Postjunctional effect of pinacidil on contractility of isolated bovine trachealis.

Potassium channel openers hyperpolarize the smooth muscle cell membrane and relax airway smooth muscle. In this study, pre- and postjunctional effects of pinacidil ((+/-) N-cyano-N'-(4-pyridil)-N"-(1,2,2-trimethylpropyl)-guanidine monohydrated), an adenosine triphosphate (ATP)-sensitive K(+)-channel opener, were determined in isolated bovine trachealis. The effects of pinacidil on the frequency-response to electrical field stimulation (EFS), 0.1-32 Hz, and on the concentration response to acetylcholine (ACh), 10(9)-10(-4) M, were compared in muscle strips from six animals. In addition, the effect of pinacidil on the inhibitory nonadrenergic noncholinergic (iNANC) system was evaluated in histamine-contracted muscle strips from another eight animals. Pinacidil (10(-6) or 10(-5) M) shifted both the EFS frequency-response and the ACh concentration-response curves significantly (p < 0.01) to the right. Glibenclamide (10(-7)-10(-5) M) antagonized these responses in a concentration-dependent manner. The inhibitory effects of pinacidil on contractions of the same magnitude induced by EFS or exogenous ACh were not significantly different (p = 0.11), suggesting that pinacidil had only a postjunctional effect. Pinacidil had no effect on iNANC-mediated muscle relaxation. We conclude that pinacidil attenuates the contraction of isolated bovine tracheal smooth muscle by postjunctional mechanisms.

Bronchial provocation test with allergen: comparison between two different techniques.

Allergen bronchial provocation tests (BPTs) are often used for assessment of treatment efficacy. Usually, the allergen dose provoking a 20% fall of forced expiratory volume in one second (FEV1) (PD20) is determined on a prestudy day, and this single dose is administered for comparisons on study days. The inhalation of allergen may cause both an isolated early asthmatic response (EAR) or, more frequently, an EAR followed by a late asthmatic response (LAR). Whether the method used to elicit EAR, i.e. the inhalation of cumulative doses up to PD20 or the inhalation of a single predetermined PD20, give comparable results has not been established. We have, therefore, compared the results obtained using the two methods. Twelve patients underwent a first BPT with the increasing doses method and a second BPT with a single dose method. EAR, LAR, and allergen-induced increase of methacholine (MCh) sensitivity were compared. Both methods gave similar EAR's and LAR's although EAR tended to be more severe with the increasing dose method than with the single dose method. The ratio of postallergen/preallergen MCh sensitivity was poorly reproducible.

Malignant arrhythmias and acute myocardial ischemia: interaction between flecainide and the autonomic nervous system.

The antiarrhythmic and proarrhythmic effects of flecainide were assessed in 21 anesthetized cats. Ventricular arrhythmias can be reproducibly induced in cats by the combination of acute myocardial ischemia and sympathetic stimulation. Premature ventricular contractions (PVCs), sustained (sVT) and nonsustained (nsVT) ventricular tachycardia (VT), or ventricular fibrillation (VF) may be induced by a 1-minute left stellate ganglion stimulation during a 3-minute coronary artery occlusion. After three trials yielding consistent results, flecainide (2 mg/kg intravenous bolus plus 2 mg.kg-1.hr-1 intravenous infusion) was injected and two additional trials performed. Eight cats also underwent two trials after propranolol (0.2 mg/kg) administered while flecainide infusion was maintained. Flecainide decreased heart rate and blood pressure and slightly prolonged JTc (9%, p < 0.05). It markedly augmented QRS duration (61%, p < 0.0001), which was increased by an additional 61% (p < 0.0001) during sympathetic stimulation. VF was observed in 8 animals and never after flecainide (p < 0.05). However, after drug administration all cats had VT (2 nsVT and 6 sVT), and 5 required cardiac massage. Flecainide did not prevent the occurrence of nsVT in 6 cats, and it worsened arrhythmias by inducing VT (4 nsVT and 2 sVT) in 6 cats with only PVCs or without arrhythmias in the control trials. Propranolol, administered while flecainide infusion was maintained, prevented the increase in heart rate and the marked QRS prolongation during sympathetic stimulation (4 +/- 3 vs 52 +/- 16 msec, p < 0.05) and abolished the proarrhythmic effect of flecainide in 4 of 5 animals. Thus flecainide, despite an antifibrillatory effect, does not prevent and actually may favor the occurrence of sVT during acute myocardial ischemia and enhanced sympathetic activity. Propranolol, by countering the increase in heart rate during sympathetic stimulation, prevented the rate-dependent conduction delay and abolished the proarrhythmic effect of flecainide. The exacerbation, whenever a transient ischemic episode is accompanied by elevated sympathetic activity, of the ischemia-induced conduction delay caused by flecainide may in part explain the mortality data in the Cardiac Arrhythmia Suppression Trial.

Development of cardiac innervation, ventricular fibrillation, and sudden infant death syndrome.

The effects of bilateral vagotomy and of right, left, and bilateral stellectomy on sinus node and on ventricular fibrillation threshold (VFT) were assessed in three groups of puppies (1, 3, and 5 wk old) and one group of adult dogs. Heart rate was increased by vagotomy and reduced by right stellectomy in all groups. After vagotomy, VFT did not change in the first week, while it decreased in the third week (-21%, P < 0.0001), in the fifth week (-20%, P < 0.001) and in the adults dogs (-18%, P < 0.005). VFT was not modified by right stellectomy in the first week and in the fifth week (0%, NS), while it decreased in the third week (-28%, P < 0.05) and in the adults (-32%, P < 0.001). Left stellectomy, performed after right stellectomy, increased VFT in the third week (+52%, P < 0.05), in the fifth week (+62%, P < 0.001), and in the adults (+45%, P < 0.01). Thus removal of either vagal or right cardiac sympathetic activity increases susceptibility to ventricular fibrillation already during the first weeks of life. By contrast, removal of left sympathetic nerves increases cardiac electrical stability. These findings are consistent with the hypothesis that a developmental abnormality in cardiac innervation may play a role in the genesis of some cases of sudden infant death syndrome.