Combined histamine H1 and H3 receptor blockade produces nasal decongestion in an experimental model of nasal congestion

We studied the pharmacological actions of combined histamine H-1/H-3 receptor blockade on the increase in nasal airway resistance (NAR) and decrease in :nasal cavity volume-produced by nasal exposure to compound 48/80, a mast cell degranulator. In the anesthetized cat compound 48/80 (1%) produced a maximum increase in NAR of 9.1 +/- 0.7 cmH(2)O . L/minute. The increase in NAR in animals pretreated with a combination of the H-1 antagonist, chlorpheniramine (CTM; 0.8 mg/kg i.v.) and increasing doses of the H-3 antagonist, thioperamide (THIO; 1.0, 3.0, and 10.0 mg/kg i.v.) were (6.1 +/- 2.1, 4.2 +/- 1.0) and 2.2 +/- 0.7 cmH(2)O . Lminute, respectively. A second H-3 antagonist, clobenpropit (CLOB: 0.03, 0.3, and 1.0 mg/kg i.v.) combined with CTM(0.8 mg/kg i.v.) also inhibited the nasal effects of compound 48/80. When the nonsedating H-1 antihistamine, loratadine (3.0 mg/kg i.v.), was substituted for CTM. it also reduced nasal congestion when given in combination with THIO (TO mg/kg i.v.). In contrast, treatment with CTM (1.0 mg/kg i.v.) and the H-2 antagonist, ranitidine (RAN; 1.0 mg/kg. i.v.) were without activity. Loratadine, CTM, CLOB, RAN, or THIO administered alone were inactive. The alpha-adrenergic agonist, phenylpropanolamine (PPA; 3.0 mg/kg i.v.) demonstrated decongestant;effects, but in contrast to H-1/H-3 blockade, PPA produced :a significant hypertensive effect. Using acoustic rhinometry (AcR) we found that combined i.v. CTM (1.0 mg/kg) and THIO (10 mg/kg) and combined oral CTM (10 mg/kg) and THIO (30 mg/kg) blocked the decrease in nasal cavity volume produced by intranasal compound 48/80 (1%, 50 mu L). The conclude that combined H-1/H-3 histamine receptor blockade enhances the efficacy of it H-1 antagonist by conferring decongestant activity to the H-1 antihistamine. We propose that :the decongestant activity of combined H-1/H-3, blockade may provide a novel approach for the treatment of allergic nasal congestion workout the hypertensive liability of current therapies.