Intracoronary Infusion Of Adenosine Research Articles

Effect of coronary sinus occlusion on coronary flow, resistance, and zero flow pressure during maximum vasodilatation in swine.

The effects of coronary sinus occlusion on the relation between coronary artery pressure and flow during maximum vasodilatation were studied in seven swine. The left anterior descending (LAD) coronary artery was instrumented with two catheters, a hydraulic occluder, and a flowprobe. Mean flow was measured at a series of pressures produced by partial LAD occlusion during maximum vasodilatation induced by an intracoronary infusion of adenosine. Observations were made under control conditions and during occlusion of the coronary sinus produced by inflating the balloon on the catheter positioned in the coronary sinus. Systemic haemodynamic variables did not change significantly after the coronary sinus was occluded. The mean right atrial pressure was 4 mmHg. At any given LAD perfusion pressure mean flow during coronary sinus occlusion was always less than during the control state: at LAD pressure 30 mmHg, control flow was 53 ml.min-1 vs occluded flow 24 ml.min-1; at LAD pressure 40 mmHg, control flow 79 ml.min-1 vs occluded flow 49 ml.min-1; and at LAD pressure 50 mmHg, control flow 105 ml.min-1 vs occluded flow 74 ml.min-1; p less than 0.001 for all comparisons. The mean (SD) LAD pressure at which flow stopped (Pzf) when the coronary sinus was unobstructed was 10(2) mmHg. The Pzf during occlusion of the coronary sinus was significantly higher at 20(4) mmHg (p less than 0.001). The slopes of the mean pressure-flow relations were not significantly different during the control state (2.62(0.65) ml.min-1 per mmHg) vs the occluded state (2.47(0.63) ml.min-1 per mmHg), indicating no change in vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic modulation of cardiac neurosympathetic activity in vivo: effects of potassium and adenosine.

The effects of intracoronary (LAD) infusion of potassium and adenosine on changes in coronary vascular resistance and regional cardiac noradrenaline overflow during graded cardiac sympathetic stimulation were assessed in non-ischaemic myocardium in the open chest anaesthetised dog. Intracoronary potassium at three concentration (10, 25, 75 mmol.litre-1) progressively increased the potassium content of local venous effluent from 3.6 to 9.4 mmol.litre-1 and produced biphasic effects on nerve stimulated regional noradrenaline overflow. At low dose it was inhibitory (peak overflow at 20 Hz stimulation being reduced from (mean(SEM)) 10.2(2.6) to 2.9(1.8) pmol.ml-1 with 10 mmol.litre-1 potassium chloride; p less than 0.01). At high dose, overflow was potentiated to 13.3(2.7) pmol.ml-1 with 75 mmol.litre-1 potassium chloride (p less than 0.05). Noradrenaline overflow from and the potassium content of circumflex territory venous effluent was unchanged. Intracoronary adenosine at high concentration (10(-3) and 10(-2) mol.litre-1) potentiated basal noradrenaline overflow from the heart producing a small negative arteriovenous concentration difference of 0.6(0.7) and 1.0(0.6) pmol.ml-1 respectively. However, noradrenaline overflow during maximal sympathetic stimulation was inhibited from 3.8(1.4) to 0.4(0.7) pmol.ml-1 with 10(-3) mol.litre-1 adenosine and to 0.7(0.6) pmol.ml-1 with 10(-2) mol.litre-1 adenosine (p less than 0.05). The changes in blood flow and coronary vascular resistance seen with sympathetic stimulation were not modified by adenosine, despite major alteration in basal coronary vascular tone. Thus both metabolites may potentially alter local neurosympathetic activity in ischaemic myocardium and act diversely to determine noradrenaline release at the nerve terminal.

Cardiac alpha-1 adrenoceptors are not involved in heart rate control of the anaesthetized dog.

To study the possible role of cardiac postsynaptic alpha-1 adrenoceptors in heart rate control of the anaesthetized open-chest dog we injected a specific alpha-1 agonist (amidephrine) into the right coronary artery or stimulated electrically the right stellate ganglion. Reflex influences were minimized by bilateral cervical vagotomy and de-afferentiation of both stellate ganglia. Activation of alpha-2, beta- and muscarinic receptors was prevented by intravenous administration of yohimbine, propranolol and atropine, respectively. Since alpha-1 receptor stimulation could affect heart rate indirectly via coronary constriction, a continuous intracoronary infusion of adenosine (0.25 mg/kg/h) was given. Amidephrine did not affect heart rate at the lower dose (1-10 microgram). After the highest dose (100 micrograms) the maximum variation in heart rate was an increase of 2.2 +/- 1.1 bpm at 3 min after injection (mean +/- SEM; P less than 0.05). This slight cardioacceleration was simultaneous with an aortic pressure rise of 13.8 +/- 3.4 mm Hg and it was abolished by alpha-1 blockade with prazosin (1 mg/kg i.v.). After propranolol (1 mg/kg +0.5 mg/kg/h) the residual positive chronotropic effect of sympathetic stimulation (12.2 +/- 4.0 bpm) was not significantly altered (13.8 +/- 5.7 bpm) by prazosin administration. Similar results were recorded without adenosine infusion. We conclude that in the anaesthetized dog chronotropic effects directly mediated by alpha-1 adrenoceptors either do not exist or lack physiological significance.

Autonomie control of ventricular tachycardia. III. Effects of adenosine and N6-R-1-phenyl-2-propyladenosine

The purpose of this study was to determine whether adenosine or the adenosine deaminase-resistant analogue, N6-R-1-phenyl-2-propyladenosine (RPIA), could slow the rate of spontaneous ventricular tachycardia occurring 24 hours after left anterior descending coronary artery occlusion. Chloralose-anesthetized, open chest dogs (n = 25) with ventricular tachycardia were studied. The left anterior descending artery was cannulated distally. Intracoronary infusions of adenosine, 10(-7) to 10(-5) M, did not alter the rate of ventricular tachycardia. Ventricular tachycardia slowed by 4.6% with adenosine, 10(-4) M. RPIA, 10(-6) to 10(-4) M, produced a concentration-dependent decrease in the rate of ventricular tachycardia when injected into the left anterior descending coronary artery. This effect of RPIA was reversed by the adenosine antagonist aminophylline, 10(-5) M. After bilateral stellate ganglionectomy, RPIA, 10(-5) M, did not, but metoprolol, 0.5 mg, did slow ventricular tachycardia after intracoronary injection. However, RPIA, 10(-5) M, produced a 43% decrease in the increment in ventricular tachycardia occurring during sympathetic neural stimulation. Therefore, when injected into the left anterior descending artery, adenosine, 10(-4) M, and RPIA, 10(-6) to 10(-4) M, decrease the rate of ventricular tachycardia in 24 hour old myocardial infarction. Furthermore, this decrease in the rate of ventricular tachycardia is the result of prejunctional sympathetic antagonism.

Release of adenosine and cyclic AMP from coronary endothelium in isolated guinea pig hearts: relation to coronary flow.

The coronary efflux of radioactive 3',5'-cyclic adenosine monophosphate (cAMP) and adenosine from isolated guinea pig hearts was measured following selective prelabelling of coronary endothelial adenine nucleotides with 10 nM [2,8,5'-3H] adenosine. Intracoronary infusion of adenosine and its derivatives 5'-N-ethyl-carboxamide-adenosine (NECA), (-)-N6-(R-phenyl-isopropyl)-adenosine (R-PIA), and (+)-N6-(S-phenyl-isopropyl)-adenosine (S-PIA) caused dose-dependent parallel increases in both coronary flow and the coronary efflux of radioactive cAMP with a rank order of potency: NECA greater than R-PIA greater than adenosine greater than S-PIA. In contrast, adenosine receptor stimulation of isolated cardiomyocytes in primary culture decreased the cellular release of cAMP below control levels with a rank order of potency: R-PIA greater than NECA. Under control conditions, coronary efflux of adenosine and cAMP was 34.3 +/- 2.3 and 3.9 +/- 0.8 pmol/min (mean +/- SEM, n = 6), respectively. NECA (12 microM) caused an increase in cardiac cAMP release of 3.8 times and elevated the specific radioactivity of cAMP 5 times to 63.7 +/- 6.0 Ci/mol, a value 11 times greater than the specific radioactivity of tissue ATP. Based on these findings, it was concluded that the coronary endothelium possesses adenosine A2 receptors linked to adenylate cyclase, which are activated in parallel with increases in coronary flow and that cardiomyocyte adenosine receptors are predominantly of the A1 subtype. In addition, the contribution of the coronary endothelium to total cardiac adenosine release was calculated to be 14% using the specific radioactivities of adenosine and cAMP released into the effluent perfusate.

Absence of coronary vascular reserve in myocardium distal to a fixed coronary stenosis.

In a study to test the hypothesis that vascular reserve is exhausted in the setting of a resting blood flow deficit, the left anterior descending or circumflex artery was cannulated and perfused from the left carotid artery. After reactive hyperaemia had been assessed a stenosis was produced with a screw clamp. In the first experiment a moderate stenosis (diastolic perfusion pressure 40 mmHg) was produced in the left anterior descending artery (three dogs) or left circumflex artery (three dogs). Blood pressure was held constant with aortic constriction during intracoronary adenosine infusion (6 mumol.min-1). The stenosis was then adjusted to the preadenosine perfusion pressure. In the second experiment the anterior interventricular coronary vein was also isolated and segment length crystals were placed in the ischaemic and non-ischaemic zones. Severe stenosis (flow reduction of at least 50% and evidence of decreased segmental shortening) was produced in the cannulated left anterior descending artery (eight dogs). Intracoronary adenosine was given with aortic pressure held constant by transfusion and coronary venous drainage. In the first experiment resting coronary flow (ml.min-1) decreased from 41(3) to 29(6) (p less than 0.05) with stenosis. Coronary flow increased from 29(6) to 34(7) (p less than 0.05) with adenosine and to 50(10) (p less than 0.05) with stenosis adjustment. Subendocardial flow (ml.g-1.min-1) decreased from 0.89(0.26) to 0.78(0.23) (p less than 0.05) with adenosine and then increased from 0.94(0.49) with perfusion pressure adjustment. Subepicardial flow tended to increase with adenosine, and increased further with stenosis adjustment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine is unimportant in controlling coronary blood flow in unstressed dog hearts.

The adenosine hypothesis of local metabolic control of coronary blood flow was tested in the unstressed heart with adenosine deaminase, which converts adenosine to nonvasoactive inosine. If adenosine is normally an important physiological regulator, then adenosine deaminase should lower coronary blood flow. The left main coronary artery was perfused at constant pressure in anesthetized, closed-chest dogs. Adenosine deaminase was deposited in one region of the left ventricle by selective infusion into a branch of the left coronary artery. Coronary blood flow measured with radioactive microspheres was not lower in the region treated with adenosine deaminase than flow measured simultaneously in an untreated control region of the same heart. This finding is contrary to the prediction of the adenosine hypothesis. Coronary vasodilation elicited by intracoronary adenosine infusion was inhibited in the adenosine deaminase-treated region compared with the control region, indicating that adenosine deaminase lowered adenosine concentration at the vascular adenosine receptor. Inhibition of exogenous adenosine vasodilation was fully reversed by intracoronary infusion of a specific inhibitor of adenosine deaminase. Measurement of adenosine deaminase activity in cardiac lymph provided evidence that adenosine deaminase reached the myocardial interstitial space. These results demonstrate that introducing adenosine deaminase into the interstitial space of the unstressed heart did not lower coronary blood flow. This finding indicates that adenosine is normally below the vasoactive threshold and therefore is not important in mediating local metabolic control of blood flow in the unstressed heart.

EVIDENCE AGAINST THE ADENOSINE-CATECHOL AMINE ANTAGONISM IN THE IN SITU DOG HEART: 183

Adenosine has been reported to attenuate the positive inotropic effects of catecholamines in in vitro-heart preparations of rodents. These results were not confirmed in anesthetized dogs during intracoronary infusion of isoproterenol. However, these experiments did not study the effects of adenosine on the inotropic effects of endogenously released catecholamines. Therefore we performed cardiac sympathetic nerve stimulation (CSNS) in 5 anesthetized, vagotomized dogs. The left circumflex coronary artery was perfused at a constant pressure of 130±4 mmHg. The contractile function of the circumflex-perfused myocardium was analyzed by sonomicrometry. CSNS at 1, 2, 5, 10 and 20 Hz increased systolic segment shortening (SScx) in a frequency-dependent manner from 10.9±2.6 at control to 15.3±3.4 % at 20 Hz. During intracoronary infusion of adenosine (50 μg/ kg/min) CSNS still increased SSCX frequency-dependently from 9.9±3.5 to 16.3±4.5 %. The lack of any adenosine-catecholamine antagonism in our experiments was not due to the sequence of procedures, nor to the marked flow increase induced by adenosine, since SSCX at rest was rather reduced with adenosine infusion and since during intracoronary infusion of papaverine and sodium-nitroprusside similar results were obtained. It seems that the observation of adenosine-catecholamine antagonism in rodents is a species dependent phenomenon. Supported by SFB 30 - Kardiologie, Dusseldorf

Absence of capillary recruitment during increased coronary blood flow in the working dog heart.

Myocardial plasma flow (MPF) and capillary permeability--surface area product (PS) were determined simultaneously on a regional basis in subendocardial and subepicardial layers of the left ventricular free wall in the working dog heart at control flow rate and during coronary vasodilation. The value for MPF was determined by the radioactive microsphere method and PS was assessed by an integral tissue-uptake method using [51Cr]-EDTA as test molecule. During coronary vasodilation achieved by intra-coronary infusion of adenosine, MPF increased markedly from 101.5 +/- 14.2 to 778.1 +/- 135.2 ml X min-1 X 100 g-1 in subendocardial layers and from 77.7 +/- 10.3 to 635.3 +/- 85.9 ml X min-1 X 100 g-1 in subepicardial layers of the left ventricular wall. Raising MPF by 800% was accompanied by a modest but statistically significant increase in PS[51Cr]-EDTA. In subendocardial layers PS increased from 49.3 +/- 5.0 to 60.0 +/- 3.3 ml X min-1 X 100 g-1 and in subepicardial layers from 43.8 +/- 4.1 to 52.1 +/- 2.4 ml X min-1 X 100 g-1, respectively. Taking into account back-diffusion of the tracer from the tissue to capillary blood which was higher at low flows than at high flows, PS[51Cr]-EDTA showed no increase with an eight-fold increment in flow. This observation rebuts the concept of additional perfusion of capillaries which are devoid of plasma flow under resting conditions during coronary vasodilation.

Intracoronary adenosine enhances myocardial reactive hyperemia after brief coronary occlusion.

Adenosine is a prime candidate for the role of mediator between myocardial metabolic state and coronary blood flow. However, there are few reports concerning the direct effects of exogenously added adenosine on coronary autoregulation. The present investigation in the open-chest dog studied the effects of a threshold dose of intracoronary adenosine infusion on reactive hyperemia following brief coronary occlusions. The infused dose did not increase nonocclusive flow by greater than 10%. Adenosine enhanced total hyperemic flow at all occlusions tested (5, 10, 15, 20, and 30 s). Aminophylline pretreatment reduced reactive hyperemia below the control level even in the presence of an intracoronary infusion of adenosine. Adenosine injected into the left atrium and intracoronarily infused papaverine did not affect hyperemic response to 5- and 15-s coronary occlusions. The results suggest that a minimum dose of exogenously added adenosine enhances myocardial reactive hyperemia, possibly by potentiating the effects of endogenous adenosine released during ischemia.

The effects of cardiopulmonary bypass on coronary blood flow in the dog

The effects of cardiopulmonary bypass on autoregulation, maximum coronary flow, and regional blood flow in the heart were investigated in 25 dogs. A Gregg cannula was inserted into the left main coronary artery, and pressure-flow relations were then measured in the autoregulating state or with vasodilation produced by intracoronary adenosine infusion before, during, and after cardiopulmonary bypass. Seventeen of the dogs had radioactive microspheres injected to investigate regional blood flow changes at the same times. (1) Autoregulation was not present after bypass for at least 3 hours. (2) Blood flow was shifted toward the subendocardium on bypass (increased subendocardial/subepicardial ratio) and tended to return to prebypass distribution following bypass. (3) Blood flow after bypass was not significantly different to the subendocardium and subepicardium. (4) Response to a coronary vasodilator (maximum coronary flow) was significantly affected by cardiopulmonary bypass: blood flow to all layers of the heart could be increased with adenosine after bypass. (5) Global lactate and oxygen metabolism were not adversely affected by bypass. We conclude that cardiopulmonary bypass abolished the normal autoregulation of coronary flow; this may predispose the incompletely revascularized patient to a "coronary steal" syndrome. However, the heart with normal coronary arteries is not underperfused in any layer after bypass. Thus, the bypass technique is not the cause of the subendocardial ischemia that sometimes complicates cardiac operations.

Coronary transport reserve in normal dogs.

This study was designed to determine an acceptable method for producing maximal coronary vasodilation for quantifying coronary blood flow reserve and coronary capillary transport reserve. The anterior descending branch of the left coronary artery was cannulated and pump-perfused while aortic, central venous, and coronary perfusion pressures, heart rate, electrocardiogram, blood gases, and coronary blood flow (CBF) were continuously monitored. All parameters were measured at four to six points along the coronary pressure-flow autoregulation curve. Myocardial extraction and permeability-surface area products (PS) of 51Cr-ethylenediaminetetraacetic acid were determined with the single-injection indicator-diffusion method in intact working hearts of anesthetized dogs. Maximal vasodilations were produced with 2-min coronary occlusions and with intracoronary infusions of adenosine (ADO), dipyridamole, ADO + dipyridamole, papaverine, and ADO + alpha 1-receptor blockade. ADO was chosen to quantify coronary transport reserve because it produced maximal CBF's and PS's that were reproducible within and among animals and produced minimal effects on the cardiovascular system. Under base-line conditions, there was no relationship between PS and perfusion pressure. Base-line PS averaged 20 +/- 2 ml X min-1 X 100 g-1. Maximal vasodilation with constant CBF had no significant effect on PS. During maximal vasodilation, CBF and PS increased linearly with increasing perfusion pressure, and PS increased linearly with increasing plasma flow. Constant pressure maximal vasodilation with ADO caused PS to increase to 36 +/- 4 ml X min-1 X 100 g-1, and CBF was increased 380%.

Influence of adenosine on basal myocardial function: observations in anaesthetised, domestic swine.

Data from experiments in isolated cardiac muscle preparations indicate that adenosine in high concentration (10(-3) mol X litre-1) exerts a negative inotropic effect on the myocardium under basal conditions. The following study was performed to test the hypothesis that adenosine exerts a similar negative inotropic effect when administered in an intact animal model in a dose sufficient to cause maximal coronary vasodilatation. Six open chest anaesthetised pigs were studied as follows. Ultrasonic length sensors were placed in the endocardium of the free wall of the left ventricle in a region perfused by the left anterior descending (LAD) coronary artery. Large increases in endocardial blood flow in response to adenosine administration, which could enhance segmental function ("garden hose effect"), were prevented by inserting an artificial stenosis (73% reduction in lumenal diameter) in the proximal third of the LAD. Measurements of haemodynamics, regional myocardial blood flow (microsphere technique), and regional systolic function were made at control 1, at the end of 10 min of intracoronary adenosine infusion (3.0 mumol X min-1) at a dose which exceeded that previously shown to cause maximal coronary vasodilatation and at second control 20 to 40 min after discontinuation of adenosine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of coronary vasodilation on ventricular fibrillation threshold: Role of exogenous vasodilators and perfusion conditions

Even without myocardial ischemia, coronary blood flow (CBF) constitutes a major determinant of ventricular fibrillation threshold (VFT). To clarify whether abnormal distribution of normal or increased CBF plays any additional role, 14 open-chest chloralose-anesthetized dogs with fixednormalized heart rate, cardiac output, and systemic arterial pressure and separate servocontrolled left main coronary artery perfusion were studied as follows: VFT was determined first with coronary perfusion pressure (CPP) set at systemic level (80 mm Hg). Then CBF index was fixed at control levels (134.0 ± 9.5 ml/min · 100 gm −1 LV) and coronary vasodilation was induced by intracoronary infusion of adenosine until CPP decreased to 49.0 ± 2.0 mm Hg. Myocardial O 2 consumption, LV pressure, LV dp dt , and surface ECG remained unchanged. However, VFT decreased in all trials by about 45% ( p < 0.001). When CPP was reset to 80 mm Hg while maintaining vasodilation, CBF index increased by 90% to 255.4 ± 15.4 ml/min · 100 gm −1 LV and VFT by 26% ( p < 0.005) from control. Yet these VFT increases in response to intraluminal pharmacologic vasodilation were about 19% ( p < 0.002) lower than expected for similar CBF index increases occurring physiologically. We conclude that intraluminal coronary vasodilation not matched by appropriate CBF increase results in substantial decrease of VFT. Moreover, at comparable increase of CBF, spontaneous physiologic vasodilation is more effective than intraluminal pharmacologic coronary vasodilation in increasing VFT.

Time-dependent response of coronary flow to prolonged adenosine infusion: doubling of peak reactive hyperaemic flow.

In 11 anaesthetised, Open chest dogs the time course and degree of the coronary vasodilating response to intracoronary adenosine infusion was assessed. Continuous adenosine infusion, at a rate of 2.5 to 13.5 mumol . min-1, produced rapid (15 to 30s) vasodilation of the same degree as that evoked by a 30 s period of ischaemia (reactive peak hyperaemia), a finding reported previously by others. However, continuing the infusion led to further coronary vasodilation, reaching a maximum 20 to 45 min from the beginning of the infusion and remaining constant for up to 2 h, independently of further increases in the dose. This late response produced, on average, vasodilatation twice as great as that observed during reactive hyperaemia and was not associated with any haemodynamic change or with the opening of arterio-venous shunts. 1) suggest the existence of a double, time-dependent response of coronary receptor(s) to adenosine; 2) demonstrate, in the presence of a prolonged vasodilating stimulus, a possible increase in coronary blood flow to a degree far beyond that of post-ischaemic reactive peak flow, which is generally considered to be the maximal value of coronary blood flow that can be achieved.

Subepicardial steal and reduction of myocardial oxygen consumption by adenosine

The direct effects of adenosine on cardiac oxygen balance, hemodynamics and regional myocardial perfusion were studied in isolated canine hearts. Intracoronary infusion of adenosine produced a dose-dependent shift in the transmural distribution of coronary blood flow away from left ventricular subendocardium and a reduction in myocardial oxygen consymption (MVO 2). The data suggest that adenosine may partially decrease MVO 2 by a redistribution of flow from a high to low oxygen-extracting region of the myocardium.

Opposite transmural gradients of coronary resistance and extravascular pressure in the working dog's heart.

In order to investigate the factors determining flow to the subendocardium independently from functional adjustments of the resistance vessels, pressure-flow curves for the bypassed left circumflex coronary artery were obtained during maximal vasodilatation induced by intra-coronary adenosine infusion in eight anaesthetised mongrel dogs with systolic and diastolic left ventricular pressures of 14.5 ± 2.3 and 0.3 ± 0.2 kPa (109 ± 17 and 2 ± 1.4 mmHg) respectively. For each experiment three or four flow rates were selected in the linear portion of the pressure flow curve for the injection of 15 ± 5 (μm diameter labelled microspheres for the measurement of regional flow in the internal (ENDO) middle (MID) and external (EPI) one third of the perfused left ventricular wall. Linear pressure-flow relationships were obtained for each of the three layers of the left ventricle using the diastolic coronary perfusion pressure and regional flow rates. The slopes (P/F) of the ENDO were in each instance significantly lower than those of the EPI. The extrapolation of the regional pressure-flow curves to zero flow showed the highest value of pressure for the ENDO and the lowest for the EPI, suggesting a transmural gradient of extravascular pressure. The results of this study agree with a waterfall model of the coronary circulation, in which the extravascular pressure decreases from the ENDO to the EPI in contrast to the vascular resistance which decreases from the EPI to the ENDO. This model explains why the subendocardial layer receives an equal or greater blood flow than the subepicardium in normal haemodynamic conditions even in the absence of autoregulation and in spite of a higher extravascular pressure; it also explains why it becomes selectively ischaemic in the presence of a low perfusion pressure such as that produced by a coronary stenosis.

Coronary vasoactivity of adenosine in the conscious dog.

Intracoronary adenosine infusions in conscious dogs produced half-maximal coronary vasodilation at 0.57 +/- 0.18 (SD) microns and at 1.01 +/- 0.25 microns in open-chest dogs. In both preparations, adenosine at concentrations in the range found in cardiac muscle by direct analysis produced coronary vasodilation equal to that attained during a maximum reactive hyperemic response. The quantitative structure-activity relationship technique was applied to data on the coronary vasoactivity of 68 adenosine analogs to identify the chemical features of this molecule that determine its vasoactivity. These are: (1) the size of the purine base; (2) the inductive effect of C-2 substituent; (3) the electron-withdrawing effect of the C-6 substituent; (4) the glycosylic torsion angle; (5) the ability of the C-2' and C-3' hydroxyls to participate in hydrogen bonding; (7) the absence of sterically hindering groups in the vicinity of C-2' and, more importantly, C-3'; and (8) the inductive effect of the C-5' substituent. The hydrophobicity of these analogs did not correlate with vasoactivity, suggesting that the hydrophilicity of the ribose moiety overshadows any hydrophobic influence of the very weakly aromatic purine base.

Release of cyclic AMP from the dog heart induced by an intracoronary infusion of adenosine: J. Lammerant and T. Huynh Thu. Department of Physiology, Faculty of Medicine, Namur, Belgium

Release of cyclic AMP from the dog heart induced by an intracoronary infusion of adenosine: J. Lammerant and T. Huynh Thu. Department of Physiology, Faculty of Medicine, Namur, Belgium

Adenosine metabolism in canine myocardial reactive hyperemia.

In pentobrabital-anesthetized open chest dogs, myocardial adenosine content is elevated by 5 or 15 seconds of left coronary artery occlusion and falls exponentially to control levels during reactive hyperemia. The rate constants for adenosine dissipation are (mean +/- SEM): -0.08 +/- 0.01 and -0.034 +/- 0.007 sec-1 after 5- and 15-second occlusion, respectively. Kinetic analysis of the reactive hyperemia flow curves (Circ Res 14/15 (suppl I): 81-85, 1963) predicts rates of -0.069 +/- 0.009 sec-1 and -0.04 +/- 0.009 sec-1, indicating that changes in adenosine levels can account for the way coronary flow changes during this response. The log (dose-) response curve relating reactive hyperemia flow to tissue adenosine concentration has a steeper slope and is half-maximal at a lower adenosine concentration than the dose-response curve obtained by intracoronary infusions of adenosine in oxygenated hearts, indicating that the coronary vasoactivity of adenosine is enhanced during reactive hyperemia. This could explain why theophylline antagonizes the coronary vasocilatory effect of adenosine in oxygenated hearts but has relatively little effect on reactive hyperemia.