We used the multiple-indicator-dilution technique to observe the capillary transport of adenosine in isolated Krebs-Henseleit-perfused guinea pig hearts. Tracer concentrations of radiolabeled albumin, sucrose, and adenosine were injected into the coronary inflow; outflow samples were collected for 10-25 s and analyzed by high-performance liquid chromatography (HPLC) and by gamma- and beta-counting. The albumin data define the intravascular transport characteristics; the sucrose data define permeation through interendothelial clefts and dilution in interstitial fluid (ISF). Parameters calculated from adenosine data include permeability-surface area products for endothelial cell uptake at the luminal and abluminal membranes and intraendothelial metabolism. We found that in situ endothelial cells avidly take up and metabolize adenosine. Tracer adenosine in the capillary lumen is twice as likely to enter an endothelial cell as it is to permeate the clefts. There was no adenosine in the arterial perfusate. Under control conditions, the steady-state venous adenosine concentration was 3.6 +/- 0.8 nM, which from the flow and the parameters estimated from the tracer data gave a calculated ISF concentration of 6.8 +/- 1.5 nM. During dipyridamole infusion (10 microM) at constant pressure, the cell permeabilities went essentially to zero, whereas the venous adenosine concentration increased to 44.0 +/- 12.6 nM, giving an estimated ISF concentration of 191 +/- 53 nM. With constant flow perfusion, venous concentration during dipyridamole infusion was 30.9 +/- 6.3 nM, and estimated ISF concentration was 88 +/- 20 mM. We conclude that in this preparation, at rest, the ISF adenosine concentration is about twice the venous concentration and the ISF adenosine concentration increases with dipyridamole administration.

If adenosine is the major factor responsible for myocardial metabolic vasodilation, its release should be sustained as long as oxygen consumption and coronary flow are augmented. To see if adenosine meets this criterion, we examined the time course of its release during norepinephrine infusion in isolated, non-working guinea pig hearts (n = 8). During an 11-minute infusion period (steady state perfusate concentration = 6 X 10(-8) M), the coronary effluent was collected over 30-second intervals for measurements of coronary flow (ml/min per g), and adenosine and inosine release (pmol/min per g). Myocardial oxygen consumption (MVO2 = microliter O2/min per g) was measured at 1, 4, 6.5, and 11 minutes. Control values of coronary flow, myocardial oxygen consumption, and adenosine and inosine release were 7.5 +/- 0.4, 85 +/- 5, 22 +/- 5, and 431 +/- 39, respectively. During norepinephrine infusion, coronary flow, myocardial oxygen consumption, and adenosine release attained maximal levels within one minute (inosine within 2 minutes). These values were 10.6 +/- 0.4, 125 +/- 9, 849 +/- 110, and 2595 +/- 581, respectively. Thereafter, coronary flow and myocardial oxygen consumption values were sustained. In contrast, adenosine and inosine release significantly declined to nadirs by 9.5 minutes. Thereafter, steady state levels were maintained at 117 +/- 24 and 960 +/- 294, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY. Morphological studies have demonstrated an age-related decrease in capillary density and capillary surface area in the developing heart. However, the consequences of these changes on myocardial perfusion are not known. We tested the hypothesis that the decreased capillary density is associated with a reduction in coronary blood flow reserve. To test this hypothesis, we studied coronary responses to adenosine and sodium nitroprusside administration, reactive hyperemia, and autoregulatory capacity. We used a Langendorff-perfused heart preparation from guinea pigs of five different age groups (1 week and 1, 2, 12, and 18 months). Data are expressed as mean ± SEM. Maximal coronary flows (ml/min per g) in response to adenosine (10~* to 10~3 M) infusion are: 27 ± 1.3, 18.5 ± 1.4, 12.2 ± 0.4, 10.3 ± 0.3, and 10.6 ± 0.8 at 1 week, 1, 2, 12, and 18 months, respectively, with the flows at 1 week and 1 month significantly higher than those at 2, 12, and 18 months. There is a similar trend for a decreased maximum coronary perfusion in response to sodium nitroprusside (10"* to 10~5 M) and following a 45-second occlusion of the coronary inlet flow. Despite the decreased maximal pharmacological and reactive hyperemic flow reserve, autoregulation of flow is not altered with growth. The pressure-flow relationship exhibits autoregulation between 25 and 55 mm Hg perfusion pressure for all but the 1-week age group, which autoregulates within a narrower range of pressures (20-45 mm Hg). Total maximal coronary flow (ml/min) increases during development; this indicates that the growth of vessels continues with development. However, since coronary perfusion, corrected per unit cardiac mass, decreases significantly, we conclude that the vascular growth lags behind that of the parenchyma. (Circ Res 57: 538-544, 1985)

Myocardial ischemia increases the release of adenosine (RADO), inosine (RINO), and norepinephrine; however, it is not known whether norepinephrine contributes to nucleoside production via the beta-adrenergic receptor. We used a Langendorff preparation (guinea pig) to study the time course of RADO and RINO during myocardial hypoperfusion (MH) produced by decreasing perfusion pressure from 60 to 30 cmH2O. Data are expressed as means +/- SE. RADO and RINO significantly increased from 21 +/- 2 and 418 +/- 89 pmol X min-1 X g-1 to 206 +/- 26 and 2,401 +/- 598, respectively, by 10 min of MH. By 20 min, RADO and RINO had decreased significantly to 111 +/- 15 and 912 +/- 169 pmol X min-1 X g-1. RADO remained at that level for the remaining 160 min, whereas RINO returned to the control level. Coronary flow and myocardial O2 consumption were constant during MH. In the presence of 10(-7) M dl-propranolol MH did not produce the initial peak RADO; RADO increased to 95 +/- 18 pmol X min-1 X g-1 at 10 min and then did not change. Also, the initial peak RINO was significantly reduced (687 +/- 67 pmol X min-1 X g-1 at 10 min). Similar results were obtained with atenolol (5 X 10(-6) M), a beta-receptor antagonist without membrane-stabilizing effects. In the presence of 10(-5) M dl-propranolol, MH did not increase nucleoside release above control. Nucleoside release was similarly blocked during MH in the presence of 5 X 10(-6) M d-propranolol, which does not have the beta-blocking properties of the l-isomer.(ABSTRACT TRUNCATED AT 250 WORDS)

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