Blood peptides, increase

Figure 2.9. Differential pharmacological effect elicited by vector-mediated delivery of a VIP analogue. The organ blood flow in brain and salivary gland was measured in conscious rats after i.v. administration of vehicle (saline), the brain delivery vector OX26-SA, the VIP peptide alone, or the chimeric peptide. While cerebral blood flow increased in the chimeric peptide group by 60% compared to the saline control, the increase in salivary gland blood flow seen with the peptide alone was abolished by coupling to the vector. The VIP analogue was biotinylated with a non-cleavable 14-atom spacer (biotin-XX) for coupling to the vector. Data from reference [95].

Calcitriol and parathyroid hormone, on the one hand, and calcitonin on the other, ensure a more or less constant level of Ca "" in the blood plasma and in the extracellular space (80-110 mg 2.0-2.6 mM). The peptide parathyroid hormone (PTH 84 AA) and the steroid calcitriol (see p. 374) promote direct or indirect processes that raise the Ca "" level in blood. Calcitriol increases Ca "" resorption in the intestines and kidneys by inducing transporters. Parathyroid hormone supports these processes by stimulating calcitriol biosynthesis in the kidneys (see p. 330). In addition, it directly promotes resorption of Ca "" in the kidneys (see p. 328) and Ca "" release from bone (see B). The PTH antagonist calcitonin (32 AA) counteracts these processes. 

Angiotensin II Angiotensin II ATI and AT2 receptor 8-residue peptide Increase blood pressure Solid-phase A -Boc chemistry... 

ANP is a 28-amino-acid peptide first discovered by de Bold et al. (2). It is released from heart atrial myocytes in response to a local arterial wall stretch. ANP acts on outer adrenal cells to decrease aldosterone production and blood pressure, increase salt and water excretion, and transudate plasma water to the interstitium (3). 

Incubation of a protein fraction from blood plasma with trypsin gives rise to peptides with conspicuous biological effects. Pain, dilation of peripheral blood vessels, increased coronary flow and enhanced capillary permeability were observed on administration of these protein fragments [8]. In the early sixties the nonapeptide bradykinin and its precursors, kallidin and methionyl-kalUdin were isolated in pure form and their amino acid sequences determined soon after. 

Vasoactive intestinal peptide, VIP an octacosa-peptide from porcine small intestine, which causes va-sodlation, lowers arterial blood pressure, increases cardiac output, enhances myocardial activity, increases glycogenolysis and relaxes the smooth muscle of trachea, stomach and gall bladder. For structure, see Secretin. 

General trends in radiopharmaceutical research emphasize the use of small peptides. These molecules, of which the agents mentioned for thrombosis localization are an example, exhibit rapid and specific binding, and rapid blood clearance, two important parameters for a successflil radiopharmaceutical. Peptides are readily labeled with Tc and lend themselves to formulation as lyophilized kits that can be rapidly and rehably reconstituted. Possible targets for these molecules are quite varied, ranging from atherosclerotic plaque to P-amyloid (for Alzheimer s disease), to a variety of somatic receptors the populations of which are increased or decreased in disease. 

Historically the only melanocortin peptide to be used clinically is the parent hormone from which all these peptides are derived from namely ACTH (see above). It has also been used in the treatment infantile spasms for epilepsy, where it is administered as an intramuscular injection only over a 2-12 weeks period. Obvious side effects include weight gain, puffy face, high blood pressure and an increased risk of infection and should never be administered to patients with diabetics, renal or heart failure. ACTH is also used as a stimulation test to measure adrenal cortex activity, i.e. production of cortisol and is used to ascertain whether someone has Addison s disease. 

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are members of a family of so-called natriuretic peptides, synthesized predominantly in the cardiac atrium, ventricle, and vascular endothelial cells, respectively (G13, Y2). ANP is a 28-amino-acid polypeptide hormone released into the circulation in response to atrial stretch (L3). ANP acts (Fig. 8) on the kidney to increase sodium excretion and glomerular filtration rate (GFR), to antagonize renal vasoconstriction, and to inhibit renin secretion (Ml). In the cardiovascular system, ANP antagonizes vasoconstriction and shifts fluid from the intravascular to the interstitial compartment (G14). In the adrenal cortex, ANP is a powerful inhibitor of aldosterone synthesis (E6, N3). At the hypothalamic level, ANP inhibits vasopressin secretion (S3). It has been shown that some of the effects of ANP are mediated via a newly discovered hormone, called adreno-medullin, controlling fluid and electrolyte homeostasis (S8). The diuretic and blood pressure-lowering effect of ANP may be partially due to adrenomedullin (V5). 

Poduslo JF, Curran GL, Kumar A, Frangione B, Soto C. Beta-sheet breaker peptide inhibitor of Alzheimer s amyloidogenesis with increased blood-brain barrier permeability and resistance to proteolytic degradation in plasma. J Neurobiol 1999 39 371-382. 

Vasopressin (antidiuretic hormone) is a peptide synthesized in the hypothalamus and secreted from the neurohypophysis of the pituitary gland. This substance plays an important role in the long-term regulation of blood pressure through its action on the kidney to increase reabsorption of water. The major stimulus for release of vasopressin is an increase in plasma osmolarity. The resulting reabsorption of water dilutes the plasma toward its normal value of 290 mOsM. This activity is discussed in more detail in Chapter 10 (the endocrine system) and Chapter 19 (the renal system). 

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