Molecular Pharmacology of Neurohypophysial Peptide Hormones and Their Cognate Receptors Essay

Arginine Vasopressin (AVP), also called antidiuretic hormone, and oxytocin are peptide hormones of the neurohypophysis, and are also called neurohypophysial peptide hormones, as they are formed in supraoptical and paraventricular nuclei of hypothalamus, where the neurosecretory neurons are located. The axons of these neurons form the supraoptical hypophysial tract that brings the secretory material of these neurons to the posterior lobe of hypophysis. Under the microscope this part of the hypophysis consists of pituicytes, capillaries, and amyelinic fibers that contain neurosecretory granules. Besides vasopressin and oxytocin, such hormones as somatostatin, thyroliberine, and substance P have been extracted from neurohypophysis.

It was demonstrated by immunocytochemical and radioimmune methods that oxytocin and vasopressin are synthesized in the neurons of supraoptical and paraventricular nuclei. The hormones that have been synthesized in the hypothalamic nuclei are transported together with the corresponding neurophysines along the axons of neurohypophysial tract into the posterior lobe of the hypophysis, where they are reserved “in case of emergency”. The hormones are transferred along the axons as granules that also contain specific proteins called neurophysines (mol. weight approx 10000). The speed of transport of the hormones along the axons is around 2-3mm/hour. The liberation of vasopressin from the granules is done by means of exocytosis. Vasopressin can be liberated not only in blood, but also in the spinal fluid, where its concentration is lower than in blood plasma. It is suspected that the secretion of hormones into the spinal fluid and the neurohypophysis is done by various neurons of the hypothalamus, as the patients with neurogenic diabetes insipidus, the total amount of vasopressin in the spinal fluid is normal.

However besides the main way of transport into the posterior hypophysial lobe, there is a second neurosecretory pathway through the portal system of the hypophysis to the cells of the anterior hypophysial lobe, where these hormones play a vital role in regulating the secretion of adrenocorticotropin. The level of vasopressin in the portal system is higher that in the plasma of the peripheral blood. This indicates the importance of vasopressin in the regulation of hypotonia, hypovolemia, and other conditions that accompany a stressful situation.

As was mentioned earlier, the membrane vesicles containing AVP and oxytocin are transported along the axons of hypothalamus’ neurons as a part of hypothalamo-hypophysial tract into the posterior part of the hypophysis, and through axo-vasal synapses are being secreted into the bloodstream. The secretion of oxytocin and AVP is regulated by impulsive axon activity of neurosecretory neurons. At this moment, oxytocin just as AVP detaches from neurophysines and proceeds into the bloodstream. The targets of oxytocin are smooth muscle cells (SMC) of myometrium and myoepithelial cells of the mammary gland. In the uterus, oxytocin stimulates the contraction of myometrium’s SMC during the act of child delivery, orgasm, and menstruation. In the mammary gland oxytocin stimulates the contraction of myoepithelial cells of the alveoli in the lactating mammary gland. The receptor of oxytocin is a transmembrane glycoproteins coupled with G protein (Kimura et al. 1992).

AVP has antidiuretic (regulation of reabsorbtion in renal canaliculi), and vasoconstriction effects. It is a nanopeptide C₄₆H₆₅N₁₅O₁₂S₂. The antidiuretic hormone is secreted in the neurosecretory neurons of paraventricular and supraoptical nuclei of the hypothalamus. The expression of AVP can be stimulated by hypovolemia via the baroreceptors of the carotid region, as well as by hyperosmolarity via the osmoreceptors of the hypothalamus. The factors that inhibit secretion of this hormone are glucocorticoids and alcohol α-adrenergic antagonists.

The main function of AVP is the regulation of water balance (sustaining constant osmotic pressure in body fluids). The metabolism of fluids is closely connected with metabolism of Sodium. The receptors of the antidiuretic hormone are cell surface vasopressin binding structures related to G-protein coupled transmembrane glycoproteins. Interaction of AVP and its receptors leads to stimulation of phospholipase C, production of phosphatidyl inositol and increase of intracellular levels of Calcium. There are three subtypes of AVP receptors: V_Ia, V_Ib, and V₂.

All three subtypes of vasopressin receptors are G-protein coupled however the activation of V₂ receptors causes the stimulation of adenylate cyclase, while activating V_Ia and V_Ib stimulates phospholipase C. V_Ia is a subtype of AVP receptors that has unique distribution among tissues, and is responsible for many effects of AVP. In liver cells the activation of these receptors stimulates glycogenolysis. In SMC of blood vessels these receptors have vasoconstricting effect. They also cause aggregation of blood platelets and have an effect on the neurons of central nervous system. V_Ib receptors are found in adenohypophysis and are responsible for modulating the secretion of adrenocorticotropin, β-endorphine, and prolactin. The V₂ AVP receptors are found only in kidney’s collecting ducts and distal convoluted tubules. They are also observed in the liver where their stimulating releases clotting factors into blood. In the renal tubules these receptors respond to AVP by maintaining water homeostasis and concentrating urine. Mutation of the gene that is responsible for V₂ subtype receptors (Albetrazzi et al. 2001) can cause nephrogenic diabetes insipidus (Pan et al. 1992; Inaba et al. 2001).

There are several pharmacological agents which are analogues of vasopressin. One of these synthetic hormones is desmopressin which is long-acting remedy during conditions characterized by low levels of AVP secretion (Griffante et al. 2005). It is also sometimes used in order to control bleeding (von Willebrand disease) and in child bedwetting (Schulz-Juergensen et al. 2007). Since 1970 analogues of antidiuretic hormone have been used during esophageal varices (Baum, Nusbaum & Tumen, 1970). Terlipressin is also analogous to AVP and used in certain conditions for vasoconstriction (Krag et al. 2007). During septic shock agonists of vasopressin are used in patients who are not responsive to adrenal agonists (norepinephrine, dopamine, etc…) (Wenzel, et al. 2004). During asystolic cardiac arrest vasopressin proved to be a more effective than norepinephrine type of treatment (Wenzel et al., 2004). When fluid restriction is failing and there are extremely high levels of vasopressin secretion which cause hyponatriemia, such antagonists of vasopressin as Demeclocycline may be used in order to block AVP action in kidneys. There are several AVP antagonists that act by blocking its receptors. Conicaptan blocks V_Ia and V₂ receptors, where Tolvaptan, Lixivaptan, and Relcovaptan block V₂ vasopressin receptors. Oxytocin is also synthesized and administered by injections or as a nasal spray. Nasal spray can be used for stimulation of breastfeeding. In form of injections this synthetic hormone induces labor, increasing the tone of the uterus. It is especially effective in postpartum hemorrhage. Atosiban is an antagonist of oxytocin, influencing its receptors and suppressing premature labor. It is also believed to reduce anxious behaviors (Bielsky et al. 2004).

References

1. Albertazzi, E., Zanchetta, D., Barbier, P., Faranda, S., Frattini, A., Vezzoni, P., Procaccio, M., Bettinelli, A., Guzzi, F., Parenti, M. and Chini, B. 2000, ‘Nephrogenic diabetes insipidus: functional analysis of new AVPR2 mutations identified in Italian families’ J Am Soc Nephrol, vol. 11, pp. 1033 – 1043.
2. Baum, S., Nusbaum, M., Tumen, H. J. 1970. ‘The control of gastrointestinal hemorrhage by selective mesenteric infusion of pitressin,’ Gastroenterology, vol. 58 p. 926.
3. Bielsky, I.F., Hu, S.B., Szegda, K.L., Westphal, H., Young, L.J. 2004, ‘Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice,’ Neuropsychopharmacology, vol. 29, pp. 483-93.
4. Griffante, C., Green, A., Curcuruto, O., Haslam, C. P., Dickinson, B. A. and Arban, R. 2005, ‘Selectivity of d[Cha4]AVP and SSR149415 at human vasopressin and oxytocin receptors: evidence that SSR149415 is a mixed vasopressin V1b/oxytocin receptor antagonist’, Br J Pharmacol, vol. 146, pp. 744 – 751.
5. Inaba, S., Hatakeyama, H., Taniguchi, N. and Miyamori, I. 2001, ‘The property of a novel v2 receptor mutant in a patient with nephrogenic diabetes insipidus,’ J. Clin. Endocrinol. Metab., vol. 86, pp. 381-385
6. Krag, A., Møller, S., Henriksen, J. H., Holstein-Rathlou, N. H., Larsen, F. S., Bendtsen, F. 2007, ‘Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome’ Hepatology, Nov 20.
7. Kimura, T., Tanizawa, O., Mori, K., Brownstein, M. J. and Okayama, H. 1992, ‘Structure and expression of a human oxytocin receptor’, Nature, vol. 356, pp. 526 – 529.
8. Pan, Y., Metzenberg, A., Das, S., Jing, B. and Gitschier, J. 1992, ‘Mutations in the V2 vasopressin receptor gene are associated with X-linked nephrogenic diabetes insipidus’, Nat Genet, vol. 2, pp. 103 – 106.
9. Resuscitation Study Group. ‘A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation’, N Engl J Med, vol. 350, pp. 105-13.
10. Schulz-Juergensen, S., Rieger, M., Schaefer, J., Neusuess, A., Eggert, P. 2007, ‘Effect of 1-desamino-8-D-arginine vasopressin on prepulse inhibition of startle supports a central etiology of primary monosymptomatic enuresis’, J Pediatr. no. 151, vol. 6, pp. 571-4.
11. Wenzel, V., Krismer, A.C., Arntz, H.R., Sitter, H., Stadlbauer, K. H., Lindner, K. H. 2004. European Resuscitation Council Vasopressor during Cardiopulmonary