Combined Histamine H 1 and H 3 Receptor Blockade Produces Nasal Decongestion in an Experimental Model of Nasal Congestion

Abstract

We studied the pharmacological actions of combined histamine H₁/H₃ 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 cmH₂0·L/minute. The increase in NAR in animals pretreated with a combination of the H₁ antagonist, chlorpheniramine (CTM; 0.8 mg/kg i.v.) and increasing doses of the H₃ 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 cmH₂0·L/minute, respectively. A second H₃ 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 H₁ antihistamine, loratadine (3.0 mg/kg i.v.), was substituted for CTM, it also reduced nasal congestion when given in combination with THIO (10 mg/kg i.v.). In contrast, treatment with CTM (1.0 mg/kg i.v.) and the H₂ antagonist, ranitidine (RAN; 1.0 mg/kg i.v.) were without activity. Loratadine, CTM, CLOB, RAN, or THIO administered alone were inactive. The α-adrenergic agonist, phenylpropanolamine (PPA; 1.0 mg/kg i.v.) demonstrated decongestant effects, but in contrast to H₁/H₃ 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 μL). We conclude that combined H₁/H₃ histamine receptor blockade enhances the efficacy of an H₁ antagonist by conferring decongestant activity to the H₁ antihistamine. We propose that the decongestant activity of combined H₁/H₃ blockade may provide a novel approach for the treatment of allergic nasal congestion without the hypertensive liability of current therapies.