RESUMO
The vascular bed in nasal mucosa of different species, including human, is highly vascularized and an extensive sinusoidal network of large capacitance vessels is present deep within the submucosa. When this network of venous sinusoids is engorged with blood, the swollen mucosa reduces the size of the airway lumen and congestion ensues. Nasal vasculature tone is strongly influenced by the sympathetic nervous system and the only drugs approved specifically to relieve vascular nasal obstruction are alpha-adrenoceptor sympathomimetic agents. Due to their vasoconstrictor action, the sympathomimetic decongestants oppose vasodilation, reducing nasal airway resistance and thus facilitating nose breathing. However, standard decongestants that are non-selective alpha-adrenoceptor agonists are associated with the potential for side-effect liabilities including hypertension, stroke, insomnia and nervousness. We propose than a selective alpha 2-adrenoceptor agonist, by acting preferentially on nasal venous capacitance vessels, will elicit decongestion with a reduced side-effect liability. In the present study, we evaluated the effects of the selective alpha 2-adrenoceptor agonist BHT-920 in a real-time tissue contractility assay using isolated pig nasal explants and in an in vivo cat model of congestion. The vasoconstrictor and decongestant effects of BHT-920 were compared to the non-selective alpha-adrenoceptor agonist epinephrine and the standard decongestant oxymetazoline. Our results showed that the alpha 2-adrenoceptor agonist BHT-920 preferentially contracts venous sinusoids confirming previous observations [Corboz MR, Varty LM, Rivelli MA, Mutter JC, Mingo G, McLeod R, et al. Effects of an alpha 2-adrenoceptor agonist in nasal mucosa. Arch Physiol Biochem 2003;11: 335-6, Corboz MR, Rivelli MA, Varty LM, Mutter J, Cartwright M, Rizzo CA, et al. Pharmacological characterization of postjunctional alpha-adrenoceptor in human nasal mucosa. Am J Rhinol 2005;19: 495-502] and displays decongestion without affecting blood pressure. Therefore, an alpha 2-adrenoceptor agonist, by causing constriction in the capacitance vessels of nasal mucosa, can produce nasal decongestion without the effects on blood pressure observed with the standard selective alpha 1-adrenoceptor and non-selective alpha-adrenoceptor sympathomimetic decongestants.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/farmacologia , Descongestionantes Nasais , Administração Tópica , Animais , Azepinas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Gatos , Relação Dose-Resposta a Droga , Epinefrina/farmacologia , Feminino , Masculino , Contração Muscular/fisiologia , Mucosa Nasal/inervação , Mucosa Nasal/fisiologia , Oximetazolina/farmacologia , Receptores Adrenérgicos alfa 2 , Suínos , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
Nasal congestion, one of the major disease features of rhinitis, is induced by the filling of venous sinusoids causing mucosal engorgement with resultant obstruction of nasal airflow. The only available drugs that directly target the underlying vascular features driving nasal obstruction are the sympathomimetic alpha-adrenoceptor agonists due to their vasoconstrictor action. However, standard decongestants are nonselective alpha-adrenoceptor agonists, which have the potential for side-effects liabilities such as hypertension, stroke, insomnia and nervousness. In the present study, the effects of nonsubtype selective alpha(2)-adrenoceptor agonists BHT-920 and PGE-6201204 were evaluated in several isolated nasal mucosa contractile bioassays including dog, pig and monkey, and in a real-time tissue contractility assay using isolated pig nasal explants for BHT-920. The decongestant activity of PGE-6201204 was evaluated in vivo in a cat model of experimental congestion. Our results showed that alpha(2)-adrenoceptor agonists (1) contract nasal mucosa of different species, (2) exert a preferential vasoconstrictor effect on the capacitance vessels (veins and sinusoids), and (3) elicit decongestion. In conclusion, a selective alpha(2)-adrenoceptor agonist causing constriction preferentially in the large venous sinusoids and veins of nasal mucosa and producing nasal decongestion is expected to show efficacy in the treatment of nasal congestion without the characteristic arterio-constrictor action of the standard nonselective sympathomimetic decongestants.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/farmacologia , Descongestionantes Nasais/farmacologia , Mucosa Nasal/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/administração & dosagem , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Azepinas/farmacologia , Gatos , Cães , Relação Dose-Resposta a Droga , Epinefrina/farmacologia , Feminino , Técnicas In Vitro , Macaca fascicularis , Macaca mulatta , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Descongestionantes Nasais/administração & dosagem , Mucosa Nasal/irrigação sanguínea , Mucosa Nasal/fisiologia , Prazosina/farmacologia , Suínos , Porco Miniatura , Vasoconstrição/efeitos dos fármacos , Ioimbina/farmacologia , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
The objective of the present experiments was to study the effects of pulmonary inflammation induced by subacute Sulfur-dioxide (SO(2)) exposure on capsaicin-induced responses in isolated primary vagal sensory neurons and cough. Additionally, we examined the effects of SO(2) exposure on respiratory function and lung histology. All experiments were conducted 24 h after 4 days of subacute SO(2) (1000 ppm, 3 h/day for 4 days) exposure. In in vitro experiments, intracellular Ca(2+) concentrations were measured in single nodose ganglia cells isolated from SO(2) treated and control guinea pigs, using a fluorescence-based methodology. In nodose ganglia cells from SO(2)-exposed animals, intracellular Ca(2+) responses evoked by capsaicin (1 x 10(-7) and 1 x 10(-6) M) were significantly augmented (87% and 59%, respectively) compared to nodose ganglia from control animals. In vivo experiments, cough responses induced by a submaximal dose of aerosolized capsaicin (30 microM) were increased approximately 50% in SO(2) exposed animals compared to control animals. The enhanced cough response produced by SO(2) was inhibited by the corticosteroid, dexamethasone (10 mg/kg, p.o. b.i.d for 4 days and 10 mg/kg, p.o. once on day 5). In separate experiments, guinea pigs exposed to SO(2) displayed a decrease in respiratory frequency and minute ventilation and an increase in enhanced pause (PenH), a surrogate measure for pulmonary obstruction. Associated with the SO(2)-induced increase in cough and changes in respiratory parameters was an increase in BAL neutrophils. BAL neutrophil counts were 5+/-4 and 691+/-141 cells x 10(3)/ml for air and SO(2)-exposed animals, respectively. The neutrophillic inflammation induced by SO(2) was attenuated by dexamethasone treatment. Finally, staining for collagen, smooth muscle and goblet cells showed inflammation, remodeling and goblet cell metaphasia in the SO(2)-exposed animals. Our results demonstrate that SO(2) exposure enhances TRPV1 receptor function at the level of the nodose ganglia. This effect occurs in parallel with an increase sensitivity of the cough response to capsaicin.
Assuntos
Poluentes Atmosféricos/toxicidade , Tosse/fisiopatologia , Inflamação/fisiopatologia , Dióxido de Enxofre/toxicidade , Canais de Cátion TRPV/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Capsaicina/toxicidade , Tosse/induzido quimicamente , Dexametasona/farmacologia , Cobaias , Inflamação/induzido quimicamente , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Gânglio Nodoso/efeitos dos fármacos , Gânglio Nodoso/metabolismo , Testes de Função Respiratória , Canais de Cátion TRPV/metabolismoRESUMO
Nonselective adrenergic alpha-agonists such as phenylpropanolamine and d-pseudoephedrine are widely used as decongestants to treat nasal congestion associated with a variety of nasal diseases. Although the activity of these drugs is well established in clinical studies, a direct comparison of their nasal decongestant effect as determined by changes in nasal cavity dimensions and nasal architecture has not been studied. Using acoustic rhinometry, we evaluated the effects of these drugs on nasal cavity volume, minimum cross-sectional area (Amin), and the distance from the nosepiece to the Amin (Dmin) in a feline, pharmacological model of nasal congestion. Administration of topical compound 48/80 (1%), a mast cell histamine liberator, into the left nasal passageway decreased nasal volume by 66%, reduced Amin by 51%, and increased Dmin by 116%. The congestive responses to compound 48/80 (1%) were reproducible through six weeks. In a subset of cats, the nasal cavity volume effect of repetitive exposure to compound 48/80, given once every two weeks for six weeks, was not different from the nasal responses after the initial exposure to compound 48/80. Pretreatment with oral phenylpropanolamine (10 mg/kg) or oral d-pseudoephedrine (10 mg/kg) attenuated the nasal effects of compound 48/80, but were associated with a pronounced increase in systolic blood pressure of +51 and +82 mmHg, respectively. A similar decongestant profile was observed with phenylpropanolamine (1%) and d-pseudoephedrine (1%) when given topically. Topical phenylpropanolamine (1%) and d-pseudoephedrine (1%) 45 minutes after dosing increased blood pressure +44 and +17 mmHg, respectively, over control animals. We conclude that oral and topical phenylpropanolamine and d-pseudoephedrine display equieffective nasal decongestant activity and produce similar cardiovascular profiles characterized by significant increases in blood pressure.
Assuntos
Agonistas alfa-Adrenérgicos/administração & dosagem , Efedrina/administração & dosagem , Descongestionantes Nasais/administração & dosagem , Obstrução Nasal/tratamento farmacológico , Fenilpropanolamina/administração & dosagem , Administração Oral , Administração Tópica , Animais , Pressão Sanguínea/efeitos dos fármacos , Gatos , Modelos Animais de Doenças , Liberação de Histamina/efeitos dos fármacos , Cavidade Nasal/efeitos dos fármacos , Obstrução Nasal/fisiopatologiaRESUMO
The effect of alpha2-selective adrenoreceptor activation on nasal cavity dimension in an experimental model of congestion has not been defined. Presently, we used acoustic rhinometry to evaluate the decongestant activity of BHT-920, a selective alpha2-adrenergic agonist against nasal congestion produced by intranasal compound 48/80. Administration of the mast cell liberator compound 48/80 (1%) into a nasal passageway decreased ipsilateral volume and minimum cross-sectional area by 73 +/- 4% and 42 +/- 6%, respectively. The congestant effect of compound 48/80 was blocked by topical BHT-920 (0.3 and 1%) in a dose related manner. In addition, the decrease in minimum cross-sectional area produced by compound 48/80 was attenuated after topical BHT-920 treatment. As a comparison we also evaluated the topical decongestant activity effects of the alpha1-adrenergic agonist phenylephrine, and the nonselective alpha-agonist oxymetazoline. Both phenylephrine (0.1-1.0%) and oxymetazoline (0.01-0.3%) produced decongestion. The blood pressure effects of these three drugs also were evaluated. At doses of 0.3 and 1.0%, BHT-920 did not produce hypertension. In contrast, oxymetaZoline (0.01-0.1%) produced a transient hypertension that peaked at 15 minutes and fully recovered 45 minutes after administration. The hypertensive effect of phenylephrine at 0.3 and 1.0% lasted over 60 minutes. The present findings indicate that selective alpha2-agonists may produce decongestant activity with an improved cardiovascular profile compared with current sympathomimetic drugs such as phenylephrine.
Assuntos
Administração Intranasal , Agonistas de Receptores Adrenérgicos alfa 2 , Azepinas/agonistas , Animais , Pressão Sanguínea/efeitos dos fármacos , Gatos , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Masculino , Modelos Animais , Cavidade Nasal/efeitos dos fármacos , Descongestionantes Nasais/agonistas , Obstrução Nasal/tratamento farmacológico , Testes de Provocação Nasal , Oximetazolina/agonistas , Fenilefrina/agonistas , Rinometria Acústica , Fatores de TempoRESUMO
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 alpha-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 microL). 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.
Assuntos
Clorfeniramina/uso terapêutico , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Descongestionantes Nasais/uso terapêutico , Obstrução Nasal/tratamento farmacológico , Piperidinas/uso terapêutico , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Gatos , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Liberação de Histamina/efeitos dos fármacos , Masculino , Cavidade Nasal/efeitos dos fármacos , Cavidade Nasal/patologia , Obstrução Nasal/induzido quimicamente , Obstrução Nasal/fisiopatologia , Nariz/efeitos dos fármacos , Nariz/fisiopatologia , p-Metoxi-N-metilfenetilaminaRESUMO
This is the first report describing the use and pharmacological characterization of nasal patency by both pressure rhinometry and acoustic rhinometry (AcR) in an experimental cat model of nasal congestion. In pressure rhinometry studies, aerosolized compound 48/80 (0.1-3.0%), a mast cell liberator, increased nasal airway resistance (NAR) 1.2 +/- 0.6, 5.8 +/- 0.5, 8.6 +/- 1.1 and 7.9 +/- 1.5 cmH2O.L/minute, respectively. Increases in NAR produced by compound 48/80 were associated with a 395% increase in histamine concentration found in the nasal lavage fluid. Pretreatment with the alpha-adrenoreceptor agonist, phenylpropanolamine (PPA; 0.1-3.0 mg/kg, i.v.), and the NO synthetase inhibitor, NG-nitro-L-arginine (L-NAME; 10 mg/kg, i.v.) attenuated the increases in NAR produced by compound 48/80. The histamine H1 antagonist chlorpheniramine (1.0 mg/kg, i.v.) and the H2 antagonist, ranitidine (1.0 mg/kg, i.v.) had no decongestant activity. Also without decongestant activity were the muscarinic antagonist atropine, the cyclooxygenase inhibitor indomethacin, and the 5-HT blocker methysergide. Aerosolized histamine (0.1-1.0%) also produced a dose dependent increase in NAR. In studies using acoustic rhinometry (AcR), intranasal application of compound 48/80 (0.1-1.0%) elicited pronounced decreases in nasal cavity volumes and minimum cross-sectional area (Amin). Pretreatment with PPA (3 mg/kg, i.v. or 10 mg/kg, p.o.) attenuated the decreases in nasal volume and Amin. The effects of topical intranasal histamine (0.1-1.0%) on nasal geometry were similar to compound 48/80. We conclude that the cat is a useful model for evaluating the pharmacological actions of potential nasal decongestants. Furthermore, we also conclude that AcR is a useful method for noninvasive assessment of nasal patency in a preclinical setting.
Assuntos
Acústica/instrumentação , Resistência das Vias Respiratórias , Modelos Animais de Doenças , Obstrução Nasal/fisiopatologia , Nariz/fisiopatologia , Otolaringologia/métodos , Aerossóis , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Gatos , Relação Dose-Resposta a Droga , Liberação de Histamina/efeitos dos fármacos , Masculino , Obstrução Nasal/induzido quimicamente , Nariz/efeitos dos fármacos , Otolaringologia/instrumentação , Otolaringologia/estatística & dados numéricos , Pressão , Fatores de Tempo , p-Metoxi-N-metilfenetilaminaRESUMO
The R-3327 prostatic tumor implanted in the male Copenhagen x Fischer F1 rat continues to grow because androgen is being supplied from an endogenous source. It follows that regimens which decrease the availability of androgen will retard the growth rate of the tumor. These experiments showed that castration, the antiandrogen flutamide, and the luteinizing hormone-releasing hormone (LHRH) agonist leuprolide inhibited tumor growth. Adrenalectomy alone had no significant effect on tumor size and did not further retard the growth of the tumor in castrated rats. Further, under the conditions of this study, there was no significant difference in tumor growth rates between the groups of rats treated with either flutamide alone or flutamide combined with leuprolide. Total ablation of androgen may not be needed for maximal inhibition of tumor growth.