Effect of pheochromocytoma and hypophysectomy on blood pressure and catecholamines in NEDH rats.

Abstract

SUMMARY The New England Deaconess Hospital (NEDH) rat provides a ratable model with which to study pbeochromocytoma (P); 59% of male rats 700 to 900 days old and 81% of those 900 days or older dereloped spontaneous P. One transplantable P (P259), when implanted into other NEDH rats, markedly increased plasma norepiuephrine and dopamine as well as blood pressure, and usually caused death within 4 weeks. Even without P, about 83% of NEDH rats became hypertensive by 13V4 weeks of age and remained moderately hypertensive until 2 years of age when some animals developed spontaneous P and hypertension became severe. Whether a common mechanism Is responsible for early appearance of hypertension and later development of P remains to be determined. Hypopfaysectomized NEDH rats remained normotensire or slightly hypotenslve despite marked elevations of plasma norepinephrine and dopamine caused by P259 implantation; furthermore, survival was prolonged to 3 months. Catecholamine concentrations in plasma and RBC were usually quite similar, indicating that red blood cells play a significant role in inactivating circulating catecholamines. Unlike the normal adrenal, P259 in NEDH rats contains mainly norepinephrine and dopamine with little epinephrine; it appears that P259 is deficient in the enzyme pbenylethanolaniine-N-methyltransferase (PNMT), which converts norepinephrine to epinephrine. Why hypophysectomy prevents hypertension and prolongs life in rats with P259 implants is unclear; adrenal cortical and thyroid deficiency may play a role. Preliminary observations indicate that hypophysectomy can prevent spontaneous development of P in NEDH rats. T HE New England Deaconess Hospital (NEDH) rat (Wistar related) provides a valuable model for studying pheochromocytoma (P). Spontaneous P occurs in NEDH rats especially with aging. P almost always arises in the adrenal medulla and about 50% occur bilaterally; very rarely it occurs in the organ of Zuckerkandl. Others'-* have reported an increased incidence of P in Wistar rats, up to 85% in old males.1 Warren and Chute* established a transplantable P (P259) from a spontaneous P. When implanted in NEDH rats (other strains reject P259) it will grow rapidly and secrete catecholamines; it causes hypertension, cardiovascular lesions, weight loss, and death usually within 1 month.

Metabolism and storage of catecholamines in rats with pheochromocytoma implants.

“…Table 1 presents the concentrations of CA and conjugated CA in the plasma of NEDH rats with pheochromocytoma implants and their controls. In agreement with earlier findings by Manger et al, 7 rats with the tumor implants showed extremely high plasma concentrations of free DA and NE. Despite the very high level of free DA, DA sulfate concentrations were not detectable and the concentrations of DA glucuronide were similar to those in the NEDH control rats.…”

“…Three days before the experiment, when the plasma NE and DA had risen to levels similar to those previously described, 7 we initiated a 24-hour urine collection, measured the BP, and took a final blood sample as described below.…”

“…4 5 However, it is possible that tissue uptake and metabolism of the released CA may also contribute to their diminished physiological activity, as has been previously suggested. 6 It is not ethically justifiable to infuse CA into patients with pheochromocytoma, but a recent experimental model of pheochromocytoma 7 using New England Deaconess Hospital (NEDH) rats implanted with a P259 tumor 8 permits study of this question. Such rats show high plasma levels of dopamine (DA) and norepinephrine (NE) and manifest high BP and cardiovascular lesions.…”