Adenosine and lymphocyte regulation

Adenosine is a potent extracellular messenger that is produced in high concentrations under metabolically unfavourable conditions. Tissue hypoxia, consequent to a compromised cellular energy status, is followed by the enhanced breakdown of ATP leading to the release of adenosine. Through the interaction with A2 and A3 membrane receptors, adenosine is devoted to the restoration of tissue homeostasis, acting as a retaliatory metabolite. Several aspects of the immune response have to be taken into consideration and even though in general it is very important to dampen inflammation, in some circumstances, such as the case of cancer, it is also necessary to increase the activity of immune cells against pathogens. Therefore, adenosine receptors that are defined as ‘sensors–of metabolic changes in the local tissue environment may be very important targets for modulation of immune responses and drugs devoted to regulating the adenosinergic system are promising in different clinical situations

Influence of contrast agent dispersion on bolus-based MRI myocardial perfusion measurements: A computational fluid dynamics study

Purpose: Bolus‐based dynamic contrast agent (CA) perfusion measurements of the heart are subject to systematic errors due to CA bolus dispersion in the coronary arteries. To better understand these effects on quantification of myocardial blood flow and myocardial perfusion reserve (MPR), an in‐silico model of the coronary arteries down to the pre‐arteriolar vessels has been developed. Methods: In this work, a computational fluid dynamics analysis is performed to investigate these errors on the basis of realistic 3D models of the left and right porcine coronary artery trees, including vessels at the pre‐arteriolar level. Using advanced boundary conditions, simulations of blood flow and CA transport are conducted at rest and under stress. These are evaluated with regard to dispersion (assessed by the width of CA concentration time curves and associated vascular transport functions) and errors of myocardial blood flow and myocardial perfusion reserve quantification. Results: Contrast agent dispersion increases with traveled distance as well as vessel diameter, and decreases with higher flow velocities. Overall, the average myocardial blood flow errors are −28% ± 16% and −8.5% ± 3.3% at rest and stress, respectively, and the average myocardial perfusion reserve error is 26% ± 22%. The calculated values are different in the left and right coronary tree. Conclusion: Contrast agent dispersion is dependent on a complex interplay of several different factors characterizing the cardiovascular bed, including vessel size and integrated vascular length. Quantification errors evoked by the observed CA dispersion show nonnegligible distortion in dynamic CA bolus‐based perfusion measurements. We expect future improvements of quantitative perfusion measurements to make the systematic errors described here more apparent

Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation

WOS: 000070954800008PubMed ID: 9463630Objective: It has been suggested that nitric oxide (NO) is involved in the regulation of myocardial function in a variety of diseases such as dilated cardiomyopathy, myocarditis, heart transplant rejection, and septic shock. However, the underlying mechanism of NO mediated reduction of cardiac contractility has not been clearly established so far. Therefore, we studied the effects of authentic NO on left ventricular function and myocardial energy status in the isolated heart. Methods: In 43 isolated perfused guinea pig hearts quantitative and kinetic changes in coronary flow (CF), left ventricular developed pressure (LVDP), the cardiac release of adenosine, lactate, cyclic GMP, and norepinephrine were measured during infusion of authentic NO. In parallel, myocardial phosphocreatine (PCr), ATP and the free energy change of ATP-hydrolysis (Delta G(ATP)) were measured using P-31 nuclear magnetic resonance spectroscopy. Results: At low concentrations (0.01 to 1.0 mu mol/L) NO increased CF only; at higher concentrations (1 to 100 mu mol/L) CF remained elevated and LVDP was significantly reduced. Onset and offset of changes in LVDP occurred always within 2 to 5 a after start and cessation of NO infusion. Contractile dysfunction was significantly correlated to a pronounced increase in adenosine formation (>70-fold), a significant decrease in myocardial PCr (-78%), ATP (-25%) and a decrease in Delta G(ATP) from -61.76 kJ/mol to -50.75 kJ/mol. This was paralleled by a significant decrease in myocardial oxygen consumption (-65%) and a tenfold increase in lactate production. Coronary vasodilation (NO: 0.001 to 1.0 mu mol/L) significantly correlated with the increase in cGMP release, whereas at negative inotropic concentrations (NO: 10 to 100 mu mol/L) a clear quantitative and kinetic dissociation between NO-induced changes in cGMP and LVDP was observed, Contractile dysfunction was not related to cardiac release of norepinephrine. Conclusions: In the isolated heart NO can potently depress myocardial energy generation thus being an effective modulator of cardiac contractility, This effect of NO may be of pathophysiological significance in cardiac muscle disorders in vivo. (C) 1997 Elsevier Science B.V

Cyclosporin and tacrolimus increase plasma levels of adenosine in kidney transplanted patients

8reservedThe immunosuppressive agents, cyclosporin (CsA) and tacrolimus (FK506), display cardioprotective activities. The mechanism would consist on the inhibition of the enzyme, adenosine kinase (AK), leading to an increase in adenosine (ADO) levels. ADO, inosine (INO) and nucleotide plasma levels were measured in kidney transplant recipients before and 1, 2, 4, 6 and 8 h after the administration of CsA or FK506. After CsA and FK506 administration, ADO plasma levels significantly increased, reaching a peak level after 2 h (483 ± 124 and 429 ± 96 nm, respectively), and then progressively declined. Calculated peak values (tmax) of ADO were slightly delayed with respect to those of CsA and FK506. Treatment with rapamycin did not influence the phenomenon. The dynamic profile of plasma changes of ADO, nucleotides and INO were consistent with the inhibition of the enzyme, AK. ADO increase may be clinically relevant in terms of anti-ischaemic, tissue protecting, and immunosuppressive activities as well as in terms of nephrotoxicitymixedCapecchi, PIER LEOPOLDO; Rechichi, Serena; Lazzerini, PIETRO ENEA; Collini, A; Guideri, Francesca; Ruggieri, Giuliana; Carmellini, Mario; LAGHI PASINI, FrancoCapecchi, PIER LEOPOLDO; Rechichi, Serena; Lazzerini, PIETRO ENEA; Collini, A; Guideri, Francesca; Ruggieri, G; Carmellini, Mario; LAGHI PASINI, Franc