Cooper, Jemsy; (1992) An investigation of the effects of potassium channel opening drugs in an in vitro innervated preparation on the guinea-pig trachea. Doctoral thesis (Ph.D.), University College London.

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Abstract

The effects of potassium channel opening drugs (KCOs) were investigated in an in vitro vagally innervated tube preparation of the guinea-pig trachea. It has previously been reported that croraakalim inhibits transmission in pulmonary cholinergic nerves, (Hall & Maclagan, 1988) . This thesis further investigates the action of KCOs on pulmonary nerves using cromakalim (racemate), lemakalim ((-) isomer), BRL38226 ((+) isomer) and SDZPC0400 (an unrelated (-) isomer). Cromakalim, lemakalim and SDZPC0400 did not significantly affect the dose related rise in intraluminal pressure elicited by the spasmogens acetylcholine, histamine or the thromboxane mimetic U46619. Therefore the KCOs do not appear to have any significant antispasmodic action nor do they inhibit postjunctional responses elicited by muscarinic receptor activation. Contractions of the trachea evoked by preganglionic stimulation of the cholinergic vagus nerve (PCS) or transmural stimulation in the presence of hexamethonium (TMS) were both inhibited by cumulative doses of cromakalim, lemakalim or SDZPC0400. The KCOs act prejunctionally on pulmonary parasympathetic cholinergic nerves since they have no action on responses to exogenous acetylcholine which contracts the trachea by acting on postjunctional muscarinic receptors. As the inhibitory effect of cromakalim was greater on responses to PCS than TMS, this suggests that cromakalim has an inhibitory action at the ganglia as well as at the final nerve terminals. The specific blocker of ATP-operated potassium channels, glibenclamide significantly reduced the inhibitory action of cromakalim, lemakalim and SDZPC0400 on contractions of the guinea-pig trachea elicited by PCS and TMS suggesting that ATP operated K"*" channels are opened by these KCOs in the pulmonary nerves, The (+) isomer of cromakalim, BRL38226 caused only a slight inhibition of responses to nerve stimulation, but its presence significantly reduced the effect of lemakalim on responses to both PCS and TMS. It is possible that BRL38226 is blocking K+ channels opened by lemakalim in the pulmonary nerves. Transmitter release in the pulmonary cholinergic nerves could be inhibited by prejunctional muscarinic M2 autoreceptors. An investigation was made into a possible interaction of muscarinic autoreceptors and potassium channels using methoctramine and pilocarpine. However results obtained did not support this theory. Inhibition of nerve-induced contractions (PGS and IMS) by cromakalim was unaffected by the presence of the M2 muscarinic antagonist, methoctramine. The M2 receptor agonist, pilocarpine caused an inhibition of contractions of the trachea to PGS and TMS which was unaffected by the presence of glibenclamide When tracheal tone was raised by the spasmogen histamine, NANC mediated relaxations were seen to transmural stimulation (in the presence of atropine, 1-propranolol and hexamethonium). Cromakalim and lemakalim facilitated these NANC mediated relaxations of the guinea-pig trachea. Experiments were performed to see if this facilitatory effect was due to a potentiation of the effect of the inhibitory NANC transmitter (possibly VIP) on the trachealis muscle. Relaxations of the trachea to VIP were facilitated by cromakalim and lemakalim to the same extent as NANCergic relaxations indicating a postjunctional action of KCOs on facilitation of NANCergic transmission. In summary, in the isolated guinea-pig trachea, opening of potassium channels inhibits cholinergic neurotransmission but facilitates NANC mediated relaxations. The in vivo bronchodilator effect of cromakalim and lemakalim in vivo is probably due to a combination of inhibition of cholinergic bronchoconstriction, a facilitation of NANC mediated relaxation and a direct effect on airway smooth muscle. These properties suggest that potassium channel opening drugs should have potential for clinical use in asthma therapy.

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