Alpha-2c-Adrenergic Receptors Contribute to Basal Nasal Patency in the Anesthetized Cat

Abstract

Background: Nasal congestion is the most troublesome symptom associated with a variety of upper airway diseases, including allergic rhinitis and the common cold. A better understanding of the mechanisms that regulate nasal cavity caliber may engender the development of novel treatment strategies. It is well accepted that α-adrenergic (both α₁ and α₂) mechanisms play a fundamental role in the control and maintenance of basal nasal patency. JP-1302 is a selective α_2c-subtype antagonist that has been recently described in the scientific literature. Thus, we sought to examine the potential effects of this new pharmacological tool on basal nasal patency. Methods: Using acoustic rhinometry, we studied the activity of the selective α_2c-antagonist JP-1302 on nasal cavity volumes in an anesthetized cat. Cumulative concentrations of JP-1302 were applied directly into the right nasal cavity. Changes in the nasal cavity geometry of the drug-treated naris relative to the untreated left nasal cavity were determined. In separate studies, the nonselective α₂-antagonist yohimbine and the nonselective α₁-antagonist prazosin were run as comparators. Systolic blood pressure was measured at the hind leg, using an ultrasonic Doppler flow detector. Results: JP-1302 (0.03, 0.1, 0.3 and 1.0%) administered by the intranasal route decreased nasal cavity volumes from baseline values by 17, 25, 40 and 40%, respectively. Yohimbine (0.03, 0.1, 0.3 and 1.0%) decreased volumes by 19, 36, 46 and 53%, and topical administration of the nonselective α₁-antagonist prazosin (0.001, 0.003, 0.01, 0.03 and 0.1%) decreased volumes by 6, 47, 56, 64 and 71%, respectively. JP-1302, yohimbine and prazosin, at the dose level tested, did not alter the blood pressure. Conclusions: The present set of experiments indicates that both α₁- and α₂-adrenergic receptors are involved in the maintenance of basal nasal patency in the cat. Moreover, α_2c-receptors may play a significant role in the sympathetic control of upper airway function.

Pharmacological Characterization of a Novel α2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)

“…Moreover, the pig ␣ 2 -adrenoceptor subtypes are pharmacologically more related to those of human than to those of rodents (Wikberg-Matsson et al, 1995). This involvement of the ␣ 2C -adrenoceptor in regulation of basal nasal patency was confirmed by Mingo et al (2010). In addition to acting selectively on large venous sinusoids and collecting veins and to causing decongestion, a selective ␣ 2C -adrenoceptor agonist should not affect blood pressure.…”

Pharmacological Evaluation of Selectiveα2c-Adrenergic Agonists in Experimental Animal Models of Nasal Congestion

“…Therefore, this report represents a natural extension of previous experiments where we demonstrated that nonselective a2-adrenergic agonists such as 6,7,azepine dihydrochloride] produced nasal decongestion in our feline model of congestion . We also previously demonstrated, using a selective a2c-adrenergic antagonist, that a2c subtypes appear to play a role in the regulation of basal patency in the cat (Mingo et al, 2010). Presently, we used acoustic rhinometry, which is a highly sensitive, noninvasive, and reliable technology increasingly used clinically to evaluate nasal patency (Hilberg et al, 1989;Grymer et al, 1991;Riechelmann et al, 1993;Austin and Foreman, 1994;Cingi et al, 2013).…”

“…Acoustic measurements were performed immediately before compound 48/80 was given and at 60 minutes after baseline. The dose of JP 1302 was selected based on historical experience (Mingo et al, 2010). JP 1302 has been shown to affect basal nasal patency (Mingo et al, 2010).…”

“…The dose of JP 1302 was selected based on historical experience (Mingo et al, 2010). JP 1302 has been shown to affect basal nasal patency (Mingo et al, 2010). However, we selected a dose that had no actions on basal nasal cavity dimensions.…”

Scientific Rationale for the Use of Alpha-Adrenergic Agonists and Glucocorticoids in the Therapy of Pediatric Stridor

“…Alpha-adrenoreceptor ( α AR) signaling has a significant regulatory role in maintaining the vasomotor tone of the upper airway [4–8]. The α 1 and α 2 AR are located in the smooth muscle (SM) of the nasal cavernous bodies and the vascular framework of the mucosa that covers the entire upper airway [4–13].…”