Syncope is a common problem experienced by up to 30% of people fainting and accounting for 3% of emergency room visits. Recurrent syncope is seen in 30-50% of patients and is associated with a poor quality of life that improves when the frequency of syncope is reduced. The majority of these patients suffer from neurally mediated syncope (NMS). The traditional model of NMS pathophysiology has focused on prior heightened sympathetic activation, followed by a sudden withdrawal of sympathetic tone and increase in vagal tone, with resultant vasodilation and bradycardia. Recent studies have found that the level of epinephrine rises PRIOR to syncope.
In Specific Aim #1, we will determine the contributions of epinephrine release and clearance to the elevated epinephrine levels. A beta adreneroreceptor agonist similar to epinephrine, isoproterenol is commonly used clinically to induce neurally mediated syncope. Beta- blocking drugs, in particular those with beta-2 antagonism (the receptor at which endogenous epinephrine promotes vasodilation), prevent tilt-induced syncope, and might prevent clinical syncope.
In Specific Aim #2, we will experimentally increase the epinephrine level and test whether this induces neurally mediated syncope. The response to epinephrine is likely to be substantially influenced by genetic heterogeneity in adrenoreceptors. Polymorphisms of these receptors might well account for inter-individual differences in sensitivity to the hemodynamic effects of epinephrine, and possibly in consequence, also susceptibility to syncope.
In Specific Aim #3, we will assess the susceptibility to syncope based upon common polymorphisms of the alpha-2B adrenoreceptor and the beta-2 adrenoreceptor. Using these Specific Aims, we will test the hypothesis that epinephrine or its receptors play an important role in the pathogenesis of neurally mediated syncope.
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