PGY452 552 Endocrine physiology 13 Endocrine regulation of ECF osmolarity Antidiuretic Hormone ADH B Aldosterone angiotensin II C Integration A Regulation of salt water in the ECF Electrolytes in ECF Part of effective circulating volume Na 135 145 mM K 3 5 5 0 mM Osmolality 290 mOs Renal excretion reabsorption Vascular dilation constriction Much of this was covered in renal last semester Four main systems 1 Antidiuretic hormone 2 Renin AngiotensinAldosterone axis 3 Atrial natriuretic peptide 4 Sympathetic nervous system Hormones ADH Angiotensin II Aldosterone 2 Antidiuretic hormone Cys Tyr Phe Gln Asn Cys Pro Arg GlyNH2 neural inputs ADH 9 amino acid peptide Posterior pituitary Vasopressin Arginine vasopressin AVP Synthesized in hypothalamic magnocellular neurons Axons extend to posterior pituitary Blood supply Regulation primarily neural inputs Receptors G q coupled ADH Arterial smooth muscle Anterior pituitary corticotrophs G s in kidney 3 ADH is secreted in response to sensory Blood volume depletion Major endocrine inputs 0 5 10 15 20 response to ECF osmolality free water 50 Osmolality The response is feedback to the stimulus simple endocrine input baroreceptors 30 20 10 AD H volume pressure ADH pM ATII 40 osmoreceptors Mostly a stress response to severe blood loss Not important in normal BP regulation 0 270 280 290 300 310 Plasma osmolality mOsm kg 4 ADH in the vasculature volume ADH Interacts with V1 G q receptor Ca2 release results in muscle contraction Increase blood pressure by decreasing vascular volume V1 q PLC PLC Contraction Mostly response to severe bleeding Ca2 5 Water conservation urine output anti diuresis H20 AQP3 AQP2 cAMP cAMP cAMP PKAii cAMP AC cAMP Transcription Transport MAJOR physiological role Lumen ADH ADH binds to G scoupled V2 receptor Stimulates aquaporin s PKAii V2 Blood ADH in the kidney conserves water PKA P distal convoluted tubule and collecting ducts 6 ADH stimulates release of ACTH Alone ADH effect is weak Ca2 CRH ACTH ACTH ACTH ADH V3 s AC P q PLC PLC cAMP Ca2 cAMP cAMP cAMP cAMP PKAii PKAii PKA CRH ADH synergistic effect Physiologically makes sense as stress response Corticotroph ACTH Ca2 7 Aldosterone The primary mineralocorticoid Made in adrenal cortex Zona glomerulosa 8 Aldosterone synthesis Progesterone Pregnenolone Cholesterol 21 hydroxylase StAR 3 hydroxysteroid dehydrogenase Cytochrome P450SCC 11 deoxycorticosterone corticosterone Aldosterone synthase 11 hydroxylase 2 Zona glomerulosa lacks 17 hydroxylase can not make cortisol Aldosterone 9 Aldosterone targets functions Few targets Major K Minor Kidney Cortical collecting tubule Na Colon Sweat glands Salivary glands Other Functions K excretion Na reabsorption more 90 Na NOT in CCT 10 still a very big deal 10 Aldosterone is similar to cortisol Similarities Structure Synthesis Signaling Aldosterone Cortisol transcription Differences 20 bound to transcortin Short t1 2 20 min Soluble 11 Cortisol aldosterone receptors are similar MCR The average circulating concentration of cortisol is 2000x that of aldosterone MCR GCR Binding affinity Cortisol GCR Cortisol MCR Why can t cortisol substitute for aldosterone 12 Aldosterone target tissues inactivate cortisol 11b hydroxysteroid dehydrogenase 2 Cortisol Cortisone 1 Cortisone is inactive 2 The reaction is irreversible GCR Aldosterone does not substitute for cortisol because It s circulating concentration is 2000x cortisol Aldosterone has little affinity for the GCR 13 And what is an MCR in a tissue without 11 HSD2 over stimulated It s a cortisol receptor Like in the brain Neuronal homeostasis homeostatic under stimulated stressed Brain cortisol Receptor occupancy MCR GCR 14 Activity K excretion Na reabsorption Cl K Na Na Na reabsorption ECF Na K ATPase Mitoch ondrial protein s NKCC2 Cl ATP ATP Pol II Lumen K K Na ADP K SGK Transporters Channels SGK kinase Ox phos proteins K excretion ATP Na K ROMK Na ENaC K Na 15 Angiotensin II controls ECV Angiotensinogin 10 amino acids Cleaved by renin Angiotensin I II effective circulating volume Angiotensin I 485 aa protein Made constitutively in liver angiotensinogen Cleavage by angiotensin converting enzyme ACE Unregulated drug target Lungs kidney epithelium Short t 1 min ATI Renin ATII 8 amino acid peptide Precursors AC E 16 Functions signaling of angiotensin 2 q i ATII Renin G q G i coupled receptors Constricts blood vessels Na reabsorption Kidney osmoreceptors Thirst Aldosterone Renin exocytosis Na reabsorption Activates osmoreceptors AD H Like ADH Much more important ADH secretion thirst Aldosterone synthesis 17 Regulation of aldosterone synthesis 1 ECF K 2 Angiotensin II K Ca2 ATII 1 2 PLC 3 Ca2 q DAG K Ca2 Ca2 StAR Ca binding protein kinase P Ca2 5 CREB 4 P450SCC Pol II Aldosterone Synthase 18 Regulation of aldosterone synthesis 1 In these cells K passes through a leak channel Elevated K ion the extracellular fluid has the effect of depolarizing the cells 2 Angiotensin II binding to its G q coupled receptor causes PLC to produce DAG and IP3 The DAG inhibits the K leak channel again depolarizing the cells DAG is synergistic with K ECF in this regard 3 The change in membrane potential causes the opening of voltage gated Ca channels allowing Ca into the cells Intracellular Ca can also be increased by IP3 mediated release from internal stores 4 The Ca binds to a calcium binding protein that then activates a Ca dependent kinase CaM kinase 2 for those of you keeping score The kinase can phosphorylate CREB activating a transcriptional program 5 I hope you can guess this next part Transcription of StAR cytochrome P450 SCC and aldosterone synthase 11 hydroxylase 2 are all increased increasing the amount of aldosterone made 19 Hormones Hormone Source Type t Angiotensin II Liver Aldosterone Adrenal Steroid Long cortex Hypothal Peptide Short amus CRH ADH Peptide Short Posterior Pituitary Peptide Short Rcpt G q G i Stimulus Renin Pressure Inhibition Simple input Major Effects Vascular constriction Na reabs Thirst nuclear K ATII Simple input G s Stress ACTH cortisol ACTH G s G q Pressure Osmolality Simple input Other ADH Aldosterone K Na water aquaporin vasc constriction Aldosterone 20 Notes SLIDE 2 The human reference range what can be considered normal runs from about 275 300 mOs but the can vary a lot depending one the methodology used to measure it SLIDE 5 Don t bother to memorize V1 vs V2 vs V3 receptors However you should be able to work out that it is a G q coupled receptor that causes contraction SLIDE 6