A guinea pig model of nasal secretory responses was developed to assess the contributions of vascular permeability and glandular secretion in the production of nasal secretions. The secretory responses to saline, histamine, chlorpheniramine (H-1-antagonist), cimetidine (H-2 antagonist), and atropine (muscarinic antagonist) on ipsilateral and contralateral (reflex) secretory responses were analyzed by measurement of total protein (Lowry method), I-125-labeled bovine serum albumin (I-125-BSA; administered intravenously) and guinea pig albumin (measured by enzyme-linked immunoabsorbant assay) in nasal secretions. Significant, dose-dependent secretion of total protein, I-125-BSA, and albumin occurred after histamine provocation on the ipsilateral challenged nostril and at several doses on the contralateral (unchallenged) nostril. Histamine-induced total protein and albumin secretion were blocked by chlorpheniramine but not cimetidine. Atropine pretreatment partially reduced total protein secretion. Guinea pig albumin immunoreactive material was detected by immunohistochemistry in superficial vessels, interstitial areas, the epithelium, between glandular cells of submucosal glands, and in gland lumens. Approximately 10% of submucosal gland cells contained albumin immunoreactive material in their cytoplasm. Autoradiography demonstrated that intravenously injected I-125-BSA moved quickly into extracellular areas and then to the epithelium and glands. These observations suggest that histamine stimulates vascular permeability, glandular secretion, and sensory nerve stimulation and that the ipsilateral and contralateral glandular secretion was at least partly due to an atropine-inhibitable cholinergic reflex.