Adenosine and Nitric Oxide Deficiency

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (Verbatim from the application): Nitric oxide (NO) and adenosine play an important role in modulating vascular tone and protecting organs from ischemia-related injury. There is increasing evidence that NO mechanisms are impaired in a number of conditions, such as in patients with hyperlypemia even before atherosclerosis is apparent. This 'NO deficiency' is believed to contribute to the greater cardiovascular risk that characterizes these patients. Animal experiments show a substantial increase in adenosine production when NO synthesis is experimentally inhibited. We will use the forearm vasculature to test the hypothesis that adenosine plays a compensatory role when NO mechanisms are impaired. We will use the vascular response to intrabrachial infusions of NO-mediated vasodilators and NO synthesis inhibitors to carefully define our patients and controls. The forearm vasculature is well characterized with regards to NO mechanisms, and our preliminary studies indicate that adenosine also contributes to vascular regulation in this model. In Specific Aims I and 2 we will determine if adenosine release and for actions are enhanced when the forearm synthesis of NO is experimentally inhibited, or when NO mechanisms are impaired in otherwise normal subjects with hypercholesterolemia. For this purpose we will measure intravascular and interstitial adenosine concentrations using the microdialysis technique. In Specific Aim 3 we will explore the contribution of adenosine to reactive and metabolic hyperemia, both in normals and in medication-free hyperlipemic patients. Conditions characterized by NO deficiency would benefit from therapeutic approaches that would potentiate the actions of both NO and adenosine. This could be obtained by combined inhibition of phosphodiesterases, thus potentiating NO-mediated cGMP increases, and inhibition of adenosine uptake. Dipyridamole shares these characteristics in vitro, but the precise mechanism of action of this drug has not been well characterized in humans. In Specific Aim 4 we will determine if dipyridamole potentiates the vascular actions of adenosine, of NO-mediated vasodilators (e.g., acetylcholine) and of c-GMP-mediated vasodilators (e.g. nitroprusside). Our focus is to determine if adenosine constitutes an effective compensatory mechanism in NO-deficient states, or if a combined impairment of NO and adenosine mechanisms is present in these patients. In either case, our ultimate target is to develop novel approaches for the treatment of NO-deficiency. This application proposes the following: (1) to determine if adenosine release and/or actions are enhanced when the forearm synthesis of NO is experimentally inhibited or when No mechanisms are impaired in otherwise normal subjects with hypercholesteroiemia (2) to explore the contribution of adenosine to reactive and metabolic hyperemia, both in normal and medication free hyperlipemic patients and (3) to determine if dipyridamole potentiates the vascular actions of adenosine of NO-mediated vasodilators and of c-GMP-mediated vasodilators.