Alan Kirk

5-Hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries : importance of the 5-HT1B receptor

The 5‐hydroxytryptamine (5‐HT) receptors mediating vasoconstriction in isolated human small muscular pulmonary arteries (SMPAs) were determined using techniques of wire myography and reverse transcription‐polymerase chain reaction (RT–PCR). The agonists 5‐HT, 5‐carboxamidotryptamine (5‐CT, unselective for 5‐HT1 receptors) and sumatriptan (selective for 5‐HT1B/D receptors) all caused contraction and were equipotent (pEC50s: 7.0±0.2, 7.1±0.3 and 6.7±0.1, respectively) suggesting the presence of a 5‐HT1 receptor. Ketanserin (5‐HT2A‐selective antagonist, 0.1 μM) inhibited 5‐HT‐induced contractions only at non‐physiological/pathological concentrations of 5‐HT (>0.1 μM) whilst GR55562 (5‐HT1B/1D‐selective antagonist, 1 μM) inhibited 5‐HT‐induced contractions at all concentrations of 5‐HT (estimated pKB=7.7±0.2). SB‐224289 (5‐HT1B‐selective antagonist, 0.2 μM) inhibited sumatriptan‐induced contractions (estimated pKB=8.4±0.1) whilst these were unaffected by the 5‐HT1D‐selective antagonist BRL15572 (0.5 μM) suggesting that the 5‐HT1B receptor mediates vasoconstriction in this vessel. RT–PCR confirmed the presence of substantial amounts of mRNA for the 5‐HT2A and 5‐HT1B receptor subtypes in these arteries whilst only trace amounts of 5‐HT1D receptor message were evident. These findings suggest that a heterogeneous population of 5‐HT2A and 5‐HT1B receptors co‐exist in human small muscular pulmonary arteries but that the 5‐HT1B receptor mediates 5‐HT‐induced vasoconstriction at physiological and pathophysiological concentrations of 5‐HT. These results have important implications for the treatment of pulmonary hypertension in which the 5‐HT1B receptor may provide a novel and potentially important therapeutic target.

Elevated Preoperative C-reactive Protein Predicts Poor Cancer Specific Survival in Patients Undergoing Resection for Non-small Cell Lung Cancer

Background: Although only the minority of patients with non-small cell lung cancer (NSCLC) are suitable for surgical resection, it offers the best possibility of cure. The aim of this study was to examine the relationship between the clinicopathological status, the preoperative systemic inflammatory response, and survival in patients undergoing potentially curative resection for NSCLC. Methods: Data from 96 patients who underwent resection of NSCLC between 2000 and 2003 were collected retrospectively and that for 2004–2006 prospectively. Results: All patients had Eastern cooperative oncology group performance status 0 or 1. No patient had T4, unresectable nodal or metastatic disease, and all macroscopic tumors were removed, with subsequent negative surgical margins. The majority of patients were older than 60 years (71%), men (57%), underwent a lobectomy (65%), and had tumor, node, metastasis stage I disease (66%). Of the markers of the systemic inflammatory response, white cell count, C-reactive protein, and albumin, only an elevated C-reactive protein (>10 mg/L) was associated with cancer-specific survival. On multivariate analysis, only tumor, node, metastasis stage (hazard ratio 1.88, 95% confidence interval 1.34–2.63, p < 0.001) and preoperative C-reactive protein (hazard ratio 1.67, 95% confidence interval 1.01–2.83, p < 0.05) retained independent significance. Those patients with a preoperative C-reactive protein concentration >10 mg/L had a median survival of 26.2 months compared with 75.9 months in those patients with a C-reactive protein ≤10 mg/L (p < 0.05). Conclusion: The results of this study indicate that the presence of a systemic inflammatory response predicts poor outcome in patients who have undergone potentially curative resection for lung cancer.