Mineralocorticoids. Introduction

Transcription

1 Mineralocorticoids Introduction concepts to remember: a) water, glucose, mineral metabolism; b) adrenal in stress and blood pressure 15 Renin - angiotensin (RAS) and kallikrein kinin (KKS) systems: synthesis, secretion receptors, mechanism of action, effects Mineralocorticoids: aldosterone synthesis, secretion, receptors, mechanism of action, hormonal effects Peptide hormones and paracrine factors: ANP, BNP, CNP, ET, adrenomedullin Integration: response to hemorrage and to dehydration Pathophysiology: RAS &KKS involvement in hypertension and in hyperaldosteronism Nephron H2O, ADH, CD glucose, PCT, Tm JGA, renin, Ag II, vasoconstriction, thirst, aldosterone, kinins, vasodilation, Na, ZG, DCT, ANP, BNP, CNP endothelin, adrenomedullin Introduction aldosterone and its story lines Ag II ALDO renin Page 1

2 Pituitary and H2O metabolism AVP AVP released from the PP controls water permeability in the DCT and collecting ducts Adrenal and Na metabolism Aldosterone secreted from the adrenal gland controls Na absorption in the DCT ALDO Page 2

3 Adrenal and Na metabolism ALDO Aldosterone secretion is stimulated by the renin-angiotensin-system (RAS) Renin - Angiotensin System the JGA secretes renin which produces Ag I (10 aa, inactive) from angiotensinogen secreted by the liver ACE, found throughout the body, converts Ag I into Ag II (8 aa). Ag II, the most potent vasoconstrictor, also stimulates aldosterone from adrenal ZG. These actions in concert mantain volume and pressure of arterial circulation, and provide major support in times of fluid loss or failing blood pressure the major stimulus for renin release is a decrease in perfusion pressure traversing the renal afferent arterioles, which is sensed by the JGA (baroreceptor) the 5 -flaking region of the AT1 receptor gene has a glucocorticoid responsive element. The receptor is a classical 7 transmembrane receptor linked to Gq Aldosterone secretion is stimulated by the renin-angiotensin-system (RAS) Page 3

4 Renin - Angiotensin System JGA cells act as miniature pressure transducers sensing renal perfusion pressure and corresponding changes in efferent arteriolar perfusion pressure. Reduction in pressure results in the release of renin. Sympathetic ANS regulates renin release in response to standing-up. Macula densa cells of DCT are in direct apposition of JGA cells and function as chemoreceptors, monitoring DCT- Na and Cl load A number of circulating factors inhibit renin release: Increasing dietary K directly decreases it and Ag II suppresses it independent of alterations in renal blood flow pressure or aldosterone secretion. ANP inhibits renin release. Angiotensinogen (liver) is release constitutively but renin (JGA) is secreted mainly via regulated pathway Aldosterone secretion is stimulated by the renin-angiotensin-system (RAS) Renin - Angiotensin System Aldosterone secretion is stimulated by the renin-angiotensin-system (RAS) Page 4

5 Renin - Angiotensin System Ag II increases aldosterone secretion and constrict vascular smooth muscle, thereby rising blood pressure and reducing blood flow. Ag II enhances central sympathetic outflow thus increasing sympathetic NE discharge from nerve terminals. Ag II also releases NE and Epi from the adrenal medulla and ADH Ag II may modify ACTH release, has poorly defined CNS functions, cellular growth in its target tissues, and may regulate ovarian and placental function, as for example modifying follicular maturation and atresia Aldosterone secretion is stimulated by the renin-angiotensin-system (RAS) Renin - Angiotensin System Aldosterone secretion is stimulated by the renin-angiotensin-system (RAS) Page 5

6 Kallikrein - Kinin System LMW Kininogen tissue kallikrein Kinin (vasodilator) Inactive products kinase I kinase II Angiotensinogen renin Angiotensin I ACE Angiotensin II (vasoconstrictor) RAS / KKS ying-yang control of vascular tone and renal function Kallikrein - Kinin System Kinins are involved in regulation of blood pressure and flow, smooth muscle contraction and relaxation, electrolyte and glucose transport, pain, ovulation, sperm mobility and cell proliferation. They play a major role in inflammation by enhancing vascular permeability Kinins vasodilator effects counterbalance the vasoconstriction effect of RAS. Tissue kallikrein cleaves kininogen to produce the vasodilator kinin called bradikinin HREs have been identified in the 5 -flank-ing region of the kallikrein gene promoter (camp, estrogen, P4 and cortisol) kallistatin, a kallikrein-bp that inhibits kallikrein activity, is a serin-proteinase inhibitor (serpin) upregulated by E2, P4, GH, T3-T4 and down-regulated in inflammation s acute phase B1 and B2 kinin receptors have only 36% homology. B1 only appears in pathological states (inflammation, trauma) is induced by IL-1, endotoxin and EGF. B2 is upregulated by camp and downregulated by salt restric-tion, water deprivation and bradykinin RAS / KKS ying-yang control of vascular tone and renal function Page 6

7 RAS, KKS and Aldosterone ALDO RAS / KKS ying-yang control of vascular tone and renal function Aldosterone Zona Glomerulosa aldosterone Aldosterone is a mineralocorticoid secreted by the adrenal s zona glomerulosa Page 7

8 Aldosterone Zona Glomerulosa ZG aldosterone Aldosterone is a mineralocorticoid secreted by the adrenal s zona glomerulosa Biosynthetic Pathway VLDL cholesterol SCCE pregnenolone 17alpha 3BD hydroxylase progesterone I 21BHL 11-deoxycorti... 11BHL corticosterone 18hydrxylase 18-hydroxycorti... 18dehydrogen... aldosterone 17 a-hydroxypreg... DHEA 3BDI 17alph desmolase a 3BDI 17 a-progesterone androstenedione 21BHL 11 - deoxycortisol ßhydroxysteroid dehydrogenase 11BHL testosterone (*) aromatase mineralocorticoid pathway mevalonic acid AcCoA pyruvate HMG-CoA reductase cortisol glucocorticoid pathway estradiol estrogen / androgen pathway (*) metyperone test Aldosterone is a mineralocorticoid secreted by the adrenal s zona glomerulosa Page 8

9 Control of biosynthetic path VLDL cholesterol AcCoA SCCE HMG-CoA reductase ACTH pregnenolone LH FSH 3BDI Ag II progesterone 21BHL 11BHL 11-deoxycorticosterone corticosterone 18hydroxylase 18- hydroxycorticosterone 18dehydrogen... aldosterone Ag II Aldosterone is a mineralocorticoid secreted by the adrenal s zona glomerulosa Basal release of Aldosterone cortisol renin aldosterone aldosterone its main regulatory mechanism is the renin / Ag II system renin stimuli for its secretion are high K, low Na, Ag II, and ACTH (disease state) it increases Na reabsorption and K secretion, volemia, blood pressure, & Na / H ion facilitated diffusion (alkalosis) its mechanism of action include: aldosterone 1) increase Na permeability; 2) increase content of Na/K ATPases; 3) increases ATP to Na / K ATPases Aldosterone s main physiological effect is the regulation of Na reabsorption at the DCT Page 9

10 Regulation of Aldosterone its main regulatory mechanism is the renin / Ag II system stimuli for its secretion are high K, low Na, Ag II, and ACTH (disease state) Aldosterone s main physiological effect is the regulation of Na reabsorption at the DCT Effects of Aldosterone it increases Na reabsorption and K secretion it increases volemia and blood pressure it increases Na / H facilitated diffusion (alkalosis) Aldosterone s main physiological effect is the regulation of Na reabsorption at the DCT Page 10

11 Mechanism of Action 1) its mechanism of action include: increase Na permeability 2) increase content of Na/K ATPases 3) increases ATP to Na / K ATPases Aldosterone s main physiological effect is the regulation of Na reabsorption at the DCT Mechanism of Action its mechanism of action include: Aldosterone s main physiological effect is the regulation of Na reabsorption at the DCT 1) increase Na permeability 2) increase content of Na/K ATPases 3) increases ATP to Na / K ATPases Page 11

12 Effect of chronic Aldosterone 1) its mechanism of action include: increase Na permeability 2) increase content of Na/K ATPases 3) increases ATP to Na / K ATPases Aldosterone s main physiological effect is the regulation of Na reabsorption at the DCT ANP,endothelin,adrenomedullin Cardiac myocytes produced, both constitutively and in a regulated fashion, 3 natriuretic hormone peptides in response to plasma volume overload or hyperosmolality. They unload the vascular tree via a combination of CNS, pituitary, adrenal, vascular, and renal actions. ANP/BNP decreased venous return by increasing renal excretion of water and solute, vasorelaxation in certain vascular beds, increased capillary permeability, and decreased cardiac output. ANP is produced in the atrium and BNP is produced in the ventricles. CNP produced in endothelium and controls access of blood-born factors not only to interstitium but also to contractile and proliferative elements of the vascular tree (e.g. endothelin, adrenomedullin). Endothelin and adrenomdellin are paracrine regulator in multiple tissue systems participating in the maintenance of circulatory pressure and tissue blood flow Aldosterone function is complemented by peptides acting as hormones and paracrine factors Page 12

13 Atrial Natriuretic Peptide (ANP) ANP secreted by the heart controls Na excretion at the level of the kidney s DCT Atrial Natriuretic Peptide (ANP) (atrium) (ventricle) (endothelium) ANP secreted by the heart controls Na excretion at the level of the kidney s DCT Page 13

14 Physiological effects of ANP (ANP = ANF) Blood volume or volemia is directly dependent on plasmatic Na concentration Physiological effects of ANP ANP, ET, adrenomedullin ANP has multiple targets beside acting on the kidney to regulate Na excretion Page 14

15 Physiological effects of ANP AVP increase venous return ( - ) decrease plasma volume and BP salt appetite, water intake volume and osmo receptors peripheral vasculature selective vasomotion Starling forces ( HCT) heart RAP brain kidney U NaV U V renin ANP adrenal ALD cortisol ANP interacts with AVP secretion in the control of blood pressure Physiological regulation of ANP Natriuretic peptides exert multiple effects and are regulated by multiple factors Page 15

16 Mechanism of action for ANP Natriuretic peptides exert their actions by activation of a membrane receptor linked to Guanylyl Cyclase Endothelin (ET) vasoconstrictors Endothelin is a paracrine regulator acting as a vasoconstrictor in multiple tissue systems Page 16

17 Physiological effects of ET Endothelin, a vasoconstrictor, participates in the maintenance of circulatory and tissue blood flow Synthesis and Regulation of ET Endothelin (vasoconstrictor) Multiple inputs have been shown to affect the promotor site of the endothelin gene Page 17

18 Adrenomedullin vasodilator Adrenomedullin is a vasodilator paracrine factor affecting tissue blood pressure and flow Effects of Adrenomedullin Adrenomedullin is a vasodilator paracrine factor affecting tissue blood pressure and flow Page 18

19 Synthesis and regulation adrenomedullin (vasodilator) Adrenomedullin is a vasodilator paracrine factor affecting tissue blood pressure and flow Hormones and hemorrage With hemorrage, the vascular volume is decreased without a change in osmolality Page 19

20 Hormones and dehydration Dehydration may result from sweating, diarrhea, vomiting, fever, alcohol, insufficient fluid intake Hypertension renal kallikrein system and hypertension: findings are consistent with the notion that genetic factors causing a decrease in renal kallikrein activity might contribute to the pathogenesis of hypertension renin - angiotensin system and hypertension: increase endogenous Ag II production is accompanied by hypertension and is reversed by ACE inhibitors. Hypertension has been reported in humans bearing a rare renin - secreting tumor, in patients having a decreased adrenal and renal vascular response to infused Ag II, and in some patients with low renin hypertension having enhanced adrenal response to Ag II on high Na intake Both increases in RAS and decreases in KKS systems are associated with hypertension Page 20

21 Primary Hyperaldosteronism adenoma removed adrenal adenoma adrenal adenoma In a primary endocrine pathology the problem lies in the endocrine organ in question Secondary Hyperaldosteronism magnetic resonance angiography showing the presence of renal artery stenosis (arrow). Renal artery stenosis In a secondary endocrine pathology the problem lies someplace else than the endocrine organ in question Page 21

22 Adrenopathologies Page 22