15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Pheochromocytoma

The synthesis of cyclooxygenase products by cultured adrenergic neuronal (pheochromocytoma-12) cells was investigated by measuring both the extent of conversion of [3H]arachidonic acid to prostanoids and the immunoreactive prostanoid concentrations in the bathing buffer. Statistically significant amounts of arachidonic acid metabolites migrated with prostaglandins (PGs) E (81 +/- 14 fmol) and F (68 +/- 13 fmol) and thromboxane B (49 +/- 12 fmol) on thin-layer chromatography plates after incubation of differentiated cells with 1 pmol of [3H]arachidonic acid. The conversion of arachidonic acid to these products was lower in undifferentiated cells, although PGE- and PGF-like metabolites were produced in significant amounts. Both immunoreactive PGE and thromboxane B were detected in the media of differentiated cells and their concentrations were elevated when the cells were exposed to arachidonic acid. The potential significance of the thromboxane production by pheochromocytoma-12 cells was investigated by examining the effect of a stable thromboxane mimetic, U46619, on potassium-stimulated norepinephrine release. The U46619 significantly enhanced norepinephrine release from potassium-depolarized cells. These results are indicative of PGE, PGF and thromboxane production by isolated adrenergic neuronal tissue. A thromboxane receptor agonist also was observed to potentiate norepinephrine release.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Arachidonic Acid; Arachidonic Acids; Cells, Cultured; Norepinephrine; Pheochromocytoma; Prostaglandin Endoperoxides, Synthetic; Prostaglandins E; Sympathetic Nervous System; Thromboxanes

Desensitization of smooth muscle contraction was studied in aortic ring segments obtained from New England Deaconness Hospital rats harboring pheochromocytomas, a norepinephrine-secreting tumor. Rats were studied 5 to 6 weeks after implantation of the pheochromocytoma, by which time severe hypertension had developed. Aortic ring segments from the pheochromocytoma rats were significantly less sensitive to the alpha-1 adrenergic agonist phenylephrine [log10 (ED50) = -7.21 +/- 0.09 vs. -7.63 +/- 0.11 in controls). In addition, the maximal force of contraction induced by phenylephrine was decreased in the aortas from pheochromocytoma rats (1.31 +/- 0.15 g) compared to controls (2.17 +/- 0.23 g). The potency of the thromboxane A2 receptor agonist U-46,619 was decreased in the aortic ring segments from pheochromocytoma rats compared to controls, although it elicited a similar maximal force of contraction. Desensitization of alpha receptor-mediated contraction was prevented by treating the pheochromocytoma-bearing rats with the reversible alpha adrenergic antagonist phentolamine (200 micrograms/kg/hr) via osmotic minipumps for 2 weeks. However, phentolamine did not decrease the hypertension in these rats. Also, large doses of the irreversible alpha adrenergic antagonist phenoxybenzamine (4 mg/kg/day i.p.) did not decrease blood pressure in rats harboring pheochromocytoma or did the drug completely block aortic alpha receptors in these rats as it did in controls. The results indicate that pheochromocytoma induces heterologous desensitization of smooth muscle contraction in rat aorta. The desensitization is due to direct effects of catecholamines unrelated to hypertension. The New England Deaconess Hospital rat harboring pheochromocytoma is an interesting model to study the effects of high concentrations of plasma catecholamines on smooth muscle contraction.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenal Gland Neoplasms; Animals; Aorta; Blood Pressure; Female; In Vitro Techniques; Male; Phenoxybenzamine; Phentolamine; Pheochromocytoma; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Vasoconstriction