Definition
The pneumadins (PMN) are decapeptides found in significant amounts in normal mammalian as well as human fetal lungs. The naturally occurring and the synthetic peptides elicit identical antidiuretic effects by releasing 8-arginine-vasopressin (AVP) from the neurohypophysis.
Discovery
In 1990 Dr M. Ashwini Kumar and his colleagues came across a new peptide which was purified to homogeneity and the amino acid sequence determined. It had antidiuretic activity and the potency was much greater when administered into the third ventricle. Human fetal lungs also contained this peptide. The antidiuretic activity of this peptide was considered to be due to the release of endogenous Antidiuretic hormone (ADH). Based upon its source and action, it was named as Pneumadin (Pneumon-antidiureticin) 1.
Structural Characteristics
Pneumadins are decapeptides. The sequence of rat PMN is: Tyr-Gly-Glu-Pro-Lys-Leu-Asp-Ala-Gly-Val-NH2. The peptide from human fetal lungs has Ala instead of Tyr 1. By means of highly specific RIA method, high concentration of PNM had been found in the rat ventral prostate. Castration resulted in a profound drop in PNM concentration, an effect prevented by testosterone replacement. By immunocytochemistry, PNM-immunoreactive substances were not found in seminal vesicles of either intact or estradiol-administered rats but found in ventral prostate 2.
Mode of Action
Normal mammalian lungs, including human fetal lungs, contain significant amounts of pneumadins which releases arginine-vasopressin from the neurohypophysis and therefore has antidiuretic activity. The direct vascular effect of PMN was determined by studying the changes in intracellular free calcium ([Ca2+]i) levels in cultured rat aortic smooth muscle cells maintained between the second and fifth passages. PMN evoked a rapid, concentration-dependent, biphasic increase in [Ca2+]]i. The [Ca2+]]i level rose from a basal value of 108 nM to a maximum increase in peak value of 170 nM. At concentrations > 100 nM, [Ca2+]]i elevations induced by PN above basal levels were no longer observed. Pretreatment with dexamethasone (100 nM for 24 hr) resulted in a significant increase (P < 0.01) in the peak [Ca2+]]i response (310 nM) to PN. The biphasic pattern in the peak [Ca2+]]i responses encountered with increasing concentrations of PN remained unaffected. The exaggerated [Ca2+]]i response to PN was abolished by preincubation of cells with either the glucocorticoid antagonist mifepristone (RU 486) or the protein synthesis inhibitor cycloheximide. Inclusion of either an AT1 antagonist (losartan), a V1 selective vasopressin antagonist (d(Ch2)5 Tyr (Me) AVP), or an a-adrenoceptor antagonist (phentolamine) failed to affect the increases in [Ca2+]]i induced by PN. PN-evoked increases in inositol 1,4,5-trisphosphate levels paralleled the [Ca2+]+]i changes. These data suggest that PMN increases Ca2+ mobilization in rat aortic smooth muscle cells via activation of phospholipase C coupled receptors. This effect is up-regulated by dexamethasone 1.
Intravenous injection of 5 nmol of pneumadin into water-loaded rats caused a rapid and significant antidiuresis and a reduction in Na+ and Cl- excretion. PMN administration did not alter mean arterial pressure, right atrial pressure, heart rate or haematocrit. Bolus intravenous injection of 20 nmol of pneumadin into non-water-loaded rats caused a significant increase in AVP within 10 min. Pneumadin administration also increased circulating atrial natriuretic peptide (ANP) but did not alter aldosterone or plasma renin activity levels. Injection of pneumadin into water-loaded Brattleboro rats, which genetically lack circulating AVP, did not change urine flow, confirming that the pneumadin induced antidiuresis is AVP dependent. Radioactive pneumadin was cleared from the circulation with a t1/2 beta of 480.3 s. Radioactive pneumadin, isolated from plasma, eluted at an altered position on reverse phase HPLC, which indicated that the peptide was modified in vivo. These results indicate that pneumadin injected into the rat caused an antidiuresis by altering circulating AVP levels 3.
Functions
Testosterone-dependent secretory, the localization of PNM in the epithelial cells could suggest that this peptide may be involved in the regulation of some testosterone-dependent secretory functions of the rat prostate 4.
Growth of adrenal cortex, Pneumadin the effects of 2-day PNM administration on the atrophic adrenal cortices of rats treated for 8 days with dexamethasone (DX) raised adrenal weight and the average volume of adrenocortical cells. Results suggest that (i) PNM enhances the growth of adrenal cortex in DX-administered rats by a mechanism involving the stimulation of ACTH release; and (ii) PNM treatment is probably too short to allow DX-atrophied adrenocortical cells to re-acquire all their differentiated secretory capacities 5.
Postnatal maturation of rat prostate, by radioimmunoassay (RIA) and light ultrastructural immunocytochemistry (ICC), PNM concentration and localization in the rat ventral prostate was analysed in postnatal development. RIA showed that PNM content increased steadily from day 20 to day 90 of postnatal life, parallel to the increase in the prostate weight. ICC demonstrated that PNM immunoreactivity was mainly located in the apical pole of epithelial cells of rat ventral prostate, especially in the subcellular organelles involved in protein secretion, i.e. rough endoplasmic reticulum cisternae, vacuoles and granules. These results suggest PNM is involved in the functional control of rat prostate during postnatal maturation, although its exact role remains to be elucidated 6.
References
1. Batra VK, Mathur M, Mir SA, Kapoor R, Kumar MA (1990). Pneumadin: a new lung peptide which triggers antidiuresis. Regul Pept., 30:77-87.
2. Batra VK, Hopfner RL, Gopalakrishnan V, McNeill JR. (1999). Pneumadin-evoked intracellular free Ca2+ responses in rat aortic smooth muscle cells: effect of dexamethasone. Biochemical Pharmacology, 58(1):177-182.
3. Watson JD, Jennings DB, Sarda IR, Pang SC, Lawson B, Wigle DA, Flynn TG (1995). The antidiuretic effect of pneumadin requires a functional arginine vasopressin system. Regul Pept., 57(2):105-114.
4. Kosowicz J, Miskowiak B, Konwerska A, Belloni AS, Nussdorfer GG, Malendowicz LK (2004). Pneumadin in the rat ventral prostate and its hormonal regulation. Hormone and metabolic research, 36:78-81.
5. Markowska A, Macchi C, Nussdorfer GG, Malendowicz LK (1996). Effects of pneumadin (PNM) on the adrenal glands. 5. Potent stimulating action of PNM on adrenocortical growth of dexamethasone-administered rats. Histol Histopathol., 11(3):583-585.
6. Miskowiak B, Brelinska R, Kosowicz J, Konwerska A, Ziolkowska A, Belloni AS, Nussdorfer GG, Malendowicz LK (2004). Pneumadin in the ventral prostate of rats during postnatal development: a radioimmunological and immunocytochemical study. International journal of molecular medicine, 13(6):801-803.