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Pulmonary Clearance of Vasoactive Intestinal Peptide

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Pulmonary Clearance of Vasoactive Intestinal Peptide Thorax: first published as 10.1136/thx.41.2.88 on 1 February 1986. Downloaded from Thorax 1986;41:88-93 Pulmonary clearance of vasoactive intestinal peptide MICHAEL P BARROWCLIFFE, ALYN MORICE, J GARETH JONES, PETER S SEVER From the Division ofAnaesthesia, Clinical Research Centre, Harrow, and the Department ofClinical Pharmacology and Therapeutics, St Mary's Hospital Medical School, London ABSTRACT Vasoactive intestinal peptide causes bronchodilatation when given intravenously but is less effective in both animals and man when given by inhalation. This difference may be due to poor transit of the peptide across the bronchial epithelium. To test this hypothesis pulmonary clearance of radiolabelled vasoactive intestinal peptide was measured in Sprague Dawley rats and compared with that of pertechnetate (Tc04 ) and diethylene triamine pentaacetate (DTPA). Despite a mole- cular weight (MW) of 3450, iodinated vasoactive intestinal peptide was cleared rapidly from the lungs, with a mean half time (t /2) of 19 minutes after an initial slower phase. This compares with a t'/2 of 10 minutes with Tc04 (MW 163) and a t1/2 of 158 minutes with DTPA (MW 492). The possibility that vasoactive intestinal peptide mediates a non-specific increase in permeability was discounted by the fact that the combination ofvasoactive intestinal peptide and DTPA did not alter DTPA clearance significantly. Chromatography and radioimmunoassay of blood taken after intra- tracheal administration of vasoactive intestinal peptide demonstrated a metabolite but no un- changed peptide. An intravenous injection ofthe peptide disappeared on first pass through the lung. copyright. It is concluded that inhaled vasoactive intestinal peptide lacks efficacy as a bronchodilator not because of slow diffusion to airway smooth muscle but because it is metabolised at an early stage of its passage through the respiratory epithelium. Our understanding of the control of airways smooth mals,7 but it is considerably less effective when ad- http://thorax.bmj.com/ muscle by the autonomic nervous system has ad- ministered via a nebuliser.7-10 vanced over the past decade with evidence of a third Several explanations have been advanced for the component, which may modulate smooth muscle apparent lack of efficacy of vasoactive intestinal pep- activity-the non-adrenergic, non-cholinergic system. tide when given by inhalation." The peptide has a Electrical field stimulation ofnerves investing airways molecular weight of about 3300 daltons and possibly smooth muscle produces an initial contraction, which such a large molecule cannot cross the respiratory epi- is cholinergically mediated, followed by relaxation thelium at a sufficient rate. Alternatively, vasoactive that is resistant to both cholinergic and adrenergic intestinal peptide may be inactivated during its blockade.' 2 A major candidate for the role of neuro- passage through the bronchial epithelium. on September 27, 2021 by guest. Protected transmitter in this bronchodilator response is vaso- In an attempt to resolve these questions we active intestinal peptide, a peptide of 28 amino acids. observed the fate of radiolabelled vasoactive Nerves containing vasoactive intestinal peptide are intestinal peptide administered via the airways to rats, present close to tracheal smooth muscle, bronchi, and and compared the pulmonary handling of the peptide major blood vessels in several species, including with that of two other radiolabelled compounds of man,3 and vasoactive intestinal peptide relaxes air- differing molecular weight. ways smooth muscle in vitro via a non-adrenergic mechanism.4 In vivo it causes bronchodilatation Methods when given intravenously both in man"6 and in ani- We used female Sprague Dawley rats, bred in a specific pathogen free unit and kept under standard Address for reprint requests: Dr A Morice, Department of Clinical animal with free access to Pharmacology, St Mary's Hospital Medical School, London W2 husbandry conditions, IPG. water and a standard rodent diet. They weighed 200-300 g and were aged 6-12 weeks at the times of Accepted 17 September 1985 study. 88 Thorax: first published as 10.1136/thx.41.2.88 on 1 February 1986. Downloaded from Pulmonary clearance of vasoactive intestinal peptide 89 Animals were anaesthetised with halothane in oxy- of the increase in counts in the chest detector and the gen, followed by 0.5 ml/kg Hyphorm (fentanyl 0.315 leg detector was determined. This ratio provided a mg/ml and fluanisone 10 mg/ml, Crown Chemical correction factor, which was subtracted from the Co, Lamberhurst, Kent) and atropine sulphate 0.6 chest counts for each minute of recording. The re- mg/kg, both given by intraperitoneal injection. Endo- maining values represent the amount of radiolabelled tracheal intubation was then performed under direct compound remaining within the lung. vision; we used as an endotracheal catheter an To identify vasoactive intestinal peptide or its unmodified 16 G Abbocath (Abbott Ireland Ltd, metabolites in the bloodstream after intratracheal Sligo, Ireland), which is marketed for intravenous administration of 1251 VIP, 4 ml blood was obtained cannulation in humans. After intubation anaesthesia from each of two rats 40 minutes after they had re- was maintained by halothane in oxygen given with ceived intratracheal 1251 VIP. Blood was centrifuged intermittent positive pressure ventilation from a Har- immediately and plasma frozen and stored at - 20°C. vard rodent respirator. An ethanolic extract of plasma was subjected to stan- The following radiolabelled compounds were used: dard thin layer chromatography for amino acids'3 on vasoactive intestinal peptide (VIP) labelled with cellulose acetate paper with a solvent consisting of iodine 125 (specific activity 2000 Ci/mmol and butanol 35%, acetone 35%, water 20%, and glacial molecular weight (MW) 3450 daltons); pertechnetate acetic acid 10%. (99mTc04-, MW 163 daltons) obtained by elution Four further rats were given intratracheal un- from a molybdenum generator; and technetium la- labelled vasoactive intestinal peptide, and venous and belled diethylenetriamine penta-acetate (99mTc arterial blood was taken for radioimmunoassay DTPA, MW 492 daltons). All the compounds were 20-40 minutes later. from Amersham International, Amersham, Bucks. Six groups of animals were studied. Group 1 con- tained six rats given 99mTcO4 -, group 2 six rats given 99mTc DTPA, and group 3 six rats given 1251 VIP. STATISTICAL ANALYSIS Peptidase inhibitors were given to two other groups: Analysis of variance was performed on log trans- formed data from the five groups. Dunnet's group 4 contained two rats given intravenous copyright. aprotinin (Bayer UK Ltd, Newbury, Berks) followed modification'4 of Students t test was then applied to by intratracheal 1251 labelled vasoactive intestinal compare group 3 with groups 1, 2, 4, and 5. Groups 2 peptide (1251 VIP), while group 5 comprised two rats and 6 were compared by Student's t test. given intravenous captopril (Squibb Pharmaceuticals, Princeton, New Jersey, USA) followed by intra- Results tracheal 1251 VIP. Group 6 comprised six rats given http://thorax.bmj.com/ 99MTc DTPA as in group 2, but this was mixed with The measured water:toluene partition coefficient of unlabelled VIP, in the same molar quantity as the vasoactive intestinal peptide was 0.0106, confirming labelled VIP given to group 3. that the peptide is appreciably hydrophilic. Each radiolabelled compound was dissolved in iso- Plots of radioactivity versus time for representative tonic saline, and instilled as a 0.1 ml bolus into the animals given each radiolabelled compound are animal's trachea by means of a fine catheter passed shown in figures 1-3. An index of pulmonary epi- through the endotracheal catheter and sited just thelial permeability was derived from the slope of the above the carina. Collimated scintillation detectors linear portion of each curve describing the fall in cor- were positioned over the thorax and over one hind rected lung activity, and expressed as the half time in on September 27, 2021 by guest. Protected leg, and the number of counts per minute was minutes for transfer from lung to blood. These values recorded from each detector for up to 60 minutes. The are summarised in the table. chest detector registers activity from vascular tissue as There was a significant difference (p < 0.01) be- well as lung tissue, and as the radiolabelled com- tween groups 3 and 1 and between groups 3 and 2, but pound is transferred into the bloodstream vascular no significant difference between groups 2 and 6 tissue contributes increasingly to the counts recorded. (p = 0.17). Jones et al12 have described a technique whereby the Chromatographic analysis of blood from rats re- true rate of clearance from the lung can be deter- ceiving intratracheal 1251 VIP only showed that the mined. It requires the recording of counts over a re- major component of plasma radioactivity did not rise mote field such as the leg, in which radioactivity with either iodotyrosine or 125I VIP. changes in the same proportion as counts in the vas- Radioimmunoassay'5 of blood from rats receiving cular tissue seen by the chest detector. At the end of intratracheal unlabelled VIP confirmed that there was the experiment therefore an intravenous injection of no significant amount of unchanged VIP 20-40 the radiolabelled compound was niade, and the ratio minnutes later. Thorax: first published as 10.1136/thx.41.2.88 on 1 February 1986. Downloaded from 90 Barrowcliffe, Morice, Jones, Sever TcO4 tor site is restricted. We believe that the results of this 100 0001 experiment preclude this hypothesis, at least in the rat. In this experiment the solutes DTPA and TC04- iv have been used to provide an index of the perme- Tc04 ability of the respiratory epithelium and vascular en- dothelium. It is difficult to determine the exact site of absorption of these compounds. A bolus delivered to the trachea is obviously in contact with a considerable 34 surface area of conducting airways before it reaches 10 000: alveoli.
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