Effects of amrinone on experimental acute myocardial ischaemic injury

Rude, Robert E.; Kloner, Robert A.; Maroko, Peter R.; Khuri, Shukri F.; Karaffa, Stephanie; DeBoer, Laurence W.V.; Braunwald, Eugene

doi:10.1093/cvr/14.7.419

Cited by 37 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Isoproterenol and glucagon, at doses that doubtlessly increased LV contractility, augmented ischemic zone ST-segment elevation during coronary artery occlusion.2 In these studies, atrial pacing produced less augmentation of ST-segment elevation than equichronotropic doses of isoproterenol, and the deleterious effects of glucagon were also partially mitigated when heart rate was maintained constant by atrial pacing.2 A study from our laboratory showed that dobutamine (20 ,g/kg/min) increased both heart rate and LV dP/dt in the anesthetized dog, and resulted in augmentation of ischemic zone epicardial ST-segment elevation during coronary occlusion; a lower dose of this agent (4 ,ug/kg/min), which raised heart rate only by [5][6][7][8][9][10] beats/min, did not augment ischemic damage despite a positive inotropic effect.' Ramanathan et al5 also showed that the inotropic stimulant dopamine, at doses that do not accelerate heart rate, does not augment ischemic zone ST-segment elevation., A dissociation of the deleterious effects of increases in heart rate and LV contractility was also noted by Vatner and Baig in conscious dogs subjected to coronary occlusion.2' Isoproterenol, in doses that increased heart rate and LV contractility, decreased ischemic zone segmental shortening and blood flow, while dobutamine and dopamine, at doses that increased LV dP/dt, did not further reduce ischemic zone contractile function or blood flow when heart rate was not increased.2' These investigators also found that ouabain given to chronically instrumented conscious dogs with temporary coronary occlusion led to an increase in LV dP/dt without a change in heart rate and improved systolic segment shortening, blood flow and ST-segment deviation in the ischemic zone.…”

Section: Discussionmentioning

confidence: 99%

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. I. Studies with dobutamine in the anesthetized dog.

et al. 1982

View full text Add to dashboard Cite

SUMMARY The effect of i.v. dobutamine on acute myocardial ischemic injury was assessed in 22 anesthetized dogs subjected to serial 10-minute occlusions of the left anterior descending coronary artery. The severity of ischemic injury was determined by mass spectrometric measurement of the increase in intramural carbon dioxide tension (zAPmco2) in the ischemic zone. In the nine protocol 1 dogs, dobutamine, 20 ,ug/kg/min, infused between the control and final occlusion, significantly increased both heart rate (HR) and left ventricular (LV) dP/dt; APmco2 was significantly higher during the dobutamine infusion than during control occlusion (76 ± 21 vs 56 + 13 mm Hg,p < 0.01). The nine protocol 2 dogs were atrially paced at a HR of 20-30 beats/min above baseline values during the control occlusion and received dobutamine (12.6 ± 7.8 ugg/kg/min) at doses necessary to attain an equal HR (mean 149-154 beats/min) during the last occlusion.Although LV dP/dt was higher after dobutamine, APmco2 was similar during the two occlusions. Protocol 3 dogs (n = 4) received lower doses of dobutamine (5.6 ± 3.2 Ag/kg/min) to produce an increase in LV dP/dt, but not in HR compared with baseline values; APmco2 was similar during control and dobutamine occlusions. There were no major changes in arterial or left atrial pressures. Rate-pressure product, an indirect measurement of myocardial oxygen consumption, was increased only by the higher doses of dobutamine in protocol 1.Thus, inotropic stimulation with dobutamine during coronary occlusion does not cause important augmentation of acute myocardial ischemic injury in the nonfailing heart unless HR is increased simultaneously.THE SEVERITY of evolving acute myocardial ischemic injury can be influenced by interventions performed before or shortly after experimental coronary artery occlusion.' Pharmacologic agents and hemodynamic alterations can affect ischemic injury. Although most reports deal with interventions that lessen myocardial ischemic injury, certain interventions can intensify ischemia or increase infarct size.2 B Even though the role of specific therapy to protect ischemic myocardium in the patient with evolving acute myocardial infarction is not clear, it is widely held that interventions that augment ischemic injury in experimental animals should be avoided in patients with myocardial ischemic syndromes.0" 11 Most deleterious influences on evolving ischemic damage are thought to be mediated by further alterations in the relationship between myocardial oxygen supply and demand in ischemic tissue. An creasing heart rate, contractile state, or left ventricular (LV) wall tension.'1 Because many studies that showed augmentation of ischemic injury used interventions that simultaneously alter several determinants of myocardial oxygen demand or supply or both, we investigated whether deleterious effects on ischemic damage also result from more selective alterations in these hemodynamic variables.Methods Twenty-two mongrel dogs that weighed 17-44 kg were anesthetized with i.v. pen...

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. I. Studies with dobutamine in the anesthetized dog.

et al. 1982

View full text Add to dashboard Cite

show abstract

“…Utilizing this system, we have shown that during regional myocardial ischemia the magnitude of rise in Pmco 2 correlated with intramural S-T segment changes (Khuri et al, 1975), with reduction in regional myocardial blood flow, and with histological evidence of ischemia (Khuri et al, 1979a). The measurement of Pmco 2 with mass spectrometry has been useful not only in quantifying the degree of regional myocardial ischemia, but also in assessing the efficacy of pharmacological interventions in ameliorating ischemic damage (Hillis, 1979(Hillis, , 1981Rude, 1980).…”

Section: Figure 7 Data From Group 2 (11 Dogs) Upper Panels: the Maxmentioning

confidence: 99%

The significance of the late fall in myocardial PCO2 and its relationship to myocardial pH after regional coronary occlusion in the dog.

Khuri¹,

Kloner²,

Karaffa³

et al. 1985

Circulation Research

View full text Add to dashboard Cite

After acute regional coronary occlusion, myocardial tissue PCO2, as measured by mass spectrometry, rises, reaches a peak, and then gradually falls. This late fall in myocardial tissue PCO2 could be due to (1) a gradual increase in tissue blood flow (and hence improved carbon dioxide washout), (2) a gradual consumption of tissue bicarbonate, (3) a gradual reduction in the production of carbon dioxide due to progressive cellular damage, or (4) an artifact caused by the continued presence of the mass spectrometer probe in the ischemic tissue. To determine which of these four mechanisms is responsible for the late fall in myocardial tissue PCO2, we subjected 27 anesthetized open-chest dogs to 3-hour occlusion of the left anterior descending coronary artery. Both myocardial tissue PCO2 and intramyocardial hydrogen ion concentration were measured in the myocardial segment supplied by the left anterior descending coronary artery. Ten dogs (group 1) were killed after the occlusion (occlusion I), and 11 dogs (group 2) underwent reocclusion (occlusion II) at the same site after a 45-minute period of reflow. Regional myocardial blood flow was measured periodically by the intramural injection of 127Xe. Changes in myocardial tissue PCO2 and hydrogen ion concentration were related to ultrastructural changes in the tissues adjacent to the myocardial tissue PCO2 probe. Regional myocardial blood flow remained unchanged throughout the 3-hour occlusion, ruling out increased carbon dioxide washout as a cause for its late fall. Tissue hydrogen ion concentration, as measured by a new lead glass electrode, correlated well with myocardial tissue PCO2, with the reduction in regional myocardial blood flow, and with ischemic damage assessed histologically. Myocardial hydrogen ion concentration also exhibited a late fall after the occlusion, from a peak of 199.8 +/- 27.8 nmol/liter to 91.9 +/- 12.1 nmol/liter (mean +/- SEM). This ruled out consumption of tissue bicarbonate as the cause for the late fall in myocardial tissue PCO2. Peak rise in myocardial tissue PCO2 after occlusion II (71.2 +/- 7.9 mm Hg) was significantly lower than peak myocardial tissue PCO2 after occlusion I (116.7 +/- 13.9 mm Hg, P less than 0.001). The difference between these latter two values, as well as the magnitude of fall in myocardial tissue PCO2 during occlusion I, related directly to the degree of histological damage observed.(ABSTRACT TRUNCATED AT 400 WORDS)

show abstract

“…Therefore, the usefulness of these drugs in the ischaemic heart is determined by the balance of these actions. In fact, deleterious effects of positive inotropic stimulation in ischaemic hearts have been reported (Rude et al, 1980;Pozen et al, 1981 (Taira, 1987), many are guanosine 3': 5'-cyclic monophosphate (cyclic GMP)-inhibited phosphodiesterase (cGI-PDE) inhibitors such as amrinone (Alousi et al, 1979). Recently, we described a new compound, OPC-18790 [(± )-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2-(lH)-quinolinone] (Fujioka et al, 1992) which is a Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of OPC‐18790, amrinone and dobutamine on cardiac function and energy metabolism in the guinea‐pig isolated ischaemic heart

Itoh

Mori

Tominaga

et al. 1995

British J Pharmacology

View full text Add to dashboard Cite

1 The effects of OPC-18790, a novel positive inotropic agent, on cardiac function and myocardial energy metabolism in the guinea-pig isolated heart with ischaemia were studied by 3'P-magnetic resonance spectroscopy (MRS) and compared with those of amrinone and dobutamine. 2 Cardiac ischaemia was induced by intracoronary infusion of 15 gm microspheres to reduce coronary perfusion flow (CPF) by 50%. Microsphere embolisation caused a 40% decrease in left ventricular systolic pressure (LVSP), cardiac contractility measured by peak of ventricular pressure development (LVdP/dt) and slightly reduced heart rate. There was also a decrease in ATP and creatine phosphate (PCr) by 20%, an increase in inorganic phosphate (Pi) by 25% and an acidic shift of intracellular pH in the ischaemic heart. 3 In the ischaemic heart, OPC-18790, amrinone and dobutamine were applied at concentrations which increased LVdP/dt by about 60%. These compounds increased LVP by 15% to 30% and increased CPF by about 10%. Amrinone and dobutamine but not OPC-18790 increased heart rate. When these drugs produced the haemodynamic changes described above, amrinone and dobutamine reduced ATP and PCr, increased Pi and produced further intracellular acidosis, whereas, OPC-18790 did not change these parameters.4 Cardiac pacing at 285 beats min-' produced decreases in LVP, LVdP/dt and CPF by about 30%, 20%, 5%, respectively and an increase in Pi, decreases in PCr and ATP, and intracellular acidosis.5 These results suggest that degradation of high energy phosphate compounds closely relates to increase in heart rate in the ischaemic heart. Positive inotropic agents without chronotropic action seem to be beneficial in support of the ischaemic heart.

show abstract

Effects of amrinone on experimental acute myocardial ischaemic injury

Cited by 37 publications

References 0 publications

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. I. Studies with dobutamine in the anesthetized dog.

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. I. Studies with dobutamine in the anesthetized dog.

The significance of the late fall in myocardial PCO2 and its relationship to myocardial pH after regional coronary occlusion in the dog.

Differential effects of OPC‐18790, amrinone and dobutamine on cardiac function and energy metabolism in the guinea‐pig isolated ischaemic heart

Contact Info

Product

Resources

About