Concomitant activity of histamine and cysteinyl leukotrienes on porcine nasal mucosal vessels and nasal inflammation in the rat.
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 D(4) (LTD(4)), 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 LTD(4) on arteries and veins, porcine nasal mucosa was isolated and cut into slices (100-300 microm 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 micromol/l) and LTD(4) (0.001-10 micromol/l) produced a concentration-dependent increase in the lumen area of nasal mucosa arteries and veins. Histamine (0.01 micromol/l) alone produced a 24 and 12% increase in cross-sectional areas of arteries and veins, respectively. LTD(4) (0.001 micromol/l) alone increased artery and vein dilation by about 17 and 9%, respectively. Combination treatment with histamine (0.01 micromol/l) and LTD(4) (0.001 micromol/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).


CONCLUSIONS
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 H(1) receptor antagonist and a CysLT(1) receptor antagonist may have greater benefit than sole treatment with these agents alone.
Lieber
Gissela
G
Neurobiology-Respiratory, Schering-Plough Research Institute, Kenilworth, N.J. 07033-0539, USA.
Jimenez
Johanna
J
Hunter
John C
JC
McLeod
Robbie L
RL
Jia
Yanlin
Y
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003521:Cyclopropanes; D003545:Cysteine / Q000037:antagonists & inhibitors / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006632:Histamine / Q000502:physiology*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology / Q000627:therapeutic use; D006967:Hypersensitivity / Q000188:drug therapy; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors / Q000502:physiology; D015289:Leukotrienes / Q000502:physiology*; D017336:Loratadine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009297:Nasal Mucosa / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011914:Rats, Inbred BN; D012220:Rhinitis / Q000188:drug therapy* / Q000276:immunology; D013440:Sulfides; D034421:Sus scrofa
D000085:Acetates; D003521:Cyclopropanes; D039563:Histamine H1 Antagonists, Non-Sedating; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; D013440:Sulfides; C112381:cysteinyl-leukotriene; D017998:Leukotriene D4; D017336:Loratadine; D006632:Histamine; D003545:Cysteine; C093875:montelukast