Adenosine is an endogenous nucleoside that exerts profound effects on the heart, blood vessel and kidneys via specific cell surface receptors. Hence, a detailed understanding of mechanisms regulating adenosine levels may provide insights into physiological processes and may suggest new therapeutic modalities for cardiovascular and renal diseases. During the past grant period, we identified a novel biochemical pathway that importantly contributes to the modulated production of adenosine. This mechanism, called the cAMP-adenosine pathway, entails the conversion of extracellular cAMP to AMP via ecto-phosphodiesterase (ecto-PDE), followed by the metabolism of AMP to adenosine via ecto-5' nucleotidase (ecto-5'-NT). Our studies indicate that the cAMP-adenosine pathway is operative in aortic vascular smooth muscle cells, pre-glomerular microvascular smooth muscle cells, mesangial cells, cardiac atrial and ventricular fibroblasts, isolated microvessels, perfused vascular beds and intact animals, Having established the existence of the cAMP- adenosine pathway, our next two objectives are to determine how the cAMP- adenosine pathway is regulated and elucidate the physiological/ pathophysiological roles of the cAMP-adenosine pathway. With regard to regulatory mechanisms, recent studies by Kitakaze et al. establish that in cardiomyocytes the alpha1-adrenoceptor agonist methoxamine markedly stimulates ecto-5-NT activity via the Gq/PI-PLC/PKC cascade, and pilot studies in our laboratory suggest that in the rat renal vascular bed methoxamine stimulates ecto-PDE activity by 500%. These findings support the hypothesis that the Gq/PI-PLC/PKC cascade enhance the cAMP-adenosine will be addressed by determining the effects of agents that activate the Gq/PI-PLC/PKC cascade on ecto-enzyme activity and isoproterenol-induced adenosine production and be determining whether these effects are blocked by selective PI-PLC and PKC inhibitors. With regard to the physiological roles of the cAMP-adenosine pathway, we have obtained evidence that the cAMP-adenosine pathway importantly contributes to renal sympathetic nerve activation-induced renal vasoconstriction, a novel concept that will also be addressed in the current proposal.
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