This study examined the hypothesis that chemical denervation with 6-hydroxydopamine (6-OHDA) would increase myocardial responsiveness to isoproterenol. Five days previously, 15 New Zealand white rabbits were given 60 mg/kg 6-OHDA intravenously. Fifteen control rabbits received vehicle. Hemodynamic, coronary blood flow (CBF), and cardiac output measurements were obtained before and during isoproterenol infusion (0.5 microgram/kg/min for 15 min). Norepinephrine tissue content, beta-adrenoceptor number (Bmax) and affinity (Kd), cyclic AMP content and cyclic AMP-phosphodiesterase (PDE) activity were measured in the subepicardium (EPI) and subendocardium (ENDO). Myocardial norepinephrine content was significantly decreased from 1263 +/- 292 (EPI) and 874 +/- 221 ng/g tissue (ENDO) in the control to 148 +/- 33 (EPI) and 90 +/- 45 ng/g tissue (ENDO) in the denervated group. There were no significant changes in cyclic AMP-PDE activity or Bmax and Kd of beta-adrenoceptors. Cyclic AMP content was similar at baseline, but controls had a significantly larger increase (123-155%) during isoproterenol infusion when compared to the denervated group (27-37%). The denervated animals showed a smaller increase in cardiac output during isoproterenol infusion (from 203 +/- 30 to 235 +/- 26 ml/min), when compared to the control animals (from 135 +/- 18 to 216 +/- 42 ml/min). Baseline CBF was significantly higher in the EPI but not ENDO of the denervated group (185 +/- 20 ml/100 g/min in EPI and 150 +/- 8 in ENDO) compared to the control group (108 +/- 13 in EPI and 133 +/- 17 in ENDO). The relative increase in CBF during isoproterenol infusion was smaller in the denervated group (44-45%) than the control group (107-109%). Isoproterenol infusions of 0.1 and 2.5 micrograms/kg/min showed similarly depressed coronary blood flow responses in denervated animals. Thus, the chemically denervated animals did not have beta-adrenoceptor upregulation, exhibited a lesser increase in cyclic AMP with isoproterenol, and had a reduced functional and coronary blood flow response to isoproterenol. This occurred without any significant change in beta-adrenoceptor number or affinity, or in cyclic AMP-phosphodiesterase activity, indicating there may be receptor uncoupling or other changes in the signal transduction pathway.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMedDate not supplied

Regional asynchrony of segmental contraction may explain the "oxygen consumption paradox" in stunned myocardium.

Despite apparently depressed function, stunned myocardium maintains oxygen consumption and has the capacity to increase contractility with inotropic stimulation. We hypothesized that during stunning, O2 demand is maintained because regional segment work is performed, but is asynchronous with global left ventricular contraction, and that inotropic stimulation would restore regional work and synchrony. Thirteen open-chest anesthetized dogs were subjected to three left anterior descending (LAD) coronary artery occlusions (10 min) and reperfusions (15 min) to produce regional myocardial stunning. Segment shortening and force development were measured independently and simultaneously in the LAD (experimental) region and circumflex (control) regions. Regional myocardial work was calculated as the integrated product of instantaneous force and shortening, during two periods: 1) over the entire cardiac cycle (Positive Work), and 2) limited to the systolic portion of the cardiac cycle (Systolic Work). Regional myocardial O2 consumption (MVO2) was calculated from regional blood flow (radiolabeled microspheres) and O2 saturation data (microspectrophotometry). Occlusion of the LAD produced a delay in onset of segment shortening in the ischemic region, but not in regional force development. A time delay of 67-81 ms persisted through the three stages of occlusions and reperfusions. Systolic regional work was depressed to a greater extent (924 +/- 182 to 149 +/- 118 g*mm*min-1) than total positive regional work (1437 +/- 337 to 857 +/- 174 g*mm*min-1). Regional subepicardial MVO2 in the stunned region was not different than in the control region (7.3 +/- 1.5 vs. 6.9 +/- 1.4 ml O2*min-1*100 g-1). Local infusion of isoproterenol reversed the delay in regional shortening from 73 +/- 7 to 21 +/- 8 ms, thereby augmenting systolic work (298%) more than positive work (60%), without a significant increase in MVO2 (7.3 +/- 1.5 to 10.5 +/- 3.2 ml O2*min-1*100 g-1). It is concluded that myocardial stunning decreases regional systolic work due to regional mechanical asynchrony, while MVO2 is used supported total positive work which was not significantly reduced. Isoproterenol restores regional work by restoring synchrony, without greatly affecting regional MVO2.

Animals↗

PubMedDate not supplied

The oxygen wasting effect of isoproterenol is altered by chemical denervation and cardiac hypertrophy.

We tested the hypothesis that isoproterenol would increase myocardial work and O2 consumption at reduced efficiency and that both left ventricular hypertrophy and chemical sympathectomy would lead to changes in this myocardial efficiency response. Left ventricular hypertrophy was produced by aortic valve plication in 23 puppies. Six months later, sympathetic denervation (6-hydroxydopamine) was produced in 12 hypertrophied and 10 non-hypertrophied dogs, 5 days prior to acute experiments. Ten non-hypertrophied and 11 hypertrophied animals were not denervated. Measurements were made before and during an isoproterenol infusion (0.5 microgram/kg/ min). Regional myocardial work was calculated as the integrated product of force (miniature transducer) and segment shortening (ultrasonic crystals). Regional O2 consumption was calculated from regional blood flow (microspheres) and regional O2 saturations (microspectrophotometry). In all groups, regional O2 consumption increased with isoproterenol (non-hypertrophied, non-sympathectomized 6.5 +/- 0.8 to 20.3 +/- 5 ml O2/min/100 g, non-hypertrophied, sympathectomized 5.0 +/- 0.7 to 10.0 +/- 1.5, hypertrophied, non-sympathectomized 9.8 +/- 1.3 to 16.2 +/- 2.2, hypertrophied, sympathectomized 6.1 +/- 0.5 to 13.3 +/- 1.6). Regional segment work also increased in all groups with isoproterenol stimulation (non-hypertrophied, non-sympathectomized 781 +/- 73 to 1197 +/- 61 g.mm/min, non-hypertrophied, sympathectomized 996 +/- 221 to 2118 +/- 412, hypertrophied, non-sympathectomized 1031 +/- 145 to 3262 +/- 753, hypertrophied, sympathectomized 721 +/- 116 to 1745 +/- 402). In the non-hypertrophied, non-sympathectomized group, efficiency (work/O2 consumption) was significantly decreased from 122 +/- 17 to 76 +/- 9 g.mm/ml O2/100 g demonstrating an "oxygen wasting" effect. In the hypertrophied, non-sympathectomized group, segment efficiency significantly increased from 94 +/- 19 to 250 +/- 63. In both sympathectomized groups, efficiency was not altered by isoproterenol. Thus the oxygen wasting effect of beta-adrenergic stimulation was reversed by left ventricular hypertrophy and blocked by sympathectomy.

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PubMedDate not supplied

Myocardial O2 supply and consumption in early cardiac hypertrophy of renal hypertensive rabbits.

This study examined myocardial O2 supply and O2 consumption in hypertension-induced myocardial hypertrophy. New Zealand white rabbits prepared as uninephrectomized (sham) controls (n = 7), or one kidney/one clip (1K1C) hypertensive rabbits (n = 7) were examined four weeks after surgery. A group of renally intact "true" controls (n = 4) was also examined. Coronary blood flow (CBF) was measured with radioactive microspheres in anesthetized open chest animals during baseline and vasodilated conditions (adenosine, 0.4 mg/kg/min). Microvascular O2 saturations were determined by microspectrophotometry. Myocardial oxygen consumption (MVO2) was calculated. Mean pressure was elevated in hypertensive animals (121 +/- 7 mmHg, means +/- SE) compared to uninephrectomized controls (74 +/- 7 mmHg). Hypertrophy was indicated by a 30% increase in heart weight to body weight ratio in the 1K1C animals. The average MVO2 was elevated in hypertrophy (12.4 +/- 0.9 vs. 9.6 +/- 0.8 ml O2/min/100 g). Baseline CBF was higher in cardiac hypertrophy (227 +/- 21 ml/min/100 g) compared to sham controls (169 +/- 14 ml/min/100 g). In hypertrophy the percent increase in CBF during adenosine infusion was reduced and the minimal vascular resistance was higher. No difference in microvascular O2 saturations was observed between groups, thus O2 extraction was similar. No subepicardial vs. subendocardial difference occurred within either the sham controls or the 1K1C animals in any parameter. Therefore, an overall increased MVO2 resulted in increased CBF and reduced coronary flow reserve in short-term renovascular hypertension-induced cardiac hypertrophy in rabbits.

Animals↗

PubMedDate not supplied

Effect of complement depletion on O2 supply and consumption in ischemic dog myocardium.

The purpose of this study was to determine whether depletion of serum complement can decrease the severity of an ischemic episode by improving regional O2 supply and consumption parameters in the ischemic region of the heart. Fourteen anesthetized dogs with serum complement intact or depleted (100 U/kg cobra venom factor given 8 hrs before) were subjected to left anterior descending coronary artery (LAD) occlusion for 6 hrs. Myocardial blood flows were determined before and 6 hrs after LAD occlusion using radioactive microspheres. Regional arterial and venous O2 saturations were determined using microspectrophotometry. In control animals, flow decreased from 122 +/- 42 to 13 +/- 14 ml/min/100 g (mean +/- SD) in the occluded LAD region. With complement depletion, LAD occlusion resulted in a flow reduction in the ischemic region (38 +/- 29 ml/min/100 g), but to a lesser degree than seen in the same region in control animals, especially in the subendocardium. O2 consumption was decreased in the ischemic region of both treatment groups, though O2 consumption was higher in this region in complement depleted animals compared to the values in control animals. The O2 supply/consumption ratio was decreased similarly in the ischemic region of control and complement depleted groups. Thus, with complement depletion, flow to the ischemic zone was improved but this region was still flow restricted. The flow increase during complement depletion was sufficient to allow an increased O2 utilization in the ischemic region.

Animals↗

PubMedDate not supplied

Propranolol and thyroxine-induced hypertrophic rabbit hearts: effect on heart size and regional O2 supply/consumption variables.

The purpose of this study was to determine the effect of acute and chronic propranolol on heart size and regional O2 supply/consumption variables in thyroxine (T4)-treated rabbit hearts. New Zealand white rabbits were given 0.5 mg/kg T4 for 3 or 16 days with and without concomitant 2 mg/kg propranolol. Another group was given 16 days of propranolol alone and another 3-day T4 group was given 2 mg/kg propranolol 1 h before the experiment began. Another group served as control. Myocardial blood flows were determined using radioactive microspheres and small arteriolar and venous O2 saturations were determined using microspectrophotometry. Treatment with T4 for 3 or 16 days increased the heart weight/body weight ratio, myocardial blood flow, and regional O2 consumption. 16-day T4 treatment resulted in myocardial flow 195% and O2 consumption 300% above control group values. When propranolol was given chronically along with T4, heart weight/body weight ratios did not increase to the degree seen with 3 or 16 days of T4, alone. Propranolol given acutely in 3-day T4-treated animals, resulted in a reduced O2 consumption and O2 extraction, though not to the extent seen with chronic propranolol treatment of T4-treated animals. Acute propranolol treatment slightly reduced myocardial blood flow in 3-day T4-treated animals, while chronic treatment significantly reduced it. Chronic propranolol treatment in 16-day T4-treated animals resulted in a significant reduction in flow and O2 consumption. Thus, T4 treatment increased O2 consumption, flow, and heart size and these effects could be attenuated using acute and chronic propranolol.

Animals↗

PubMedDate not supplied

Regional oxygen supply and consumption balance in experimental left ventricular hypertrophy.

The aim of the present study was to determine if the relationship between myocardial O2 supply and O2 consumption was preserved after prolonged pressure overload due to aortic valve stenosis. This was examined in anesthetized open-chest dogs in which the aortic valve was plicated 6 months previously. We measured coronary blood flow with radioactive microspheres and regional small vessel O2 saturation with microspectrophotometry, to obtain O2 supply, and O2 consumption. Regional O2 consumption was calculated as the product of flow and O2 extraction. The left ventricular weight/body weight ratio was 81% greater in the dogs with aortic valve stenosis. There were no hemodynamic differences between the groups except that left ventricular systolic pressure was 38 +/- 22 mm Hg greater than aortic in the hypertrophied group. Coronary blood flow did not differ between the control and hypertrophied groups nor were there subepicardial vs subendocardial differences. When maximal coronary flow was determined with chromonar (10 mg/kg), the flow increase was significantly attenuated in the hypertrophied subendocardium (242.1 +/- 82.3 (hypertrophy) vs 512.4 +/- 204.1 ml.min-1.100 g-1 (control). There were no significant differences in O2 extraction or O2 consumption/g between control and hypertrophied animals. There was a significantly lower O2 supply/consumption ratio in the subendocardium compared to the subepicardium of both groups. However, the O2 supply/consumption ratio was not decreased by hypertrophy. Thus, despite significant hypertrophy, a loss of flow reserve and a high left ventricular pressure, O2 supply/consumption balance is preserved in valvular aortic stenosis at rest.

Animals↗

PubMedDate not supplied

Effect of ouabain on O2 supply/demand in normal and ischemic heart.

The effect of ouabain (15 microgram/kg) on subepicardial and sub-endocardial blood flow, oxygenation, and small-vessel blood content was studied in anesthetized open chest rabbits with hearts subjected to acute coronary occlusion. 10 minutes after occlusion, blood flow was 48% lower than in the control region. Ouabain lowered blood flow significantly in the non-occluded region and insignificantly in the occluded area. Small-vessel blood content, a measure of open capillary density, was unaffected by occlusion or ouabain. After occlusion, relative tissue PO2 fell to a greater extent in the affected subendocardium than the affected subepicardium. Ouabain, therefore, appears to be well tolerated in both the control and ischemic regions in terms of oxygen supply and consumption.

Animals↗

PubMedDate not supplied

Regional blood flow and oxygenation of the rabbit heart subjected to acute coronary occlusion - effect of phenoxybenzamine.

The effect of phenoxybenzamine (2 mg/kg) on subepicardial (EPI) and subendocardial (ENDO) blood flow and oxygenation was determined in ischemic and non-ischemic areas of hearts subjected to acute coronary occlusion in 24 pentobarbital-anesthetized open-chest New Zealand white rabbits. Ten minutes after occlusion, blood flow measure with radioactive microspheres was 57% lower in the occluded region compared to the non-occluded area. There were no EPI vs. ENDO differences at this time. Phenoxybenzamine was then administered and one hour after occlusion, flow in all areas was significantly reduced. Flow in the occluded area fell to a lesser extent than in the non-occluded area. ENDO flows were lower than EPI in both areas. After occlusion, relative tissue PO2 fell significantly in the affected areas. No other changes were significant. Phenoxybenzamine lowered relative tissue PO2 in the occluded ENDO but had no other effect. This indicates that the relationship of O2 supply to consumption is preserved in the heart after phenoxybenzamine except in the occluded ENDO. In this region, the fall in relative tissue PO2 indicates that the reduction in flow is large compared to any change in metabolism. The reduction in this relationship may be due to reduced perfusion pressure for collateral flow and/or "coronary steal".

Animals↗

PubMedDate not supplied

Effect of dopamine on regional myocardial function and oxygen consumption in experimental left ventricular hypertrophy.

We investigated the hypothesis that the capacity of left ventricular myocardium to respond to an inotropic challenge by dopamine would be diminished in left ventricular hypertrophy induced by plication of the aortic valve. Seven mongrel dogs (LVH group) aged 6-8 weeks and weighing 4-6 kg, were subjected to preliminary surgery in which the noncoronary sinus of Valsalva was plicated. Six months later these animals, as well as a control group of dogs, were subjected to acute experiments in which the effect of dopamine (7.5 and 15 micrograms/kg/min) on regional and global myocardial function and oxygen consumption was studied. Myocardial segment length was measured with ultrasonic dimension transducers, and left ventricular and aortic blood pressures were recorded from catheter-tip transducers. Regional coronary blood flow was determined with radioactive microspheres, and regional oxygen saturation in small arteries and veins was measured using microspectrophotometry. Regional myocardial O2 consumption was calculated from these parameters. Heart weights were significantly elevated in the LVH group, and a pressure gradient of about 25 mm Hg was observed across the aortic valve. In both groups, dopamine infusion produced a dose-dependent increase in heart rate, left ventricular pressure, and LV dP/dtmax. Prior to dopamine infusion, percent shortening per beat was greater in the LVH group (13.97 +/- 1.2%) than in the control group (9.49 +/- 1.07%). Although the maximum speed of segment shortening was elevated by dopamine in both groups, percent shortening was not elevated in the LVH group. Stimulation by the high dose of dopamine produced a threefold elevation in regional coronary blood flow in both groups. Oxygen extraction was unchanged; the proportion of small veins with low O2 saturation was not elevated in LVH hearts, even during dopamine stimulation. Regional myocardial O2 consumption was elevated by dopamine (15 micrograms/kg/min) to about the same extent in both the control and LVH groups (19.1 +/- 2.3 and 17.5 +/- 2.3 ml O2/min/100 g) respectively. It is concluded that, in dogs with six months of aortic stenosis, dopamine does not exhaust functional reserve and the relationship between O2 supply and consumption is not significantly impaired.

Animals↗

PubMedDate not supplied

An experimental technique for estimating regional myocardial segment work in vivo.

We determined the capabilities and limitations of an experimental approach to measure segment work (force x distance) of myocardial regions in the in vivo beating heart. In 18 open-chest anesthetized dogs, segment length was measured using ultrasonic dimension transducers, and developed force was measured with miniature force transducers. Work was defined as the integrated multiples of instantaneous force and shortening during a single (averaged) beat, corresponding to the area under the length-force loop. Changes in work over a range of 9.78 x 10(-4) to 2.93 x 10(-2) J/g/min were produced by vena caval constriction, aortic constriction, atrial pacing, and isoproterenol (0.5 and 1.0 micrograms/kg/min). Work was measured in both major and minor axes. In 60% of the animals, work in the minor axis was 9.2-fold greater than in the major axis. In the others, all interventions changed regional work to the same extent in both axes (r = 0.802; p < 0.05). Work changes were also compared between the base, anterior, and posterior walls. The response was directionally similar in all regions, ranging from -79 +/- 1% during caval occlusion to 278 +/- 98% during isoproterenol. The effective size of the measured muscle mass was limited to the transducer area because the amplitude and pattern of both force development and segment shortening were not changed until deep myocardial cuts were as close as 2 mm from the measuring area. We conclude that work measurement in the minor axis is quantitatively representative of fiber work in that region.

Animals↗