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Long-term exposure to beta 2-receptor agonist specifically desensitizes beta-receptor-mediated venodilation
1Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
Abstract:
Desensitization of human vascular smooth muscle has not been shown after long-term exposure to agonist. Using the dorsal hand vein compliance technique, we measured the vascular sensitivity to isoproterenol, alprostadil, and nitroglycerin. Nine volunteers were studied after receiving no treatment or after 7 days of the beta 2-agonist terbutaline (5 mg three times daily). Terbutaline pretreatment desensitized the vascular response to isoproterenol, resulting in a fourfold increase in the dose of isoproterenol required to produce 10% vasodilation (geometric mean after terbutaline, 100.8 ng/min; without terbutaline, 26.7 ng/min; p < 0.001). The desensitization was specific for beta 2-receptor-mediated effects. We have therefore shown that dynamic regulation of vascular responsiveness by long-term exposure to beta 2-receptor agonist occurs in humans. This selective desensitization of vascular beta-adrenergic responsiveness will result in mixed alpha- and beta-adrenergic agonists, such as epinephrine, becoming relatively more vasoconstrictive, and it also has important implications in blood pressure response to stress.
Insights
Long-term exposure to beta 2-agonist terbutaline desensitizes human vascular smooth muscle to isoproterenol. This selective beta-adrenergic desensitization impacts blood pressure regulation and agonist effects.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Smooth Muscle Biology
Background:
- Vascular smooth muscle desensitization to agonists after long-term exposure has not been previously demonstrated in humans.
- Understanding dynamic regulation of vascular responsiveness is crucial for cardiovascular health.
Purpose of the Study:
- To investigate the effects of long-term beta 2-agonist exposure on human vascular smooth muscle responsiveness.
- To determine if terbutaline desensitizes vascular responses to specific agonists in humans.
Main Methods:
- Utilized the dorsal hand vein compliance technique to measure vascular sensitivity.
- Assessed responses to isoproterenol, alprostadil, and nitroglycerin before and after 7 days of terbutaline administration in nine volunteers.
Main Results:
- Terbutaline pretreatment significantly desensitized the vascular response to isoproterenol, requiring a fourfold higher dose for 10% vasodilation (p < 0.001).
- This desensitization was specific to beta 2-receptor-mediated effects, with no significant changes in response to alprostadil or nitroglycerin.
- Demonstrated dynamic regulation of vascular responsiveness in humans following prolonged beta 2-receptor agonist exposure.
Conclusions:
- Long-term terbutaline exposure induces selective beta 2-adrenergic desensitization in human vascular smooth muscle.
- This selective desensitization can alter the relative vasoconstrictive effects of mixed adrenergic agonists like epinephrine.
- Findings have significant implications for understanding blood pressure regulation under stress and therapeutic interventions.