Background-Left ventricular myocardial blood flow is spatially heterogeneous. The hypothesis we tested was whether myocardial areas with a steady-state flow Ͻ0.5 times mean flow are underperfused and areas with flow Ͼ1.5 times mean flow are overperfused. Methods and Results-In anesthetized beagle dogs (nϭ10), the relationship between local blood flow versus S-adenosylhomocysteine (SAH) concentration, a measure of the free intracellular adenosine concentration, and lactate, a measure of the myocardial NADH/NAD ϩ ratio, were determined under control conditions and after coronary constriction. Control local myocardial blood flow was 0.99Ϯ0.46 mL ⅐ min Ϫ1 ⅐ g Ϫ1 , with a coefficient of variation of 0.36Ϯ0.12 (nϭ256 per heart; sample wet mass, 125Ϯ30 mg). Tissue concentrations of SAH (3.4Ϯ2.5 nmol/g) and lactate (1.88Ϯ0.80 mol/g) were not elevated in low-flow samples. However, after coronary artery constriction, poststenotic blood flow decreased from 1.00Ϯ0.27 to 0.49Ϯ0.22 mL ⅐ min Ϫ1 ⅐ g Ϫ1 (PϽ0.04), with significant correlation between local SAH and flow (rϭϪ0.59) and lactate and flow (rϭϪ0.50). Although nearly all samples from control high-flow regions showed increased SAH concentrations if relative flow after stenosis was Ͻ1.0, control low-flow samples frequently displayed low SAH concentrations. The percent reduction in flow determined the changes in the local SAH and lactate concentration, independent of the local control blood flow. Conclusions-When the coronary inflow is unrestricted, the oxygen supply to control low-flow regions meets metabolic demand. Flow to control high-flow regions reflects a higher local demand rather than overperfusion. Thus, blood flow heterogeneity most likely reflects differences in aerobic metabolism. (Circulation. 1998;98:262-270.)

The decreased contraction amplitude of isolated cardiac myocytes from guinea pigs exposed to lipopolysaccharide (LPS) was reported to be partially reversed by nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS) [Brady, et al., Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1963-H1966, 1992]. We have tested the potential involvement of NO formation in LPS-induced cardiac depression in the intact heart. Isolated perfused hearts of LPS-treated guinea pigs (4 mg/kg 4 h before organ removal) displayed a greatly decreased left ventricular pressure (LVP) when compared with untreated controls (48 +/- 11 vs. 93 +/- 18 mmHg, n = 6 hearts each), whereas heart rate and coronary flow were similar. Perfusion of LPS-treated hearts with L-NMMA or L-NAME (100 microM each) at constant flow did not increase LVP (50 +/- 14 and 44 +/- 11, respectively, vs. 52 +/- 14 mmHg). However, coronary resistance increased significantly. There was no difference between LPS-treated and control hearts in venous adenosine release (104 +/- 58 vs. 133 +/- 86 pmol.min-1.g-1). Measurement of the activities of the induced (iNOS) and constitutive forms of NOS revealed that there was no difference in total NOS activity (237 +/- 82 vs. 181 +/- 97 fmol.min-1.mg protein-1. There was no measurable induction of iNOS in the LPS-treated hearts either. Finally, cardiac energy status was studied by 31P nuclear magnetic resonance spectroscopy. There was no difference between LPS-treated and control hearts in myocardial ATP, creatine phosphate, pH, and free ADP (59 +/- 20 vs. 50 +/- 27 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

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The concentration of heat-shock proteins of 70 kD (HSP70) in heart tissue has been shown to increase during transient myocardial ischaemia and to persist during several hours of reperfusion. In this study the relationship between the local myocardial HSP70 concentration and blood flow was addressed for control physiological conditions and acute myocardial ischaemia. A specific aim of this study was to address the question of whether low flow areas under control physiological conditions have undergone a transient ischaemia during the preceding hours and thus may be in a state of hibernation or stunning. In 12 anaesthetized, open-chest beagle dogs (6 control and 6 with 60-min coronary artery stenosis) heart rate, mean aortic pressure, mean arterial partial pressure of O2 and partial pressure of CO2 averaged 85+/-16 beats/min, 94+/-14 mmHg, 102+/-17 mmHg and 39+/-6 mmHg, respectively. Regional HSP70 and myocardial blood flow (RMBF) were measured using an HSP70-enzyme-linked immunosorbent assay and the tracer microsphere technique, respectively, in samples of 250 mg wet mass. In the control group the mean RMBF was 1.06+/-0.59 ml.min-1.g-1 and the local HSP70 concentration was 7.08+/-1.03 microg/mg cytosolic protein. Myocardial HSP70 showed a blood flow-independent regional biological heterogeneity, equivalent to a coefficient of variation of 0.31. Local HSP70 concentrations did not differ (P>0.05) between control low and high flow samples, 6.16+/-1.0 vs 6.08+/-0.75 microg/mg cytosolic protein, respectively. However, after 60 min of coronary artery occlusion the local HSP70 concentration increased from 7.08 +/-1.03 to 13.43+/-3.19 microg/mg cytosolic protein (P<0. 001). There was a significant inverse relationship between the percent reduction of local blood flow and HSP70 (r=-0.56, P<0.001). From these results it is concluded that: (1) low flow samples under control physiological conditions are unlikely to be in a state of hibernation or stunning since their HSP70 concentration is normal and (2) the increase in the local HSP70 concentration during myocardial ischaemia reflects the degree of impairment of O2 delivery.

Patients treated by allogeneic bone marrow transplantation (aBMT) suffer prolonged oropharyngeal mucositis pain. The aim of this study was to prospectively compare patient-controlled analgesia (PCA) with an established regimen of staff-controlled analgesia using pethidine (meperidine). Twenty patients undergoing aBMT for haematologic neoplasias or malignant lymphomas randomly received pethidine intravenously either continuously plus supplemental bolus doses on request through the transplant unit staff or by PCA. Pain intensity was assessed by patient self report using a visual analogue scale (VAS) and daily pethidine intake was documented. In addition, the pethidine consumption of 20 aBMT-patients receiving staff-controlled analgesia prior to initiation of the study, but not reporting pain, was compared retrospectively with that of patients receiving the same analgesia regimen under study conditions. PCA significantly diminished both pethidine consumption and pain intensity compared with staff-controlled analgesia. The maximum pethidine intake was 440.1 +/- 111.8 mg/24 h in the patient-controlled and 640.9 +/- 128.9 mg/24 h in the staff-controlled analgesia group (mean +/- 95% CI). Mean pain scores remained under 50% but reached 70% in the staff-controlled analgesia group. Pethidine dosage by staff-controlled analgesia increased under study conditions, suggesting that mere pain-assessment and a 'competing' analgesic method motivated the BMT-unit staff to administer higher pethidine doses. This observation is discussed as a possible Hawthorne effect. Previous studies using morphine demonstrated that PCA diminishes opioid requirement compared to continuous or staff-controlled application in bone marrow recipients. In contrast to these studies, PCA additionally improved pain relief in the present investigation.

(1). Local physiological ferritin content in myocardium is heterogeneous and unrelated to control myocardial blood flow. (2). Ischaemia results in an enhanced ferritin content in relation to the degree of ischaemia. (3). The increase of myocardial ferritin requires a severe degree of ischaemia.

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Eleven Beagle dogs were studied to elucidate the possible role of L-arginine-derived nitric oxide on local blood flow distribution in left and right ventricular myocardium. Local blood flow was determined in 256 samples from the left and 64 samples from the right ventricle per heart using the tracer microsphere technique (mean sample mass 319 +/- 131 mg). Nitric oxide production was effectively inhibited by intravenous infusion of 20 mg/kg nitro-L-arginine methylester (L-NAME) as evidenced by a shift of the dose/response curve for the effect of intracoronary administration of bradykinin (0.004-4.0 nmol/min) on coronary blood flow. L-NAME enhanced left and right ventricular systolic pressures from 132 +/- 18 to 155 +/- 15 mm Hg and from 26 +/- 3 to 29 +/- 3 mm Hg respectively (both P = 0.043). Mean left ventricular blood flow was 1.14 +/- 0.38 before and 0.99 +/- 0.28 ml min-1 g-1 after L-NAME (P = 0.068), while right ventricular blood flow fell from 0.72 +/- 0.28 to 0.53 +/- 0.20 ml min-1 g-1 (P = 0.043). Coronary conductance of left and right ventricular myocardium fell by 31 and 43% respectively (both P = 0.043). The coefficient of variation of left ventricular blood flow was 0.26 +/- 0.07 before and 0.29 +/- 0.07 after L-NAME (P = 0.068), that of right ventricular blood flow was 0.27 before and after L-NAME. Skewness (0.51) and kurtosis (4.23) of left ventricular blood flow distribution were unchanged after L-NAME, while in the right ventricle skewness decreased from 0.54 to 0.09 (P = 0.043) and kurtosis (3.68) tended to decrease after L-NAME (P = 0.080). The fractal dimension (D = 1.20-1.27) and the corresponding nearest-neighbor correlation coefficient (rn = 0.37-0.53) of left and right ventricular myocardium remained unchanged after infusion of L-NAME. From these results it is concluded that firstly, local nitric oxide release does not explain the higher perfusion of physiological high flow samples and secondly, that spatial myocardial blood flow coordination is not dependent on nitric oxide.