Our aim with this proposal is to obtain pilot data to guide the development of hypothesis and experiments. The goal of this study is to investigate the hypothesis tha acetylcholine (Ach) released from motor neurons with muscle recruitment can alter vascular smooth muscle tone and thereby assist in the coordination of muscle perfusion to the metabolic needs of the active tissue. A major component of this hypothesis is that Ach can evoke vasodilation within a single and brief contraction. A second goal of this proposal is to assess the mechanism by which ACh might alter vascular tone. It is hypothesized that a primary mechanism of Ach-induced dilation in vivo would be the ability of Ach to inhibit release of norepinephrine from adrenergic neurovascular junctions. Thus motor unit recruitment would essentially disconnect sympathetic vasoconstriction thereby facilitating a rapid but passive dilation. Upon arrival at the GCRC, each subject will be weighed and measured for height and forearm volume. The subject will lie supine on a table that is capable of tilting upwards or backwards. Each subject will perform three maximal voluntary isometric contractions on a handgrip device to determine the mean ,maximal strength. The subject will then consume the designated drug preparation for that test. The subject will be instrumented for Doppler measures of brachial aretry blood velocity, mean arterial pressure and heart rate measures. After 45 minutes in the supine position and 30 minutes after drug administration, the study will begin. The study requires that the individual perform single voluntary contractions that vary in intensity and duration. Handgrip exercise will be performed that requires the lifting and lowering of known weight a distance of 5 cm. The weights lifted will be of 4, 8 and 12 kg. These weights have been shown in preliminary pilot studies to elicit maximal expulsion of venous outflow suggesting that the muscle pump effect should not be different across study conditions. nonetheless, the exercising forearm will be elevated 10 cm above the heart to drain the veins and diminish muscle pump contributions to flow dynamics. These single contraction tests will be performed in each of three orally administered drug conditions with each condition occuring on a separate day. In the control condition, no drug will be given. In the second condition, 30 mg of pyridostigmine will be taken. In the third drug day, 60 mg of pyridostigmine will be consumed. To address the issue of the interaction of cholinergic and sympathetic nervous system regulation of vascular tone these tests will be performed in the supine position and while the individual is in a 30 degree head up tilt position. This degree of head up tilt results in an increase sympathetic nervous system discharge with minimum alterations to mean arterial pressure. At least five minutes of head up tilt will occur before data collection to normalize sympathetic output levels. For this study, the tilt test will always follow the baseline supine test. If pyridostigmine administration results in greater increases in blood flow for a given contraction, then Ach from the neuromuscular junction may be impacting on vascular smooth muscle tone. This conclusion would be supported if the flow response is greater with greater doses of pyridostigmine or with greater degrees of contrsaction strength or duration, when increased Ach is expected. If, on the other hand, the flow response is graded with contraction intensity or duration but is not altered by the pyridostigmine this would implicate that an agent released from the skeletal muscle upon contraction (i.e. potassium) is mechanistically involved in the early increase in blood flow.
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