title: Epinephrine regulation of hemodynamics in catecholamine knockouts and the pithed mouse.
abstract: Phenylethanolamine N-methyltransferase (PNMT) catalyzes synthesis of epinephrine (E) and is present in the brain, heart, and adrenal. E is a neurotransmitter and important hormone; however, its role in regulating cardiovascular dynamics is still unclear. We generated an E-deficient mouse model by knocking out the PNMT gene. The PNMT KO mouse had normal resting blood pressure, while treadmill exercise caused hypertension, suggesting an impaired response to stress in the absence of the stress hormone E. As PNMT occurs at a lower concentration in many extra-adrenal tissues including the brain, we set up a pithed mouse model to study the peripheral effects of E on cardiovascular dynamics, using pithing to eliminate central and reflex effects. The pithed mouse requires different surgical techniques and stimulation voltages than rats, and showed voltage- and frequency-dependent blood pressure responses to electrical stimuli. Stimulation with the alpha-adrenergic agonist phenylephrine gave a marked systolic pressor response, while the beta2 agonist salbutamol lowered diastolic blood pressure. The pithed PNMT KO mouse had an exaggerated blood pressure response to salbutamol, suggesting beta2 receptor supersensitivity. A targeted KO of tyrosine hydroxylase in PNMT-producing cells produced a mouse deficient in catecholamines in the adrenal. These targeted KO mice displayed significantly smaller pressor responses than pithed control mice. We find that E release during stress prevents an excessive increase in blood pressure.
authors.affiliation: Department of Medicine, University of California at San Diego, San Diego, California 92103-8341, USA. mziegler@ucsd.edu
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.forename: Xuping
authors.initials: X
authors.lastname: Bao
authors.forename: Hamzeh
authors.initials: H
authors.lastname: Elayan
authors.forename: Milos
authors.initials: M
authors.lastname: Milic
authors.forename: Fujun
authors.initials: F
authors.lastname: Liu
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ziegler
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002395:Catecholamines / Q000235:genetics*; D003655:Decerebrate State; D004558:Electric Stimulation; D004837:Epinephrine / Q000378:metabolism / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010625:Phenylethanolamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D000322:Adrenergic Agonists; D002395:Catecholamines; D010625:Phenylethanolamine N-Methyltransferase; D004837:Epinephrine