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Acetic acid was found to have actions on urinary bladder smooth muscle in our routine ion channel screening assays. Numerous studies have examined the mechanisms of bladder irritation by acetic acid; however, the direct effect of acetic acid on ion channels in detrusor smooth muscle cells has not been evaluated. We used whole-cell patch-clamp techniques to examine the effect of acetic acid on large-conductance Ca2+-activated K+ channels (BKCa) from guinea pig detrusor smooth muscle cells and CHO cells expressing recombinant human BKCaalphabeta1 (CHO BKCaalphabeta1) and human BKCaalpha (CHO BKCaalpha). Acetic acid activated BKCa currents in a concentration-dependent (0.01% to 0.05% v/v) manner in all the cell systems studied. Acetic acid (0.05%) increased BKCa current at +30 mV by 2764+/-918% (n=8) in guinea pig detrusor smooth muscle cells. Acetic acid (0.03%) shifted the V1/2 of conductance-voltage curve by 64+/-14 (n=5), 128+/-14 (n=5), and 126+/-12 mV (n=4) in CHO BKCaalpha, CHO BKCaalphabeta1 and detrusor smooth muscle cells, respectively. This effect of acetic acid was found to be independent of pH and was also not produced by its salt form, sodium acetate. Automated patch-clamp experiments also showed similar activation of CHO BKCaalphabeta1 by acetic acid. In conclusion, acetic acid directly activates BKCa channels in detrusor smooth muscle cells. This novel study necessitates caution while interpreting the results from acetic acid bladder irritation model.

The effects of labetalol and carvedilol and local cutaneous microvascular perfusion and calculated local cutaneous microvascular resistance were investigated in anesthetized rats at submaximal doses that produced equivalent reductions in blood pressure and heart rate. Labetalol decreased cutaneous perfusion (-25 +/- 3%) without significantly affecting cutaneous vascular resistance (-6 +/- 3%). In marked contrast, carvedilol dramatically increased cutaneous perfusion (+64 +/- 9%) and significantly reduced cutaneous vascular resistance (-57 +/- 3%). These results suggest that carvedilol and labetalol possess differences in the mechanisms by which they produce vasodilation in vivo.

The administration of [D-Ala2,Met5]enkephalinamide (DAME, 10-250 micrograms/kg) or morphine sulfate (MS, 2 mg/kg) into the right atrium (RA) of spontaneously breathing decerebrate rats caused an increase in lung resistance (RL) and a decrease in dynamic compliance (Cdyn). The maximal percentage increase in RL for DAME (250 micrograms/kg) and MS (2 mg/kg) was 120 +/- 21 and 160 +/- 40%, respectively, occurring during the first 30 s following an initial period of apnea, and subsiding within 1.5-2.0 min. The fall in Cdyn (DAME = -31 +/- 8%; MS = -35 +/- 4%) followed a more prolonged time course returning to control within 4-5 min. These responses were completely abolished by pretreatment with naloxone HCl (100 micrograms/kg i.v.), as well as bilateral cervical vagotomy. Pretreatment with antihistaminic, antiserotinergic, and antimuscarinic agents had no effect on the opioid induced changes in RL and Cdyn. Further studies carried out in ventilated animals showed blockade of the mechanical responses following the administration of neuromuscular blockers, C7 spinal cord transection, and ventral midline opening and retraction of the chest. Electromyograms obtained from intercostal muscles showed excitation of expiratory motor units and inhibition of inspiratory motor units following the administration of opioids. Similar results were obtained with phenyldiguanide (PDG), a known stimulant of pulmonary J-receptors. However, PDG effects were not blocked by naloxone. It was concluded that changes in RL resulted from a decrease in thoracic volume and resultant decrease in the radial traction of the airways. Changes in Cdyn were caused by spasm of expiratory muscles of the chest wall.

[D-Ala2,Met5]enkephalinamide (DAME), [D-Ala2,Leu5]enkephalinamide (DALE) and morphine sulfate (MS) increase activity in the recurrent laryngeal nerve (RLN) within 1 s subsequent to right atrial administration. The activation of the RLN was correlated with a large increase in the resistance to airflow in the in situ isolated larynx. Single unit recurrent laryngeal motoneuron recordings showed that the increase in laryngeal resistance was caused by the continuous activation and recruitment of expiratory motoneurons. Results obtained with opioids mimicked those of phenyldiguanide (20-40 micrograms/kg RA), an agent known to stimulate pulmonary J-receptors. Opioid-induced increases in laryngeal resistance were blocked by bilateral section of the RLN and pretreatment with naloxone (100 micrograms/kg RA). Naloxone had no effect on PDG responses. During the initial period of laryngeal motoneuron activation, the phrenic nerve (PN) was inhibited, however, the activation of the RLN was not dependent upon PN inhibition. It was concluded that stimulation of pulmonary opiate receptors, which may be associated with vagal afferents, elicit a reflex activation of expiratory recurrent laryngeal motoneurons resulting in an increase in laryngeal resistance.

The administration of [D-Ala2,Met5]enkephalinamide (D-AME) and [D-Ala2,Leu5]enkephalinamide (D-ALE) into the right atrium of decerebrate rats caused bradycardia, a slight transient biphasic blood pressure response and apnea within 1-2 sec. Apnea was followed by rapid shallow breathing. These effects were dose related (1-1000 micrograms/kg) and blocked by pretreatment with naloxone. Atropine blocked the bradycardia. Sectioning the vagi at the level of the diaphragm did not affect the responses, whereas bivagotomy below the cardiac branches abolished all responses. The triad of responses was attributed to a reflex action arising from vagal afferents within the lung. These results were confirmed in paralyzed , artificially ventilated animals. In these animals, the enkephalin analogues produced a cessation of phrenic nerve (PN) activity followed by a decrease in the duration of bursts. The recurrent laryngeal nerve (RLN) was concomitantly excited in a continuous decremental fashion. This excitation was independent of PN inhibition. Recordings of single and near single pulmonary vagal afferents demonstrated no effect of D-AME or D-ALE on stretch and irritant receptors. However, type J-receptors were stimulated.