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PubMed1982

Influence of carbocromen on some metabolic parameters of isolated working guinea pig hearts.

The influence of carbocromen (chromonar) on both functional and some metabolic parameters of isolated guinea pig hearts was tested over a broad concentration range and with different exogenous substrates. As revealed from a shift of the myocardial respiratory quotient, carbocromen (in the upper coronary active concentration range) induced an increased glucose utilization at the expense of FFA oxidation. Theoretically, this may indicate a relative reduction of myocardial oxygen demand, but the therapeutic relevance of this observation still remains obscure, as an additional exogenous FFA supply may override this biochemical carbocromen effect.

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↗
PubMed1977

Intracoronary versus intravenous nitroglycerin on the transmural distribution of coronary blood flow.

The effect of intracoronary versus intravenous administration of nitroglycerin (GTN) on the transmural distribution of coronary blood flow (epi/endo) was studied in an isolated canine heart preparation and intact dogs. The distribution of blood flow between epicardium and endocardium of the left ventricle was determined by use of radioactive microspheres (15 micrometer diameter). Intracoronary infusion of GTN in the isolated heart significantly increased epi/endo during a constant coronary blood flow, whereas no change in epi/endo was observed during a constant coronary perfusion pressure. When maximal coronary vasodilatation was produced by chromonar, the epi/endo increased significantly, however intracoronary GTN produced no further vasodilatation and did not improve epi/endo. In contrast, intravenous infusion of GTN in intact hearts significantly decreased epi/endo. These results suggest that intracoronary GTN does not enhance endocardial perfusion and may even produce a coronary steal, whereas intravenous GTN may improve endocardial perfusion via indirect haemodynamic actions.

Animals↗
PubMedDate not supplied

Effects of oral carbocromene pretreatment on infarct size following experimental coronary artery occlusion.

This study examines the acute effects of the antianginal drug carbocromene (chromonar) in dogs (20 mg/kg p.o., twice daily for 8 weeks) on mortality, hemodynamics, coronary collateral blood flow, and myocardial infarct size. Following the chronic pretreatment and during acute phase of the experiments, the animals received an intravenous bolus of 4 mg/kg of carbocromene 15 min prior to left anterior descending coronary artery occlusion, and 40 micrograms/kg/min as an infusion during occlusion and reperfusion. Total mortality 2 days postocclusion was 50% in saline control experiments but 20% in carbocromene-treated animals (p less than 0.05). Hemodynamics were not significantly changed during drug administration except for a significant ST-segment elevation during vessel occlusion. Coronary collateral blood flow increased after carbocromene treatment by 30% (p less than 0.05) in the ischemic endocardial region and by 60% (p less than 0.02) in the border zone of the area at risk of infarction. Flow in nonischemic myocardium did not change so that "coronary steal" was not observed. At reperfusion, a flow increase occurred in the ischemic and border zones. Myocardial infarct size was 24% smaller after carbocromene than in control animals (p less than 0.02) when compared to the AR, and 46% smaller (p less than 0.01) in relation to the total left ventricle. We conclude that carbocromene administered orally before acute coronary artery occlusion and intravenously during occlusion and subsequent reperfusion can reduce infarct size by salvage of lateral and subepicardial border zones.

Administration, Oral↗
PubMed1981

Pharmacologic- vs. ischemia-induced coronary artery vasodilation.

Responses of total coronary and regional myocardial blood flow to ischemia- or drug-induced coronary artery vasodilation were studied in open-chest anesthetized dogs. Systolic, diastolic, and mean coronary blood flow after addition of chromonar (8 mg/kg iv), adenosine triphosphate (400 micrograms/min intracoronary), or adenosine (500 micrograms/min intracoronary) exceeded the respective flow at the peak of reactive hyperemia (90-s occlusion period). Whereas the regional distribution of total coronary flow favored the subendocardium of the left ventricle during reactive hyperemia, flow was preferentially distributed to subepicardium during drug-induced maximal coronary artery vasodilation. These results were independent of type of anesthesia, vasodilator agent, or degree of autonomic innervation. These data indicate that total coronary vasodilator reserve is greater than that observed at the peak of reactive hyperemia and that there is a transmural gradient of vasodilator reserve within the left ventricle. A greater regional vasodilator reserve is present in subepicardial than in subendocardial layers.

Adenosine↗
PubMed1984

Increased number of myocardial blood flow measurements with radionuclide-labeled microspheres.

We evaluated the use of a least-squares radionuclide separation technique to allow an increased number of myocardial blood flow measurements with radionuclide-labeled microspheres in dogs. Two sets of labeled microspheres were studied: a set of eight labeled with 125I, 153Gd, 57Co, 51Cr, 113Sn, 85Sr, 95Nb, and 46Sc; and a set of nine in which 125I and 46Sc were replaced with 114In, 54Mn, and 65Zn. For each microsphere label the nuclide activities determined by least-squares separation compared favorably with those actually added to in vitro samples containing a fixed amount of the other nuclides in the set. For the set of eight radionuclide-labeled microspheres, myocardial flow measurements made with the least-squares separation technique and the reference sample method were usually within 15% and almost all within 20% of direct measurements of coronary venous outflow in a right heart bypass preparation. Serial left atrial injections of 15-micron microspheres totaling 48 X 10(6) caused no significant changes in systemic hemodynamics, regional myocardial flows, or coronary pressure-flow relations, whether the coronary bed was autorelating or vasodilated with chromonar. We conclude that at least nine myocardial blood flow measurements can be made in dogs with acceptable accuracy and without evidence of dysfunction due to embolization of the coronary vascular bed. With appropriate validation, this method should be applicable to other organs and animal models as well.

Animals↗
PubMed1987

Maximum myocardial oxygen transport during anemia and polycythemia in dogs.

The purpose of this study was to determine the effect of hematocrit changes on coronary pressure-flow relations during maximum vasodilation to define the relative importance of changes in hemoglobin concentration, blood viscosity, and perfusion pressure in determining maximum myocardial oxygen transport. An anemic group and a polycythemic group of dogs were studied under halothane anesthesia at the hematocrit extremes and after serial exchange transfusions to intermediate hematocrits. Circumflex pressure-flow relations were generated at each hematocrit during maximum pharmacological vasodilation (adenosine 20 micrograms X kg-1 X min-1 or chromonar 8 mg/kg). Maximal coronary vascular conductance (incremental conductance) decreased in an approximately linear fashion with increasing hematocrit. Maximum myocardial oxygen transport showed an "inverted U-shape" relation to hematocrit with the peak occurring at or slightly above normal hematocrit. Hemoglobin concentration, viscosity, and perfusion pressure were all found to be physiologically important determinants of maximal myocardial oxygen transport. Given normal perfusion pressure, arterial oxygen saturation, and myocardial oxygen extraction, we found that maximum myocardial oxygen delivery greatly exceeds the level necessary to supply basal myocardial oxygen needs at all hematocrits studied.

Adenosine↗
PubMed1994

Maximal vascular conductance in right ventricular myocardial circulation.

With acutely increasing right ventricular (RV) hypertension, failure eventually occurs because of RV ischemia. This study examines the effects of RV hypertension on the diastolic right coronary circulation. Conscious dogs instrumented to measure right coronary artery pressure and blood flow were studied after maximal coronary vasodilation with chromonar. Diastolic coronary pressure-flow relations, described by slope (conductance) and zero-flow, pressure axis intercept (Pf = 0), were generated before and during RV hypertension. Diastolic Pf = 0 increased from 11.8 +/- 6.5 to 17.1 +/- 7.1 (means +/- SD, P < 0.01) Torr, with no change in conductance. During RV hypertension, RV diastolic pressure increased. To examine possible mechanisms for the increase in Pf = 0, pressure-flow relations were generated before and after volume loading, without systolic hypertension. Diastolic Pf = 0 increased from 15.5 +/- 3.1 to 20.8 +/- 4.1 Torr, suggesting that changes in Pf = 0 with RV hypertension were mediated by increased filling pressures. Pressure flow relations were derived from mean right coronary flow and RV driving pressure before and during RV hypertension. Under these conditions, Pf = 0 is close to zero; the use of RV driving pressure provides a method for calculating maximal right coronary conductance.

Animals↗
PubMed2001

Effect of estrogen replacement therapy on distribution of myocardial blood flow in female anesthetized rabbits.

Estrogen replacement therapy reduces risk of cardiovascular events by altering coronary vasoregulation and distribution of blood flow. Vessel reactivity and blood flow distribution were assessed in anesthetized female rabbits in the following groups: 1) sham, 2) ovariectomy, 3) ovariectomy + 17beta-estradiol, and 4) ovariectomy + dehydroepiandrosterone. After a 2-wk treatment, cardiac hemodynamics, vascular reserve, and blood flow were evaluated during the following infusions: 1) NaCl, or vehicle (0.5 ml/min), 2) acetylcholine (2 mg/kg), 3) isoproterenol (2 mg. kg(-1). min(-1)), and 4) chromonar (8 mg/kg). In hearts from ovariectomized rabbits, autoregulatory blood flow was preserved despite lower diastolic perfusion pressures (55 +/- 8 vs. 64 +/- 8 mmHg in sham) and rate-pressure product (14.4 +/- 0.8 vs. 19.3 +/- 0.8 beats/min. mmHg x 10(-3)). Estrogen replacement therapy restored coronary pressure and reserve, and all drugs increased vascular conductance. In conclusion, in hearts from ovariectomized rabbits, vascular reserve declined because coronary pressure was lower; however, blood flow was preserved at a higher level than expected for oxygen demand. Estrogen replacement therapy restores myocardial oxygen supply-demand indices and returns coronary pressure-flow data to levels observed in animals with intact ovaries.

Acetylcholine↗
PubMed1987

Measurement of myocardial blood flow by ultrafast computed tomography.

Myocardial blood flow was analyzed by radioisotope-labeled microspheres and ultrafast computed tomography (CT) in 16 closed-chest, anesthetized dogs. The first set of 10 dogs had CT and microsphere measurements before and after chromonar-induced increases in myocardial blood flow. A second set of six dogs had flows measured at control and during temporary reductions in regional flow produced by balloon cuff occlusion of the left anterior descending coronary artery. All dogs had four-slice, 20-instance CT scans after injection of a medium bolus (0.35 ml/kg) of contrast medium into a femoral vein simultaneous with injection of microspheres into the left atrium. CT myocardial flow was calculated as the change in myocardial CT numbers divided by the area from a blood pool time-density curve. A wide range of myocardial blood flows was produced as determined by microspheres (0 to 6.7 ml/min/g). Global flow of the first set of dogs was shown to have excellent correlation (r = .95, n = 17) for a limited range (.4 less than X less than 1.4 ml/min/g) of flows. Regional flows of these measurements demonstrated less correlation (r = .63, n = 110) but extended the range of flow to 1.7 ml/min/g. At higher flows (greater than 2.5 ml/min/g) the correlation for global and regional flows was not significantly different than zero. Regional ischemic flow correlation extended the linear range of flow to 0 ml/min/g (r = .62, n = 17). These results show that CT can measure myocardial blood flow over a limited but clinically relevant range of flows defined as slightly above normal to ischemic. These results indicate that another preparation of CT flow measurement must be sought for quantification of myocardial perfusion values significantly above normal.

Animals↗
PubMed1975

Effects of several antianginal agents on pacing-induced S-T Segment depression in the atherosclerotic rabbit.

Several agents used clinically in the treatment of angina pectoris were studied in an atherosclerotic rabbit model previously shown to be useful in differentiating antianginal drug activity. Intravenously administered isosorbide dinitrate afforded protection against pacing-induced S-T segment depression in a dose-related manner. Drugs with no protective effect included pentaerythritol tetranitrate, chromonar, and papaverine. Propranolol also did not prevent pacing-induced S-T segment depression, due in part to the overriding of the beneficial negative chronotropic effect of this drug by pacing.

Angina Pectoris↗
PubMed1982

Role of autoregulation in the beneficial action of propranolol on ischemic blood flow distribution and stenosis severity in the canine myocardium.

The effect of propranolol (0.1 mg/kg i.v.) on distal coronary pressure (DCP), distal bed (DR) and stenosis resistances (SR) and regional myocardial blood flow [endocardial-epicardial (endo/epi)] was studied in two groups of anesthetized dogs with a severe stenosis of the left circumflex coronary artery. In group 1, the ability of the DR to autoregulate was left intact, whereas in group 2, the DR was maximally dilated by pretreatment with the coronary vasodilator, chromonar. Despite similar global hemodynamic effects in both groups after propranolol treatment significant differences were observed in the ischemic area. In group 1, propranolol produced a significant increase in subendo blood flow, endo/epi and DCP in the ischemic region. In addition, DR (1.7 +/- 0.4 to 3.3 +/- 0.6 U) increased and SR decreased (3.4 +/- 0.5 to 1.7 +/- 0.3 U) significantly. In group 2, the changes in endo/epi, DCP, DR and SR were prevented by maximal vasodilation. These results suggest that the favorable changes produced by propranolol on ischemic myocardium are the result of a restoration of the ability of the resistance vessels to autoregulate. This allows for a passive decrease in coronary arteriolar dilation which results in an increase in DR and DCP and a decrease in SR. The increase in DCP may also contribute to the increase in ischemic subendo blood flow after propranolol.

Animals↗
PubMed1981

Effects of carbocromene on myocardial oxygen consumption in isolated dog hearts.

In isolated empty beating and isovolumetrically working supported dog hearts, the effects of intracoronary administration of the antianginal agent carbocromene (chromonar) and its corresponding acid metabolite on coronary blood flow and myocardial oxygen consumption were investigated. After administration of 1.0 and 2.0 mg of carbocromene per heart, coronary flow increased significantly between 61 (P less than .05) and 155% (P less than .01) in both types of experiments. However, the carbocromene acid did not alter coronary flow. Both compounds decreased with the used doses myocardial oxygen consumption between 18 (P less than .05) and 36% (P less than .05) in empty beating as well as in working hearts. Both agents did not cause significant changes in heart rate and inotropy of the isolated hearts in both types of experiments. It is suggested that carbocromene decreases myocardial oxygen consumption by a direct effect on myocardial oxygen metabolism as is evident from the fact that this decrease is not accompanied by changes in any of the parameters which influence oxygen consumption. This effect of the drug is independent from its coronary vasodilating properties as the metabolite doses not change coronary flow but decreases myocardial oxygen consumption in both types of experiments.

Animals↗
PubMedDate not supplied

Physiological tone regulation and drug susceptibility of coronary smooth musculature of extramural stem arteries.

The great extramural coronary stem arteries (as well as extramural collaterals and anastomoses) deserve particular interest with respect to their peculiar susceptibility to autonomic neurotransmitters and drugs. Obviously these arteries, preferentially affected by atherosclerotic processes, are most responsive to such vasodilators which block vascular tone and contractility by interference with Ca-dependent excitation-contraction coupling. This applies first of all to the new pharmacological family of Ca-antagonists but also to the classical nitrites. As we have emphasized in 1971. Ca-antagonism is a new principle of coronary vascular dilation with profound clinical implications (5). In fact, the Ca-antagonists have become, within a few years, the drugs of choice for the treatment of all spastic forms of angina. By contrast adenosine, dipyridamole, chromonar and theophylline preferably dilate the small intramural resistance vessels, but do not significantly reflex the extramural stem arteries. Therefore, in coronary heart disease, the latter drugs do usually not produce major circulatory improvement.

Acetylcholine↗
PubMed1994

Effect of young age on coronary adaptations to left ventricular pressure overload hypertrophy in sheep.

OBJECTIVES: This study attempted to determine the effect of young age on changes in coronary conductance and capillary density with left ventricular pressure overload hypertrophy. Mechanisms responsible for age differences in perfusion capacity were examined. BACKGROUND: Hypertension in adults causes alterations in the coronary vasculature, resulting in diminished coronary perfusion capacity and myocardial ischemia. These processes are worsened in adults by advanced age. Young age may provide advantages in coronary adaptation to hypertension. METHODS: Coronary conductance was examined in conscious chronically instrumented 10-week old lambs and adult sheep with progressive ascending aortic stenosis of 6-week's duration and age-matched control sheep by means of the microsphere technique and vasodilators. Capillary density was measured post-mortem. RESULTS: Adult sheep with aortic stenosis had a decrease in left ventricular subendomyocardial capillary density by 17% and maximal coronary conductance with adenosine by 67%. In the nonhypertrophied right ventricle, maximal coronary conductance was depressed by 47%, whereas capillary density was normal, implying an effect of coronary hypertension on resistance vessels. In contrast, lambs with aortic stenosis maintained normal left ventricular capillary density, maximal coronary conductance and coronary reserve and had relatively little impairment of conductance in the right ventricular coronary bed (-15%, p = NS). Similar responses were found with other vasodilators, isoproterenol and chromonar. CONCLUSIONS: Young age confers advantages to coronary adaptation to left ventricular pressure overload, including angiogenesis proportionate to hypertrophy, resulting in normal capillary density and coronary conductance. There is also less hypertension-induced impairment of coronary conductance distinct from the effects of hypertrophy.

Adaptation, Physiological↗
PubMed1986

Coronary vasodilation shifts the diastolic pressure-dimension curve of the left ventricle.

The volume of blood in the left ventricular wall increases as coronary perfusion pressure or coronary blood flow increase, but it is unclear whether such an increase in volume can acutely alter the diastolic pressure-dimension relationship of the intact, working left ventricle. In 19 dogs, we measured left ventricular pressure with a catheter tip transducer and dimensions with an epicardial echo transducer and, during each experiment, compared the diastolic pressure-dimension relationship during two states of coronary blood flow: control and maximal vasodilation (induced by intravenous chromonar). Diastolic pressure-dimension relationships for diastolic pressures from 0 to 25 mmHg were obtained during transfusion with blood in 11 dogs with the pericardium open and in eight dogs with the pericardium closed. Left ventricular epicardial diameter did not change during maximal coronary blood flow compared with control, but endocardial diameter was less, wall thickness was greater, and the diastolic pressure-dimension relation was shifted to the left. The average magnitude of the increase in diastolic pressure at comparable diastolic dimensions was small when the pericardium was open (2.6 mmHg) and larger when the pericardium was closed (4.1 mmHg). The mechanism of this shift appears to be an alteration of the ratio of diastolic chamber volume to wall volume. Interaction of diastolic pressures between the right and left ventricles may contribute to the larger increase in diastolic pressure with the pericardium closed.

Animals↗
PubMed1983

Role of the pericardium in the regulation of myocardial blood flow and its distribution in the normal and acutely failing left ventricle of the dog.

The effects of the pericardium on the amount and distribution of left ventricular myocardial blood flow were studied. In 10 normal dogs, transfusion of blood from a donor dog resulted in modest increases in coronary flow and ventricular diameter that were greater with an open than a closed pericardium. The ratio of subendocardial to subepicardial flow remained normal with or without the pericardium, at low and high diastolic ventricular pressure, and before and after pharmacological vasodilation with chromonar. In 18 dogs, cardiac failure was induced by constant infusion of the metabolic inhibitor, phenformin. Modest ventricular dilatation occurred if the pericardium was open. A progressive rise in myocardial blood flow developed in those with the pericardium open (1.06 rising to 3.02 ml . g-1 . min-1). A lesser increase (0.62 to 1.75 ml . g-1 . min-1) was seen in dogs with the pericardium closed; they selectively increased subendocardial flow, producing an average subendocardial to subepicardial flow ratio of 2.25. Pharmacological vasodilatation then resulted in uniform transmural flow. The pericardium can influence myocardial flow indirectly by influencing myocardial metabolic demand, when the heart is stressed. It may have a beneficial role in preventing the increased oxygen and coronary flow requirements produced by ventricular dilatation.

Animals↗
PubMed1994

Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs.

BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is angiogenic in vitro and in vivo. It has been hypothesized that VEGF plays a role in myocardial collateral formation; however, the effects of VEGF on collateral flow to ischemic myocardium are unknown. METHODS AND RESULTS: We studied the effect of VEGF on collateral blood flow in dogs subjected to gradual occlusion of the left circumflex coronary artery (LCx). Beginning 10 days after placement of an LCx-constricting device, VEGF 45 micrograms (n = 9) or saline (n = 12) was administered daily via an indwelling catheter in the distal LCx, at a point just beyond the occlusion. Treatment was maintained for 28 days. Collateral blood flow was determined with microspheres 7 days before treatment, immediately before treatment (day 0), and 7, 14, 21, and 28 days into the treatment period. Collateral blood flow was quantified during chromonar-induced maximal vasodilation and expressed as a collateral zone/normal zone (CZ/NZ) ratio. Treatment with VEGF was associated with a 40% increase in collateral blood flow (final CZ/NZ blood flow ratios of 0.49 +/- 0.06 and 0.35 +/- 0.02 in the VEGF-treated and control groups, respectively, P = .0037) as well as an 89% increase in the numerical density of intramyocardial distribution vessels (> 20 microns diameter) in the CZ (6.6 +/- 1.4 versus 3.5 +/- 0.7 vessels/mm2 in VEGF-treated and control dogs, respectively, P < .05). CONCLUSIONS: We conclude that intracoronary VEGF enhances the development of small coronary arteries supplying ischemic myocardium, resulting in marked augmentation of maximal collateral blood flow delivery. These results demonstrate the feasibility of pharmacological enhancement of collateral growth and suggest a new therapeutic approach for the treatment of myocardial ischemia.

Animals↗