Michael F. Michelis, M.D., F.A.C.P., F.A.S.N.

Director, Division of Nephrology

Lenox Hill Hospital, New York

Clinical Professor of Medicine

New York University School of Medicine

ARGININE VASOPRESSIN (AVP)

AFFECTS BLOOD PRESSURE AND RENAL WATER REABSORPTION

WHAT ELSE DOES IT DO?

AVP AND THE HYPOTHALAMO-PITUITARY SYSTEM

Koshimizu T et al. Physiol Rev 2012;92:1813-1864

AVP MOLECULEAVP MOLECULE

Regulate Vascular Tone

Regulate H2OReabsorption by the Kidney

AVP (ADH)

V1a Receptors V2 Receptors

Regulation of AVP Secretion

Both increased plasma osmolality and decreased blood volume stimulate AVP secretion, but with different thresholds and sensitivities

Stricker et al. In: Fundamental Neuroscience. 2nd ed. 2003;1011-1029

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Nonpressor and Nonantidiuretic Actions of Nonpressor and Nonantidiuretic Actions of VasopressinVasopressin

Arginine Vasopressin Receptors and Arginine Vasopressin Receptors and Their LocationsTheir Locations

V1a Receptors

Smooth Muscle Cells

Brain

Adrenal Cortex

Adipose Tissue

Hepatocytes

Osteoblasts

Osteoclasts

Arginine Vasopressin Receptors and Arginine Vasopressin Receptors and Their Locations Continued..Their Locations Continued..

V1b Receptors V2 Receptors

Anterior Pituitary Basolateral Membrane of Collecting Ducts

Adrenal Medulla Alveolar Epithelial Cells

Islet Cells of Langerhans

Osteoblasts

White Adipose Tissue

Osteoclasts

AVP AND HEMOSTASISAVP AND HEMOSTASIS

DDAVP increases serum levels of vWF, DDAVP increases serum levels of vWF, factor 8 and t-PA via V2 receptors on renal factor 8 and t-PA via V2 receptors on renal and nonrenal epithelial cellsand nonrenal epithelial cells

Useful for treatment of Von Willebrand’s Useful for treatment of Von Willebrand’s disease and hemophiliadisease and hemophilia

AVP AND PAIN PERCEPTIONAVP AND PAIN PERCEPTION

AVP exerts analgesic actionsAVP exerts analgesic actions

AVP can increase pain threshold when given AVP can increase pain threshold when given by intraventricular route (animal study)by intraventricular route (animal study)

Analgesic actions blocked by V1a receptor Analgesic actions blocked by V1a receptor antagonist. Intrathecal and intranasal AVP antagonist. Intrathecal and intranasal AVP also can reduce painalso can reduce pain

AVP AND AGING, SOCIAL BEHAVIOR AVP AND AGING, SOCIAL BEHAVIOR AND COGNITIONAND COGNITION

Klotho increases resistance to oxidative Klotho increases resistance to oxidative stress (anti-aging), reduces 1,25 Vitamin D stress (anti-aging), reduces 1,25 Vitamin D (anti-hyperphosphatemia)(anti-hyperphosphatemia)

Klotho levels are reduced in dehydrated mice Klotho levels are reduced in dehydrated mice and in studies by high levels of AVPand in studies by high levels of AVP

AVP increases anxiety (V1a). Neuroleptic AVP increases anxiety (V1a). Neuroleptic drugs decrease AVP levels. Autism linked to drugs decrease AVP levels. Autism linked to mutation in V1a receptor genes.mutation in V1a receptor genes.

Dehydration affects cognitive function and Dehydration affects cognitive function and decreases in function are associated with decreases in function are associated with AVPAVP

Ohnishi M et al. FASEB J 24: 3562-3571, 2010

AVP AND BONEAVP AND BONE

AVP receptors V1a and V2 on osteoblasts AVP receptors V1a and V2 on osteoblasts and osteoclastsand osteoclasts

AVP stimulates osteoclasts and inhibits AVP stimulates osteoclasts and inhibits osteoblastsosteoblasts

Hyponatremia also activates osteoclasts and Hyponatremia also activates osteoclasts and limits defense against ROS by limiting limits defense against ROS by limiting movement of Vitamin C into cellsmovement of Vitamin C into cells

Hyponatremia-Induced Osteoporosis

Verbalis JG et al. J Bone Miner Res 25(3): 554-563, 2010

Animal Study: Hyponatremia produced greater bone loss than aging alone after three months.

NHANES III: Data revealed hyponatremia was associated with increased odds of osteoporosis at the hip adjusted for age, sex, race, vitamin D25. (OR = 2.85, p<0.01)

NORMONATREMIC

SOLID+DDAVP

HYPONATREMIC

LIQUID+DDAVP

Verbalis JG et al. J Bone Miner Res 25(3): 554-563, 2010

AVP AND HYPOTHALAMIC PITUITARY AVP AND HYPOTHALAMIC PITUITARY AXISAXIS

HPA axis involves central CRH and AVP HPA axis involves central CRH and AVP (V1b) responses. V1b is more important in (V1b) responses. V1b is more important in stress situations.stress situations.

AVP also acts on receptors in adrenal gland AVP also acts on receptors in adrenal gland (V1a cortex and V1b medulla) for peripheral (V1a cortex and V1b medulla) for peripheral stress reactions.stress reactions.

AVP AND INFLAMMATION AND AVP AND INFLAMMATION AND CELL PROLIFERATIONCELL PROLIFERATION

Inflammatory cytokines such as IL-6 and CRP Inflammatory cytokines such as IL-6 and CRP increase AVP levels (hyponatremia) and AVP increase AVP levels (hyponatremia) and AVP via V2 stimulation can reduce inflammation in via V2 stimulation can reduce inflammation in lungs by local decrease in IL-6lungs by local decrease in IL-6

Defective response of hypothalamus (CRH and Defective response of hypothalamus (CRH and AVP) decreases ACTH and thereby cortisol AVP) decreases ACTH and thereby cortisol response which fails to suppress inflammationresponse which fails to suppress inflammation

AVP increases cell proliferation in studies on AVP increases cell proliferation in studies on intestinal epithelial cells, renal mesangial cells intestinal epithelial cells, renal mesangial cells (V1a, VEGF) and blockade decreased lung (V1a, VEGF) and blockade decreased lung cancer cell growth cancer cell growth

Chiu T et al. Am J Physiol Cell Physiol 282: C434–C450, 2002

AVP AND INFECTIONAVP AND INFECTION

Response to infection involves innate Response to infection involves innate immunity, TLRs, and renal tubular epithelial immunity, TLRs, and renal tubular epithelial cells. TLR4 recognizes LPS on gram negative cells. TLR4 recognizes LPS on gram negative organisms and activates factors which organisms and activates factors which destroy the organism.destroy the organism.

DDAVP inhibits LPS induced activation of anti DDAVP inhibits LPS induced activation of anti gram negative organism factors. This can be gram negative organism factors. This can be prevented by V2 blockers.prevented by V2 blockers.

Dehydration and increased AVP may play a Dehydration and increased AVP may play a role in susceptibility to infection. role in susceptibility to infection.

AVP AND METABOLIC SYNDROMEAVP AND METABOLIC SYNDROME

Metabolic Syndrome includes:Metabolic Syndrome includes:

• Insulin Resistance (DM)Insulin Resistance (DM)

• DyslipidemiaDyslipidemia

• HypertensionHypertension

• Obesity, Sleep Apnea, Fatty LiverObesity, Sleep Apnea, Fatty Liver

AVP actions include liver and pancreas effectsAVP actions include liver and pancreas effects

and ACTH secretion. and ACTH secretion.

AVP AND DIABETIC MELLITUSAVP AND DIABETIC MELLITUS

V1a receptors on hepatocytes cause V1a receptors on hepatocytes cause glycolysis and V1b receptors are found on glycolysis and V1b receptors are found on pancreatic alpha cells (glucagon) and beta pancreatic alpha cells (glucagon) and beta cells (insulin) but V1b receptors on alpha cells (insulin) but V1b receptors on alpha cells are more sensitive to AVPcells are more sensitive to AVP

AVP also stimulates ACTH via V1b receptors AVP also stimulates ACTH via V1b receptors in the pituitary and V1a receptors in the in the pituitary and V1a receptors in the adrenal cortex to increase cortisol (glucose)adrenal cortex to increase cortisol (glucose)

Cells, Receptors and the Effects of Arginine Vasopressin on the Blood

Glucose Levels

Hepatocytes V1a-Glycolysis

Beta islet cells V1b- Insulin release

Alpha islet cells V1b- Glucagon release

CNS (Pituitary) cells V1b- ACTH release increases glucocorticoids

Adrenal Cortex V1a- increases glucocorticoids

AVP AND ACTH AND STRESSAVP AND ACTH AND STRESS

CRH and AVP cause ACTH to be released CRH and AVP cause ACTH to be released from pituitaryfrom pituitary

stress stress V1b V1b releases ACTH releases ACTH cortisol cortisol glucose glucose

ACTH released by AVP does not respond to ACTH released by AVP does not respond to negative feedback via cortisol as does CRH negative feedback via cortisol as does CRH induced ACTH releaseinduced ACTH release

COPEPTIN AND AVPCOPEPTIN AND AVP

Copeptin surrogate marker of AVP as it is Copeptin surrogate marker of AVP as it is secreted with AVPsecreted with AVP

Easier to use as a marker since longer half Easier to use as a marker since longer half life, not attached to plateletslife, not attached to platelets

Higher levels correlate with Mets, increased Higher levels correlate with Mets, increased TG levels and predictor of obesity, TG levels and predictor of obesity, proteinuria, and DM (15+ years Swedish proteinuria, and DM (15+ years Swedish study)study)

COPEPTIN AND SERUM OSMOLALITY

Fenske W K et al. JASN 2014;25:2376-2383

©2014 by American Society of Nephrology

AVP AND LIPIDSAVP AND LIPIDS

AVP stimulates sympathetic nerve activity in the AVP stimulates sympathetic nerve activity in the CNS which can increase fatty acidsCNS which can increase fatty acids

AVP has an antilipolytic effect involving V1a AVP has an antilipolytic effect involving V1a receptors in adipose tissue. V1a regulates insulin receptors in adipose tissue. V1a regulates insulin mediated glucose uptake.mediated glucose uptake.

V1a deficient rodents demonstrate increased V1a deficient rodents demonstrate increased lipolysislipolysis

AVP stimulates glycogenolysis in liver increasing AVP stimulates glycogenolysis in liver increasing glucose and triglyceride levelsglucose and triglyceride levels

Blockade of V1b can suppress lipolysis and Blockade of V1b can suppress lipolysis and increase lipogenesis by increasing insulin increase lipogenesis by increasing insulin sensitivitysensitivity

AVP AND HYPERTENSIONAVP AND HYPERTENSION

AVP deficiency contributes to vasodilation in AVP deficiency contributes to vasodilation in septic shockseptic shock

Studies over last 40 years have cited issues Studies over last 40 years have cited issues with sodium excretion (less efficient) in black with sodium excretion (less efficient) in black vs white subjectsvs white subjects

Bankir, Parucca and MH Weinberger 2007 Bankir, Parucca and MH Weinberger 2007 published a comprehensive study published a comprehensive study demonstrating more concentrated urine, demonstrating more concentrated urine, higher pulse pressure and delay in sodium higher pulse pressure and delay in sodium excretion in black individualsexcretion in black individuals

Bankir, L et al. CJASN 2: 304-312, 2007

AVP AND CKD PROGRESSIONAVP AND CKD PROGRESSION

Not only previously mentioned actions regarding Not only previously mentioned actions regarding diabetes mellitus and hypertension but also data diabetes mellitus and hypertension but also data relating low urine volumes and CKD progressionrelating low urine volumes and CKD progression

AVP stimulates the renin-angiotensin system via AVP stimulates the renin-angiotensin system via the V2 receptor. May decrease sodium excretion the V2 receptor. May decrease sodium excretion and cause hyperfiltrationand cause hyperfiltration

DDAVP infusion increases urine osmolality and DDAVP infusion increases urine osmolality and increases UAE. AVP infusion increases GFR increases UAE. AVP infusion increases GFR with increased urine concentration and with increased urine concentration and decreased FENAdecreased FENA

Efffects can be altered by ACE and V2 blockadeEfffects can be altered by ACE and V2 blockade

Meijer, E. et al. Kidney Int. 77: 29-36, 2010

Bankir, L. et al. Nat. Rev. Nephrol 9: 223-239, 2013

Bardoux P et al. NDT 18:1755-1763, 2003

IN SUMMARYIN SUMMARY

Arginine vasopressin exerts a variety of Arginine vasopressin exerts a variety of actions on multiple functions such as pain actions on multiple functions such as pain perception, behavior and cognitionperception, behavior and cognition

Integrity of bone, inflammatory reactions, cell Integrity of bone, inflammatory reactions, cell proliferation, and responses to infection and proliferation, and responses to infection and stress are also influenced by AVPstress are also influenced by AVP

Actions of AVP related to metabolic syndrome Actions of AVP related to metabolic syndrome involving glucose, lipids and blood pressure involving glucose, lipids and blood pressure and effects relating to hydration status, and effects relating to hydration status, hyperfiltration and proteinuria may influence hyperfiltration and proteinuria may influence the progression of chronic kidney diseasethe progression of chronic kidney disease

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