Since adenosine functions as an endogenous anti-vasoocclusive/cardioprotective autacoid, it is important to elucidate the biosynthetic pathways that regulate the levels of adenosine in and around the vascular tree and to determine whether these pathways are altered by vascular disease. Recent in vitro studies in cultured vascular smooth muscle cells and in isolated kidneys support the existence of a cyclic AMP-adenosine pathway that mediates vascular adenosine production. The cyclic AMP-adenosine pathway is initiated by stimulation of adenylyl cyclase, which triggers egress of intracellular cyclic AMP into the interstitial space via an active transport mechanism. Extracellular phosphodiesterase (ecto-PDE) and ecto-5'-nucleotidase (ecto-5'-NT) in the vascular wall then metabolizes extracellular cyclic AMP to AMP and hence to adenosine. Whether the cyclic AMP-adenosine pathway functions in vivo is unknown. Therefore, the goal of Specific Aim #1 of this proposal is to determine whether the cyclic AMP-adenosine pathway actually exists in vivo. This will be accomplished by examining the effects of intrarenal infusions of cyclic AMP and isoproterenol on the urinary excretion rates of cyclic AMP and adenosine in control rats and in rats pretreated with inhibitors of total PDE, ecto-PDE, ecto-5'-NT, and B-adrenoceptors. It is well-accepted that hypertension-induced damage to blood vessels alters the ability of vascular elements to synthesize autacoids. Moreover, the pilot studies strongly suggest that the cyclic AMP-adenosine pathway is markedly attenuated by hypertension. Since adenosine likely functions as an anti-vasoocclusive/cardioprotective autacoid, hypertension-induced reductions in the cyclic AMP-adenosine pathway could contribute importantly to the vascular sequelae of hypertension. Therefore, the goal of Specific Aim #2 of this proposal is to determine whether the cyclic AMP-adenosine pathway is attenuated in vivo by hypertension-induced vascular damage. This will be accomplished by determining the relationship between urinary cyclic AMP excretion versus urinary adenosine excretion in rats with low, normal and high-renin hypertension.
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