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Altered muscarinic receptor properties and function in the heart in diabetes
Abstract:
The cardiac cholinergic system was studied in streptozotocin (STZ)-diabetic and age-matched control rats. STZ-diabetic rats (8-10 weeks) were supersensitive to the negative chronotropic effects of acetylcholine, carbamylcholine and bethanechol; inotropic responses to these muscarinic agonists were unaltered. This phenomenon was associated with a decrease in acetylcholinesterase activity but no change in the rate and extent of neuronal choline uptake. [3H]N-methylscopolamine bound to muscarinic receptors in atria from both groups of rats with the same high affinity. The density of [3H]N-methylscopolamine binding sites, however, was 34% lower in atria from STZ-diabetic rats. Agonist binding affinity was lower in diabetes; carbamylcholine had a lower affinity for both the high- and low-affinity receptors. These results indicate that cardiac cholinergic supersensitivity in right atria in diabetes occurs before the development of autonomic neuropathy insofar as neuronal [3H]choline uptake is unaltered at this stage of STZ diabetes. Changes in agonist binding conformation, without a concomitant change in antagonist binding affinity, suggest that supersensitivity of right atria to muscarinic agonist may be a consequence of altered coupling of muscarinic receptor to transduction mechanisms involved in chronotropism in diabetes.
Insights
Diabetic rats show increased sensitivity to acetylcholine
Area of Science:
- Cardiovascular Physiology
- Neuropharmacology
- Diabetic Complications
Background:
- The cardiac cholinergic system plays a crucial role in regulating heart rate and contractility.
- Diabetes mellitus is known to affect autonomic nervous system function, including cardiac innervation.
- Understanding early changes in the cardiac cholinergic system during diabetes is vital for managing cardiovascular complications.
Purpose of the Study:
- To investigate alterations in the cardiac cholinergic system in streptozotocin (STZ)-induced diabetic rats.
- To determine the effects of diabetes on muscarinic receptor binding and function in the rat heart.
- To explore the relationship between cardiac cholinergic changes and the early stages of diabetic autonomic dysfunction.
Main Methods:
- Studied streptozotocin (STZ)-diabetic and age-matched control rats.
- Assessed chronotropic and inotropic responses to muscarinic agonists (acetylcholine, carbamylcholine, bethanechol).
- Measured acetylcholinesterase activity, neuronal choline uptake, and [3H]N-methylscopolamine binding to muscarinic receptors in atrial tissue.
Main Results:
- STZ-diabetic rats exhibited supersensitivity to the negative chronotropic effects of muscarinic agonists, while inotropic responses remained unchanged.
- A decrease in acetylcholinesterase activity was observed in diabetic rats, but neuronal choline uptake was not altered.
- [3H]N-methylscopolamine binding revealed a 34% lower density of muscarinic receptors and reduced agonist binding affinity in diabetic atria.
Conclusions:
- Cardiac cholinergic supersensitivity in the right atria of diabetic rats precedes overt autonomic neuropathy.
- Altered muscarinic receptor-effector coupling, rather than changes in receptor density or choline uptake, likely underlies the observed chronotropic supersensitivity.
- These findings highlight early, specific changes in cardiac muscarinic receptor function in diabetes, impacting heart rate regulation.