Recent evidence suggests that activation of airway C-fibers, besides causing afferent transmission, also causes release of transmitters from peripheral endings, probably via local axon reflexes, resulting in effects on vascular and bronchial smooth muscle, i.e., vasodilatation, increase in vascular permeability, and bronchoconstriction. In the present study, the release of tachykinins was investigated in the perfused guinea pig lung by various ways of neuronal activation. Substance-P-like immunoreactivity (SP-LI) and neurokinin-A-like immunoreactivity (NKA-LI) was determined by radioimmunoassay in the perfusates. A significantly increased outflow of both SP-LI and NKA-LI was observed during perfusion of the lung with high potassium concentration (60 mM), the C-fiber activator capsaicin (1 microM), bradykinin (1 microM), histamine (100 microM), or the nicotinic agonist dimethylphenyl piperazinium (DMPP) (32 microM). Release of both SP-LI and NKA-LI could also be achieved by electrical stimulation of vagal nerves. The percental increase varied from 80 to 1,000% depending on the kind of stimulus. The release of tachykinins by K+ or capsaicin was greatly reduced in calcium-free medium. Release by histamine was completely inhibited by 1 microM mepyramine, and release by DMPP was abolished by 20 microM hexamethonium. High performance liquid chromatography indicated that NKA-LI consisted of several cross-reacting substances, presumably other peptides of the tachykinin family. Among the isolated mammalian tachykinins, NKA was the most potent one to contract tracheal smooth muscle of guinea pigs in vitro, followed by neurokinin B and by SP. Both NKA and SP relaxed the guinea pig pulmonary artery with similar potency.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac ultrasound investigation of 68 prospectively studied patients with histologically proven midgut carcinoid tumors showed right heart disease in 66%. The abnormal findings included morphologic and functional aberrations of the tricuspid valve in 52% and 83%, respectively, right atrial and ventricular enlargement in 53% and 30%, and paradoxical systolic septal contractions in 19%. The patients with the most pronounced right heart disease had significantly higher (p<.01) plasma levels of the tachykinins neuropeptide K and substance P as well as higher (p<.001) urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid. These patients also had the most extensive tumor disease. The occurrence of echocardiographic abnormalities of the left heart was similar to that in healthy individuals of the same age, but abnormalities were less frequent among the patients with severe right heart disease. Electrocardiographic changes were nonspecific. Right heart disease thus seems to be present more often than previously reported in patients with malignant midgut carcinoid tumors. The severity of cardiac involvement does not seem to be related to the duration of carcinoid disease but more to the extent of the disease, i.e., higher plasma levels of serotonin and tachykinins. Circulation 77, No. 2, 264-269 1988. PATIENTS with carcinoid syndrome often develop a characteristic heart disease previously reported to occur in 19% to 53% of cases. l-6 In a majority of the patients the endocardial fibrous lesions considered to be pathognomonic of carcinoid heart disease2' 7-10 involve the cavities and valves of the right heart. Only a small number of cases with typical changes of the left heart have been reported. l -13 In many patients with carcinoid heart disease, the predominant terminal symptoms and death may be attributed directly to the cardiac disease.1' [14][15][16][17] ever, none of these substances has been found responsible for the characteristic cardiac lesions.The present study was designed to investigate prospectively the extent of cardiac disease in patients with carcinoid tumors by means of ultrasound investigation. In an effort to study possible etiologic agents the urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) and the plasma levels of the tachykinins neuropeptide K (NPK) and substance P (SP) were compared in patients with midgut carcinoid tumors and different degrees of carcinoid heart disease. MethodsStudy population. Cardiac ultrasound studies were performed in 68 consecutive patients (36 women and 32 men) with a midgut type of malignant carcinoid tumor admitted to the Department of Internal Medicine, University Hospital, Uppsala, Sweden, over a 6 year period (1979)(1980)(1981)(1982)(1983)(1984)(1985). The diagnosis of a carcinoid tumor was histologically proven by the Grimelius and Mason silver-staining techniques18' 19 on tumor tissue obtained at biopsy or operation. The patients median age was 64 years (range 38 to 83) and at the time of the cardiac investigation, carcinoid...

In a prospective study of 103 patients with carcinoid tumors consecutively referred for medical treatment, the most common sites of the primary tumors were the ileum (73%), bronchi (7%), and jejunum (4%). All patients had local metastases, and 96 (93%) also had liver metastases. The most common initial symptoms were diarrhea (32%), ileus (25%), and flush (23%). The overall frequency of diarrhea was 84% and of flush was 75%. Heart insufficiency caused by cardiac valve disease was seen in 33% of the patients. The carcinoid syndrome, including flush, diarrhea, and elevated urinary 5-hydroxyindole acetic acid (5-HIAA) concentrations, was manifested by 69 patients (67%), 64 of whom (93%) had carcinoid tumors of mid-gut origin. Elevated urinary 5-HIAA was found in 91 patients (88%), of which 89 displayed liver metastases. The plasma concentration of the tachykinin neuropeptide K (NPK) was elevated in 67 patients (66%), 63 of whom had tumors of the mid-gut region. Serum pancreatic polypeptide (PP) and human chorionic gonadotrophin alpha levels were elevated in 43% and 28% of the patients, respectively, and the highest levels were found in patients with metastatic bronchial carcinoid tumors. Thirty-nine of the 103 patients are now dead; 18 died of tumor progression, whereas 14 patients died of heart failure secondary to a carcinoid tricuspidal valve insufficiency. The estimated median survival from the time of histologic diagnosis was 14 years, and from the time of carcinoid syndrome was 8 years.

By using indirect immunofluorescence histochemistry combined with the elution-restaining technique, the presence of a neurotensinlike peptide in some catecholamine neurons in the rat brain has been demonstrated. At the level of the medulla oblongata neurotensinlike immunoreactivity was observed in most of the small-sized catecholamine (adrenaline) cell bodies in the dorsolateral part of the nucleus of the solitary tract and in some catecholamine (noradrenaline) cells in the medial part. Neurotensin-positive fibers were found throughout the solitary tract nucleus with increasing concentrations in the rostral direction. Very few neurotensin fibers were seen in the vagal dorsal motor nucleus, which contained a dense network of adrenaline fibers. In the ventral mesencephalon, neurotensinlike immunoreactivity was seen mainly in dopamine cell bodies in the ventral tegmental area, including midline structures, with only single examples of coexistence in the substantia nigra. The dopamine cell bodies of both the A9 and A10 cell groups were surrounded by dense to medium-dense networks of neurotensin fibers. In the hypothalamus numerous dopamine neurons in the arcuate nucleus exhibited neurotensinlike immunoreactivity. Neurotensin-positive nerve terminals, partially overlapping catecholamine (mainly dopamine) fibers, were seen in the external layer of the median eminence. The present results demonstrate coexistence of neurotensinlike immunoreactivity and catecholamines in populations of neurons in some of the central catecholamine cell groups and provide a morphological basis for interactions between the peptide and amines.

In this paper, we describe the results of a series of experiments which have examined the distribution within the arcuate nucleus of the hypothalamus of neurons containing the following immunoreactivities: TH-LI, GAD-LI, NT-LI, GAL-LI, GRF-LI, Met-ENK-LI, Leu-ENK-LI, Met-ENK-7-LI, Met-ENK-8-LI, metorphamide-LI, DYN-LI, NPY-LI, SOM-LI, FMRFamide-LI, and CLIP-LI and ependymal tanycytes containing DARPP-32-LI. Using elution-restaining and double antibody staining techniques we have established numerous patterns of coexistence of these various neurotransmitters and neuropeptides. Thus, neurons containing TH-LI were, in some instances, also found to contain GAD-LI, NT-LI, GAL-LI, GRF-LI, Met-ENK-8-LI, Leu-ENK-LI, or DYN-LI or combinations of these compounds. For example, some TH-IR neurons also contained GAL-LI and GRF-LI, while other TH-IR. neurons were also seen to contain GRF- and NT-LI. These neurons may, in fact, contain even more compounds. NPY-IR neurons and those containing SOM-LI and CLIP-LI were distinct and separate from those containing TH-LI. The distribution of these different neurochemical types of neurons and their patterns of coexistence are summarized in Fig. 34, while the relative distribution patterns of immunoreactive fibres in the median eminence are summarized in Fig. 35.