KININ RECEPTORS

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PHARMACOLOGY OF KININS THERE RECEPTOR AND TRANSDUCER MECHANISM

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KININ RECEPTORS:

KININ RECEPTORS Toshit Sharma M.Pharm-1 st year (Pharmacology) ADVANCE INSTITUTE OF BIOTECH AND PARAMEDICAL SCIENCES, KANPUR,UP

CONTENTS:

CONTENTS AUTACOIDS PLASMA KININS HISTORY OF KININS GENERATION AND DEGRADATION OF KININS KININS AND ACE INHIBITORS RECEPTOR CLASSIFICATION(B1 and B2) STRUCTURAL ASPECTS OF KININ RECEPTORS AND THERE GENES BASIC PHARMACOLOGICAL ACTIONS OF KININS EFFECT OF KININS ON CVS AND THERE DISEASES EFFECT OF KININS ON RENAL SYSTEM AND THERE DISEASES Novel Development in BK System

AUTACOIDS:

AUTACOIDS These are local hormones produced by wide variety of cells in the body having intense biological activity at the site of synthesis and release. Autacoids are involved in number of physiological and pathological processes like - Reaction to injury Immunological insult Serve as transmitters or modulators in nervous sy stem

CLASSIFICATION:

CLASSIFICATION Amine autacoids- histamine, serotonin Lipid autacoids- prostaglandins, leukotrienes and PAF Peptide autacoids- plasma kinins , angiotensin

PLASMA KININS :

PLASMA KININS Plasma kinins are proinflammatory polypeptides that mediates various vascular and pain responses to tissue injury. Two important plasma kinins are- KALLIDIN- decapeptide BRADYKININ- nonapeptide

HISTORY OF KININS AND THERE RECEPTORS :

HISTORY OF KININS AND THERE RECEPTORS Werle and Frey (1930)- kallikrein from pancreas Rocha e Silva et al (1949)- bradykinin identification Elliot and boissonnas (1959)- BK isolation from plasma and in 1960 its structure was resolved. Regoli and coworkers (1970)- molecular characterization of kinin receptors B1 and B2.

GENERATION AND DEGRADATION OF PLASMA KININS :

GENERATION AND DEGRADATION OF PLASMA KININS

KININOGEN SPLITTING:

KININOGEN SPLITTING

RECEPTOR CLASSIFICATION:

RECEPTOR CLASSIFICATION B1 B2 Amino acid composition 353 391 Gene/chromosome BDKRB1/14q32.2 BDKRB2/14q32.2 Selective agonist Lys-des- Arg -BK BK Selective antagonist Lys- Leu -des- Arg -BK Icatibant,Omapatrilat Location and primary function Smooth muscles of Larger arteries and veins -contraction 1.Visceral smooth muscle-contraction 2.VE- NO release, vasodilation , inc.permeability 3.Sensory nerves-acute pain Primary G protien coupling Gq / Gi Gq / Gi

B2 RECEPTOR ANTAGONIST:

Omapatrilat   is a novel antihypertensive agent that inhibits both  Neutral Endopeptidase (NEP) and ACE. NEP inhibition results in elevated  natriuretic peptide levels, promoting  natriuresis ,  diuresis ,  vasodilation , and reductions in preload and ventricular remodeling. USE- CHF B2 RECEPTOR ANTAGONIST

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Icatibant is peptidomimetic for the B2 receptor, with an affinity similar to bradykinin .  HERIDITERY ANGIOEDEMA  is caused by an absence or dysfunction of C1-esterase-inhibitor a regulator of comlement cascade that leads to bradykinin production. Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE.

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STRUCTURAL ASPECTS OF KININ RECEPTORS AND THERE GENES

HUMAN B2 RECEPTOR:

HUMAN B2 RECEPTOR GPCR FAMILY-consisting of single polypeptide chain that spans membrane 7 times. N terminal-extracellular C terminal-intracellular Three consensus sites for N-linked glycosylation are found in extracellular domains. DRY and NPXXY- embeded in cytosolic receptor domains. C terminal tail contains serine and threonines that are putative phosphorylation sites and cysteines putative sites for acylation . B1-Homologous to B2 receptor(36% identity at amino acid sequence level)

B1 RECEPTOR GENE:

B1 RECEPTOR GENE BRKRB1 composed of three exons . The entire coding region for receptor is contained within third exon . A variety of polymorphisms have been identified. One, G/C single nucleotide polymorphism, in the promoter region has been associated with diseases. Expression of C allele is higher than G allele, and patients with G allele have greater incidence of inflammatory bowel disease and endstage renal disease 

B2 RECEPTOR GENE:

B2 RECEPTOR GENE BRKRB1 is composed of three exons , of which exon 2 and exon 3 provide coding region for receptor. Promoter region for B2 receptor contains a single nucleotide polymorphism; T/C. C allele has been demonstrated to be independent risk factor for essential hypertension in several ethnic groups

PHARMACOLOGICAL ACTIONS:

PHARMACOLOGICAL ACTIONS CVS - potent vasodilators than Ach and histamnine Injected iv cause flushing,throbbing,headache and fall in B.P. Increase capillary permiability . No direct action on heart reflex stimulation occur due to fall in B.P Smooth muscles -slow intestinal contraction Bronchioconstriction Neurons - stimulate nerve endings that stimulate pain and produce burning sensation Kidney -increase renal blood flow and facilitate salt and water excretion by action on tubules

EFFECT OF BRADYKININ IN-:

EFFECT OF BRADYKININ IN- 1.Cardiovascular system 2.cardiovascular diseases 3.Renal system 4.Renal diseases

EFFECT OF BK ON CVS:

EFFECT OF BK ON CVS

EFFECT OF BK ON CVS DISEASES:

EFFECT OF BK ON CVS DISEASES Kinins exhibited inhibition of apoptosis, inflammation, hypertrophy, and fibrosis, and promoting angiogenesis and neurogenesis in heart, kidney, brain, and blood vessels. These results indicate that BK, through B2 receptor activation and NO formation, can protect against oxidative damage in cardiovascular and renal diseases and ischemic stroke

HYPERTENSION:

HYPERTENSION Vasodilatation in most areas of circulation, reduction of total peripheral vascular resistance and regulation of sodium excretion from kidney. The role of kinins in hypertension was established with observations that urinary kallikrein excretion is significantly decreased in hypertensive patients. This led to the suggestion that reduced urinary kallikrein excretion might result from a defect in kinin generation in hypertensive situations.  

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When BK is injected into renal artery, it causes diuresis and natriuresis by increasing renal blood flow. These consequences of BK have been attributed to PG release in renal circulation

CARDIAC FAILURE AND ISCHEMIA:

CARDIAC FAILURE AND ISCHEMIA The local and systemic administration of BK can increase coronary blood flow and improve myocardial metabolism kinins are continuously released during cardiac hypoxia and ischemia. They act as cardioprotective agents in perfusion and participate in the process of ischemic precondition . Kinins improve cardiac function, and reduced myocardial infract size, incidence of ventricular fibrillation and apoptosis after acute ischemia-reperfusion via activation signal transduction pathways generating NO and PG

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LVH -BK can counter the acceleration of LVH in rats with hypertension. BK has a role in protecting heart against developing LVH by releasing NO. deficiency in components kinin system in heart may be the reason of myocardial dysfunction in maintaining high blood pressure and cardiac LVH STROKE – kinins have potential protective role in stroke, because it reduced stroke-induced mortality, blood pressure, and aortic hypertrophy. they significantly lowered ischemia induced neurological deficits, cerebral infract volume and apoptosis.

ROLE OF BK IN RENAL SYSTEM:

ROLE OF BK IN RENAL SYSTEM Enhanced renal functions were accompanied by increased vasorelaxation factors, such as, NO, cyclic Guanosine Mono Phosphate ( cGMP ), and cAMP in kidney and urine. So, these findings suggest that BK effects in renal system, which are, protection of kidney from renal injuries, improvement of renal function, natriuresis , and diuresis depend on NO synthesis

ROLE OF BK IN RENAL DISEASES:

ROLE OF BK IN RENAL DISEASES Kinins and renal protection- KININS show protection against salt and drug induced renal injury by inhibiting oxidative stress and inflammation. Reversed salt-induced renal fibrosis in renal interstitium and vasculature and glomerular hypertrophy and restored NO production. These protective effects of kinins were antagonised by icatibant

Novel Development in BK System:

Novel Development in BK System Staphylococcus aureus  ( S. aureus ) is a major grampositive pathogen. The examination of vascular leakage (VL) activity of two cysteine proteinases that are secreted by  S. aureus  showed that both induced VL in BK B2-receptor-dependent-manner.   S. aureus  also produced VL activity from human plasma, apparently by acting directly on kininogens to release BK. Collectively, these data suggest that production of BK is new mechanism of  S. aureus  virulence and bacterial shock. Therefore, BK-receptor antagonists could be used to treat this disease

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In humans, BK induces potent bronchoconstriction and cough when inhaled in asthmatic patients and it causes rhinitis-like symptoms when instilled into the nose. Furthermore, BK is generated in human nasal secretions during rhinoviral infections and allergic rhinitis. B2 receptor antagonists has been hypothesized for treatment of airways inflammatory pathologies associated with hyper responsiveness to BK, such as, chronic bronchial asthma, or with release of BK, like, perennial and seasonal allergic rhinitis 

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