EFFECT OF ENDOGENOUS ADENOSINE ACCUMULATION ON REGIONAL BLOOD FLOW
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Adenosine is known to participate in the regulation of several circulatory functions. Its action is mediated through distinct receptor subtypes mainly located in tnyocardial and vascular endothelial and smooth muscle cells. The hypotensive and vasodilator effect of exogenously administered adenosine has been previously described. However, a vasoconstrictor action of adenosine on some vascular beds has also been reported. This study was designed to explore the effect of modifying the concentration of endogenous adenosine on the blood flow through three different arterial resistance beds (renal, mesenteric and hindquarters vascular beds). Augmentation of endogenous adenosine concentration was achieved via the use of two agents with two different modes of action: monophosoryl lipid A (MLA), the 5 nucleotidase activator and nitrobenzylthioinosine (NBMPR), the adenosine transport blocker. These two mechanisms lead to the accumulation of both extracellular and intracellular adenosine. MLA and NBMPR were infused in two different dose levels and blood flow theough the renal, mesenteric and inferior abdominal aorta was detected using flow probe co;:necter: to electromagnetic flowmeter. MLA in low dose induced renal and mesenteric vasodilatation but no change in hindquarters blood flow. In contrast, high dose of MLA induced hypotension, bradycardia, renal and hindquarters vasoconstriction and no change in mesenteric blood flow. NBMPR produced qualitatively similar but quantitatively different results. The adenosine (Al and A2) receptor antagonist, 8 psulfophenyl theophylline (8SPT) abolished the vasodilator but not the vasoconstrictor effects of both drugs indicating that the vasoconstrictor effects are either indirect through hyotension induced pressor refelexs, or mediated through different adenosine receptor subtype. The dual effect of adenosine may suggest an important role in regulation of these organs blood flow The hypotensive and vasodilator effects of exogenously administered adenosine or its analogues have been reported. Adenosine dilated Coronary (Kitakaze et al., 1993), renal (Dunham and Vince, 1986) , pulmonary (Konduri et al., 1996) and mesenteric (Mian and Marshall, 1995) vascular beds. Other contradictory results were obtained by some investigators. A vasoconstrictor effect of adenosine both in vivo (Shepherd et al., 1996) and in vitro in renal (Silldorff et al., 1996) and mesenteric (Rubino et al., 1995) vascular beds have been demonstrated. However, studies in which adenosine is administered exogenously have limited implication as adenosine is exposed to extensive metabolism before reaching the interstitial fluid. thus, a correlation between adenosine dose and its concentration in the interstitial fluid can not be accurately estimated (Van Wylen, 1994). This study was designed to explore the effect of augmenting endogenous adenosine production on the vascular resistance of three important arterial beds (renal, mesenteric and hindquarters vascular beds). Two pharmacological strategies were used to augment the adenosine production: (1) using monophosoryl lipid A (MLA) to activate 5' nucleotidaes enzyme, the enzyme which catalyze the dephosphorylation of 5AMP to adenosine. (2) blocking the extracelular adenosine transport through using the membrane transporters blocker, nitrobenzylthioinosine (NBMPR). MLA, NBMPR and 8 SPT doses were deteremined by pilot experiments guided by the references (Guo et al., 1995; Deussen, 1995) Materials: MLA and 8SPT were from Sigma Chemical Company, Saint Louis (Missouri, USA). NBMPR was from Aldrich Chemical Company, Milwaukee (Wisconsin, USA). These drugs were gifted to Dr. Mt Shehab by Dr. A. S. Abdel-Fattah of Virginia University during his work there. Thiopentone were obtained from EPICO pharmaceutical company, Egypt. NBMPR was dissolved in 0.8% DMSO solution. All other drugs were dissolved in 0.9% NaC1 . Statistical analysis: All data are expressed as mean ± S.E. The results were analyzed by one-way analysis of variance followed by Duncan's multiple range test in comparing results from different groups using the computer program Pharmacological Calculation System. P<0.05 was selected as the level of statistical significance.