ALPHA ADRENERGIC REGULATION OF AIRWAY BLOOD FLOW

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DESCRIPTION (Adapted from the applicant's abstract): Asthma is considered to be an inflammatory airway disease. The airway circulation is therefore likely to participate in some of its manifestations including exercise induced bronchoconstriction, airway wall edema and the clearance of locally released spasmogens. However, in contrast to airway smooth muscle responsiveness, information on the effect of inflammation on airway vascular smooth muscle responsiveness is lacking. The airway vasculature is part of the systemic circulation and norepinephrine (NE) is the principal neurotransmitter for the local adrenergic regulation of airway blood flow. In recent studies, the principal investigator has shown that asymptomatic asthmatics have an exaggerated vasoconstrictor response in the airway to an inhaled adrenergic agonist and that repeated antigen challenge potentiates NE-induced contraction of small bronchial arterial rings in sensitized rabbits. These observations indicated that inflammation causes alpha-adrenergic hyperresponsiveness of the airway vasculature, possibly as an adaptive mechanism to counteract inflammatory vasodilation. The present proposal is based on the hypothesis that the inflammatory increase in alpha-adrenergic vascular responsiveness is due to upregulated alpha-adrenergic signaling in vascular smooth muscle or decreased alpha-adrenergic generation of endothelial relaxing factors, or both. This will be tested by 1) assessing the effects of short-term and long-term inflammatory stimulation on alpha1 and alpha2-receptor expression and adrenergic signal transduction in rabbit bronchial arterial smooth muscle and in endothelium, 2) correlating these findings with NE-induced bronchial arterial contraction and its endothelial modulation, 3) comparing alpha-adrenergic responsiveness of airway blood flow between asthmatics and normals, and 4) determining the effect of glucocorticosteroids on enhanced alpha-adrenergic responsiveness. These experiments are expected to yield new information on the regulation of the airway circulation in bronchial asthma and possibly identify novel therapeutic approaches.