Concomitant Activity of Histamine and Cysteinyl Leukotrienes on Porcine Nasal Mucosal Vessels and Nasal Inflammation in the Rat

Abstract

Background: Histamine and cysteinyl leukotrienes are pivotal mast cell mediators which contribute considerably and likely complementary to the symptoms of allergic rhinitis. Currently, we sought to explore the direct actions of histamine and leukotriene D₄ (LTD₄), a cysteinyl leukotriene, on porcine nasal arteries and veins. We also studied combined blocks of histamine and cysteinyl leukotrienes using loratadine and montelukast in an in vivo model of allergy-mediated nasal inflammation. Methods: For the evaluation of the action of histamine and LTD₄ on arteries and veins, porcine nasal mucosa was isolated and cut into slices (100–300 µm thick). Real-time images of the nasal arteries and veins were recorded and vessel activities estimated by changes in cross-sectional area before and after the tested drugs. For the in vivo studies, the effect of loratadine and montelukast given alone and in combination was examined on upper airway inflammation in ovalbumin-sensitized and -challenged Brown Norway rats. Results: Both histamine (0.001–10 µmol/l) and LTD₄ (0.001–10 µmol/l) produced a concentration-dependent increase in the lumen area of nasal mucosa arteries and veins. Histamine (0.01 µmol/l) alone produced a 24 and 12% increase in cross-sectional areas of arteries and veins, respectively. LTD₄ (0.001 µmol/l) alone increased artery and vein dilation by about 17 and 9%, respectively. Combination treatment with histamine (0.01 µmol/l) and LTD₄ (0.001 µmol/l) increased vessel dilation by 65% (arteries) and 26% (veins). In our in vivo Brown Norway rat studies, oral loratadine (0.01–10 mg/kg) and montelukast (0.01–10 mg/kg) significantly reduced antigen-induced total nasal inflammatory cell infiltration in a dose-dependent manner. The antiinflammatory dose-response curve of loratadine was shifted to the left when studied in combination with montelukast (0.01 mg/kg). Similarly, the dose-response characteristics of montelukast (0.01–10 mg/kg) was shifted in the presence of loratadine (0.01 mg/kg). Conclusion: Our studies support the position that histamine and cysteinyl leukotrienes may act collaboratively to elicit allergic nasal pathologies such as upper airway inflammation and nasal vessel dilation (which may translate into increased nasal mucosal engorgement). Furthermore, the current results are supportive of the hypothesis that combined treatment of allergic rhinitis with an H₁ receptor antagonist and a CysLT₁ receptor antagonist may have greater benefit than sole treatment with these agents alone.

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)

“…Blood vessel constriction in porcine nasal mucosa explants was measured as described previously (Lieber et al, 2010). Porcine nasal turbinates from domestic pigs (male and female, 110 -250 kg) were provided by a local abattoir, Animal Parts (Scotch Plains, NJ).…”

<p>Effects of loratadine, a histamine H₁ receptor antagonist, on the skeletal system of young male rats</p>

“…daily for 4 weeks. We used the dose of 5 mg/kg, because that dose induced some slight skeletal effects in our previous study carried out on mature female rats26 and was in the range of doses which had been earlier used in rats 45. It should be stated, however, that there is very small number of preclinical studies on loratadine administered orally in rats.…”

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

“…We used a pig nasal mucosa explant model to elucidate potential mechanisms of nasal decongestion elicited by compound A and compound B. Specifically, our porcine assay allowed the evaluation of real-time artery and vein activities independently in the nasal mucosa (Lieber et al, 2010). Selective activation of a2c-receptors by both compound A and compound B produced vascular constrictions of arteries and veins; however, a superior pharmacological effect was noted in capacitance vessels.…”

“…The nasal mucosa explant technique was used to evaluate real-time differential vessel constriction of arteries and veins in nasal mucosa as described previously (Lieber et al, 2010). In brief, pig snouts from male and female domestic pigs (110-230 kg) were provided by a local abattoir, Animal Parts (Scotch Plains, NJ).…”