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Cutaneous flushing was provoked in seven patients with metastatic carcinoid tumours and the carcinoid syndrome by an intravenous injection of pentagastrin (0.6 micrograms.kg-1 body weight). The patients were studied before and 1 h after a subcutaneous injection of the long-acting somatostatin analogue octreotide 50 micrograms (Sandostatin). The severity of the carcinoid flush in all the patients was reduced by administration of the analogue. The rise in facial temperature was 1.3 (0.3) degree C before and 0.8 (0.2) degree C after octreotide. Six patients responded to pentagastrin with a rise in the circulating neurokinin A-like immunoreactivity (NKA-LI) and five patients with a rise in circulating substance P-like immunoreactivity (SP-LI). No cutaneous flushing or rise in tachykinin concentration was observed in healthy subjects (n = 6) after injection of pentagastrin. The rise in NKA-LI in the patients was decreased by 61 (14)% and the rise in SP-LI by 54 (13)% after octreotide. Although flushing still occurred, the tachykinin response in two patients was completely abolished. The data demonstrate that the release of tachykinins from carcinoid tumours during pentagastrin-induced flushing is subject to partial inhibition by octreotide. However, the occurrence of a flush in some patients in the absence of a detectable rise in circulating tachykinins indicates that the latter peptides cannot be the sole causative agent of the carcinoid flush.

Bradykinin and structurally related peptides are potent vasodilators and a role for these kinins in the aetiology of the carcinoid flush has been proposed. Using an antiserum directed against the COOH-terminal region of bradykinin in radioimmunoassay, the concentrations of bradykinin-like immunoreactivity in extracts of peripheral blood were compared in patients with carcinoid syndrome (n = 11) and healthy subjects (n = 6). In the fasted state, the concentrations of bradykinin-like immunoreactivity in the patients (10 +/- 5 ng/l) were not significantly different from the concentrations in healthy subjects (6 +/- 3 ng/l). An intravenous injection of pentagastrin (0.6 micrograms/kg) provoked a flush of differing degrees of severity in all patients. In four patients, the flush was concurrent with large rises (277-, 26-, 11- and 10-fold over mean basal values) in bradykinin-like immunoreactivity that was resolved by high performance liquid chromatography into lysyl-bradykinin and bradykinin (approximate ratio 1:2). In two patients, small rises in immunoreactivity (2.4- and 1.7-fold) occurred after the flush and in the remaining five patients no rise in bradykinin-like immunoreactivity was measured. In the healthy subjects, the pentagastrin injection did not provoke a flush and no rises in bradykinin-like immunoreactivity were observed. The data support earlier results obtained using bioassays that the carcinoid flush in some patients is associated with the appearance in blood of bradykinin-related peptides. It has been shown, however, that these kinins cannot be the sole causative agent of the flush. It is suggested, therefore, that the aetiology of the flush is probably multi-factorial.

Intravenous injection of pentagastrin (0.6 microgram/kg body wt) into two patients with metastatic carcinoid tumours evoked a severe carcinoid flush. Analysis by reverse-phase HPLC of acetone-extracts of peripheral blood taken from the patients during the flush indicated the presence of a peptide identified as the residues (1-33) fragment of the alpha-chain of haemoglobin. The peptide was not detected in blood taken from the patients immediately before stimulation of the flush or in the blood of healthy subjects after pentagastrin injection. The observation is interpreted as evidence that the pentagastrin-induce carcinoid flush is associated with the activation and possible release of a tumour protease that result in damage to erythrocytes.