Effect of hypertonic mannitol and intraaortic counterpulsation on regional myocardial blood flow and ventricular performance in dogs during myocardial ischemia.

Studies were performed to determine if intervention with hypertonic mannitol and intraaortic balloon counterpulsation increases regional myocardial blood flow during acute myocardial ischemia. Anesthetized dogs on right heart bypass were studied. Heart rate was kept constant by atrial pacing. Myocardial ischemia was provided by ligating the proximal left anterior descending coronary artery for 12 minute periods. Infusion of hypertonic mannitol begun immediately after ligation increased coronary blood flow to the ischemic area by 36 +/- 9.0% (standard error) (P less than 0.01) and to the nonischemic left ventricle by 21 +/- 8.8% (P less than 0.05) as compared with flow in the same regions during the control coronary ligation. Intraaortic balloon counterpulsation begun immediately after ligation increased regional coronary flow to the ischemic region by 20 +/- 8.4% (P less than 0.05) but did not significantly alter flow to the nonischemic left ventricle as compared with levels during the control ligation. Combined intraaortic counterpulsation and hypertonic mannitol increased coronary flow to the ischemic region by 46 +/- 13% (P less than 0.02) and to the nonischemic left ventricle by 59 +/- 22% (P less than 0.05) as compared with flow during occlusion of the left anterior descending artery with mannitol alone. The data demonstrate that both hypertonic mannitol and intraaortic counterpulsation increase left ventricular ischemic regional flow and that combined hypertonic mannitol and intraaortic balloon counterpulsation provide a greater increase in regional coronary blood flow to both the ischemic and nonischemic regions of the left ventricle than mannitol alone.     

Retrograde coronary blood flow after mannitol in intact anesthetized dogs

Summary In control dogs mannitol produced a moderate increase in coronary blood flow, a decrease in coronary vascular resistance, and a moderate increase in cardiac output. In dogs with coronary occlusion mannitol increased retrograde coronary blood flow (+25%) and collateral conductance suggesting increased blood availability to ischemic myocardium.

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Retrograder koronarer Blutstrom nach Gaben von Mannitol bei gesunden anästhesierten Hunden

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With 1 figure and 3 tables

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Performed during the tenure of a Pre-doctoral Fellowship, National Institutes of Health.

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Performed during the tenure of a Post-doctoral Fellowship, National Institutes of Health.

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This work was supported in part from grants from the National Institutes of Health, HL 5364 and HL 07754 and the Wisconsin Heart Association.     

Influence of dobutamine on regional myocardial blood flow and ventricular performance during acute and chronic myocardial ischemia in dogs.

The data from this study document that dobutamine is a powerful inotropic agent in anesthetized dogs with acute myocardial ischemia and in awake, unsedated ones with chronic myocardial infarction. Dobutamine significantly increases heart rate at relatively small doses in anesthetized dogs with acute myocardial ischemia but considerably larger amounts of dobutamine are required to significantly increase heart rate in awake, unsedated dogs with myocardial infarction. Dobutamine also significantly increases regional myocardial blood flow to all areas of the heart at 20mug/kg/min in both anesthetized dogs with acute myocardial ischemia and awake, unsedated ones with myocardial infarction. However, in anesthetized dogs 20mug/kg/min of dobutamine significantly increases epicardial ST-segment elevation during acute myocardial ischemia. Propranolol prevents the inotropic and chronotropic effects of dobutamine in both anesthetized and awake, unsedated dogs. This study suggests that during experimental acute myocardial ischemia dobutamine given at doses that significantly increase heart rate and contractility may increase the extent of myocardial damage. The data also suggest that this agent should be of value in the setting of severe myocardial depression without associated severe coronary artery disease to increase cardiac contractility at doses that do not markedly alter heart rate. The hemodynamic and coronary blood flow effects of dobutamine in patients with and without severe coronary artery disease should be evaluated.     

Regional myocardial blood flow and ventricular arrhythmias following one-stage and two-stage coronary artery occlusion in anesthetized dogs

Experiments were performed in 29 anesthetized dogs to compare effects of one-stage and two-stage coronary artery occlusion on ventricular arrhythmias and regional myocardial blood flow (MBF). Two periods of arrhythmias were observed and both were associated with evidence suggesting reentry; i.e., activity in ischemic zone electrograms which bridged the diastolic intervals preceding ventricular ectopic beats. Early ventricular arrhythmias followed progressive deterioration of conduction in the ischemic zone, whereas later arrhythmias occurred unexpectedly with the sudden appearance of bridging activity. One-stage occlusion produced a higher incidence of ventricular arrhythmias and ventricular fibrillation than two-stage occlusion. However, there was no difference in central ischemic zone blood flow, indicating that the protective effect of two-stage occlusion was not due to greater blood flow in this region. These results suggest that factors other than the degree of MBF reduction are important determinants of the incidence and severity of ventricular arrhythmias following coronary artery occlusion.     

Effect of selective beta-adrenergic blockade and stimulation on regional myocardial blood flow following acute coronary artery occlusion in the awake dog

This study was designed to evaluate the effects of alterations of beta-receptor activity on intercoronary collateral blood flow after acute coronary artery occlusion in the awake dog. Blood flow following acute circumflex coronary occlusion was measured during: 1) control conditions; 2) selective beta1-blockade with practolol; 3) combined beta1 and beta2 blockade with propranolol; and 4) selective beta2 stimulation. Neither practolol nor propranolol significantly altered the volume or distribution of blood flow into the normally perfused or ischaemicmyocardial areas, while beta2 stimulation increased blood flow to the normally perfused myocardium from 1.13 +/- 0.12 to 1.28 +/- 1.10 cm3 .min-1 .g-1 (P <0.05). This increase in flow, which was directed preferentially to the subepicardium, was mediated by a significant decrease in coronary vascular resistance. In contrast to the effect on normally perfused myocardiu, beta2 stimulation resulted in a 47 +/- 12% decrease in collateral flow into the central ischaemic zone (P <0.05), which was mediated by a combination of decreased arterial pressure and increased collateral vascular resistance during beta2-agonist administration. Thus, although beta2 stimulation produced a modest increase in blood flow to normally perfused myocardium, in the setting of acute myocardial ischaemia, beta2 stimulation resulted in a significant decrease in intercoronary collateral flow.     

Relations between ventricular refractoriness and regional myocardial blood flow after acute coronary occlusion

Myocardial ischemia has been associated with dispersion of ventricular refractory periods and this dispersion has been related to the ventricular arrhythmias seen with coronary occlusion. This study relates the degree of change in measured ventricular refractory period with the degree of regional myocardial blood flow abnormality after coronary occlusion. When regional myocardial blood flow is less than 70 percent of that of nonischemic areas, refractory periods are significantly (P < 0.001) shortened. The greatest change in refractory periods occurs in areas with a regional myocardial blood flow that is 21 to 40 percent of that of non-ischemic areas. Marked (less than 20 percent) and minimal (61 to 80 percent) reductions in regional myocardial blood flow are associated with less, but still significant, shortening of ventricular refractory periods. Thus dispersion of refractoriness can be related to the inhomogeneity of regional myocardial blood flow after acute coronary occlusion. Interventions designed to salvage ischemic myocardium by increasing regional myocardial blood flow may affect dispersion of ventricular refractory periods in complex and divergent ways.     

Effect of nifedipine on myocardial blood flow during exercise in dogs with chronic coronary artery occlusion

The effect of nifedipine, 0.010 mg/kg intravenously, on myocardial blood flow was studied in 15 dogs 4 weeks after placement of an Ameroid constrictor on either the left circumflex or left anterior descending coronary artery to produce total coronary occlusion. Myocardial blood flow was measured with radionuclide-labeled microspheres at rest and during two levels of treadmill exercise to achieve a heart rate of 190 (light exercise) and 230 (heavy exercise) beats/min. During control conditions, increasing exercise resulted in a progressive increase in myocardial blood flow in normally perfused areas, but was associated with worsening subendocardial hypoperfusion in collateral-dependent areas. Nifedipine administration resulted in a transient reduction of arterial pressure and an increase in heart rate. To determine whether nifedipine exerted significant persistent effects on the coronary collateral circulation, measurements of myocardial blood flow were repeated beginning 30 minutes after nifedipine administration, at a time when heart rate and arterial pressure had returned to control levels. In normally perfused areas, nifedipine did not significantly alter myocardial blood flow at rest, but increased mean myocardial blood flow from 2.06 +/- 0.15 to 2.40 +/- 0.20 ml/min per g during light exercise (p less than 0.01), while blood flow during heavy exercise was not significantly altered. In collateral-dependent myocardial areas, the volume and transmural distribution of myocardial blood flow were not significantly altered after nifedipine administration either at rest or during exercise. These results fail to demonstrate persistent vasodilation of the coronary collateral vessels after the systemic hemodynamic effects of nifedipine have subsided.     

Relationship between changes in left ventricular bipolar electrograms and regional myocardial blood flow during acute coronary artery occlusion in the dog.

The purpose of this study was to determine whether a quantitative relationship existed between a reduction in regional myocardial blood flow, measured by radiolabeled microspheres, and the degree and type of changes in myocardial activation recorded in bipolar left ventricular subepicardial and subendocardial electrograms, in open-chest dogs following acute coronary artery occlusion. We found that the degree of regional myocardial ischemia was related quantitatively to the reduction in amplitude recorded with bipolar electrograms in the subepicardium and subendocardium, and to the increase in duration of subepicardial electrograms. Other characteristics measured in electrograms did not relate to the degree of ischemia. Despite a comparable reduction in regional myocardial blood flow, subepicardial conduction delay exceeded that recorded in the subendocardium, which often exhibited accelerated conduction.     

Effect of hypertonic mannitol and isoproterenol on regional coronary flow following right ventriculotomy.

We studied the changes which occurred in regional coronary blood flow after right ventriculotomy and the subsequent effects of hypertonic mannitol or isoproterenol infusion. Regional coronary flows were measured with radioactive microspheres (9 micron) in open-chest anesthetized dogs. Either hypertonic mannitol (25%) was infused at 3.2 ml/min or 7.6 ml/min for 30 minutes, or normal saline at 7.6 ml/min for 30 minutes followed by isoproterenol at 0.05-0.10 mug/kg/min. In the mannitol treated animals right ventricular, left artrial and aortic pressures, heart rate, and cardiac output did not change significantly following vertical ventriculotomy, whereas in the saline-isoproterenol treated animals aortic pressures fell significantly. Coronary flow to the peri-incisional area fell from 41 to 24 ml/min-100 g (P less than 0.05) following ventriculotomy, increased by 34% (P less than 0.05) when osmolality rose after mannitol by 37 mOsm, but was unchanged with isoproterenol. The data indicate that a vertical ventriculotomy reduces flow to adjacent myocardium and that subsequent infusion of hypertonic mannitol at moderate rates significantly increases coronary flow to this region.     

Effects of oral pretreatment with metoprolol on left ventricular wall motion,infarct size,hemodynamics, and regional myocardial blood flow in anesthetized dogs during thrombotic coronary artery occlusion and reperfusion

Summary Objectives. To study the effects of oral pretreatment with metoprolol over 3 days on hemodynamics, left ventricular function, regional myocardial blood flow, and infarct size in an anesthetized dog model of thrombotic occlusion of the anterior descending coronary artery treated with thrombolysis.Methods. Ten dogs received 200 mg metoprolol (Selozok) orally and 8 dogs received placebo for 3 days twice daily and 1 hour before the experiment. Under general anesthesia, thrombotic occlusion was provoked by the copper-coil technique. Intracardiac pressures and their derivatives, cardiac output (thermodilution method), regional coronary blood flow (microspheres), global and regional left ventricular function (ventriculography), and infarct size (triphenyltetrazolium staining) were measured. Measurements were performed during control, after 60 minutes of occlusion, and after 30 and 90 minutes of reperfusion. Thrombolysis was performed in all dogs 60 minutes after occlusion by intravenous infusion of 10 µg/kg/min of rt-PA for 30 minutes.Results. During control cardiac output was lower, total peripheral resistance higher, and Tau and the left ventricular isovolumic relaxation time greater in the metoprolol group. During occlusion and after reperfusion, there were no significant hemodynamic differences between both groups. Blood flow to the area at risk and circumflex territory during occlusion were, respectively, 12.8±5.80 ml/100 g/min versus 9.65±8.35 ml/100 g/min (p>0.05) and 42.58±7.86 ml/100 g/min versus 61.52±20.43 ml/100 g/min (p=0.01) in the metoprolol- and placebo-treated dogs. The ratios of flow area at risk/circumflex territories in the epicardial, midmyocardial, and endocardial layers were, respectively, 0.44±0.20, 0.19±0.09, and 0.20±0.13 in the metoprolol- versus 0.24±0.16, 0.08±0.06, and 0.06±0.07 (p0.04) in the placebo-treated dogs. The ratio of flow endocardium/epicardium was higher (p0.02) in the active treatment group during the control period, both in the area at risk and circumflex territory; this was also the case in the circumflex territory at the end of the experiment (p=0.003). Thirty minutes after occlusion, blood flow to the three layers of the area at risk rose to 2–3 times control values in both groups; a significant increase above control values also occurred in the circumflex territory. After 90 minutes reperfusion, blood flow to both territories was similar in both groups but was comparable to the control; however, in necrotic tissue of the subendocardial layer of both groups, flow fell below control values (p<0.05). End-systolic volume rose from 21.2±7.4 ml to 36.1±11.5 ml (p<0.05), end-diastolic volume remained constant (46.0±13.8 vs. 47.9±12.1 ml; p>0.05), and ejection fraction fell from 53.9±8.3% to 25.8±10.2% (p<0.05) at the end of the experiment in the metoprolol group. Respective figures for the placebo group were 19.4±7.9 versus 27.9±10.9 (p<0.05), 38.5±13.0 versus 42.1±11.0 (p>0.05), and 50.6±5.7 versus 35.5±11.7 (p<0.05). Fractional shortening of the chords analyzed was similar in both groups during the control period; it fell significantly at the end of the experiment in three chords of the metoprolol group and in five chords of the placebo group. The apical chord in the placebo, but not in the metoprolol, dogs was dyskinetic: fractional shortening was –0.86±9.7 versus 7.5±13.5% (p>0.05). The area at risk was 41.6±10.6 cm² in metoprolol- and 40.5±7.2 cm² in placebo-treated dogs (p>0.05); the infarct size, expressed as a percentage of the area at risk, was 29.0±22.5% and 45.3±23.6% (p=0.02), respectively.Conclusions. Oral pretreatment with metoprolol limited infarct size and improved regional left ventricular function, probably due to its negative chronotropic and inotropic effects, and also due to an enhancement of collateral flow from the circumflex territory to the area at risk.     

Diastolic synchronized retroperfusion versus reperfusion: effects on regional left ventricular function and myocardial blood flow during acute coronary occlusion in dogs

The effects of 170 minutes of diastolic synchronized retroperfusion of the coronary sinus with arterial blood during 180 minutes of coronary artery occlusion on regional myocardial contractility (ultrasonic crystals) and blood flow (microspheres) were investigated in open-chest dogs. These effects were compared with those of 180 minutes of coronary occlusion and those of 170 minutes of anterograde reperfusion after 10 minutes of coronary occlusion in separate groups of dogs. Retroperfusion was able to almost restore transmural blood flow in the moderately ischemic zones and to increase it back to 47% of its preocclusion value in the severely ischemic zones with, in both zones, a favorable redistribution of flow toward the endocardium. Simultaneously, retroperfusion significantly improved segment length shortening in the moderately ischemic zones and significantly reduced the extent of paradoxical bulging in the severely ischemic zones. These partial recoveries in regional contractility and blood flow during retroperfusion were intermediate between those induced by 170 minutes of anterograde reperfusion and those of 180 minutes of coronary artery occlusion. Thus, in the presence of coronary artery occlusion, retroperfusion appears to exert a beneficial effect by improving both regional perfusion and function in the ischemic zones and may be proposed as a medical circulatory support to the jeopardized myocardium.     

Influence of tachykradie on regional myocardial flow in chronic experimental coronary occlusion

Summary The influence of tachycardia on regional myocardial flow was studied in normal dogs and in dogs with chronic coronary artery occlusions. Coronary vasodilation was induced by coronary occlusion and subsequent release, i.e. by reactive hyperemia. Local myocardial blood flow was determined with the tracer microspheres technique. In normal hearts atrial pacing produced a slight but significant increase in coronary resistance in the subendocardial layers of the left ventricle. The coronary resistance of the subepicardium remained unaffected. In the right ventricle atrial pacing had no influence on the resistance to flow.In hearts with multiple coronary occlusions tachycardia-induced changes of coronary resistance were more pronounced. In the collateral dependent subendocardium coronary resistance increased from 0.4–2.2 resistance units when the heart rate was raised to 200 beats/min.Perfusion of the right ventricular myocardium became also rate-dependent when the right coronary artery was chronically occluded.We conclude that regional perfusion depends upon the relationship between the effective perfusion pressure, which is reduced in chronic coronary occlusion, and the time integral of effective tissue pressure, which is increased with tachycardia. The results cannot be explained by assuming excessive O₂-demand but rather by a rate-induced lowered O₂-supply.

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Einfluß von Tachykardie auf die Regionaldurchblutung bei chronischen experimentellen Koronararterienverschlüssen

Zusammenfassung Der Einfluß von Tachykardie auf die Regionaldurchblutung des Herzens wurde an normalen Hundeherzen und an solchen mit chronischen Koronarverschlüssen untersucht. Die Versuche wurden in maximaler Vasodilatation während reaktiver Hyperämie ausgeführt, und die Regionaldurchblutung wurde mit Hilfe von Tracer Microspheres bestimmt. Beim normalen Herzen nahm der Gesamtwiderstand im subendokardialen Gibiet des linken Ventrikels durch Elektrostimulation (Herzfrequenz bis 220/min) deutlich zu. Das Subepikard zeigte keine Frequenzabhängigkeit, ebenso nicht die freie Wand des rechten Ventrikels. Beim Herzen mit chronischen Koronarverschlüssen, aber ohne Infarkte, war der Tachykardieeffekt wesentlich ausgepräger. Im Subendokardium entstand ein Perfusionsdefizit, und auch das Subepikardium zeigte eine geringe Frequenzabhängigkeit. Die Durchblutung des rechten Ventrikels wurde ebenfalls frequenzabhängig.Aus den Daten ergibt sich, daß bei einem ungünstigen Verhältnis von Perfusionsdruck zu Gewebsdruck, wie es beim Koronarverschluß vorliegt, die Durchblutung des Subendokards durch Frequenzbelastung abnimmt. Die Bestimmung der Angina-Schwelle unter klinischen Bedingungen durch Elektrostimulation basiert also nicht nur auf der Zunahme des myokardialen Sauerstoffverbrauchs, sondern im wesentlichen auf der Abnahme der Sauerstoffzufuhr.

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With 4 figures     

Effects of p-chlorophenoxyisobutyrate on myocardial free fatty acid extraction, ventricular blood flow, and epicardial ST-segment elevation during coronary occlusion in dogs.

The effect of p-chlorophenoxyisobutyrate (CPIB) on ST-segment elevation in epicardial electrocardiographic recordings was studied during coronary artery occlusion in dogs. Occlusion alone raised the sum of ST-segment elevations (sigmaST) to 26 +/- 6 mV (mean +/- SEM). Intravenous (i.v.) administration of CPIB 30 min before re-occlusion reduced sigmaST to 14 +/- 3 mV (P less than 0.03). A continuous i.v. infusion of isoproterenol increased sigmaST to 74 +/- 11 mV. Pretreatment with CPIB reduced sigmaST during isoproterenol infusion to 40 +/- 7 mV (P less than 0.005). CPIB had no effect on mean aortic blood pressure, heart rate, or regional myocardial blood flow, as measured by radioactive microspheres. Arterial free fatty acid (FFA) concentrations were reduced by CPIB from 466 +/- 41 to 221 +/- 44 muEq/L (P less than 0.001) in the basal state, and from 1966 +/- 183 to 1429 +/- 209 muEq/L (P less than 0.001) during isoproterenol infusion. The reduction in arterial FFA concentration was associated with a proportionate decrease in the myocardial extraction of FFA. Similar changes were observed when CPIB was administered during an occlusion which had been established 10 min earlier. These observations support other evidence that the severity of acute myocardial ischemic injury in dogs is positively correlated with the myocardial extraction of FFA, and that the severity of the ischemic injury can be reduced by effective antilipolytic therapy.     

Dissociation of effects of nitroglycerin on regional refractoriness and regional myocardial blood flow following acute coronary occlusion.

Nitroglycerin is known to affect the electrophysiological properties of the ischaemic ventricle, possibly by altering regional myocardial blood flow. This study correlated the effects of nitroglycerin, given after acute coronary occlusion, on regional ventricular refractoriness and regional myocardial blood flow. Nitroglycerin returned ventricular refractory periods to their pre-occlusion values in spite of no significant effect on regional myocardial blood flow. Although the beneficial electrophysiological effects of nitroglycerin were not explained by increased regional flow to the ischaemic myocardium, an improved myocardial oxygen supply-demand balance may have produced these favourable effects. This study emphasises the need for electrophysiological evaluation of the effects of interventions intended to limit infarct size.     

Effects of oxyfedrine on regional myocardial blood flow in patients with coronary artery disease

Summary Medical treatment of angina pectoris is largely based on the use of beta-blocking agents, calcium antagonists, and nitrates. Oxyfedrine, an amino ketone derivative and partial agonist at beta receptors, has been shown to have potent antianginal properties and to increase coronary blood flow in normal and ischemic myocardial regions in experimental studies. We assessed the effects of intravenous oxyfedrine on regional myocardial blood flow, using positron emission tomography (15-oxygen water), in six patients with chronic stable angina, positive exercise tests, and documented coronary artery disease. Myocardial blood flow was measured in all patients before (baseline) and 10 minutes after the intravenous administration of a single bolus (0.11–0.13 mg/kg) of oxyfedrine. Compared to baseline, heart rate and systolic blood pressure remained almost unchanged after the administration of oxyfedrine. Mean baseline myocardial blood flow was 0.90±0.15 ml/g/min in areas supplied by arteries with significant coronary stenosis and 1.08±0.19 ml/g/min in areas supplied by nonstenotic coronary vessels (p<0.05). After the adminsitration of oxyfedrine, myocardial blood flow increased significantly in both the regions supplied by stenotic vessels (by 25%; from 0.90±0.15 to 1.20±0.31 ml/g/min; p=0.002) and in areas supplied by angiographically normal coronary vessels (by 22%; from 1.08±0.19 to 1.38±0.49 ml/g/min; p<0.05). The results of this study indicate that in patients with coronary artery disease, intravenous oxyfedrine significantly increases regional myocardial blood flow, both in areas supplied by critically obstructed vessels and in areas supplied by normal or less severely narrowed coronary arteries.     

Measurement of regional myocardial blood flow with N-13 ammonia and positron-emission tomography in intact dogs

N-13 ammonia mimics certain properties of microspheres. It rapidly clears from blood into myocardium where it becomes fixed in proportion to myocardial blood flow. Used with positron emission tomography as a means for quantifying in vivo myocardial indicator concentrations, N-13 ammonia may be useful for noninvasive determination of myocardial blood flow with the arterial reference sampling technique. This possibility was examined in 27 experiments in 10 chronically instrumented dogs at control, high and low blood flows. Myocardial blood flow was calculated in vivo from the myocardial N-13 tissue activity concentrations derived from serial cross-sectional images of the heart, the 2 minute arterial input function and the withdrawal rate of arterial blood. These calculations were compared with blood flow determined by the standard microsphere technique. Blood flow determined in vivo with N-13 ammonia and positron emission tomography correlated with microsphere blood flow by y = -36.2 + 1.53x -0.0027x2 (r = 0.94 with a standard error of the estimate of 16 ml/min per 100 g). For flows from 44 to 200 ml/min per 100 g, the relation between in vivo and in vitro measured myocardial blood flow was nearly linear but reached a plateau at flows higher than 200 ml/min per 100 g. These results indicate that in dogs, blood flow in the physiologic range can be quantified in vivo with N-13 ammonia and positron emission tomography.     

Influence of minoxidil on myocardial hemodynamics,regional blood flow,and morphology in beagle dogs

Summary Studies were made of the effects of two doses of minoxidil (3 mg/kg), given 24 hours apart, on cardiovascular hemodynamics, regional myocardial blood flow, and cardiac morphology in beagle dogs. Minoxidil caused increases in mean right atrial and left ventricular end-diastolic pressure. Systemic and pulmonary vascular resistance were reduced; cardiac output was increased. Left ventricular stroke work and the systolic pressure time index were unchanged by monoxidil administration. The diastolic pressure time index and ratio of diastolic/systolic pressure time index were decreased by minoxidil. Regional myocardial blood flow, measured with radioactive microspheres, increased in all regions of the heart except to the left ventricular papillary muscles. Minoxidil increased blood flow to left ventricular subendocardial tissue; however, this increase was significantly less than that observed in corresponding areas of subepicardial tissue, thus reducing the subendocardial/subepicardial tissue blood flow ratio. These results suggest that minoxidil is an effective peripheral vasodilator but may result in inadequate subendocardial perfusion. Morphologic studies disclosed two types of minoxidil-induced cardiac lesions: left ventricular papillary muscle necroses, and hemorrhagic lesions which were most prominent in right atrium and were associated with inflammation, intramural hemorrhage, and fibrinoid necrosis of small arteries. The papillary muscle necroses were attributed to hypoxia. The atrial lesions were not of ischemic or hypoxic origin, because minoxidil did not decrease blood flow to atrial tissue. It is suggested that the atrial lesions are related to excessive vasodilatation.