dihydropyridines and Bronchial-Hyperreactivity

Candesartan, an AT(1) receptor antagonist, has been reported to have no association with persistent cough in subjects with hypertension, but there has been no study on the safety of its administration to hypertensive patients with symptomatic asthma. The aim of this study was to compare the adverse effects of candesartan and calcium antagonists on cough, pulmonary function, and bronchial hyperresponsiveness in these patients.. Sixty mildly to moderately hypertensive patients with bronchial asthma received either candesartan (n=30) or the calcium antagonists nifedipine or manidipine (n=30) for 6 months. The candesartan group included 5 subjects with a history of ACE inhibitor-induced cough. There were no differences between the 2 groups in patient characteristics, ACE gene polymorphism, pulmonary function, or bronchial hyperresponsiveness to methacholine. Control of hypertension was the primary end point; new cough detected by self-administrated questionnaire and an increase in cough frequency by visual analog scale were the second end point. No patient complained of persistent cough. Neither mean visual analog scale score nor pulmonary functions changed during this study. Bronchial hyperresponsiveness had a tendency to improve in the candesartan group, but there was no difference between the 2 groups.. Incidence, frequency, and severity of persistent cough, pulmonary functions, and bronchial hyperresponsiveness did not change in either the candesartan or calcium antagonist group. It is suggested that candesartan is as effective and safe as calcium antagonists in the treatment of hypertension associated with symptomatic asthma.

Topics: Adult; Aged; Antihypertensive Agents; Asthma; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bronchial Hyperreactivity; Calcium Channel Blockers; Cough; Dihydropyridines; Female; Genetic Testing; Humans; Hypertension; Incidence; Male; Methacholine Chloride; Middle Aged; Nifedipine; Nitrobenzenes; Pain Measurement; Peptidyl-Dipeptidase A; Piperazines; Polymorphism, Genetic; Respiratory Function Tests; Tetrazoles; Treatment Outcome

The effects of minoxidil sulphate, an "atypical" K(ATP) channel opener, and bimakalim, a benzopyran-type classical K(ATP) channel opener, on guinea pig airways in vitro and in vivo and on isolated portal veins from rats and guinea pigs were compared. Minoxidil sulphate inhibited the spontaneous activity of isolated guinea pig and rat portal vein preparations with pD2 values of 7.83+/-0.08 and 7.14+/-0.03, respectively (Emax=100% in both preparations). Bimakalim caused a more potent inhibition with pD2 values of 8.80+/-0.05 and 8.20+/-0.04, respectively (Emax=100% in both preparations). Minoxidil sulphate reduced the spontaneous tone of isolated guinea pig tracheal rings with a pIC50 value of 3.92+/-0.02 and the same efficacy as isoprenaline. Bimakalim was more potent (pIC50=7.25+/-0.02) but less efficacious (Emax=75% of the Emax of isoprenaline). The airway relaxant effect of bimakalim, but not minoxidil sulphate, was antagonised by glibenclamide (pA2=7.50) at concentrations above 0.1 microM. Bombesin-induced bronchoconstriction in anaesthetised, ventilated, normoreactive guinea pigs (measured as increase in total lung resistance) was dose-dependently reversed by intratracheally (i.t.) administered bimakalim (ED50=4 microg/kg; Emax=92% of maximally possible inhibition), but not by minoxidil sulphate, at doses up to 1 mg/kg i.t. In the same animals, following i.t. administration of higher doses, both minoxidil sulphate and bimakalim reduced blood pressure. Airways hyperreactivity to histamine induced by acute treatment of guinea pigs with immune complex was dose-dependently reversed by bimakalim (ED50=0.5 microg/kg i.t., Emax=100%). This effect was antagonised by glibenclamide (30 mg/kg i.v.). Minoxidil sulphate had a biphasic effect on airways hyperreactivity: at 1 microg/kg i.t., airways hyperreactivity was augmented, whereas at doses above 3.2 microg/kg i.t. it caused reversal of airways hyperreactivity. Both of the effects of minoxidil sulphate were insensitive to glibenclamide (30 mg/kg i.v.). It is concluded that the pharmacological profile of minoxidil sulphate in guinea pig airways is completely different from that of classical K(ATP) channel openers such as bimakalim. Minoxidil sulphate is either only weakly active or even inactive at K(ATP) channels in guinea pig airways or interacts with these channels in a different manner. The current results are consistent with there being differences between the K(ATP) channels in airways and blood vessels.

Topics: Adenosine Triphosphate; Animals; Antigen-Antibody Complex; Benzopyrans; Blood Pressure; Bronchial Hyperreactivity; Dihydropyridines; Female; Glyburide; Guinea Pigs; Heart Rate; Histamine; In Vitro Techniques; Male; Minoxidil; Muscle Relaxation; Muscle, Smooth; Muscle, Smooth, Vascular; Portal Vein; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar; Trachea

The intravenous (i.v.) or oral administration of the platelet-activating factor (PAF) antagonist, PCA-4248, to guinea-pigs blocked selectively the bronchoconstriction induced by PAF, as well as the accompanying thrombocytopenia and leucopenia. In addition, PCA-4248 i.v. or intratracheal (i.t.) administration blocked the bronchoconstriction caused by the i.t. instillation of PAF. As in the case of other PAF antagonists, bronchoconstriction caused by the i.t. instillation of antigen was only inhibited by PCA-4248 in guinea-pigs that did not receive a booster injection of antigen during sensitization whereas the booster injection of antigen made anaphylactic bronchoconstriction resistant to the compound. In vitro, when lungs from non-sensitized guinea-pigs were perfused with Krebs-bovine serum albumin (BSA) solution supplemented with PCA-4248, bronchoconstriction and the formation of thromboxane A2 by PAF were blocked. In this in vitro model of perfused lungs, active sensitization with a booster injection of antigen leads to bronchopulmonary hyperresponsiveness to PAF and failure of other PAF antagonists to inhibit the effects of PAF itself. Surprisingly, in lungs isolated from actively sensitized and boosted guinea-pigs, PCA-4248 blocked the effects of PAF, indicating that this compound possesses additional original properties in this model.

Topics: Anaphylaxis; Animals; Blood Cell Count; Bronchial Hyperreactivity; Bronchoconstriction; Dihydropyridines; Female; Guinea Pigs; Histamine Release; Immunization; In Vitro Techniques; Injections, Intravenous; Lung; Male; Platelet Activating Factor; Radioimmunoassay; Thromboxane B2