Effect of Polymorphisms in the Adenosine a2a Receptor Gene and AMPD2 Gene on Adenosine-Induced Vasodilation and Reactive Hyperemia

Condition(s) targeted: Blood Flow in Healthy Volunteers

Intervention: Intra-arterial infusion of adenosine (Drug); intra-arterial infusion of caffeine (Drug); intra-arterial infusion of acetylcholine (Drug); intra-arterial infusion of sodium nitroprusside (Drug); Occlusion of arm-circulation by inflation of upper-arm cuff to 200mmHg for 2, 5 and 13 minutes (Procedure)

Phase: N/A

Status: Completed

Sponsored by: Radboud University

Official(s) and/or principal investigator(s):
Gerard Rongen, MD, PhD, Principal Investigator, Affiliation: Radboud University
Paul Smits, MD, PhD, Principal Investigator, Affiliation: Radboud University

The endogenous nucleoside adenosine can induce various cardiovascular and neurohumoral effects by stimulation of specific adenosine receptors. taken together these effects protect against ischaemia-reperfusion injury of (myocardial)muscles and agsinst the development of atherosclerosis. Genetic variations in genes encoding for adenosine receptors or for enzymes involved in the formation or breakdown of adenosine could potentially modulate these effects. In this study, we aim to determine the functional effects of two frequent genetic polymorphisms in the adenosine receptor and AMPdeaminase (involved in the formation of adenosine) on the vascular effects of adenosine.

Official title: The Influence of the 1976T>C Polymorphism in the Adenosine A2A Receptor Gene on Adenosine-Induced Vasodilation and the Influence of the 34C>T Polymorphism in the AMP Deaminase Gene on Post-Occlusive Reactive Hyperemia.

Study design: Diagnostic, Non-Randomized, Open Label, Active Control, Parallel Assignment, Pharmacodynamics Study

Primary outcome:

A2A: adenosine- and caffeine induced vasomotion (blood flow)

AMPD:post-occlusive reactibe hyperemic blood flow

Detailed description: The endogenous nucleoside adenosine can induce various cardiovascular and neurohumoral effects by stimulation of specific adenosine receptors. taken together these effects protect against ischaemia-reperfusion injury of (myocardial)muscles and agsinst the development of atherosclerosis. Genetic variations in genes encoding for adenosine receptors or for enzymes involved in the formation or breakdown of adenosine could potentially modulate these effects. In this study, we aim to determine the functional effects of two frequent genetic polymorphisms in the adenosine receptor and AMPdeaminase (involved in the formation of adenosine) on the vascular effects of adenosine.

In 100 healthy young volunteers, we will determine the genotype of the adenosine A2A receptor gene. We expect to find approximately 15 subjects with the 1976T>C polymorphisms. It is known that this polymorphism is associated with an increased neuropsychological sensitivity to caffeine administration.

We will explore whether this polymorphism is associated with a different vasodilating response to the administration of adenosine and caffeine into the brachial artery. Blood flow will be measured with venous occlucion plethysmography.

Secondly, we will also determine the genotype of the AMPD1 gene. We expect to find 15 subjects with the 34C>T mutation, which is a loss-of-function-mutation. Cardiovascular patients with this mutation are known to have a survival benefit. We will explore whether the post-occlusive reactive hyperemia in the forearm is potentiated, because during ischaemia, more adenosine is formed in these subjects.

Minimum age: 18 Years. Maximum age: 40 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 18-40 year

Exclusion Criteria:

- hypertension

- diabetes

- cardiovascular or pulmonary disease

- asthma

Radboud University Nijmegen Medical Centre, Nijmegen, Gelderland 6500HB, Netherlands

Starting date: November 2005
Ending date: February 2006
Last updated: April 4, 2007