10-28-09 Vasoactive Peptides and NO 1.

Diagram the synthesis and metabolism of kinins and know what pathophysiological factors trigger kinin formation. Kinin synthesis occurs in response to tissue damage, allergic reactions, and acute chronic in!lammation" #hey are produced !rom kininogen su$strates $y kallikrein en%ymes& 1" HIGH molecular weight kininogen'plasma (alli(rein en%yme)bradykinin 2" LOW molecular weight kininogen'tissue (alli(rein en%yme)lysyl bradykinin Kinin meta$olism occurs *ith the en%ymes kininase I and kininase II 'angiotensin converting en%yme and dipeptidyl car$o+ypeptidase)" Kinins have a hal! li!e o! less than 1, seconds -rady(inin is 90. hydroly%ed during a single passage through the pulmonary vascular $ed /ide note on (inin mechs o! action& #here are t*o receptors& -1 and -2 !1 is upregulated during 0N123443#0ON !" is constitutively e+pressed and has a high a!!inity !or $rady(inin5 it6s 7-protein5 coupled and activates phospholipase 32 and phospholipase 8P30N /ide note on general e!!ects o! (inins& Kinins vasodilate arterial vascular $eds Kinins vasoconstrict most veins #hese result in the 9:943 that is commonly ao$served in in!lammation, as *ell as -;ON8<O/P3/4 in asthmatics 3s mentioned a$ove, -1 causes in!lammation *hile -2 causes pain 0n neonates, $rady(inin results in dilation o! the !etal pulmonary artery, closure o! the ductus arteriosus, and constriction o! um$ilical arteries #ce inhibitors $loc( (inninase 00, resulting in (inin elevation and su$se=uent hypotensive e!!ects" ". Diagram the synthesis and specify the mechanisms of action of the $asoacti$e peptide angiotensin. !e familiar with the clinical use of drugs acti$e on the rennin angiotensin system. 3ngiotensin synthesis #he en%yme, renin, is made, stored, and released $y juxtaglomerular cells in the (idney #he su$strate, angiotensinogen, is made in the liver 3ngiotensinogen levels are increased $y corticosteroids, thyroid hormones and estrogen #he hypertension associated *ith 8ushing6s /yndrome, pregnancy, or oral contraceptive use may re!lect heightened angiotensinogen $lood level #ngiotensin con$erting en%yme &#'() is present on the luminal sur!ace o! vascular endothelium

Process& 3ngiotensinogen'renin en%yme)3ngiotensin 0389 en%ymeangiotensin 00 ;ate limiting& renin secretion and circulating angiotensinogen >nder negative control o!& vascular stretch receptors, sodium and alpha adrenergic tonus >nder positive control o!& $eta1 adrenergic receptors >nder negative !eed$ac( $y& angiotensin 00 3ngiotensin 00 is =uic(ly meta$oli%ed $y several peptidases in the $lood

3ngiotensin mechanism o! action #here are t*o (no*n angiotensin receptors& 3#1 and 3#2, *ith 3#1 mediating most (no*n actions #*1& 7-protein coupled receptor that activates P28, *hich then generates 0P? and diacyclglycerol" 1inal result is smooth muscle contraction" 3ngiotensin 00 is @0 times more potent than norepi in vasoconstriction5 it potentiates norepi release and reduces its reupta(e 3ngiotensin 00 stimulates aldosterone and glucocorticoid synthesis, causes renal vasoconstriction and sodium rea$sorption, stimulates drin(ing, and stimulates vasopressin '3:<) release 3llo*s !or maintenance o! !luid homeostasis in situations o! great $lood loss 3ngiotensin clinical use ;enin inhi$itors suppress angiotensin 00 productioner $lood pressure in hypertensives 389 inhi$itors 'captopril, enalapril) $loc( conversion o! angiotensin 0 to angiotensin 00, and it cata$olism o! $rady(ininhypotensive e!!ect Non-peptide angiotensin antagonists 'losartan, $alsartan) are orally active, e+hi$iting the e!!ects o! 389 inhi$itors *ith lo*er side e!!ects o! cough and edema +. Diagram synthesis and inacti$ation of ,O. (-plain its effects on the $ascular. peripheral. and central ner$ous systems. and its role in inflammation. Describe the relationship between ,O and cG/0 and the pharmacological treatment of erectile dysfunction. NO is a short lived vasodilator" NO synthesis #hree iso!orms o! nitric o+ide synthase 'NO/)& cNO/AnNO/, iNO/, and eNO/ cNO/AnNO/ is a constitutive en%yme present in epithelial cells and neurons iNO/ is an induci$le en%yme present in macrophages and smooth muscle cells eNO/ is a constitutive en%yme present in endothelial cells all three are flavoproteins *hich use l-arginine as a su$strate in com$o *ith N3:P<, !lavin adenine dinucleotide, and tetrahydro$iopterin as co!actors" #he process& l-arginine'NO/ iso!orms)l-citrulline NO NO then di!!uses *idely in tissue

Note that NO donors nitroprusside and nitroglycerin spontaneously generate NO NO inactivation NO is meta$oli%ed $y heme and superoxide NO is enhanced $y antio+idantsB Glutathione interacts *ith NO to !orm /-nitrosoglutathione, a long lived carrier o! NO

NO mechanism o! action and e!!ects NO acts $y activating solu$le guanylyl cyclase, producing c74P *hich turns on protein (inase 7 8ardiovascular e!!ects& NO maintains normal vascular tone NO-induced c74P rela+es smooth muscle NO acts as an antio+idant and blocks oxidation of LDL, preventing !oam cell !ormation in atherosclerosis NO inhibits platelet aggregation, reducing the chances o! throm$us !ormation NO inhi$itors increase vascular tone, arterial pressure and potentiate vasopressor drugs :ia$etes, atherosclerosis, and cardiac ischemia all result in decreased NO and increased !ree radicals resulting in tissue damage 8N/ e!!ects& NO acts as a second messenger to !acilitate release of neurotransmitters li(e glutamate, potentiating developmental, learning and memory !unctions 9+cessive glutamate release may induce cytoto+icity, a se=uel to ano+ic $rain damage 9+cessive NO also to+ic to retinal neurons ,on adrenergic non cholinergic &,#,') neurons have the capacity to release NO and innervate 70 and reproductive tracts Penile erection is dependent on N3N8 and the su$se=uent elevation o! c74P, *hich rela+es penile smooth muscle and allo*s lood in!lu+ sildenafil a(a Viagra potentiates NO-induced c74P !ormation $y inhi$iting phosphodiesterase '*hich normally $rea(s do*n c74P) in!lammation& NO/ inhi$itors reduce edema and vascular permea$ility in acute in!lammation Protective e!!ect in chronic arthritis due to reduction in NO-induced elevation in 8OC2