Regulation of spontaneous tone in guinea pig trachea

Asthma is a common disease, characterized by periods of bronchoconstriction of unclear origin. This thesis examines a specific behavior of airway smooth muscle, the so-called spontaneous airway tone. It was suspected that a defect regulation of this tone may be a cause of asthmatic bronchoconstriction. The experiments shows that tracheal preparations can display two types of spontaneous tone. In traditionally high (94 %) oxygen, preparations display a strong, smooth, irregular type of tone, while in 12 %, they display a weaker, regularly oscillating spontaneous tone. The different behavior was found to be caused by the neuroepithelial endocrine (NEE) cells releasing powerful relaxing and contracting factors only in low oxygen environments. Capsaicin, the pungent principal of red peppers, was found to be able to strongly suppress both types of tone. This effect is proposed to be caused by a reduction of the release of substance P from the sensory C-fibers. Substance P is believed to be the "motor" of the spontaneous tone, and it appears to act through a new receptor, that is resistant to the blocking effect by presently available tachykinin antagonists. Interestingly, it proves that some inhibitory nerves, that are important for the development of the spontaneous airway tone, are resistant to the blocking action of tetrodotoxin. It is argued that the oscillating spontaneous tone in 12 % oxygen is physiologically normal. Furthermore, the findings that the NEE cells release powerful relaxing and contracting factors, and the suggestion that substance P stimulates the tone through a new substance P receptor, may result in new therapies for asthma

SAR studies of capsazepinoid bronchodilators. Part 1: The importance of the catechol moiety and aspects of the B-ring structure.

Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This part concerns the catechol moiety of the A-ring as well as the 2,3,4,5-tetrahydro-1H-2-azepine moiety (the B-ring) of capsazepine. It is revealed that a conformational constrain (as a fused ring) is important and that compounds with a six-membered B-ring (as a 1,2,3,4-tetrahydroisoquinoline) in general are more potent than the corresponding isoindoline, 2,3,4,5-tetrahydro-1H-2-benzazepine and 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives

SAR studies of capsazepinoid bronchodilators. Part 2: Chlorination and catechol replacement in the A-ring.

Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This paper concerns the chlorination of the A-ring as well as the replacement of the catechol with bioisosteric groups. It is revealed that chlorination of the A-ring has a profound effect on activity. Moreover, di-chlorination of the 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline structure results in a 10-fold increase in potency compared to capsazepine

SAR studies of capsazepinoid bronchodilators 3: The thiourea part (coupling region) and the 2-(4-chlorophenyl)ethyl moiety (C-region).

Certain derivatives and analogues of capsazepine are potent in vitro inhibitors of bronchoconstriction in human small airways. During an investigation of the dependency of the potency on the structural features of the capsazepinoids in the thiourea moiety (coupling region) and the 2-(4-chlorophenyl)ethyl moiety (C-region), it was revealed that capsazepinoids with a thiourea or an amide link between the B-ring and the C-region in general have a good bronchorelaxing activity, while urea is a less attractive choice. Further, it was shown that 1,2,3,4-tetrahydroisoquinolines with a 2-(phenyl)ethyl derivative as the C-region are considerably more potent than those with an octyl group, while 2,3,4,5-tetrahydro-1H-2-benzazepines were found to be more insensitive to the nature of the C-region

Oral iodinated activated charcoal improves lung function in patients with COPD.

The effect of 8 weeks treatment with oral iodinated activated charcoal (IAC) on lung function of patients with moderate chronic obstructive pulmonary disease (COPD) was examined in a double blind randomized placebo controlled parallel group study with 40 patients. In the IAC group, patients showed a statistically significant improvement of FEV1 baseline by 130 ml compared to placebo, corresponding to 8.2% improvement (p = 0.031*). Correlation statistics revealed that the improvement of FEV1 baseline was significantly correlated both to FEV1 post-bronchodilator (p = 0.0020**) and FEV1 post-exercise (0.033*) values. This demonstrates that the improved baseline lung function by IAC did not inhibit a further beta2-adrenoceptor relaxation, and thus that patients did not reach a limit for maximal improvement of the lung function after IAC treatment. Eight patients in the IAC group developed abnormal thyroid hormone levels transiently during the treatment. This side effect was not correlated to improvement of lung function (p = 0.82). No serious adverse effects directly related to the treatment were recorded. In summary, this study demonstrates that iodinated activated charcoal surprisingly and significantly improved lung function of patients with moderate COPD. The underlying mechanism of action is unclear, but is likely to be different from the drugs used today. The immediate conclusion is that further studies are now justified in order to determine clinical efficacy of IAC in COPD and explore possible mechanisms of action

Effects of capsazepine on human small airway responsiveness unravel a novel class of bronchorelaxants.

Capsazepine is known as a transient receptor potential channel vanilloid subfamily 1 (TRPV1) antagonist that inhibits bronchoconstriction evoked in animals by TRPV1 agonists. In this study, effects of capsazepine and chemically related analogues, so called capsazepinoids, were examined in vitro on contractile effects in human small airway preparations. Repeated cycles with 1 h of LTD4-free physiological saline solution followed by 30 min exposure to LTD4 (10 nM) demonstrated that the contractile responsiveness of the preparations exhibited little change over time despite repeated challenges (> 12 h). Capsazepine (1-100 mu M) reversibly and concentration-dependently inhibited the contractile response to LTD4 with EC50 similar to 10 mu M and similar to 90% relaxation at 100 mu M. Capsazepine (10 M) was approximately equally effective to attenuate the contractions evoked by several different inflammatory contractile agonists (LTD4, PGD(2), histamine), and it relaxed preparations with established tonic contraction due to LTD4. Higher concentrations of capsazepine were needed to relax ACh-contractions. The effect of capsazepine on LTD4-induced contractions was not significantly reduced by pre-treating the preparations with either of propranotol (10 mu M) + atropine (1 mu M), L-NAME (1 mM), indomethacin (1 mu M), iberiotoxin (0.1 mu M), capsaicin (10 mu M), and nifedipine (10 mu M). Although the mechanism of action of the present capsazepine-induced bronchorelaxation remains unknown it emerged here that they represent a generally effective principle exerting a functional antagonism against contractile mediators but distinct from beta receptor agonists and inhibitors of L-type calcium channels. The inhibitory effect of capsazepine is shared by chemical analogues, but not with other TRPV1 antagonists, suggesting the possibility that capsazepine represents a novel class of bronchorelaxants effective in human small airways. These findings were not predicted by previous observations that have concerned quite limited effects of capsazepine on airway tone in different animal test systems. If potency can be further increased and the results translated to in vivo, compounds representing the capsazepinoid class of bronchorelaxants might become useful in the treatment of patients suffering from asthma and COPD

Discovery of a potent and long-acting bronchorelaxing capsazepinoid, RESPIR 4-95

BACKGROUND: Current drugs including beta-agonists have limited smooth muscle relaxant effects on human small airways. Yet this is a major site of obstruction in asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: This study explores human small airway relaxant effects of RESPIR 4-95, a novel chemical analogue (capsazepinoid) to capsazepine. Capsazepine was recently shown to relax small airways in a way which was independent of its TRPV(1) antagonism and independent of current bronchodilator drug mechanisms. METHOD: In vitro preparations of human small airways, 0.5-1.5mm in diameter and responding with reproducible contractions to leukotriene D(4) (LTD(4)) for 12h, were used. RESULTS: RESPIR 4-95 reversibly prevented LTD(4)-induced contractions as well as relaxed the established tonic contraction by LTD(4). RESPIR 4-95 exhibited marked improvements over the reference capsazepinoid, capsazepine, by being 10 times more potent, exhibiting twice as long duration of action after wash-out (9h), and inhibiting equally well LTD(4)-, histamine-, prostaglandin D(2) (PGD(2))-, and acetylcholine (ACh)-induced contractions. RESPIR 4-95 was distinguished from l-type calcium channel antagonist nifedipine by its greater efficacy and potency and by exhibiting increased relaxant effect by repeated exposures. Furthermore, RESPIR 4-95 was more efficacious and longer acting than the long-acting beta-agonist formoterol. CONCLUSION: Efficacy, potency, duration of action, and inexhaustibility of its relaxation of human small airways make RESPIR 4-95 an interesting lead compound for further developments aiming at drug treatment of small airway obstruction in asthma and COPD. Further work is warranted to unveil the molecular biology behind its relaxant actions