J. Holtz

Effect of increased blood fluidity through hemodilution on coronary circulation at rest and during exercise in dogs.

SummaryCoronary flow and myocardial oxygen consumption were measured in conscious dogs at rest and during two levels of submaximal treadmill exercise (3 and 7 km/h at 15% grade, respectively) during adaptation to progressive hemodilution with dextran 60. At rest coronary flow increased to more than seven-fold with diminishing hematocrit to 12.5% in order to cover myocardial oxygen consumption which increased from 6.5±0.3 ml/min· 100 g at hematocrit 47.5% to 13.5±0.8 ml/min· 100 g at hematocrit 12.5%. The dilatory capacity of the coronary vessels, estimated from the reactive hyperemia after a 12 sec occlusion of the left circumflex coronary artery, dropped from 602% at control to 45% at lowest hematocrit levels.During the superimposed stress of exercise coronary flow and myocardial oxygen consumption increased further, so that the dilatory capacity of the coronaries was exhausted at hematocrit levels between 16 and 22%.Myocardial oxygen consumption per unit of oxygen delivered to peripheral tissues increased substantially with progressive hemodilution. In the presence of the reduced arterial oxygen content the augmented myocardial oxygen demand limits the overall adaptability to hemodilution by an exhaustion of the coronary dilatory capacity.

Transmural distribution of myocardial blood flow and of coronary reserve in canine left ventricular hypertrophy

Left ventricular hypertrophy was induced by banding of the ascending aorta in puppies at the age of 6 weeks. At the age of one year left ventricular weight per body weight was increased by 87% compared to control litter mates. While myocardial perfusion and myocardial oxygen consumption per 100 g were identical in the hypertrophy and control group, there was a significantly diminished ratio of subendocardial/subepicardial flow in the hypertrophy group during moderate exercise. With maximal coronary dilation subendocardial diastolic resistance (mm Hg/ml · min-1 per 100 g) was 0.16 ± 0.03 in the control group and 0.26 ± 0.03 in the hypertrophy group. This diminished coronary reserve indicates an insufficient growth of the vascular bed in these hypertrophied hearts.

Transmural distribution of myocardial blood flow and of coronary reserve in canine left ventricular hypertrophy@@@Transmurale Verteilung der Myokarddurchblutung und der Koronarreserve in Hunden mit Hypertrophie des linken Ventrikels

SummaryLeft ventricular hypertrophy was induced by banding of the ascending aorta in puppies at the age of 6 weeks. At the age of one year left ventricular weight per body weight was increased by 87% compared to control litter mates. While myocardial perfusion and myocardial oxygen consumption per 100 g were identical in the hypertrophy and control group, there was a significantly diminished ratio of subendocardial/subepicardial flow in the hypertrophy group during moderate exercise. With maximal coronary dilation subendocardial diastolic resistance (mm Hg/ml·min−1 per 100 g) was 0.16±0.03 in the control group and 0.26±0.03 in the hypertrophy group. This diminished coronary reserve indicates an insufficient growth of the vascular bed in these hypertrophied hearts.ZusammenfassungJungen Hunden im Alter von 6 Wochen wurde ein Ring um die Aorta ascendens gelegt. Dadurch wurde eine Hypertrophie des linken Ventrikels induziert, so daß im Alter von einem Jahr das Gewichtsverhältnis des linken Ventrikels pro Körpergewicht um 87% höher war als in normalen Wurfgeschwistern. Während die Myokardperfusion und der myokardiale Sauerstoffverbrauch pro 100 g in der normalen Gruppe und in der Gruppe mit Hypertrophie identisch waren, ergab sich bei Arbeit ein signifikant erniedrigtes Verhältnis der subendokardialen Druchblutung zur subepikardialen Durchblutung in den Hunden mit hypertrophierten Herzen. Bei maximaler Koronardilatation betrug der subendokardialen Durchblutung zur subepikardialen Durchblutung in den Hunden in normalen Hunden und 0,26±0,03 in Hunden mit Herzhypertrophie. Diese verminderte Koronarreserve spricht für ein nicht ausreichendes Wachstum des Koronargefäßbettes in diesen hypertrophierten Herzen.

Intracapillary Hemoglobin Oxygen Saturation and Oxygen Consumption in Different Layers of the Left Ventricular Myocardium

SummaryOxygen consumption in subendocardial and subepicardial layers of left ventricular myocardium was studied. Oxygen consumption was calculated from regional perfusion data obtained by the microsphere technique and regional O2 extraction derived from intracapillary HbO2 saturation (i.c. HbsO2). I.c. HbsO2 data were obtained cryomicrophotometrically from shock-frozen, transmural tissue specimens removed from thoracotomized dogs. Left ventricular myocardial blood flow at the time of the specimen removal was 63±9 ml/min · 100 g. The ratio of subendocardial to subepicardial blood flow was 1.27 ±0.17. Coronary sinus blood oxygen saturation was 31±2% and left ventricular oxygen consumption was 8.4±1.1 ml/min · 100 g. A mean i.c. HbsO2 of 47±18% was obtained. 23% of all measured i.c. HbsO2 values were lower than the respective coronary sinus value. The mean subendocardial i.c. HbsO2 (41±19%) was significantly lower than the mean subepicardial value (53±16%). From these data a ratio of subendocardial to subepicardial oxygen consumption of 1.57 was calculated. This result is in agreement with recent hypotheses, stating that myocardial fiber shortening and energy demands in deeper layers of left ventricle exceed those of superfical layers.

Hemodynamic and myocardial effects of long-lasting venodilation in the conscious dog

SummaryThe effect of molsidomine-induced venodilation on cardiac preload was studied in conscious resting dogs, instrumented to analyze left ventricular function and inyocardial perfusion. Direct effects on veins were studied during chloralose anesthesia by measuring regional venous capacitance changes with an induction angiometer. Kinetics of molsidomine-induced effects were compared to those induced by nitroglycerin and isosorbide dinitrate. This comparison was restricted to low i.v. dosages, causing only transient threshold effects on peripheral resistance and heart rate.During molsidomine-induced venous pooling, neither any direct effect on the coronary circulation nor any direct cardiac depressant activity of the drug was detected. 100 μg/kg molsidomine caused a reduction of left ventricular preload by 5 mm Hg, lasting at least 4 hours. This effect was significantly more pronounced than that induced by 1 μg/kg nitroglycerin or by 25 μg/kg isosorbide dinitrate, lasting 2 min or 20 min, respectively. However, in raising regional venous capacitance, these nitrate dosages were equi-effective to 100 μg/kg molsidomine, the effect of which was persistent and with a greater delay in onset. These results indicate that the lasting persistance of venodilation is a decisive factor for the amount of volume pooled in the capacitance system and, consequently, for the extent of preload reduction obtained. It is concluded, that lasting vasodilation, restricted to the veins, is beneficial for ventricular performance in ischemic heart disease.ZusammenfassungDie Wirkung von Molsidomin-induzierter Venendilatation auf die Vordehnung des Herzens wurde an wachen, ruhenden Hunden untersucht, bei denen die Funktion der linken Herzkammer und die Myokarddurchblutung analysiert werden konnten. Direkte Wirkungen auf die Venen wurden in Chloralose-Narkose durch Messung lokaler Kapazitätsänderungen mit einem Induktionsangiometer untersucht. Die Kinetik der Molsidomin-Wirkung wurde mit der von Nitroglyzerin und Isosorbid-Dinitrat verglichen. Dabei war dieser Vergleich auf niedrige, intravenös verabreichte Dosierungen begrenzt, die jeweils nur eine vorübergehende, minimale Wirkung auf den peripheren Widerstand und die Herzfrequenz hatten.Während der Molsidomin-induzierten Venendilatation war weder eine direkte Wirkung des Medikaments auf die Koronardurchblutung noch eine abschwächende Wirkung auf die Herzkraft erkennbar. 100 μg/kg Molsidomin verursachten eine Erniedrigung des linksventrikulären Füllungsdruckes um 5 mm Hg während eines Zeitraumes von 4 Stunden. Dieser Effekt war deutlich stärker als die entsprechende Wirkung von 1 μg/kg Nitroglyzerin oder von 25 μg/kg Isosorbid-Dinitrat, die 2 bzw. 20 Minuten lang anhielt. Diese beiden Nitrat-Dosierungen waren jedoch ebenso wirksam wie 100 μg/kg Molsidomin bei der Erhöhung der lokalen Venenkapazität, wobei Molsidomin nach verzögertem Beginn lang anhaltend wirkte. Diese Ergebnisse deuten darauf hin, daß die Dauer der Venendilatation wichtig ist für das Ausmaß der Volumenansammlung im Kapazitätssystem und damit für das erzielbare Ausmaß der Herzentlastung durch Erniedrigung des Füllungsdruckes. Es wird gefolgert, daß anhaltende, auf die Venen beschränkte Vasodilatation günstig ist für die Arbeitsweise des Herzens bei ischämischer Herzerkrankung.

Transmural differences in myocardial blood flow and in coronary dilatory capacity in hemodiluted conscious dogs

SummaryIn 16 conscious resting dogs regional myocardial blood flow and the local coronary dilatory capacity were studied with the particle distribution technique during isovolemic hemodilution (hct=13%). Postischemic peak coronary hyperemia following release of temporary circumflex coronary artery occlusion was used for quantification of regional coronary dilatory capacity. In hemodilution (arterial blood oxygen content less than one third of normal) left ventricular blood flow (LVBF) was 460±36 ml/100 g·min, subendocardial/subepicardial flow amounted to 1.3±0.1. During postischemic peak hyperemia LVBF increased by 33% up to 606±63 ml/100 g·min. This 33% increase in LVBF was distributed mainly to the subepicardial layer, while in the subendocardial layer there was no significant flow increase. It is concluded that the increase in heart rate and systolic coronary vascular compression in addition to the lowered arterial oxygen content lead to exhaustion of the dilatory reserve in the subendocardium during hemodilution. Therefore the remainingoverall dilatory capacity is without functional significance.ZusammenfassungDie Verteilung der Myokarddurchblutung und der Dilatationsreserve der Koronargefäße wurde in 16 wachen Hunden in Ruhelage mit der Partikelverteilungsmethode bestimmt bei isovolämischer Hämodilution. Die postischämische Hyperämie der Koronargefäße nach Eröffnung eines zeitweiligen Verschlusses der Zirkumflexarterie wurde zur Beurteilung der lokalen Dilatationsreserve herangezogen. Unter Hämodilution (mit einem arteriellen Sauerstoffgehalt von weniger als einem Drittel des Normalwertes) betrug die Durchblutung des linken Ventrikels 460±36 ml/100 g·min.Das Verhältnis von subendokardialer/subepikardialer Durchblutung betrug 1,3±0,1. Während postischämischer Hyperämie stieg die Ventrikeldurchblutung um 33% auf 606±63 ml/100 g·min. Diese 33% ige Durchblutungszunahme erstreckte sich hauptsächlich auf die subepikardiale Schicht der Ventrikelwand, während in der subendokardialen Schicht keine signifikante Durchblutungszunahme nachweisbar war. Es wird gefolgert, daß die Zunahme der Herzfrequenz und der systolischen Koronargefäßkompression zusammen mit dem erniedrigten arteriellen Sauerstoffgehalt zu dieser Erschöpfung der Dilatationsreserve in der Innenschicht unter Hämodilution führen. Deshalb ist die verbleibende gemittelte Dilatationsreserve der gesamten Ventrikelwand ohne funktionelle Bedeutung.

Demonstration of alpha-adrenergic coronary control in different layers of canine myocardium by regional myocardial sympathectomy

SummaryThe direct effects of sympathetic coronary innervation in conscious dogs were analyzed by comparison of myocardial blood flow in a sympathectomized section of the left ventricle with blood flow in another section of the same ventricle with intact sympathetic innervation. Regional myocardial sympathectomy was accomplished by a protocol of intracoronary application of 6-hydroxydopamine (6-OHDA). Regional adrenergic nerve function was checked by studies on accumulation, retention and stimulus-induced release of labelled norepinephrine together with studies on regional ventricular contractility during stellate ganglion stimulation. These tests demonstrated complete sympathectomy in the 6-OHDA-treated section and an unimpaired adrenergic nerve function in the untreated control section.In these dogs at rest, myocardial blood flow (MBF) was 66±14 ml/min·100 g in the left ventricular control section and 108±16 ml/min·100 g in the 6-OHDA-treated section. Transmural distribution of MBF was similar in these two sections: subendocardial MBF/subepicardial MBF was 1.28±0.17 in the control section and 1.36±0.12 in the 6-OHDA-treated section. Application of 1.0 mg/kg propranolol i.v. did not modify MBF and its distribution in either section. Following 1.0 mg/kg phentolamine i.v., MBF in the control section approached that in the 6-OHDA-treated sympathectomized section.These results demonstrate that a substantial α-adrenergic constrictive coronary tone is operative in the ventricular control section in these conscious dogs at rest, which is of similar magnitude in different layers of the left ventricular wall.

Treadmill exercise in dogs under -adrenergic blockade: adaptation of coronary and systemic hemodynamics.

SummaryThe role of the β-adrenergic system in the adaptation of cardiac output and coronary flow to exercise was investigated in 9 conscious dogs. Some of the experiments were carried out in dogs with experimental atrio-ventricular block and paced heart rates.β-Adrenergic stimulation at rest and during exercise was modified by administration of the β-adrenergic blocking agents Kö 1366 and propranolol. Submaximal treadmill exercise under β-adrenergic blockade (β-Bl) was tolerated with a decrease in cardiac output of 22.3±4.2%, in coronary flow of 25.2±6.0% and in mean arterial pressure of 8.2%.When heart rate was experimentally kept constant, results were qualitatively similar. In these experiments, in which the depressant effect of β-Bl on heart rate could be eliminated, during exercise at identical heart rates a decrease of 26.1±4.3% in maximal rate of increase of aortic flow (an index of myocardial contractility) under β-Bl was observed.Determinations of coronary sinus O2-content revealed a fall in myocardial oxygen consumption (MVO2) of 18.5±4.0% during exercise at 6 km/h under β-Bl (Kö 1366).The results indicate that submaximal exercise can be tolerated with a diminished cardiac output, coronary flow and mean arterial pressure and with a definitely slowed adaptation response of these parameters. Despite diminished contractility, β-Bl did not result in a change of MVO2 per unit of external heart work (cardiac output x arterial pressure) under these conditions.

Effect of Chemical Sympathectomy on Coronary Flow and Cardiovascular Adjustment to Exercise in Dogs

SummaryThe exercise capacity and the increase of coronary and systemic hemodynamics under treadmill exercise were studied in 5 dogs, chemically sympathectomized with 6-hydroxy-dopamine.Completeness of adrenergic denervation was verified by stimulation of the right stellate ganglion, by intravenous administration of tyramine, and by demonstration of supersensitivity to exogenous norepinephrine.These dogs demonstrated a retarded adaptation of hemodynamics to a sudden start of exercise. A fall in mean arterial pressure below 45 mmHg within 10 to 15 sec lead to collapse. After a recovery period of 60–90 sec, moderate treadmill exercise could be continued; steady state attainment of hemodynamic parameters was considerably delayed.A steady state of exercise with an O2-consumption (vO2) of 29.6±2.6 ml/min · kg and a cardiac outupt (CO) of 307±16 ml/min · kg was tolerated for at least 20 min.An increase of vO2 up to 42.0±1.7 ml/min · kg and of CO up to 357±13 ml/min · kg under exercise was tolerated for 5 min with steady state, maximal heart rate being 160±4 min−1 at this level of exercise.Mean arterial pressure and total peripheral resistance were significantly reduced at rest and during steady state of exercise as compared to controls prior to sympathectomy identical vO2, whereas CO remained unchanged.The significant fall in left circumflex coronary flow was proportional to the decline in external heart work due to sympathectomy both at rest and under exercise.

Discrepancy between initial and steady-state resistance vessel responsiveness to short-term nitroglycerin exposure in the hindlimb of conscious dogs

Since much of the antianginal efficacy of nitroglycerin can be ascribed to its ability to dilate large arteries and venous capacitance vessels at dosages that have little steady-state effect on vascular resistance, we re-examined the reasons for low responsiveness of resistance vessels to nitroglycerin in a peripheral vascular bed in vivo. In chronically instrumented conscious dogs, intra-iliac nitroglycerin (0.15, 0.5, and 1.5 μg/kg/min) resulted in substantial dose-dependent initial increases in iliac flow (35% μ 7%, 60% μ 11%, and 106% μ 12%. respectively). However, unlike the responses of iliac large artery diameter, these dilations were not sustained during a 6-min infusion. In contrast, doses of nitroprusside, acetylcholine, and adenosine, which gave initial dilations comparable to nitroglycerin, resulted in considerably greater steady-state responses (p < 0.001). Nitrate tolerance, autoregulatory escape, reflex vasoconstriction, and the influence of cyclooxygenase products were ruled out as potential explanations of this selective pattern of nitroglycerin response. It is proposed that the rapid attenuation of nitroglycerin-induced dilation in a representative peripheral vascular bed cannot be attributed to currently accepted hypotheses and contributes more to the unique and beneficial spectrum of nitrate vascular action than an a priori lack of sensitivity of resistance vessels.