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Selective down regulation of vascular beta 1 adrenergic receptors after prolonged isoproterenol infusion
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Insights
Prolonged isoproterenol infusion downregulates beta-adrenergic receptors in rat blood vessels. Beta-1 receptors showed greater sensitivity loss than beta-2 receptors, impacting cardiovascular drug therapy and understanding agonist mechanisms.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Adrenergic Receptor Research
Background:
- Prolonged isoproterenol infusion reduces cardiac and vascular beta-adrenergic receptor sensitivity.
- Previous studies indicated no change in alpha 1 agonist or phosphodiesterase inhibitor responsiveness.
- The current study investigates differential down-regulation of vascular beta-1 and beta-2 adrenergic receptors.
Purpose of the Study:
- To determine if beta-1 and beta-2 vascular receptors exhibit similar down-regulation following prolonged isoproterenol infusion.
- To compare the susceptibility of beta-1 versus beta-2 adrenergic receptors to desensitization in vascular tissue.
- To explore the implications for congestive heart failure therapy and beta-agonist mechanisms.
Main Methods:
- Utilized rat jugular vein preparation for assessing vascular smooth muscle relaxation.
- Administered prolonged isoproterenol infusion (400 µg/kg/h for 4 days) to experimental rats.
- Compared responses to isoproterenol (beta-2 mediated) and norepinephrine (beta-1 mediated) in infused versus saline-treated rats.
Main Results:
- Isoproterenol-induced relaxation was reduced approximately threefold in tissues from isoproterenol-infused rats compared to controls.
- Norepinephrine-induced relaxation in jugular veins was virtually abolished in isoproterenol-infused rats relative to saline-treated animals.
- Demonstrated differential down-regulation, with beta-1 receptors being significantly more affected than beta-2 receptors.
Conclusions:
- Vascular beta-1 adrenergic receptors are considerably more susceptible to down-regulation than beta-2 adrenergic receptors.
- This differential sensitivity may be crucial for understanding congestive heart failure treatment strategies.
- Provides insights into the mechanisms underlying the inotropic effects of beta receptor agonists.
Abstract:
Prolonged isoproterenol infusion (400 micrograms/kg/h for 4 days) in rats was previously shown to produce a reduction in the sensitivity of both cardiac and vascular beta-adrenergic receptors without affecting responsiveness to alpha 1 agonists or phosphodiesterase inhibitors in either vascular or cardiac muscle. The present study was designed to determine if the loss in beta receptor responsiveness was similar for both beta 1 and beta 2 vascular receptors. The rat jugular vein was previously shown to relax in response to both norepinephrine and isoproterenol with norepinephrine-induced relaxation being mediated by interaction with beta 1 adrenergic receptors and isoproterenol-induced relaxation being mediated by its interaction with beta 2 vascular receptors. Using this preparation, tissues from isoproterenol-infused rats were approximately threefold less responsive to isoproterenol when compared to responses in tissues from saline-treated rats. Relaxation to norepinephrine in jugular veins from isoproterenol-infused rats was virtually abolished relative to the response in saline-treated animals. These data suggest that beta 1-adrenergic receptors in blood vessels are considerably more susceptible to down regulation than are beta 2-adrenergic receptors. This observation may have importance in both the therapy of congestive heart failure, where down regulation of beta-adrenergic receptors has been observed, and in our understanding of the mechanism for the inotropic effects of beta receptor agonists.