Edward M. Khouri

Effect of Exercise on Cardiac Output, Left Coronary Flow and Myocardial Metabolism in the Unanesthetized Dog

Cardiac output, left coronary artery flow, central aortic blood pressure and myocardial metabolism have been studied in the intact unanesthetized dog during exercise. Cardiac output and left coronary artery flow increase 350 to 400% during moderately severe exercise. The primary mechanical determinant of this increase appears to be cardio-acceleration; the stroke volume and stroke coronary flow contribution is relatively mild. Myocardial oxygen usage increases 300% or more with only a small elevation of the percentage of extraction of oxygen. The large increase of coronary flow in the dog and the significant elevation in hematocrit supply the extra oxygen.

Phasic right coronary artery blood flow in conscious dogs with normal and elevated right ventricular pressures.

We studied phasic right coronary blood flow in well trained normal dogs and dogs with pulmonic stenosis. We installed electromagnetic flow transducers and pressure tubes under anesthesia to monitor right coronary blood flow, cardiac output, central aortic blood pressure, and right ventricular pressure. In norraotensive dogs, systolic flow amplitude equaled early diastolic flow levels. The ratio of systolic to diastolic flow at rest was substantially greater in the right coronary bed (36 ± 1.3%) than in tbe left circumflex bed (13 ± 3.6%). Right diastolic flow runoff, including the cove late in diastole, resembled left circumflex runoff. Blood flow to the normotensive right (37 ± 1.1 ml/min 100-1 g) and the left (35 ± 1.0 ml/mln-1 g) ventricular myocardium indicated equal perfusion of both cardiac walls. Throttling of systolic flow was related directly to the right ventricular systolic pressure level in the dogs with pulmonic stenosis. Retrograde systolic flow occurred in severe right ventricular hypertension. The late diastolic runoff pattern in dogs with pulmonic stenosis appeared the same as for the normotensive dogs. We obtained systolic to diastolic flow ratios of 1/3 the value of normotensive hearts in high and severe pulmonic hypertension. Electrocardiograms and studies of pathology suggested restricted blood flow to the inner layers of the right myocardium in the dogs with severe and high right ventricular hypertension. Normotensive and hypertensive peak hyperemic flow responses were similar, except for an increased magnitude of diastolic flow, with proportionately less systolic flow in hypertensive states.

Evidence for an adenosine receptor on the surface of dog coronary myocytes.

Adenosine and theophylline were linked covalently to oxidized stachyose to produce compounds too large to penetrate cell membranes. These compounds were used in two conscious and six open-chest anesthetized dogs to test the hypothesis that there is an adenosine receptor on the surface of the coronary myocyte. Intracoronary infusions of the adenosine derivative produced dose-dependent coronary vasodilation which was antagonized by theophylline; two types of theophylline derivative antagonized the coronary vasodilator) action of adenosine. Although these results show that both adenosine and theophylline exert their coronary effects at the surface of the smooth muscle cell, this evidence does not establish that they are competing for a common receptor.

Systemic and Coronary Energetics in the Resting Unanesthetized Dog

This report is an initial attempt to study the coronary circulation in the chronic unanesthetized dog. A standardized preparation has been developed in which phasic aortic pressure and flow, phasic left coronary inflow, and myocardial metabolism have been studied for many weeks in the unanesthetized dog under resting conditions. The flow patterns in the main left coronary artery and in its major branches are very similar. In the resting dog, the left coronary inflow during systole is 7 to 45% of that during diastole. We believe that much of this flow into the epicardial arteries penetrates into the myocardium. Stroke coronary flow can change considerably without significant alterations of blood pressure and heart rate. Despite this, the coronary flow values (37 to 58 cc) and oxygen usage values (4.4 cc to 8.6 cc) per 100 grams left ventricle per minute are low. Since, however, these measurements can vary considerably not only in different dogs but also in the same dog on the same day, and from day to day, it is suggested that these animals were in a semiresting state and probably not in a basal state.

Flow in the Major Branches of the Left Coronary Artery during Experimental Coronary Insufficiency in the Unanesthetized Dog

The dynamic changes in the coronary circulation and the response to drugs were studied following experimentally induced coronary insufficiency. Flow measurements were made in the left circumflex and descending branches of the coronary artery, and in the ascending aorta; pressures were measured in the ascending aorta and the left ventricle. As the left circumflex coronary artery branch was gradually constricted, reactive hyperemia following a 10-second occlusion of that vessel decreased. When the Degrees of constriction became such that the control resting flow began to fall, there was no reactive hyperemia, and the contractility index of the heart decreased. Within less than 24 hours, flow in the descending branch of the left coronary artery rose, and the cardiac contractility index returned to control; peak flow rate in the descending branch during reactive hyperemia after a 10-second occlusion also increased. The response to isoproterenol, nitroglycerin, and dipyridamole was similar in direction before and after the partial reduction of flow in the left circumflex coronary artery branch. The response was less in the coronary vessel with partial occlusion; in the unimpeded descending coronary artery branch, the response increased progressively. These results are consistent with the development of collateral vessels.

Coronary Circulation in the Conscious Dog with Cardiac Neural Ablation

The left coronary circulation at rest and during its response to natural stresses was studied in five conscious dogs whose hearts had been externally denervated (stripping technique). The values were compared to those obtained under similar conditions in normal dogs of comparable weight and training. A high degree of hyperemia after temporary circumflex occlusion and a coronary flow pattern with a dominant diastolic component under the different conditions were similar to that of the normal dog. At rest, circumflex flow and myocardial oxygen use were only about half the values obtained in the normal dog. In moderate exercise, the rise of circumflex flow was delayed 10−30 seconds, being always preceded by an elevation of stroke volume. In excitement, the increase in circumflex flow was delayed 7−12 seconds, and this was also generally preceded by a rise in stroke volume. The large rise of coronary flow in exercise was associated with a marked increase in myocardial blood oxygen extraction; in excitement, coronary flow also rose greatly but oxygen extraction decreased markedly. Although these trends during natural stress states were similar to those found in the normal dog, the maximum coronary flow and myocardial oxygen use were no more than half those found in the normal dog for an equivalent stress. The addition of beta-receptor blockade still further reduced the coronary responses to these natural stresses. Thus the denervated heart appears to function at a lower metabolic level than the heart with intact cardiac nerves.

Left Circumflex Coronary Artery Hemodynamics in Conscious Dogs with Congenital Subaortic Stenosis

Coronary arterial hemodynamics were studied in three conscious dogs with congenital fibrous ring-type subaortic stenosis. Flow characteristics were recorded with electromagnetic flow transducers chronically implanted on the circumflex branch of the left coronary artery. Circumflex resting flow (ml/min 100 g−1 myocardium) was below that previously found in normal dogs studied by the same methods. Phasic coronary flow patterns at rest were abnormal, being characterized by reversed flow throughout most of ventricular systole. The mean reactive hyperemic response after 10 seconds of mechanical occlusion was comparable to that in normal dogs despite the essential absence of systolic forward flow. In one dog, moderate treadmill exercise substantially increased total circumflex flow despite a large increase in reversed circumflex flow.

Coronary vasoactivity of adenosine covalently linked to polylysine

Abstract Adenosine was covalently linke to polylysine nonapeptide by reacting adenosine-5-carboxaldehyde with polylysine at pH 9.5, then reducing the Schiff base with NaBH4. The product (PLADO), which contained an average of two adenosine residues per molecule, did not penetrate cell membranes. When administered to two conscious instrumented dogs PLADO caused maximum coronary vasodilation at a concentration of 4 μM in coronary plasma water. This coronary vasodilatory effect was antagonized by aminophylline. Thus, after the administration of this methylxanthine coronary conductance increased by only 46% of maximum at a PLADO concentration of 6.9 μM. This result confirms earlier work using adenosine coupled to oxidized oligosaccharides that indicates the possibility of adenosine receptors on the surface of coronary myocytes.

Direct Measurement of Coronary Collateral Blood Flow in Conscious Dogs by an Electromagnetic Flowmeter

The development of collateral circulation has been indirectly monitored by determining peripheral coronary pressure and 133Xe clearance. In the present experiments, the development of collateral blood flow following gradual (three dogs) and rapid (three dogs) complete occlusion of the central circumflex branch, during partial central occlusion, and in parallel with a rise in peripheral coronary pressure was directly demonstrated by finding phasic coronary flow patterns in distal branches of the circumflex coronary artery. Collateral blood flow patterns were not consistently observed until a flow of 4–6 ml/ min developed. In five dogs branch flow before central occlusion averaged 20 ml/min, but peak collateral blood flow after occlusion averaged 11.6 ml/min (range 7 to 17 ml/min). To circumvent central occlusion collateral blood flow must enter the circumflex bed retrograde; we proved this fact by finding collateral blood flow patterns that were mirror images of normal antegrade patterns and flow values that were negative with respect to mechanical reference zeros. Unexpectedly, collateral blood flow was antegrade in some branches indicating a redistribution of retrograde collateral blood flow within the circumflex bed. In a terminal open-chest experiment, there was indirect evidence of alternate collateral blood flow opposing measured collateral blood flow; this finding could explain some of the small reactive hyperemias observed after the release of a temporary occlusion of a distal branch. In summary, phasic collateral blood flow patterns in distal epicardial branches that developed rapidly in response to occlusion of the central circumflex branch and in conjunction with a rise in peripheral coronary pressure were demonstrated, and reversal from antegrade to retrograde collateral blood flow was documented.

Use and Application of the Cuvette Densitometer as an Oximeter

A method has been developed for the continuous recording of oxygen saturation in blood by the use of a cuvette densitometer. The device consists of a light source, a cuvette through which the blood flows and a photosensitive element. It is simple to operate and has an acceptable sensitivity and stability. The instrument is applicable to a number of investigative problems.