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In canine right atrial hypertrophy, the cross-sectional area (Axs) of right atrial myocytes increases, whereas the Axs of the broader interatrial band myocytes does not. In the current study, myocyte reconstructions showed that right atrial myocyte length increased in proportion to Axs in right atrial hypertrophy. On the other hand, mean interatrial band myocyte length in both normal and right atrial hypertrophy dogs was roughly inversely proportional to mean Axs, as expected if interatrial band myocyte volume was constant. Plotting mean Axs vs. myocyte length for individual interatrial band myocytes revealed a distribution whose border defined a maximal volume curve; many myocytes were well beneath that curve. Mononuclear myocytes (generally diploid) were limited by a 65,000-micrometer 3 curve, which many binuclear myocytes (generally tetraploid) surpassed; myocyte ploidy thus constrained myocyte volume. However, because many mononuclear and binuclear myocytes had lower volumes, their failure to hypertrophy cannot be attributed to attainment of the maximal volume possible for their ploidy.

Vascular reserve, which defines the capacity for further vasodilation in a given physiological or pathological condition, has not been measured in the canine atria. This study defines, in normal dogs, the regional vascular reserve simultaneously measured in the atria (appendage, nonappendage regions) and in the ventricles during rest and two levels of exercise. Blood flow was determined using 11.4 +/- 0.1 microns radiolabeled microspheres. Vascular reserve (percent for each region) is the ratio of vascular conductance during each condition to maximum vascular conductance. Maximum vascular conductance was estimated by infusing adenosine intravenously. For a given physiological condition regional vascular conductance varied two- to threefold. The vascular reserve of each of the regions decreased progressively from rest to mild exercise to moderate exercise. Regional vascular reserve for both atria, the right ventricle, and the epicardial layer of the left ventricle was essentially uniform for a given condition: rest 93 +/- 0.4%, mild exercise 81 +/- 1.2%, and moderate exercise 69 +/- 1.5%. This similarity in vascular reserve implies that for a given physiological condition a common mechanism precisely regulates myocardial perfusion in these cardiac regions as a function of the total vasodilator capacity.

To investigate regional variation of myocyte response to atrial hypertrophy, control dogs were compared with dogs with right atrial hypertrophy created by induction of tricuspid regurgitation; after 1 yr, right atrial-to-body weight ratio increased 122% over controls. One section from the interatrial band, appendage and nonappendage roofs, and nonappendage side of each atrium of each dog was stained to reveal myocyte outlines and transverse tubules; myocyte cross-sectional areas were measured and transverse tubule prevalence was estimated. In control dogs, interatrial band myocytes were significantly larger and had more transverse tubules than other atrial myocytes. With atrial hypertrophy, right interatrial band myocytes did not increase significantly in size, whereas other right atrial myocytes nearly doubled in size, approaching the size of interatrial band myocytes without approaching the content of transverse tubules. Left atrial myocytes did not increase in size. Thus hypertrophic response of atrial myocytes to hemodynamic stress depends on the region in which the myocytes are found, and atrial hypertrophy does not demand transverse tubule proliferation.

Global and regional atrial blood flow was measured with radioisotope-labeled microspheres in eight dogs during rest and two levels of exercise. Both mean right and left atrial blood flow increased significantly (P < 0.05) to a similar degree with each level of exercise (right atria: 0.27 +/- 0.04, 0.89 +/- 0.11, and 1.57 +/- 0.21 ml.min-1 x g-1; left atria: 0.35 +/- 0.04, 0.90 +/- 0.09, and 1.61 +/- 0.17 ml.min-1 x g-1). Atrial blood flow during exercise is greater than anticipated if increased heart rate was the sole cause. In both right and left atria the ratio of appendage to nonappendage flow was significantly (P < 0.005) less than one during resting conditions (0.42 +/- 0.04 and 0.81 +/- 0.05, respectively), not different from unity during mild exercise, and significantly (P < 0.02) greater than one during moderate exercise (1.10 +/- 0.03 and 1.16 +/- 0.05, respectively). This disparity in the blood flow to the appendage and nonappendage regions suggests that the appendage plays an augmented hemodynamic role during exercise, thus requiring a larger proportion of the nutrient flow.

Myocardial oxygenation may be altered markedly by changes in tissue blood flow. During brief ischemia and reperfusion produced by transient occlusion of the left anterior descending artery in 10 open-chest dogs, changes in the oxygenation of tissue hemoglobin (Hb) plus myoglobin (Mb) and the oxidation-reduction (redox) state of mitochondrial cytochrome aa3 were monitored continuously using near-infrared spectroscopy. The nondestructive optical technique indicated that coronary occlusion produced an abrupt drop in tissue oxygen stores (tHb02 + Mb02), tissue blood volume (tBV), and the oxidation level of cytochrome aa3. Changes in the cytochrome oxidation state were related inversely to transmural collateral blood flow within the ischemic region (r = 0.77) measured with radiolabeled microspheres. Furthermore, there was a direct relationship (r = 0.91) between collateral blood flow and the tissue level of desaturated Hb and Mb (tHb + Mb). Reperfusion after 2 min of ischemia led to a synchronous overshoot of baseline in coronary flow and tBV followed by supranormal increases in tHb + Mb02 and the oxidation level of cytochrome aa3. The tHb + Mb level increased transiently during reperfusion. This response correlated inversely with collateral flow during ischemia (r = 0.91). Accordingly, the time required to reach peak tHb + Mb levels was shortest in dogs with high collateral flows (r = 0.75). Thus collateral blood flow partially sustains myocardial oxygenation during coronary artery occlusion and influences tissue reoxygenation early during reperfusion.

Compliance of the left atrial chamber was estimated with and without the appendage intact in six isolated canine left atria. Pressure-volume determinations were measured over a range of 5-30 mmHg for the whole left atrium and were repeated with the appendage excluded. The slope of the pressure vs. normalized volume data for the left atrium without the appendage (10.45 +/- 0.87) was significantly greater (P less than 0.01) than with the appendage intact (4.10 +/- 0.72). These data suggest that the left atrial appendage is more compliant than the remaining left atrium. Assuming that this relationship remains in vivo, the left atrial appendage may play an augmented role in maintaining hemodynamic function when filling pressures are elevated.

Studies were conducted to determine the effects of adenosine on transmural myocardial blood flow distribution. Both maximal and submaximal vasodilatory doses of adenosine were infused into awake resting dogs chronically instrumented with coronary flow probes and aortic and left atrial pressure catheters. Radioactive microspheres (8-10 micron) were used to determine regional coronary blood flow. Four experimental protocols were evaluated: 1) the effects of maximal (1.00 mg . kg-1 . min-1) as well as submaximal (0.45 mg . kg-1 . min-1) vasodilatory levels of adenosine, 2) the dose-response characteristics of adenosine, 3) the dose-response characteristics of dipyridamole, and 4) the effects of adenosine in the presence of an increased arterial PO2. The data indicate that maximal vasodilatory doses of adenosine have little effect on the endocardial-to-epicardial blood flow ratio, whereas submaximal doses result in a marked preferential endocardial perfusion. This relative increase in endocardial perfusion was not altered by hyperoxia. Dipyridamole, in submaximal doses, produced a similar preferential flow to the endocardial layer. These data demonstrate that the vasodilator reactivity to adenosine infusion is greater in the endocardial layer,

Conductance of the coronary collateral circulation during the course of two abrupt circumflex coronary occlusions (pre- and posttreatment with nitroglycerin) was measured in awake dogs approximately 2 wk after collateral vessels were stimulated to develop. The pressure gradient from the central aorta to the distal circumflex coronary artery was measured, and myocardial blood flow was determined by 9-microns radioactive microspheres at 30 s and 4 min after coronary occlusions. Collateral conductance was calculated as mean collateral blood flow divided by the mean aorta-coronary pressure gradient. Before nitroglycerin, collateral conductance increased in all eight dogs from 30 s to 4 min by a mean value of 0.006 +/- 0.003 ml.min-1.g-1.mmHg-1. After nitroglycerin administration, the conductance at 30 s increased from the prenitroglycerin control value of 0.009 +/- 0.008 to 0.014 +/- 0.012 ml.min-1.g-1.mmHg-1, P less than 0.03. The mean change in conductance from 30 s to 4 min postnitroglycerin 0.003 +/- 0.003 ml.min-1.g-1.mmHg-1 was significantly less than during prenitroglycerin (P = 0.01). These data indicate that an increase in conductance during coronary occlusion occurs even in the immature collateral circulation. This effect presumably takes place in the arterial smooth muscle at the origin of the collateral vasculature.

A reproducible model for the production of moderate to severe concentric left ventricular hypertrophy has been developed in this laboratory. Coarctation-banding of the ascending aorta was performed successfully in 10 puppies. There were no late deaths related to aortic rupture, and in the dogs surviving for 1 yr no evidence of congestive heart failure was present. A second operative procedure was performed in seven dogs for chronic instrumentation, and all survived. Severe supravalvular aortic stenosis with a marked peak systolic pressure gradient was noted in each dog. Postmortem examination revealed a substantial increase in left ventricular mass and in the ratio of left ventricular to body weight.

The purpose of this study was to correlate dimensions and transmural blood flow in a segment of myocardium supplied by a coronary artery undergoing gradual closure. Nine adult dogs were instrumented with an electromagnetic flow probe, pneumatic occluder, and an ameroid constrictor on the circumflex coronary artery. Ultrasonic crystals were implanted 10 mm from the external surface of the left ventricle in a segment perfused by the circumflex artery. Regional blood flow was determined with 7- to 10-microns radiolabeled microspheres. Data were collected in the awake state at rest before closure began (control), during partial closure, and immediately after total closure. Seven of the nine animals were studied after occlusion during treadmill exercise. During both partial and total closure at rest the rate and extent of systolic shortening as well as the transmural blood flow were unchanged from control. During treadmill exercise mean flow increased. However, flow was redistributed away from the inner two layers causing deterioration in both the rate and extent of shortening of this segment. These data suggest that, although regional myocardial function and flow can be maintained at rest by the immature canine collateral circulation, these parameters are impaired markedly during augmented flow with exercise.

The transient decrease in left circumflex coronary artery blood flow during atrial contraction (atrial coves) was examined in open-chest, heart-blocked dogs. Prominent atrial coves were observed in left circumflex flow during both diastole and systole as a result of the asynchrony of atrial and ventricular contractions. In eight open-chest dogs, atrial contractions decreased diastolic circumflex coronary flow by 0.016 +/- 0.002 ml and systolic flow by 0.014 +/- 0.001 ml compared with diastolic and systolic intervals during which no atrial contractions occurred. The diastolic and systolic flow reductions in this vessel were not significantly different (P greater than 0.14). In five of the eight dogs no diastolic atrial coves were observed in left anterior descending coronary flow, and only minimal diastolic coving was present in the remaining three dogs; no systolic coves were present in this vessel in any of the eight dogs. In five additional open-chest dogs, brief inflation of a balloon in the left atrium produced elevations of left ventricular diastolic pressure comparable to those produced by atrial contraction. Only minimal atrial coves were associated with these balloon inflations. These data are consistent with the hypothesis that atrial contraction limits flow through the atrial blood vessels and results in a transient decrease in flow in the atrial arteries that arise from the left circumflex coronary artery. Although increases in ventricular diastolic pressure may be partially responsible for the appearance of atrial coves in the left circumflex coronary artery, mechanical contraction of the atrial musculature appears to be of significant importance.

The effect of 100% oxygen inhalation on regional transmural myocardial blood flow following 45 s of actue total left circumflex coronary artery occlusion was studied in six awake dogs chronically instrumented with a coronary occluder and catheters in the aorta and left atrium. After inhalation of either room air or 100% oxygen for at least 30 min and following the 45-s occlusion, transmural myocardial blood flow was determined with radioactive microspheres (7--10 micrometers). Each dog underwent two occlusions of the left circumflex coronary artery; one during inhalation of rrom air and the other during 100% oxygen. During room air inhalation, mean regional myocardial blood flow to nonischemic, intermediate, and ischemic regions was 0.92 +/- 0.05, 0.51 +/- 0.08, and 0.10 +/- 0.02 ml . min-1 . g-1, respectively. During 100% oxygen administration, flow was significantly diminished in each region to 0.75 +/- 0.04, 0.41 +/- 0.07, and 0.06 +/- 0.01 ml . min-1 . g-1, respectively. Transmural blood flow to each layer was uniformly reduced in all regions. These data indicate that 100% oxygen further reduces myocardial blood flow to ischemic regions.

The effect of pacing-induced tachycardia on transmural myocardial blood flow distribution was studied in 16 awake dogs with left ventricular hypertrophy secondary to modified aortic coarctation banding done at 7-10 wk of age. They were studied between 11 and 50 mo of age. In those dogs with mild and moderate left ventricular hypertrophy, the blood flow distribution was normal during resting conditions and remained normal during an increased heart rate of 250 beats/min. In the six dogs with severe hypertrophy (left ventricle/body wt greater than 7.0 g/kg) a reduced flow to the endocardial layers was present during resting conditions (endocardial/epicardial 0.91 +/- 0.09), but during tachycardia the endocardial-to-epicardial ratio normalized to 1.26 +/- 0.08 (mean +/- SEM). These data indicate that, in dogs with significant left ventricular hypertrophy, the vasoregulator mechanism functions adequately to maintain normal transmural myocardial blood flow distribution during tachycardia. In addition, studies were carried out to compare the magnitude of hypertrophy with the hemodynamic load secondary to coarctation banding.

Purine and pyrimidine nucleotides are essential energy sources for basic metabolic reactions and play important roles in protein, glycogen, and nucleic acid synthesis, cyclic nucleotide metabolism, and energy transfer reactions. Brief coronary occlusions (12 min) were produced in seven open-chest dogs, and repetitive myocardial samples were taken in order to determine the response of the nucleotide pool to ischemia and reperfusion. During ischemia adenosine 5'-triphosphate (ATP) decreased to 57% of control, and similar decreases occurred in the guanosine 5'-triphosphate (GTP), cytidine 5'-triphosphate (CTP), uridine 5'-triphosphate (UTP), and nicotinamide adenine dinucleotide (NAD+) pools. The decrease in nucleotides was accompanied by an increase in nucleosides and bases. After 60 min of reperfusion the content of all nucleotides had increased but was still significantly less than nonischemic values. The content of nucleosides and bases decreased immediately upon reperfusion. In contrast, creatine phosphate (CP) fell to 10% of control during ischemia but rebounded to above control values immediately upon reperfusion. Thus depletion of all nucleotide pools occurs during ischemia, and with reperfusion nucleotide content is restored only slowly. Delayed repletion is not caused by a defect in mitochondrial synthesis of ATP because CP content is restored rapidly. The slow repletion of nucleotides may be secondary to loss of nucleotide precursors during reperfusion and may result in widespread alterations in myocardial metabolism.

Phasic coronary flow and transmural myocardial perfusion were studied during coronary artery constriction in 10 dogs with electromagnetic flowmeters and hydraulic occluders on the left circumflex coronary artery. Regional blood flow was estimated using left atrial injections of radionuclide-labeled microspheres 9 micron in diameter. During control conditions, 14+/-0.7% of coronary flow occurred in systole and subendocardial (endo) flow exceeded subepicardial (epi) flow in the region of the posterior papillary muscle (endo/epi=1.16). Immediately following partial inflation of the occluder to reduce coronary inflow 39+/-3%, systolic flow was unchanged while diastolic flow fell 42+/-3%, thereby increasing the portion of flow in systole to 22+/-1.4%. At this time blood flow was reduced nearly uniformly across the wall of the left ventricle. When coronary constriction was maintained for 30 s, an additional shift of flow from diastole to systole occurred (systolic flow=29+/-2.3% of total inflow), and transmural perfusion was redistributed from subendocardium to subepicardium (endo/epi=0.37). This redistribution of flow was accompanied by a fall in coronary pressure distal to the occluder, indicating vasodilation of the distal coronary vasculature.

This study determined whether the reactive hyperemic response to a 400-ms diastolic coronary occlusion is dependent on ventricular systole. Studies were obtained on 11 conscious dogs with complete heart block paced at 60 beats/min. A pressure catheter was chronically implanted in the aorta. An electromagnetic flow probe and pneumatic occluder were implanted on the circumflex coronary artery. Three interventions were employed: 1) interruption of pacing for a single beat generating a long diastolic period of 2,000 ms in duration (LDC); 2) introduction of a 400-ms diastolic coronary occlusion early in a long diastole (LD4); and 3) a 400-ms diastolic occlusion during uninterrupted pacing (400R). The rise in diastolic coronary vascular resistance index noted during LDC was inhibited significantly in the last 600 ms of diastole during LD4. Thus an intervening systole is not required for a reactive hyperemic response to a diastolic coronary occlusion. During 400R, the resistance index was lower than that found during LD4. The reactive hyperemic response may be caused by either a myogenic or metabolic mechanism or by both. The greater vasodilatation observed after the postocclusion systole in 400R probably reflects metabolic influences.

We tested the hypothesis that coronary reactive hyperemia following a single brief diastolic occlusion and subsequent systole is coupled to myocardial metabolic activity and myocardial O2 consumption (MVO2). Sixteen conscious dogs with Formalin-induced heart block were studied. A 400-ms diastolic occlusion was introduced during normal ventricular pacing, resulting in a reactive hyperemic repayment of 216 +/- 22%. A 400-ms diastolic occlusion was also introduced during a higher level of myocardial metabolic activity induced by ventricular paired pacing. MVO2 and mean coronary blood flow were significantly increased relative to these parameters during normal pacing, but reactive hyperemic repayment (189 +/- 18%) was not significantly changed. A third set of conditions was designed to measure the response to a 400-ms occlusion during normal pacing while eliminating the difference in magnitudes of myogenic influences that may exist between paired pacing and normal pacing. Adenosine and phenylephrine were infused intravenously during normal pacing to maintain mean aortic pressure and mean coronary flow at paired pacing levels. MVO2 was similar to O2 consumption during normal pacing in the absence of drug infusion, but the reactive hyperemic repayment was significantly reduced (94 +/- 22%) relative to paired pacing. Thus the magnitude of reactive hyperemic response after a brief diastolic occlusion is related primarily to myocardial metabolic activity.