Vasoactive Peptides and NO
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| kinins | peptide autacoids that act locally to cause pain, vasodilation, increased vascular permeability, and synthesis of prostaglandins.
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| initiates synthesis of kinins | tissue damage, allergic reactions, acute and chronic infammation
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| 3 kinds of kinins | bradykinin, kallidin, methionysl-lysylbradykinin
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| serine protease required for kinin synthesis | kallikrens (exist as proenzyme "prekallikrein" until activated
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| substrate for kallikrein | kininogens (either heavy-molecular-weight or low-molecular-weight)
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| formed by plasma kallikrein cleaving HMW-kininogen | formed by tissue kallikrein cleaving LMW-kininogen
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| enzymes that metabolize kinins | kinase I and kinase II (Angiotenisn Converting Enzyme; dipeptidyl carboxypeptidase)
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| half-life of kinins | less than 15 seconds
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| receptors for kinins | B1 and B2
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| kinin receptor upregulated during inflammation and seems to be responsible for most of kinins inflammatory effects | B1
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| kinin recetor with high affinity for bradykinin | B2
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| kinin receptor coupled to a G-protein and activates phospholipase A2 and phospholipase C | B2
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| effects of kinins on arterial vascular beds | vasodilation
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| mechanism of kinin effects on arterial vascular beds | 1. Direct 2. Indirect (mediated through EDRF and synthesis of PGE2 and PGI1)
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| effect of kinins of veins | vasoconstriction, probably due to PGF2alpha production)
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| main effect of kinins on the cardiovascular system | edema due to arteriole vasodilation, venous constriction, and contraction of epithelial cells
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| role of kinins in inflammation | edema and bronchospasm in asthmatics
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| role of kinins in pain | B2 receptors mediate acute pain while B1 recetors mediate chronic inflammation
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| effects of bradykinin on neonates | dilation of fetal pulmonary artery, closure of the ductus arteriosis, and constricture of umbilical arteries
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| clinical uses of kinins | no approved uses yet, but ACE inhibitors block kinase II, which causes kinin elevation and subsequent hypotensive action
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| potent vasoconstriction peptide | angiotensis
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| first enzyme in the biosynthesis of angitoensin II | renin
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| location of synthesis, storage, and release of renin | juxtaglomerular cells of kidney
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| renin substrate | angiotensiogen
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| site of angiotensiongen synthesis | liver
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| converts angiotensin I to angiotensin II | Angiotensin Converting Enzyme (ACE)
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| location of ACE | luminal surface of vascular endothelial cells
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| synthesis pathway of Angiotensin II | Angiotensinogen cleaved by renin->angiotensin I->converted to Angiotenisn II by ACE
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| rate-limiting factors for Angiotensin II production | renin secretion and circulating angiotensin
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| comounds that increase concentrations of angiotensinogen | corticosteroids, thryoid hormones, estrogen
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| provides negative feedback for the production of angiotensin | vascular stretch receptors, sodium, alpha adrenergic tonus
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| postive feedback on angiotensin II production | beta 1 adrenergic receptors
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| metabolism of angiotensin | rapidly removed from blood
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| mechanism of angiotensin II action | AT1 is a G-protein coupled receptor-->activate PLC-->IP3 and DAG-->smooth muscle contraction. Also increases NE release and decreases NE reuptake. Stimulates release of NE and E from adrenals
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| effect of angiotensin II on the cardiovascular system | very potent vasoconstrictor (via smooth muscle contraction, and some CNS and ANS). Its effects on NE potentiate sympathetic transmission
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| effect of angiotensin II on the adrenal cortex, kidney, and CNS | stimulates aldosterone and glucocorticoid biosynthesis, renal vasoconstriction, renal sodium reabsorption, stimulation of drinking response, vasopressin release (ADH),
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| clinical effect of renin inhibitors | suppress angiotensin II production-->lower blood pressure in HTN patients
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| clinical effect of ACE inhibitors | block conversion of Angiotensin I to Angiotensin II, as well as inhibiting metabolism of bradykinin. Overall effect is to maintain vasodilation and decrease blood pressure
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| ACE inhibiting drugs | captopril (Capoten) and enalapril (Vasotec)
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| side-effect of ACE inhibitors | cough due to build-up of kinins in lung and edema
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| conditions treated by ACE inhibitors | hypertension and congestive heart failure
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| angiotensin II agonists that are orally active and have the useful effects of ACE inhibitors without the coughing and edema | non-peptide Angiotensin II agonists (losartan, valsartan)
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| ubiquitous short-lived vasodilator | NO (also known as Endothelium Derived Relaxing Factor)
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| 3 enzymes that produce NO | cNOS(nNOS), iNOS, eNOS
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| constitutive NO enzyme present in neurons and epithelial cells | cNOS (nNOS)
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| inducible NO enzyme present in macrophages and smooth muscle cells | iNOS
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| constitutive NO enzyme present in endothelial cells | eNOS
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| all three NOS isoforms are flavoproteins (T/F) | True
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| substrate for NOS | 1-arginine
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| cofactors required for NOS isoforms | NADPH, flavine adenine dinucleotide, tetrahydrobiopterin
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| products of NOS | 1-citrulline and NO
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| NO donors that spontaneously release NO | nitroprusside, nitroglycerin
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| inactivate NO | heme and superoxide (free radical)
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| increase potency and duration of NO | antioxidants
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| product of glutathione interaction with NO | S-nitrosoglutathione (long-lived carrier of NO)
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| NO mechanism | activates soluble guanylyl cyclase-->produce cGMP-->activate protein kinase G-->smooth muscle relaxation
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| effects of NO on cardiovascular system | maintenance of normal vascular tone
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| effect of NO inhibitors on cardiovascular system | increase vascular tone, increase arterial pressure, potentiate vasopressor drugs.
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| effects of diabetes, atherosclerosis, and cardiac ischemia on NO | decreased NO (and increased free radicals)
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| NO effect on LDL | acts as an antioxidant to block its deposition on arterial walls (one of first steps in atherosclerosis)
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| NO effect on platelets | decrease aggregation-->decrease chance of thrombus formation
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| NO effects on CNS | diffusible second messenger that can facilitate the release of NTs-->potentiate developmental, learning, and memory functions
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| effect of excessive NO | toxic to retinal neurons
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| type of neurons innervating the GI tract | Non-adrenergic non-cholinergic (NANC) neurons that release NO
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| cause of penile erection | NO release from NANC neruons-->increase cGMP-->relax smooth muscle-->allow blood influx-->erection
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| drug that potentiates NO-induced cGMP by inhibiting the phosphodiesterase that normally breaks down cGMP | sildenafil (Viagra)
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| effect of NOS inhibitors on actue inflammation | reduce edema and vascular permeability
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| effect of NOS inhibitors on arthritis | reduce NO-induced COX2 activity-->decreased release of inflammatory prostaglandins
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| captopril (Capoten) drug type | ACE inhibitor
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| enalapril (Vasotec) drug type | ACE inhibitor
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| losartan (Cozaar) drug type | AT1 receptor agonist
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| valsartan (Diovan) drug type | AT1 receptor agonist
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| Nitroprusside drug type | NO donor
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| Nitroglycerin drug type | NO donor
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| sildenafil (Viagra) drug type | selective inhibitor of the PDE that breaks down NO-dependent cGMP
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