Nitric Oxide and Compensatory Coronary Vasodilation

Project: Research project

Project Details

Description

DESCRIPTION: (Verbatim from the application): Ischemic heart disease is the
leading cause of death in Western cultures. Ischemia is caused by an imbalance
in the heart's consumption of oxygen and the delivery of oxygen by the coronary
circulation. Under normal conditions, the heart avoids ischemia by tightly
matching myocardial oxygen consumption to coronary blood flow. To date, the
mechanistic basis of this matching remains unknown. Many coronary vasodilators
have been implicated in this process but conclusions have been confounded by
the repeated observation that inhibitors of a single dilator do not impair
physiologic adjustments in coronary blood flow. Several recent studies indicate
a different paradigm, one in which coronary blood flow is not controlled by a
singe vasodilator but by a network of redundant vasodilators. When one
vasodilator in this network is inhibited, another increases their contribution
such that coronary blood flow is preserved. In this regard, several studies
have suggested a link between nitric oxide (NO) and adenosine in moderating
coronary blood flow. Specifically, when NO is inhibited, the contribution from
adenosine may increase, serving as a mechanism of compensatory vasodilation.
The mechanism by which this occurs, however, remains unclear. The application
tests the novel idea that NO directly reduces response to adenosine and that,
when NO production is inhibited, responses to adenosine are potentiated. We
find that, in animals chronically treated with the eNOS inhibitor L-NAME, the
contribution of adenosine to metabolic hyperemia is increased. Based on this
evidence, we hypothesize that adenosine plays an important role as a
compensatory vasodilator when NO production is impaired. This hypothesis will
be tested in 3 specific aims. 1) We hypothesize that increased vasodilator
sensitivity to adenosine is an important compensatory mechanism that maintains
normal coronary blood flow if NO production is chronically impaired. To
complete this aim, we will examine coronary blood flow, microvascular diameter,
interstitial adenosine concentrations and vascular reactivity to receptor
blockade on basal and hyperemic flow I both normal and NO-impaired animals. 2)
We hypothesize that adenosine A2a receptor mediated coronary vasodilation is
augmented by chronic impairment of NO production. We will test this hypothesis
by determining whether the dilation to adenosine A2a receptor stimulation is
enhanced in coronary arterioles in vitro. We will assess the specificity of
this augmentation by determining if alternative dilator pathways are also
augmented by chronic reductions in NO production. (3) We hypothesize that, in
the context or chronic impairment of NO production, the increased vasodilatory
sensitivity to adenosine is associated with an increased expression of
adenosine A2a receptors. We will test this hypothesis by using comparative
RT-PCR analysis of individual coronary arterioles and determining if A2a
receptors are upregulated without changes in other adenosine signaling
molecules. Taken together, these studies will provide a thorough examination of
the role and mechanisms of action of adenosine as a compensatory vasodilator
during chronic NO impairment. This mechanism may contribute to the ability of
the coronary circulation to maintain cardiac perfusion and avoid ischemia
during the early stages of coronary artery disease when NO-dependent dilation
is compromised.
StatusFinished
Effective start/end date9/1/018/31/05

ASJC

  • Medicine(all)