The functional importance of saliva is apparent in patients with xerostomia where lack of saliva results in painful tongue and mucosa; problems with taste and phonation, swallowing, chewing, tooth decay and loss; and increased risk of microbial overgrowth in the oral cavity. Physiologic regulation of salivation results from release of norepinephrine from nerves supplying the parotid gland, which subsequently activates alpha-1 adrenoceptors (alpha1-AR) on parotid acinar cells causing fluid and electrolyte secretion. Alpha1-AR mediated fluid secretion results from the opening of receptor activated Ca2+-dependent Cl- channels. The alpha1-AR subtype causing activation of Ca2+-dependent Cl- channels and fluid secretion is unknown. This study will determine the alpha1-AR subtype that activates Ca2+-dependent Cl- channels in freshly dissociated single cells from rat parotid glands. Alpha1-AR activation of whole-cell Ca2+-dependent Cl- currents will be measured using the perforated-patch configuration of the patch-clamp technique. Alpha1-AR activation of whole-cell Ca2+-dependent Cl- currents in the presence and absence of 5-methylurapidil, WB-4101, and prazosin will be used to determine the alpha1-AR subtype coupled to Cl- efflux and fluid secretion. These drugs are competitive antagonists which are useful in distinguishing the alpha1-AR subtypes known to be present on parotid acinar cells. The effects of oxymetazoline, cirazoline, and xylometazoline in stimulating alpha1-AR induced activation of whole-cell Ca2+-dependent Cl- currents will be measured. These imidazoline agonists will be used to obtain information about the required drug structures needed for varying degrees of receptor-activated Cl- current. Whether or not alpha1-AR modulate Na+-K+ pump activity will be examined using the patch-clamp technique to measure its net outward current. The alpha1-AR subtype modulating Na+-K+ pump activity will also be determined. The present study will add to our understanding of the physiological role of alpha1-AR in regulating fluid secretion in the parotid gland and may provide a rational basis for the design of drugs selective for treating xerostomia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Small Research Grants (R03)
Project #
1R03DE012530-01A1
Application #
2856667
Study Section
Special Emphasis Panel (ZDE1-WG (28))
Project Start
1999-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Creighton University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68178
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Bockman, Charles S; Bruchas, Michael R; Zeng, Wanyun et al. (2004) Submandibular gland acinar cells express multiple alpha1-adrenoceptor subtypes. J Pharmacol Exp Ther 311:364-72
Bockman, C S; Bradley, M E; Dang, H K et al. (2001) Molecular and pharmacological characterization of muscarinic receptor subtypes in a rat parotid gland cell line: comparison with native parotid gland. J Pharmacol Exp Ther 297:718-26