Effects of a thromboxane receptor antagonist on prostaglandin D2 and histamine induced bronchoconstriction in man.

Abstract

Many prostanoids including are prostaglandin (PG) F2 alpha and PGD2 are potent bronchoconstrictor agents. There is evidence to suggest that airway thromboxane (TP) receptor may act as a common receptor for their bronchoconstrictor actions. We tested the hypothesis that inhaled prostaglandin (PG) D2-induced bronchoconstriction is mediated by interacting with the TP receptor antagonist, ICI 192605, on the bronchoconstrictor response to inhaled PGD2 in a double-blind, placebo-controlled and crossed-over trial in normal subjects. The effect of ICI 192605 on histamine induced bronchoconstriction served as control for non-specific bronchodilatory actions. The study had two phases; the first consisted of two inhaled PGD2 challenge study days, and the second phase was that of inhaled histamine. Each study day was separated by at least a week. On each study day, the challenge tests were carried out 30 min after ingestion of 100 mg ICI 192605 or placebo. Doubling concentrations of agonist were given till more than 35% fall in post-diluent specific airway conductance (sGaw) occurred. The concentration needed to cause a fall in a sGaw of 35% post-diluent value (PC35sGaw) was then determined from linear interpolation of the log dose-response. Eight male subjects (median age 26, range 20-35 years) completed the study. ICI 192605 did not change baseline airway calibre 30 min after ingestion on either PGD2 or histamine study days. ICI 192605 significantly shifted the dose-response curve to inhaled PGD2 to the right by a median of 3.4 fold (Wilcoxon rank sign test, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin D2and the role of the DP1, DP2and TP receptors in the control of airway reflex events

“…Using a range of pharmacological tools and vagal tissue from receptor deficient mice (although mice do not cough their vagal afferent responses are in many cases similar and comparable to guinea pigs and humans) we have provided significant evidence to suggest that the PGD 2 -induced sensory nerve activation is mediated by the DP 1 (and not DP 2 or TP) receptor. The TP receptor was investigated alongside DP 1 and DP 2, even though TP receptor agonists are not thought to cause cough [33], because PGD 2 is known to mediate airway smooth muscle contraction through the TP receptor [32,34], a finding that was confirmed in this study. One possibility that cannot be ruled out is that PGD 2 -induced bronchoconstriction (via TP activation) could cause cough indirectly via activation of mechanosensitive RARs.…”

“…This was shown to be an effect on airway specific afferents evidenced by the observation that PGD 2 evoked calcium influx into airway specific jugular cells. Furthermore, PGD 2 and a selective DP 1 receptor agonist, but not a DP 2 receptor agonist, caused C-fibre firing in an in vivo electrophysiological model [32]. Using a range of pharmacological tools and vagal tissue from receptor deficient mice (although mice do not cough their vagal afferent responses are in many cases similar and comparable to guinea pigs and humans) we have provided significant evidence to suggest that the PGD 2 -induced sensory nerve activation is mediated by the DP 1 (and not DP 2 or TP) receptor.…”

Evidence of mast cell activation and leukotriene release after mannitol inhalation

“…PGD 2 , as well as 9a,11b-PGF 2 , are potent bronchoconstrictors in man [17], mainly acting on the TP-receptor [18,19]. Pretreatment with selective TP-receptor antagonists attenuated both PGD 2 -and allergen-induced, but not histamine-induced, bronchoconstriction [20][21][22]. Release of PGD 2 into the airways has been further documented after bronchial provocation with allergen [23].…”

Therapeutic Potential of Hematopoietic Prostaglandin D2 Synthase in Allergic Inflammation

“…The role of DP1 in asthma remains elusive; however, in preclinical models of asthma and acute lung injury, DP1 agonism attenuated type 2 inflammation and endothelial cell damage, respectively [8,14]. In contrast, concentrations of PGD 2 and the DP1 agonist BW245c in the micromolar range trigger smooth muscle contraction and bronchoconstriction via the thromboxane receptor [111]. A study involving atopic asthmatic patients could show, however, that thromboxane receptor blockade only partially reduced bronchoconstriction in response to PGD 2 and PGD 2 -induced bronchoconstriction potentially involves a vascular component [112].…”