The main hypothesis of this study is that activation of Alpha2 receptors in the brain lowers blood pressure (BP) and heart rate (HR), and that BP and HR are maintained at low levels in the conscious unstressed state by endogenous activation of these receptors. Certain (but not all) physiologic and pharmacologic interventions may increase BP and HR by acting in the central nervous system to inhibit Alpha2 tone. Conscious sheep chronically instrumented with carotid artery, venous or right atrial, aortic, and cerebral ventricular catheters, and with electromagnetic flowmeters on their main pulmonary arteries, will be used to test the following hypotheses: 1) Control BP and HR are maintained by central Alpha2 tone; stress increases BP and HR by removing this tone. Experiments will be performed to characterize hemodynamic and hematologic responses to mild emotional stress; to show that the Alpha2 antagonist yohimbine raises control (unstressed) BP and HR; and that the Alpha2 agonist clonidine decreases BP during stress but does not lower BP in unstressed sheep. 2) Central PGE-2 increases BP and HR by removing Alpha2 tone. Experiments will show that Alpha2 agonists, Aplha-2 antagonists, and stress (but not phenylephrine) prevent centrally-administered PGE-2 from raising BP. The mechanism of this action of clonidine on the PGE-2 pressor response will be exmained. 3) Not all centrally-acting pharmacologic pressor agents increase BP by inhibiting Alpha2 tone; central angiotensin (AII) raises BP by other mechanism(s). Experiments will show that clonidine, yohimbine, and stress do not prevent centrally-administered AII from raising BP. The relative contributions of sympathetic activation and vasopressin release to the central AII pressor response in conscious sheep will be determined. Demonstration that central AII receptor blockage does not lower BP during stress will show that increased brain AII is not repsonsible for stress-induced increases in BP. 4) Endogenous opioids contribute to central Alpha2 tone. Experiments will show that opiate receptor antagonists raise BP and HR in conscious unstressed sheep. The hemodynamic and hematologic effects and the peripheral mechanism(s) of action of naloxone will be characterized. The effects of manipulating Alpha2 tone with clonidine, yohimbine, stress, and PGE-2 will be studied. We are able to perform all of these experiments and have abundant pilot data to prove feasability. These studies will demonstrate the importance of central Alpha2 receptors in maintaining low (normal) BP and HR. Important new knowldege of central BP control will result.
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