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The kinin peptides exert their pro-inflammatory effects by the selective activation of two distinct G-protein coupled receptors, termed B1 and B2. The principle kinin peptides involved in the acute inflammatory response are bradykinin (BK) and Lys-BK, which produce their effects via the selective activation of constitutively expressed B2 receptors. The B1 receptor in contrast is not normally expressed, but is induced selectively by certain inflammatory stimuli. Additionally, the B1 receptor is selectively activated by the des-Arg9kinin metabolites, namely des-Arg9BK and Lys-des-Arg9BK, the synthesis of which are also increased during inflammation. Recent investigations into the molecular mechanisms of B1 receptor induction and their distribution and function have shown that, following an inflammatory stimulus, the B1 receptor is induced and may play an important role in the progression of an acute inflammatory response to a more sustained chronic inflammatory state characterised by leukocyte recruitment. This review summarises recent studies on B1 receptor expression and function, and discusses the role of these receptors in regulation of inflammation and their potential as therapeutic targets.

Functional 5-HT4 receptors have been reported to be present in numerous isolated tissue preparations including the rat oesophagus, guineapig ileum, and human colon. The pharmacological properties of the novel, potent and selective 5-HT4 receptor antagonists SB203186 (1-piperidinyl)ethyl 1H-indole 3-carboxylate, SB205008 (1-butyl-1-methyl4-piperidinylmethyl)-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate iodide, and SB207710 (1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4 benzodioxan-5-carboxylate) were studied in these tissues. The nature of antagonism of the 5-HT-induced effects was investigated on the above isolated tissue preparations.

1The pharmacological properties of 5‐hydroxytryptamine (5‐HT), the 5‐HT4receptor agonists, DAU 6236 and SC 53116 and the 5‐HT4receptor antagonist, GR 113808, were studied in the rat oesophagus, rat ileum and human colon.25‐HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus >>human colon > rat ileum with EC50values of 189 ± 15 nM, 157±4nM, 306 ± 72 nM, respectively. 5‐HT also inhibited the spontaneous contractions of the human colon with an EC50value of 119± 1 nM. The effect of 5‐HT on the human colon was not affected by methysergide (10 μM) or ondansetron (1 μAM).3The use of the uptake and metabolism inhibitors, cocaine (30μM) and pargyline (100μM), did not increase the potency of 5‐HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 μM) produced a reduction in carbachol‐induced tone of 22.2 ± 0.6% and reduced the 5‐HT maximum effect by 52.0 ± 0.4%.4The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5‐HT. DAU 6236 relaxed the human colonic circular muscle with an EC50value of 129 ± 16 nM but its efficacy was less than that of 5‐HT. DAU 6236 (1 μM) also antagonized the 5‐HT‐induced relaxation of the human colon with a dose‐ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50value was 1.2 ±0.7μM. DAU 6236 also antagonized the effect of 5‐HT in the rat oesophagus in a non‐surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50value of 91 ± 4 nM, with an efficacy less than that observed to 5‐HT; however, at 200 nM it did not antagonize the 5‐HT‐induced relaxation of the rat oesophagus. SC 53116 showed no agonist activity in the rat ileum and human colon, but at 1 μMit did antagonize the effect of 5‐HT in the human colon with a dose‐ratio of 11.3±0.3.5GR 113808 competitively antagonized the 5‐HT4receptor‐mediated relaxation of the rat oesophagus with a pA2value of 8.59 (8.18‐9.00) against 5‐HT and 9.05 (8.79‐9.31) against SC 53116. GR 113808 (0.01 μM) also antagonized the 5‐HT‐induced relaxation of human colonic circular muscle with an apparent pA2value of 9.02 ±0.12. However at 1 μMthe apparent pA2value was significantly lower than that measured at 0.01 and 0.1 μM. GR 113808 (0.01 μM) antagonized the 5‐HT4receptor‐mediated relaxation of the rat ileum with an apparent pA2value of 9.30 ±0.21.6In conclusion, these studies have shown that the human colon, rat oesophagus and rat ileum contain functional 5‐HT4receptors. However, the 5‐HT4receptor agonists displayed differences in these tissues making it necessary to be cautious when extrapolating from animal to human tissue. This emphasizes the importance of the use of human tissue in the development of therapeutic drugs. The pharmacological properties of 5‐hydroxytryptamine (5‐HT), the 5‐HT4receptor agonists, DAU 6236 and SC 53116 and the 5‐HT4receptor antagonist, GR 113808, were studied in the rat oesophagus, rat ileum and human colon. 5‐HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus >>human colon > rat ileum with EC50values of 189 ± 15 nM, 157±4nM, 306 ± 72 nM, respectively. 5‐HT also inhibited the spontaneous contractions of the human colon with an EC50value of 119± 1 nM. The effect of 5‐HT on the human colon was not affected by methysergide (10 μM) or ondansetron (1 μAM). The use of the uptake and metabolism inhibitors, cocaine (30μM) and pargyline (100μM), did not increase the potency of 5‐HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 μM) produced a reduction in carbachol‐induced tone of 22.2 ± 0.6% and reduced the 5‐HT maximum effect by 52.0 ± 0.4%. The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5‐HT. DAU 6236 relaxed the human colonic circular muscle with an EC50value of 129 ± 16 nM but its efficacy was less than that of 5‐HT. DAU 6236 (1 μM) also antagonized the 5‐HT‐induced relaxation of the human colon with a dose‐ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50value was 1.2 ±0.7μM. DAU 6236 also antagonized the effect of 5‐HT in the rat oesophagus in a non‐surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50value of 91 ± 4 nM, with an efficacy less than that observed to 5‐HT; however, at 200 nM it did not antagonize the 5‐HT‐induced relaxation of the rat oesophagus. SC 53116 showed no agonist activity in the rat ileum and human colon, but at 1 μMit did antagonize the effect of 5‐HT in the human colon with a dose‐ratio of 11.3±0.3. GR 113808 competitively antagonized the 5‐HT4receptor‐mediated relaxation of the rat oesophagus with a pA2value of 8.59 (8.18‐9.00) against 5‐HT and 9.05 (8.79‐9.31) against SC 53116. GR 113808 (0.01 μM) also antagonized the 5‐HT‐induced relaxation of human colonic circular muscle with an apparent pA2value of 9.02 ±0.12. However at 1 μMthe apparent pA2value was significantly lower than that measured at 0.01 and 0.1 μM. GR 113808 (0.01 μM) antagonized the 5‐HT4receptor‐mediated relaxation of the rat ileum with an apparent pA2value of 9.30 ±0.21. In conclusion, these studies have shown that the human colon, rat oesophagus and rat ileum contain functional 5‐HT4receptors. However, the 5‐HT4receptor agonists displayed differences in these tissues making it necessary to be cautious when extrapolating from animal to human tissue. This emphasizes the importance of the use of human tissue in the development of therapeutic drugs.