Information has emerged in the last few years to suggest that nucleotides and their purinoceptors may be important in mediating the pathophysiology of endotoxin-induced acute lung injury. With the use of an adenosine receptor (A1) antagonist we will investigate the hypothesis that endotoxin produces acute pulmonary hypertension and thromboxane release by acting on an A1 receptor. In animals receiving a continuous intravenous infusion of endotoxin, with the use of a 5'-nucleotidase inhibitor, we will investigate the hypothesis that endotoxin produces persistent pulmonary hypertension by altering 5' nucleotidase activity thus favoring the formation of the proaggregatory nucleotide ADP and vascular thrombosis. We will also investigate the therapeutic value of a potent pulmonary vasodilator and inhibitor of ADP-induced platelet-aggregation, an adenosine receptor (A2) agonist-5'-N-ethylcarboxamidoadenosine (NECA) in the treatment of endotoxin induced pulmonary hypertension. These investigations of mechanisms of acute lug injury may lead to the development of pharmacological interventions that may reduce the mortality of this disease which remains at 50- 70%. Moreover, we have previously shown, under conditions of controlled blood flow nad left atrial pressure that adenosine and ATP produce dose-dependent and tone-dependent responses in the pulmonary vascular (PV) bed of the intact chest, spontaneously breathing cat. With the use of an adenosine receptor antagonist BWA1433U, we have demonstrated that the vasodilator responses of adenosine receptor does not mediate vasodilation produced by ATP. Using selective probes of purinoceptors, adenosine sensitive (P1), A1 and A2 receptors and ATP sensitive (P2), P2x and P2y receptors, an adenosine uptake inhibitor and other pharmacological probes, we will complete the pharmacological analysis of these receptors in the PV bed and identify their mechanisms of action. Because nucleotides are released locally, metabolized locally by stereoselective ectonucleotidases and act on their own local receptors, defining the mechanisms of how these autacoids effects vascular tone may lead to the development of a selective pulmonary vasodilator.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL044434-02
Application #
3473011
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Neely, C F; Jin, J; Keith, I M (1997) A1-adenosine receptor antagonists block endotoxin-induced lung injury. Am J Physiol 272:L353-61
Neely, C F; Matot, I; Batra, V K et al. (1996) P2X purinoceptors in the feline pulmonary vascular bed: distribution and selective in vivo pharmacological probes. Am J Physiol 270:L889-97
Neely, C F; Matot, I (1996) Pharmacological probes for A1 and A2 adenosine receptors in vivo in feline pulmonary vascular bed. Am J Physiol 270:H610-9
Neely, C F; Matot, I; Haile, D et al. (1995) Tone-dependent responses of histamine in feline pulmonary vascular bed. Am J Physiol 268:H653-61
Matot, I; Neely, C F (1995) Pulmonary vasodilator responses to nicardipine: comparison with other vasodilators. Crit Care Med 23:1851-7
Neely, C F; Haile, D; Matot, I (1993) Tone-dependent responses of 5-hydroxytryptamine in the feline pulmonary vascular bed are mediated by two different 5-hydroxytryptamine receptors. J Pharmacol Exp Ther 264:1315-26
Matot, I; Neely, C F; Katz, R Y et al. (1993) Pulmonary uptake of propofol in cats. Effect of fentanyl and halothane. Anesthesiology 78:1157-65