Slide 1Regulation of salt & water in the ECFAntidiuretic hormoneADH is secreted in response to sensory inputsADH in the vasculature  volumeADH in the kidney conserves waterADH stimulates release of ACTHAldosteroneAldosterone synthesisAldosterone targets & functionsAldosterone is similar to cortisolCortisol & aldosterone receptors are similarAldosterone target tissues inactivate cortisolAnd what is an MCR in a tissue without 11β HSD2?Activity: K⁺ excretion & Na⁺ reabsorptionAngiotensin II: controls ECVFunctions & signaling of angiotensin 2Regulation of aldosterone synthesisRegulation of aldosterone synthesisHormonesNotesNotes (cont.)Review questionsPGY452/552: Endocrine physiology13. Endocrine regulation of ECF osmolarityA. Antidiuretic Hormone (ADH)B. Aldosterone & angiotensin IIC. IntegrationRegulation of salt & water in the ECFElectrolytes in ECFNa+: 135-145 mMK+: 3.5-5.0 mMOsmolality: ≈290 mOsPart of effective circulating volumeRenal excretion & reabsorptionVascular dilation & constrictionMuch of this was covered in renal last semesterFour main systems1. Antidiuretic hormone2. Renin-Angiotensin-Aldosterone axis3. Atrial natriuretic peptide4. Sympathetic nervous system2HormonesADHAngiotensin IIAldosteroneHormonesADHAngiotensin IIAldosteroneAntidiuretic hormoneADH Vasopressin Arginine vasopressin (AVP)9 amino acid peptidePosterior pituitarySynthesized in hypothalamic magnocellular neurons Axons extend to posterior pituitaryBlood supplyRegulation  primarily neural inputsReceptors Gαq-coupled Arterial smooth muscle Anterior pituitary corticotrophsGαs in kidney3ADHCys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2neural inputsneural inputsADH is secreted in response to sensory inputs4Osmolalityvolume/pressureADH (pM)10020304050270280300290 310Plasma osmolality(mOsm/kg)0 5 10 15 20Blood volume depletion (%)Mostly a stress response to severe blood lossNot important in normal BP regulationMostly a stress response to severe blood lossNot important in normal BP regulationMajor endocrine response to  ECF osmolality → free waterMajor endocrine response to  ECF osmolality → free waterThe response is feedback to the stimulus → simple endocrine inputThe response is feedback to the stimulus → simple endocrine inputADHbaroreceptorsosmoreceptorsATIIADH in the vasculature  volume5ContractionContractionInteracts with V1 - Gαq receptorCa2+ release results in muscle contractionIncrease blood pressure by decreasing vascular volumePLCβγαqV1PLCADHCa2+Mostly response to severe bleedingMostly response to severe bleedingADH in the kidney conserves water6LumenBloodH20AQP2AQP2ADH binds to Gαs-coupled V2 receptorStimulates aquaporinTranscriptionTransportMAJOR physiological roleβγαs V2ADHACPKAPKAPKAiPKAicAMPcAMPcAMPPKAiPKAicAMPcAMPAQP3AQP3PPWater conservation →  urine output →anti-”diuresis”Water conservation →  urine output →anti-”diuresis”distal convoluted tubule and collecting ductsADH stimulates release of ACTH7ACTHCorticot rophPLCβγαqV3PLCADHCa2+ACTHCa2+Ca2+ACPKAPKAβγαsCRHcAMPPKAiPKAicAMPcAMPcAMPPKAiPKAicAMPPPACTHACTHAlone: ADH effect is weakAlone: ADH effect is weakCRH+ADH → synergistic effectPhysiologically makes sense as stress responseCRH+ADH → synergistic effectPhysiologically makes sense as stress responseAldosteroneThe primary mineralocorticoidMade in adrenal cortex → Zona glomerulosa8Aldosterone synthesis9PregnenoloneProgesteroneAldosterone3β-hydroxysteroid dehydrogenase21α-hydroxylaseZona glomerulosa lacks 17α-hydroxylase → can not make cortisolZona glomerulosa lacks 17α-hydroxylase → can not make cortisolcorticosterone11-deoxycorticosteroneCytochrome P450SCCCytochrome P450SCCStARStARAldosterone synthase(11β-hydroxylase 2)CholesterolAldosterone targets & functionsFew targetsMajor KidneyCortical collecting tubuleMinorColonSweat glandsSalivary glandsOtherFunctions K+ excretion Na+ reabsorption more>90% Na⁺ NOT in CCT<10% still a very big deal10Na+K+Aldosterone is similar to cortisolSimilaritiesStructureSynthesisSignaling: transcriptionDifferencesSoluble → 20% bound to transcortinShort t1/2 (≈20 min)11CortisolAldosteroneCortisol & aldosterone receptors are similar 12Binding affinity:Cortisol•GCR ≈ Cortisol•MCRThe average circulating concentration of cortisol is 2000x that of aldosterone! The average circulating concentration of cortisol is 2000x that of aldosterone! Why can’t cortisol substitute for aldosterone?Why can’t cortisol substitute for aldosterone?GCRMCRMCR13Aldosterone target tissues inactivate cortisol11b hydroxysteroid dehydrogenase 21. Cortisone is inactive2. The reaction is irreversible*Aldosterone does not substitute for cortisol because:It’s circulating concentration is 2000x < cortisolAldosterone has little affinity for the GCRAldosterone does not substitute for cortisol because:It’s circulating concentration is 2000x < cortisolAldosterone has little affinity for the GCRCortisolCortisoneGCRAnd what is an MCR in a tissue without 11 HSD2?βIt’s a cortisol receptorLike in the brain14MCRGCR[Brain cortisol]Neuronal homeostasisReceptor occupancyunder stimulatedhomeostaticover stimulatedstressedActivity: K excretion & Na reabsorption⁺ ⁺15LumenECFMitochondrial proteinsMitochondrial proteinsATPATPSGKSGKATPATPNa+K+ADPK+Na+Na+K+K+Na+K+K+Cl⁻Na+Cl⁻Na+Pol IITransportersChannelsSGK kinaseOx/phos proteinsROMK ENaCNa/K ATPaseNKCC2K⁺ excretionK⁺ excretionNa⁺ reabsorptionNa⁺ reabsorptionAngiotensin II: controls ECV8 amino acid peptidePrecursorsAngiotensinogin: 485 aa protein Made constitutively in liverAngiotensin I 10 amino acidsCleaved by reninAngiotensin I → IICleavage by angiotensin converting enzyme (ACE)Unregulated drug targetLungs & kidney epitheliumShort t½ (~1 min)16angiotensinogenangiotensinogenReninReninATIIACEeffective circulating volumeATIATIFunctions & signaling of angiotensin 2Gαq & Gαi -coupled receptorsConstricts blood vessels Like ADHMuch more importantKidney Renin exocytosis Na+ reabsorptionActivates osmoreceptors ADH secretion thirst Aldosterone synthesis17βγαqαi βγ Na+ reabsorption Na+ reabsorptionReninReninADHosmoreceptorsATII Aldosterone