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Desensitization of aortic smooth muscle contraction in rats harboring pheochromocytoma
Abstract:
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.
Insights
Pheochromocytoma in rats causes smooth muscle desensitization in aortic rings, independent of hypertension. This desensitization is linked to high catecholamine levels, not blood pressure effects.
Area of Science:
- Pharmacology
- Physiology
- Endocrinology
Background:
- Pheochromocytomas cause severe hypertension due to norepinephrine secretion.
- Understanding catecholamine effects on vascular smooth muscle is crucial.
Purpose of the Study:
- To investigate smooth muscle contraction desensitization in rat aorta due to pheochromocytoma.
- To determine if desensitization is related to hypertension or direct catecholamine effects.
Main Methods:
- Studied aortic ring segments from rats with pheochromocytoma.
- Assessed sensitivity to alpha-1 adrenergic agonist phenylephrine and thromboxane A2 agonist U-46,619.
- Investigated the effects of phentolamine and phenoxybenzamine on contraction and blood pressure.
Main Results:
- Aortic rings from pheochromocytoma rats showed reduced sensitivity and maximal contraction to phenylephrine.
- U-46,619 potency was decreased, but maximal contraction was similar.
- Phentolamine prevented desensitization but not hypertension; phenoxybenzamine was ineffective.
Conclusions:
- Pheochromocytoma induces heterologous desensitization of aortic smooth muscle contraction.
- Desensitization is caused by direct catecholamine effects, independent of hypertension.
- This rat model is valuable for studying high catecholamine concentrations on smooth muscle.