak left ventricular (+) dP/dt (micromanometer) and WTh in both control and post-stenotic myocardium at rest, during and after the run. WTh in the ischaemic area was reduced to approximately the same levels during running with BM 13.177 (not significantly different from control exercise) and remained depressed for at least 30 min after the run. Regional myocardial blood flow was not affected by BM 13.177. Thus, selective thromboxane A2 receptor blockade with BM 13.177 had a modest negative inotropic effect and did not improve regional function or blood flow in post-stenotic ischaemic subendocardium.

Animals↗

PubMed1989

Characteristics of regional myocardial stunning after exercise in dogs with chronic coronary stenosis.

Persistent impairment of regional contraction of the left ventricle after restoration of blood flow following transient coronary occlusion has been termed "stunning," and reversible regional dysfunction has also been observed during recovery from exercise-induced regional ischemia. To determine whether limitation of subendocardial blood flow after exercise is a determinant of such dysfunction in the presence of chronic coronary stenosis, nine conscious chronically instrumented dogs having an Ameroid constrictor were studied before, during, and after treadmill runs that induced regional ischemia. During exercise, systolic wall thickening (%WTh, sonomicrometers) in the ischemic region decreased from a normal level of 22.1 +/- 9.1% at rest to 8.8 +/- 5.2% (+/- SD, P less than 0.01), whereas subendocardial blood flow (microspheres) in the ischemic region decreased from 0.75 +/- 0.25 to 0.45 +/- 0.27 ml.min-1.g-1 (P less than 0.05). %WTh in the ischemic region gradually improved after exercise but remained depressed (75% of control) at 30 min after the run (P less than 0.05). Postexercise dysfunction was not related to simultaneous regional hypoperfusion, since at 5 and 10 min after running there was a tendency toward subendocardial hyperemia (control 0.75 vs. 1.33 and 1.30 ml.min-1.g-1, NS) with a return to control by 30 min. Thus persistent regional dysfunction after exercise-induced regional ischemia in the conscious dog is not due to sustained subendocardial ischemia in the presence of chronic coronary stenosis and represents an example of myocardial stunning.

Animals↗

PubMed1989

Mechanisms of improved ischemic regional dysfunction by bradycardia. Studies on UL-FS 49 in swine.

In anesthetized swine, the left anterior descending coronary artery was cannulated and perfused at constant blood flow levels during two grades of ischemia. In one group (n = 10), moderate ischemia reduced percent systolic wall thickening (by sonomicrometry) from 25 +/- 7% to 6 +/- 2%, whereas in the other group (n = 7), severe ischemia reduced percent wall thickening from 24 +/- 6% to -0.5 +/- 4%. Heart rate was paced in both groups at 91 beats/min. After reperfusion and complete return to control conditions, administration of the bradycardic agent UL-FS 49 (0.37 mg/kg i.v.) decreased the heart rate to 55 +/- 5 beats/min. During subsequent ischemia at the same coronary inflow as before bradycardia, percent wall thickening in the ischemic zone during moderate ischemia was increased from 6 +/- 2% to 25 +/- 6% (p less than 0.01) (not significantly different from control without ischemia), and during severe ischemia, percent wall thickening increased from -0.5 +/- 4% to 13 +/- 7% (p less than 0.01). During moderate ischemia, bradycardia caused an increase in the subendocardial blood flow from 0.24 +/- 0.60 to 0.42 +/- 0.17 (ml/min)/g (p less than 0.009) and during severe ischemia, bradycardia caused an increase from 0.14 +/- 0.08 to 0.2 +/- 0.1 (ml/min)/g (p less than 0.001). At each level of ischemia, a more marked improvement occurred in subendocardial blood flow per beat ([(ml/min)/g]/heart rate). The relation between myocardial blood flow and wall function at a heart rate of 55 beats/min (n = 14) was plotted and compared with that studied at a heart rate of 122 beats/min in another group of pigs (n = 14). The increase in subendocardial blood flow per minute during bradycardia was not sufficient to explain the striking increase in function; thus, an independent relation (p less than 0.05) between blood flow per minute and contractile function (percent wall thickening) was found for for each heart rate. In contrast, when myocardial blood flow was normalized for heart rate and expressed per beat, data from both heart rate groups could be described by a single relation. Thus, the subendocardial blood flow per beat predicted wall function independently of heart rate and accounted for changes in both oxygen supply and demand.

Animals↗

PubMed1989

Consequences of regional inotropic stimulation of ischemic myocardium on regional myocardial blood flow and function in anesthetized swine.

Determination of the effect of inotropic stimulation on regionally ischemic and hypokinetic myocardium is complicated when intravenous administration of the inotropic agent also causes stimulation of nonischemic adjacent and distant regions, thereby altering global ventricular hemodynamics. To obviate such events, 16 anesthetized swine were studied during regional inotropic stimulation by infusion of dobutamine hydrochloride (2.5 +/- 1 microgram/min) into the cannulated left anterior descending coronary artery. Coronary inflow was controlled by a pump in an extracorporeal circuit. Two groups of swine with different degrees of ischemia were studied. In the first group of animals (n = 8), reduction in coronary inflow to produce a fall in coronary artery pressure (CAP) from 114 +/- 7 mm Hg to 62 +/- 2 mm Hg caused a decrease in percent systolic wall thickening (%WTh) from 34.6 +/- 8.1% to 25.4 +/- 5.8% (p less than 0.005). In the second group of animals (n = 8), CAP was decreased to 46 +/- 5 mm Hg (control: 115 +/- 8 mm Hg) and % WTh decreased from 34.1 +/- 16.4% to 10.4 +/- 6.9% (p less than 0.001). Subendocardial blood flow was reduced from 1.41 +/- 0.38 ml/min/g to 0.65 +/- 0.13 ml/min/g (group 1, p less than 0.001) and from 1.08 +/- 0.22 ml/min/g to 0.24 +/- 0.08 ml/min/g (group 2, p less than 0.001). Regional infusion of dobutamine caused asynchronous ventricular contraction with early systolic augmentation in wall thickening followed by late systolic thinning. Therefore, during hypoperfusion regional myocardial function assessed by %WTh remained unchanged (26.2 +/- 5.8%, p = NS) in group 1 and decreased significantly to 1.6 +/- 5.1% (p less than 0.041) in group 2. Subendocardial blood flow decreased to 0.44 +/- 0.15 ml/min/g in group 1 (p less than 0.005) and to 0.15 +/- 0.07 ml/min/g in group 2 (p less than 0.012). To account for the augmented early systolic thickening that occurred during asynchronous contraction, a myocardial work index was developed in which the sum of the instantaneous left ventricular pressure-wall thickness product was calculated for estimation of regional myocardial work. Increases in this work index were apparent with the addition of dobutamine at both levels of hypoperfusion. This significant enhancement in regional myocardial function in group 2 caused a significant increase of 16% (p less than 0.009) in overall left ventricular power during ejection. Thus, regional inotropic stimulation with dobutamine caused enhancement of maximum work of the ischemic myocardium in the steady state despite a further decrease in subendocardial blood flow.

Animals↗

PubMed1989

Cardiac function, substrate utilization, and myocardial energy metabolism studied with 31-P NMR spectroscopy during acute hypoglycemia and hyperketonemia.

Whether severe hypoglycemia alone or in combination with hyperketonemia might cause deterioration of cardiac function has been controversial. Therefore, the influence of acute hypoglycemia (mean 33 mg/dL) with and without hyperketonemia (mean 1.3 and 3.3 mM) on cardiac function, substrate utilization, and myocardial high energy phosphate levels was studied in 10 mongrel dogs. After 45 min of hypoglycemia, mean aortic pressure, total peripheral resistance, and myocardial oxygen consumption had increased significantly, but other hemodynamic parameters and regional myocardial function had not changed. Additional infusion of 3-hydroxybutyrate did not affect hemodynamic variables significantly. During both metabolic interventions in vivo phosphorus-31 nuclear magnetic resonance spectroscopy showed stable levels of myocardial phosphocreatinine, ATP, as well as the phosphocreatinine/ATP (3.0-3.2) ratio. Biochemical measurements revealed that hyperketonemia led to significant alterations in arterial concentrations and arteriocoronary venous differences of selected citric acid cycle intermediates, thus confirming previous reports which suggested a blockade of the 2-oxoglutarate-dehydrogenase reaction induced by ketone body oxidation. However, despite this blockade, the energy supply to the heart was not impaired as shown by normal nuclear magnetic resonance spectroscopy and cardiac performance. It is speculated, that the blockade might be due to an enhanced NADH/NAD ratio.

Adenosine Triphosphate↗