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Desensitization of postjunctional alpha 1- and alpha 2-adrenergic receptor-mediated vasopressor responses in rat
Abstract:
Prolonged stimulation of tissues by adrenergic agonists may lead to diminished responsiveness of the tissues to subsequent activation by catecholamines; this phenomenon has been termed desensitization or tachyphylaxis. We have examined the in vivo consequences of prolonged stimulation of vascular alpha-adrenergic receptors in rats harboring pheochromocytoma, a tumor that secretes catecholamines. In both early (3-4 weeks after implantation) and late (6-7 weeks after implantation) stages of tumor development, New England Deaconess Hospital rats with transplanted pheochromocytomas developed hypertension and tachycardia and had plasma dopamine and norepinephrine concentrations markedly greater than controls. In both these stages of pheochromocytoma, pressor responses to several vasoconstrictors were examined after pithing. Rats with the tumor were found to become progressively subsensitive to alpha-adrenergic agonists. In the early phase of pheochromocytoma, loss in sensitivity was found for both alpha 1- and alpha 2-adrenergic agonists, whereas responsiveness to the nonadrenergic vasoconstrictors Arg-vasopressin and angiotensin-II was intact (homologous desensitization). However, in the later stage of pheochromocytoma, pressor responses to all these vasoconstrictive agents and also to stimulation of the complex sympathetic outflow were found to be subsensitive (heterologous desensitization). In plasma membranes prepared from mesenteric arteries of early stage tumor-bearing rats, [3H]prazosin binding sites were significantly decreased to 150 +/- 12 fmol/mg vs. 234 +/- 19 fmol/mg in controls. [3H]Yohimbine binding sites were not significantly altered. Our results show that both postjunctional alpha 1- and alpha 2-adrenergic receptor-mediated vasopressor responses can be specifically attenuated in the presence of chronically elevated endogenous catecholamine levels produced by pheochromocytoma and that each alpha-receptor subtype may be differently regulated in the development of desensitization.
Insights
Prolonged exposure to high catecholamine levels from pheochromocytoma causes reduced sensitivity to alpha-adrenergic agonists in rats. This desensitization affects both alpha-1 and alpha-2 receptors, impacting blood pressure regulation.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Endocrinology
Background:
- Prolonged stimulation by adrenergic agonists can lead to tissue desensitization or tachyphylaxis.
- Pheochromocytoma is a tumor that secretes catecholamines, providing a model for studying chronic adrenergic stimulation in vivo.
Purpose of the Study:
- To investigate the in vivo consequences of prolonged stimulation of vascular alpha-adrenergic receptors in rats with pheochromocytoma.
- To characterize the desensitization of adrenergic receptors under conditions of chronically elevated endogenous catecholamines.
Main Methods:
- Transplantation of pheochromocytomas into rats to induce chronic catecholamine excess.
- Measurement of blood pressure, heart rate, and plasma catecholamine levels.
- Assessment of pressor responses to various vasoconstrictors, including alpha-adrenergic agonists, Arg-vasopressin, and angiotensin-II.
- Quantification of alpha-adrenergic receptor binding sites ([3H]prazosin and [3H]yohimbine) in mesenteric artery plasma membranes.
Main Results:
- Rats with pheochromocytoma developed hypertension and tachycardia with elevated plasma catecholamines.
- Progressive subsensitivity to alpha-adrenergic agonists was observed in tumor-bearing rats.
- Early stages showed homologous desensitization (alpha-1 and alpha-2 receptors), while later stages exhibited heterologous desensitization (non-adrenergic vasoconstrictors also affected).
- [3H]prazosin binding sites were significantly decreased in mesenteric arteries of early-stage tumor-bearing rats, indicating reduced alpha-1 receptor density.
Conclusions:
- Chronically elevated endogenous catecholamine levels, as seen in pheochromocytoma, can specifically attenuate alpha-1 and alpha-2 adrenergic receptor-mediated vasopressor responses.
- The study demonstrates homologous desensitization of alpha-adrenergic receptors in early pheochromocytoma stages.
- Alpha-receptor subtypes may be differentially regulated during the development of desensitization in response to chronic catecholamine excess.