Thursday, June 25, 2009

Bradykinins, Analogs and Sequences

Definition
Bradykinin is a nonapeptide that is mainly found in animal preparations that are treated with the venom of the snake, Bothrops jararaca1,2. It dialates blood vessels that in turn leads to decrease in blood pressure2. Bradykinin analogs are slightly modified structural derivatives of bradykinin that perform similar functions as bradykinin3.

Discovery
Bradykinin was discovered in the blood plasma of animals that were treated with the venom from the Brazilian snake, Bothrops jararaca1,2. The discovery was part of a study that was related to toxicology of snake bites. Bradykinin analogs were synthesized by solid-phase techniques in 1975 and their function was studied in rats and rabbits3.

Classification
Bradykinin is a 9 amino acid peptide that belongs to the kinin family of proteins4. It has homologs in several animals including other snakes, frog, dog and humans4.

Structural Characteristics
Bradykinin has the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg3. Several analogs of bradykinin have been synthesized. They are also nanopeptides containing substitutions of various amino acids of bradykinin. For example two analogs of bradykinin were synthesized one with 7-beta-homo-L-proline and the other with 8-beta-homo-L-phenylalanine substitutions3. It was found that both of them are resistant to enzymatic degradation3.

Mode of action
Bradykinin binds to two different kinin G protein coupled receptors- B1 and B25. Upon binding to these receptors it induces conversion of GTP to GDP which in turn triggers the conversion ATP to cAM which then acts as a second messanger resulting in the activation of genes. B1 receptor is expressed as a result of tissue injury and is found to play a role in inflammation while B2 receptor participates in the vasodilatory role of bradykinin5,6. Bradykinin analogs function is a similar fashion although depending on their structure they might have varying affinities to the receptors compared to bradykinin7. Also analogs of bradykinin have been synthesized that are specific to one of these receptors7.

Functions
Bradykinin is a potent endothelium-dependent vasodilator, causes contraction of non-vascular smooth muscle, increases vascular permeability and also is involved in the mechanism of pain. Bradykinin also causes natriuresis, contributing to a drop in blood pressure8. Bradykinin raises internal calcium levels in neocortical astrocytes causing them to release glutamate9. Overactivation of bradykinin is thought to play a role in a rare disease called Hereditary Angioedema, also known as Hereditary Angio-Neurotic Edema10.

Some analogs of bradykinin have been found to have prolonged hypotensive action compared to bradykinin (Eg: beta-H-Pro-bradykinin)3. Some analogs have relative or even lower potencies compared to bradykinin (Eg: HArg1-Bradykinin and HArg9 Bradykinin)7. Other analogs have been studied for their potential of finding bradykinin antagonists that might be useful in the treatment of angio-neurotic edema.

References
1.Partridge, SM (1948). (Title or abstract not available), Biochem. J., 42, 238.
2.Allen PK, Kusumam J, Yoji S, Yoshitaka N, Berhane G, Sesha R and Michael S (1998). Bradykinin formation: Plasma and tissue pathways and cellular interactions. Clinical reviews in allergy and immunology, 16, 4, 403-429.
3.Ondetti MA, Engel SL (1975). Bradykinin analogs containing beta.-homoamino acid, J. Med. Chem.,18 (7), 761–763.
4.Roseli A, Gomes S, Jair RC, Luis J and Valdemar H (1996). Met-Lys-Bradykinin-Ser, the kinin released from human kininogen by human pepsin. Immunopharmacology, 32, 76-79.
5.Peter GM, Amrita A, and Mauro P (2000). Association between Kinin B1 Receptor Expression and Leukocyte Trafficking across Mouse Mesenteric Postcapillary Venules. J Exp. Med., 192, 367-380.
6.Duchene J, Lecomte F, Ahmed S, Cayla C, Pesquero J, Bader M, Perretti M and Ahluwalia A, (2007). A Novel Inflammatory Pathway Involved in Leukocyte Recruitment: Role for the Kinin B1 Receptor and the Chemokine CXCL5. J Immunol., 179, 4849-4856.
7.Max ES, Phyllis AL (1974). Synthesis and pharmacology of homoarginine bradykinin analog. J. Med. Chem., 17 (11), pp 1227–1228.
8.Dendorfer A, Wolfrum S, Wagemann M, Qadri F, Dominiak P, (2001). Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats. Am J Physiol Heart Circ Physiol., 280:H2182
9.Kuoppala A, Lindstedt KA, Saarinen J, Kovanen PT, Kokkonen JO (2000). Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma. Am J Physiol Heart Circ Physiol, 278(4):H1069-74.
10.Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G (2007). Nonallergic angioedema: role of bradykinin. Allergy, 62(8):842-56.

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