Rise In Coronary Flow Research Articles

ATP is involved in myocardial and vascular effects of exogenous bradykinin in ejecting guinea pig heart.

It has recently been reported that bradykinin induces selective left ventricular (LV) relaxation in isolated guinea pig hearts via the release of nitric oxide. Exogenous bradykinin also induces vasodilation, which is only partly due to nitric oxide release. In the present study we investigated the role of adenyl purines on these bradykinin-induced effects. Isolated ejecting guinea pig hearts were studied. LV pressure was monitored by a 2-Fr micromanometer-tipped catheter. ATP concentrations were measured using a luciferin-luciferase assay. Bradykinin (1 and 100 nM) caused a progressive acceleration of LV relaxation together with a transient increase in coronary flow. These effects were inhibited by the nonselective P(2) purinoceptor antagonist suramin (1 microM, n = 6) but were unaffected by the selective P(2x) purinoceptor antagonist pyridoxal phosphate 6-azophenyl-2',4'-disulfonic acid (1 microM, n = 6). These myocardial and vascular effects of bradykinin were associated with increased ATP levels in coronary effluent. These data suggest that the selective enhancement of LV relaxation and rise in coronary flow induced by exogenous bradykinin involve endogenous ATP and the subsequent stimulation of P(2) purinoceptors.

Nitric oxide enhances the inotropic response to beta-adrenergic stimulation in the isolated guinea-pig heart.

Nitric oxide (NO) exerts several effects on myocardial contraction, including enhancement of relaxation and diastolic function, modulation of beta-adrenergic inotropic responses, and inotropic effects in the absence of agonist pre-stimulation. Different effects have been observed in different species and preparations, and it is unclear whether they are species- or preparation-specific, or whether they represent a range of responses that can manifest in most mammalian species. We therefore examined the effects of NO on the inotropic response to beta-adrenergic stimulation in the isolated guinea-pig heart, a species in which we have previously shown that NO enhances basal left ventricular (LV) relaxation and modulates the Frank-Starling response. Isolated ejecting hearts were perfused with Krebs buffer at constant placed heart rate (1 microM) indomethacin, 37 degrees C, constant loading conditions), and high fidelity LV pressure was monitored by an apical 2 F Millar catheter. All hearts were initially treated with dobutamine (0.1 microM) and then, once the peak inotropic and chronotropic response had been established, with either (a) no further treatment (n = 6), (b) the NO donor sodium nitroprusside (1 microM, n = 6; 10 microM, n = 6), or (c) the specific agonist for NO release, substance P (0.1 microM, n = 6). Dobutamine (0.1 microM) produced a rapid positive inotropic and chronotropic response, associated with a fall in LV end-diastolic pressure (LVEDP) and a rise in coronary flow. The positive inotropic effect of dobutamine declined over 20-28 minutes, while the chronotropic response persisted over this period. Low dose sodium nitroprusside (1 microM) delayed the decline in the inotropic response to dobutamine and exaggerated the fall in LVEDP. Similar effects were observed with substance P (0.1 microM). In contrast, a higher dose of sodium nitroprusside (10 microM) did not alter the response to dobutamine. These data indicate that "low dose" NO augments the inotropic response to beta-adrenergic stimulation in the isolated ejecting guinea-pig heart, in addition to its previously reported effects on basal LV relaxation in the same preparation.

Hypoxia-induced coronary flow changes in the perfused rat heart: Effects of high L-carnitine concentrations

1. 1. Hemodynamic effects of physiological (0.04 and 0.07 mM) and high (8, 15 and 25 mM) L-carnitine (LC) concentrations were tested on the normally oxygenated and hypoxic perfused rat heart. 2. 2. No effect was detected on aerobic hearts, whereas a dose-dependent rise in coronary flow (CF) during both the hyperemic and constrictive phases was observed in hypoxic hearts with 8, 15 and 25 mM LC. This action was apparently unrelated to a resting tension (RT) improvement, which was observed only with 25 mM LC. 3. 3. When 11 mM glucose was replaced by 11 mM mannitol in the perfusion buffer, LC effects on the hyperemic phase were abolished; however, 25 mM LC resulted in CF-values still significantly higher than those detected without the drug, though RT was similar in these glucose-free groups. 4. 4. It may be concluded that LC is ineffective on the perfused rat heart in aerobic conditions, whereas high LC concentrations can enhance CF only during hypoxia, these effects being independent of heart function improvements and partly unrelated to glucose presence.

Control of cardiac energy turnover by cytoplasmic phosphates: 31P-NMR study

Energy flux, estimated from the cardiac work index (pressure-rate product) and the rate of oxygen consumption, was varied in different ways; and the free concentrations of cytosolic phosphates were detected by the 31P-nuclear magnetic resonance method. A reversible decrease in phosphocreatine (PCr) and concomitant increase in [ADP] at nearly constant Pi were induced by 2-deoxyglucose (2-DG) treatment and its subsequent washout and were followed by a reversible suppression of pressure-rate product and elevation of end-diastolic pressure. 2-DG treatment also resulted in an irreversible and severe reduction of the cytosolic adenine nucleotide pool (to approximately one-third of control value) that did not recover during 2-DG washout. Reduction of the energy turnover rate, either by suppression of the PCr shuttle with iodoacetamide or by inhibition of the respiratory chain with amytal, was associated with a drop of PCr level, an elevation of both [ADP] and [Pi], and a rise of end-diastolic pressure. In contrast, a decrease in energy flux by reduction of perfusate Ca2+ led to a PCr rise and a fall in [ADP] and [Pi]. Most of these experimental groups were exposed to two types of loads, isoproterenol stimulation and coronary flow (CF) elevation. Iodoacetamide-treated hearts showed a poor mechanical response to both types of loads compared with other groups. The metabolic response to isoproterenol was uniform in all groups and was associated with some decrease in PCr and increase of [ADP] and [Pi], implying limitations in the respiratory chain. In contrast, activation of energy flux by a CF rise in control and amytal-inhibited hearts did not affect the concentrations of PCr, ADP, and Pi. Thus cytosolic phosphates can serve as a feedback signal for energy production and utilization when the single control point is located in oxidative phosphorylation pathway or contractile system. If control of energy metabolism is equally distributed among producing and utilizing systems (CF variation), other regulatory mechanisms seem to be involved, e.g., cytosolic [Ca2+]. contraction-relaxation; creatine kinase; cytosolic phosphates; isolated rat heart; oxygen consumption

Acute antiischaemic properties of high dosages of intravenous diltiazem in humans in relation to its coronary and systemic haemodynamic effects.

The antiischaemic properties of intravenous diltiazem in recommended therapeutic doses are disputed. In 17 patients with coronary artery disease the systemic and coronary haemodynamic effects of diltiazem were assessed during a high-dose infusion (0.4 mg kg-1 per 5 min, followed by 0.4 mg kg-1 per 10 min). In addition, its potential antiischaemic properties were investigated during identical pacing stress tests, 30 minutes before (P1) and immediately after diltiazem administration (P2). Diltiazem reduced left ventricular systolic pressure from 133 +/- 5 to 116 +/- 5 mmHg (P less than 0.005, means +/- SEM), persisting until after P2. It decreased systemic and coronary resistance by 32% (P less than 0.001) and 29% (P less than 0.005), respectively, with a sustained increase in cardiac output from 5.9 +/- 0.4 to 7.3 +/- 0.6 l min-1 (P less than 0.01), but a brief 20% rise in coronary flow (P less than 0.05), after the bolus infusion only. Heart rate, contractility, left ventricular filling pressure and myocardial O2 consumption remained unchanged. Despite high plasma levels (673 +/- 81 micrograms l-1) diltiazem was well tolerated. During identical maximal pacing rates diltiazem considerably reduced myocardial O2 demand (double product: 16.3 +/- 0.8 (P2) vs 21.1 +/- 1.1 (P1), P less than 0.005), due to an 18% decrease in left ventricular systolic pressure, resulting in diminished coronary flow and myocardial O2 consumption during P2 (14% and 15%, respectively, P less than 0.05 vs P1). Diltiazem also significantly reduced pacing-induced ischaemia, indicated by normalization of myocardial lactate extraction (1 +/- 8% (P2) vs -41 +/- 12% (P1), P less than 0.05), and left ventricular filling pressure (13 +/- 2 (P2) vs 27 +/- 3 mmHg (P1), P less than 0.01), less ST-segment depression (0.12 +/- 0.01 (P2) vs 0.24 +/- 0.02 mV (P1), P less than 0.01) and improved contractility (Vmax 59 +/- 5 (P2) vs 48 +/- 3 s-1 (P1), P less than 0.05). Angina was absent or less in 15 patients during pacing after diltiazem. Thus, diltiazem, in high dosages, induces continuing systemic but short lasting coronary vasodilation, improves pump function without negative chronotropic and inotropic effects and has pronounced antiischaemic properties, predominantly due to diminished myocardial O2 demand.

Calcitonin gene-related peptide: a potent modulator of coronary flow

Calcitonin gene-related peptide (CGRP) has been identified in nerve fibers innervating cardiovascular elements and particularly in coronary arteries (CA). To investigate its potential role in modulating coronary blood flow, we injected rat-CGRP into the CA of pentobarbital anesthetized, open chest pigs. Significant dose-related increments in coronary flow were observed. The rise in coronary flow was characterized by unusually, slow onset, late peak and prolonged duration. Arterial pressure, heart rate (HR) and myocardial contractility were unchanged, except at the highest dose (3.0 nmol), which produced mild systemic hypotension and sinus tachycardia. Coronary levels of catecholamines and 6-keto-PGF 1α were uncharged by CGRP. The direct, sustained, and potent dilatory activity of CGRP, in coronary arteries of the pig together with anatomical CGRP localization in this site suggest a role for this neuropeptide in hemodynamic regulation.

Unique coronary vasodilator induction by leukotriene D4.

Coronary blood flow (CBF) and myocardial contractility decrease markedly in response to intracoronary administration of leukotriene D4 (LTD4). With steady infusion, however, both CBF and contractility escape, approaching preinfusion values despite ongoing LTD4 administration. To clarify the mechanism of this escape, we reinfused plasma from the coronary vein draining the myocardial area receiving LTD4. Introducing this plasma into a coronary artery caused a marked rise in coronary flow for the duration of the plasma infusion. Coronary flow reduction with vasopressin or mechanical occlusion matching that caused by LTD4 failed to elicit vasodilator production. Thus a unique coronary vasodilator factor is induced by LTD4. Whole blood or platelet-rich plasma incubated with LTD4 in vitro produced the same pattern of coronary dilation on intracoronary infusion; LTD4 incubation with platelet-poor plasma failed to elicit a vasodilation. The vasodilator factor is stable and is not potassium, a prostaglandin, catecholamine, histamine, serotonin, adenosine, adenosine diphosphate, or platelet-activating factor. Production of this leukotriene-induced vasodilator factor may account for the escape from LTD4-induced coronary constriction.

The effect of calcium on cardiac anaphylaxis in guinea-pig Langendorff heart preparations

This study was designed to determine the effects of different calcium concentrations on the perfused isolated guinea-pig heart preparation subjected to cardiac anaphylaxis. Following challenge both physiological and biochemical effects were determined on hearts from guinea-pigs previously sensitized to ovalbumin. Perfusion media containing either 1,2.54 or 5 mM of calcium was used. In comparison to nonsensitized controls challenged to ovalbumin, challenged sensitized hearts (CSH) perfused with 1 mM Ca2+ showed an initial increase in dF/dt, a prolonged rise in H.R. and depressed coronary flow. Raising the calcium concentration to either 2.54 or 5 mM in CSH preparations resulted in a marked increase in the release of lactate dehydrogenase (LDH) into the coronary effluent and depressed coronary flow. Perfusing CSH preparations with increasingly higher calcium concentrations more often produced severe tachyarrhythmias and fibrillation. The highest level of histamine released into the coronary effluent occurred immediately following challenge and then declined exponentially over the next 20 min. Both challenge and the administration of histamine induced an immediate but transient increase in H.R., a rise in dF/dt, and LDH release. The infusion of histamine produced an increase in coronary flow, but on porcine tubular coronary arterial segments only a direct constricting effect was obtained. The prior administration of cimetidine (10(-5) M) attenuated the rise in LDH and dF/dt in CSH and nonsensitized preparations infused with histamine (3 micrograms). However, although cimetidine did not affect the decreased coronary flow in CSH preparations, it initially attenuated the rise in coronary flow in preparations infused with histamine. These results suggest that calcium enhances the likelihood of tachyarrhythmias in cardiac anaphylaxis. The release of LDH in histamine-infused preparations and those CSH preparations perfused with 2.54 and 5 mM calcium-containing media also suggests the possibility that calcium enhances the damaging effects on the myocardial cell in cardiac anaphylaxis.

Coronary hemodynamics following intravenous or intracoronary injection of diltiazem in man.

We measured coronary sinus blood flow by continuous thermodilution technique and aortic pressure after administration of diltiazem to 23 patients with coronary artery disease. In one group of patients (n = 12) the drug was infused at a rate of 0.15 mg/kg during 2 min followed by an infusion of 0.05 mg/kg during 8 min. Heart rate was unchanged except at 5 min when it decreased slightly. Aortic pressure was significantly (p less than 0.01) decreased, while coronary sinus flow increased slightly and transiently. A second group of patients (n = 5) received an intracoronary injection of 0.15 mg/kg of diltiazem into the left coronary artery. In a third group of patients (n = 7) 0.05 mg/kg of diltiazem was injected into the left coronary artery. In both these two groups the drug induced a marked increase of coronary sinus flow and a decrease of aortic pressure, while myocardial oxygen consumption was unchanged. This effect was dose related, since the rise in coronary flow was 47% with an injection of 0.15 mg/kg but only 23% with a dose of 0.05 mg-kg. These changes were short-lasting with values returning to normal within 10 min after the injection. We conclude that diltiazem is a potent dilator of coronary arteries.

Role of mitochondrial oxidative phosphorylation in regulation of coronary blood flow.

Regulation of coronary blood flow was studied in isolated rat hearts perfused under various metabolic conditions. Alterations in coronary flow were induced by hypoxia, amobarbital (Amytal) infusion, increase in work load of the heart, and adenosine infusion. Hypoxia induced, on the average, a 92.5% rise in coronary flow; 0.88 mM Amytal, a 85.7% increase; 12 microM adenosine, a 49.5% rise; and increased work load (elevation of the perfusion pressure from 6.9 kPa to 12.8 kPa), a 53.4% increase. In normoxia, adenosine, inosine, and hypoxanthine were present in the effluent in very low concentrations, and these greatly increased in response to hypoxia. In contrast, increased coronary flow caused by Amytal infusion or by elevated perfusion pressure was not accompanied by elevation in the effluent concentration of adenosine and its catabolites. Infusion of Amytal was followed by decrease in oxygen consumption of the heart and increase in oxygen tension in the effluent. This indicates that tissue oxygen tension per se can not be responsible for the regulation of coronary blood flow. Analysis of the data showed that under conditions in which there was a decrease in the tissue [ATP]free/[ADP]free[Pi] an increase in coronary flow was observed irrespective of the nature of the vasodilatory stimulus. It is concluded that mitochondrial oxidative phosphorylation provides a link between tissue oxygen metabolism and coronary blood flow. Mechanisms are discussed whereby changes in the cellular energy state ([ATP]free/[ADP]free[Pi]) are coupled to vasodilation, including possible direct effects on the vascular smooth muscle and/or generation of "second messengers."

Effect of atrial fibrillation on coronary circulation and blood flow distribution across the left ventricular wall in anesthetized open-chest dogs.

Effects of atrial fibrillation on coronary circulation and on blood flow distribution across the left ventricular wall were studied in anesthetized open-chest dogs. Atrial fibrillation was induced by pressing down mechanically the left atrial appendage or by stimulating electrically the left atrial appendage. Heated cross-thermocouples were used for measuring regional myocardial blood flow. The results showed a marked decrease in coronary blood flow with a significant increase in coronary vascular resistance; average values (SD) of flow and resistance during control simus rhythm were 71.6 +/- 7.36 ml/min . 100g heart muscle and 1.38 +/- 0.15 mmHg/ml/min . 100g heart muscle, respectively, and 54.0 +/- 13.60 ml/min . 100g and 1.54 +/- 0.18 mmHg/ml/min . 100gjust prior to cessation of atrial fibrillation. The termination of fibrillation caused a remarkable rise in coronary flow and a fall in coronary resistance. Pacing-induced tachycardia, similar to the average ventricular rate during atrial fibrillation, increased coronary blood flow and decreased coronary vascular resistance. These show that active coronary vasodilatation and an increase in extravascular support of coronary bed are produced by atrial fibrillation. Subendocardial myocardial blood flow during atrial fibrillation was reduced 22.0 +/- 14.8% from control levels followed by marked increase in flow after cessation of fibrillation, while subepicardial flow decreased only slightly. Thus, atrial fibrillation itself diminishes coronary flow reserve, especially in the subendocardial layer, partly due to the increase in myocardial component of coronary vascular resistance, and it is possible that irregular ventricular rhythm may play an important part in a rise in extravascular support.

Myocardial glucose uptake and breakdown during adenosine-induced vasodilation.

In isolated K+ (16.2 mM)-arrested cat hearts perfused at constant pressure adenosine infusions (0.8 mumoles - min-1 - 100 g-1 for 10 min) caused an increase in myocardial 14C-glucose uptake and release of 14CO2 + H14CO3- AND 14C-lactate simultaneously with a rise in coronary flow. The ratio of the release of 14CO2 + H14CO3- to that of 14C-lactate and the specific activity of lactate in the effuate were not altered. In K+ -arrested hearts perfused with constant volume neither glucose uptake nor glucose breakdown were influenced by 0.8 or 100 mumoles - min-1 - 100 g-1 adenosine with 0.1 - 5 mM glucose in the perfusion medium. It is concluded that adenosine does not affect directly the myocardial glucose carrier system, aerobic or anaerobic glucose breakdown or glycogenolysis, but enhances glucose uptake secondarily by increasing coronary flow. This interpretation is substantiated by the finding that mechanically produced increases in perfusion volume caused similar increases in myocardial glucose uptake as were observed with comparable adenosine-induced coronary flow increments.

Effect of nitroglycerin and papaverine on coronary flow in man

Blood flow has been measured in 28 aortocoronary saphenous vein bypass grafts performed for chronic angina pectoris using the electromagnetic flowmeter. Nitroglycerin, 0.4 mg. intravenously or 0.1 mg. into the graft, and papaverine 30 mg. intravenously or 15 mg. into the graft, were studied. Intravenous nitroglycerin increased coronary flow a maximum of 4 per cent for 20 seconds followed by 23 per cent decline as mean arterial pressure fell 23 per cent. Intra-arterial nitroglycerin increased coronary flow 74 per cent in 15 seconds with return to control by 90 seconds. Intravenous papaverine elevated coronary flow 76 per cent at 30 seconds with stabilization of flow 15 to 20 per cent above control. Intra-arterial papaverine achieves a maximum flow of 215 per cent at 45 seconds with return to control at five minutes. Although nitroglycerin produces a small but significant rise in coronary flow it is doubtful whether this increase occurs with oral administration in the presence of coronary disease. Thus, the therapeutic effect of nitroglycerin lies in its systemic effects rather than in its coronary effect.

Effect of excitement on coronary and systemic energetics in unanesthetized dogs.

The effect of excitement on phasic aortic pressure and flow, phasic left coronary flow, and myocardial metabolism has been studied in dogs 1–8 weeks after implantation of appropriate flowmeters and other devices. The rapid increase in heart rate and mild increase in blood pressure in the first few seconds tend to maintain coronary flow per minute despite a decrease in stroke cardiac output and coronary flow throughout the cardiac cycle. The main response is a delayed rise in coronary flow per minute resulting from further elevation of heart rate and blood pressure, a moderate increase in stroke cardiac output and a sizeable increase in stroke coronary flow, the latter being divided fairly evenly between systole and diastole. From 60 to 90% of the increase in mean coronary flow arises from the increase in stroke coronary flow, and the remainder from the increased number of heartbeats per minute. Some of the possible mechanisms concerned are discussed.

EFFECTS OF NOREPINEPHRINE ON THE CORONARY CIRCULATION IN MAN.

The effect of norepinephrine infusion on the coronary circulation has been studied in 21 subjects. In doses ranging from 2 to 17 µg. base per minute norepinephrine caused a pari passu rise in perfusing pressure and coronary flow of 16 per cent above the control state. Despite an increase in cardiac oxygen consumption, coronary vascular resistance was unchanged, suggesting no vasodilatation in the coronary bed. On the contrary, oxygen extraction across the heart increased, implying that oxygen needs were inadequately met by rise in flow. An increase in vascular tone induced by norepinephrine is inferred from the unchanged coronary resistance at a higher perfusion pressure. Responses of the normal and failing left ventricle groups were qualitatively the same as for the group as a whole. The failure group showed greater tendency to meet oxygen needs by increased extraction than did the normal hearts. Although these observations are not strictly applicable to the role and effects of norepinephrine in states of clinical shock, nonetheless it seems likely that norepinephrine induces a suboptimal rise in coronary flow that may set the stage for ultimate myocardial ischemia, particularly when coronary perfusion pressure is inadequate.

Effects of heart rate on coronary flow and cardiac oxygen consumption.

The effects of electrically-induced heart rate (up to 300 beats/min.) on coronary flow and cardiac oxygen consumption has been studied in an open-chested intact preparation. A significant correlation between heart rate, coronary flow and cardiac oxygen consumption has been found at each level of cardiac work. Coronary flow and cardiac oxygen consumption increase with a rise in heart rate and seem to approach a limit at extremely rapid heart rates. Nomograms relating heart rate, work and oxygen consumption of the heart have been constructed. From these it is seen that heart rate is an important factor in determining the myocardial oxygen consumption; this is true at each level of cardiac work. The significance of these findings have been discussed relative to the unanesthetized animal. Under conditions of excessive heart rate or cardiac load which presumably lead to unusually high energy requirements, a radical departure from the expected ‘normal’ values was found in coronary flow, coronary A-V oxygen difference and cardiac oxygen consumption. This confirms the presence of ‘spontaneous’ change previously described by us. Its meaning and significance is discussed. Under these conditions of ‘spontaneous’ change coronary flow was increased, oxygen consumption decreased and coronary venous oxygen was raised as the coronary A-V oxygen difference declined. This ‘spontaneous’ change shifted the relationship of coronary flow to oxygen consumption. Furthermore, it led to a rise in coronary flow despite an elevation in coronary venous oxygen. It would seem that at this time the energy metabolism of the heart must change in that less oxygen is extracted from the blood despite an increase in its availability. The heart may therefore operate anaerobically in part or may make use of other hydrogen acceptors in the blood. The fact that this kind of metabolism may last as long as an hour or more, excludes the ordinary type of ‘oxygen debt.’