Epinephrine regulation of hemodynamics in catecholamine knockouts and the pithed mouse

Ann N Y Acad Sci. 2008 Dec:1148:325-30. doi: 10.1196/annals.1410.078.

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.

MeSH terms

  • Adrenergic Agonists / pharmacology*
  • Animals
  • Blood Pressure / physiology
  • Catecholamines / genetics*
  • Decerebrate State*
  • Electric Stimulation
  • Epinephrine / metabolism
  • Epinephrine / pharmacology*
  • Heart Rate / drug effects
  • Heart Rate / physiology
  • Hemodynamics / drug effects*
  • Hypertension / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Phenylethanolamine N-Methyltransferase* / genetics
  • Phenylethanolamine N-Methyltransferase* / metabolism
  • Rats

Substances

  • Adrenergic Agonists
  • Catecholamines
  • Phenylethanolamine N-Methyltransferase
  • Epinephrine