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INTRODUCTION

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The kidney filters the extracellular fluid volume across the renal glomeruli an average of 12 times a day, and the renal nephrons precisely regulate the fluid volume of the body and its electrolyte content via processes of secretion and reabsorption. Disease states such as hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis may disrupt this balance. Diuretics increase the rate of urine flow and Na+ excretion and are used to adjust the volume or composition of body fluids in these disorders. Precise regulation of body fluid osmolality is also essential. It is controlled by a finely tuned homeostatic mechanism that operates by adjusting both the rate of water intake and the rate of solute-free water excretion by the kidneys—that is, water balance. Abnormalities in this homeostatic system can result from genetic diseases, acquired diseases, or drugs and may cause serious and potentially life-threatening deviations in plasma osmolality.

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Part I of this chapter first describes renal physiology, then introduces diuretics with regard to mechanism and site of action, effects on urinary composition, and effects on renal hemodynamics, and then integrates diuretic pharmacology with a discussion of mechanisms of edema formation and the role of diuretics in clinical medicine. Specific therapeutic applications of diuretics are presented in Chapters 28 (hypertension) and 29 (heart failure). Part II of this chapter describes the vasopressin system that regulates water homeostasis and plasma osmolality and factors that perturb those mechanisms and examines pharmacological approaches for treating disorders of water balance.

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ABBREVIATIONS

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Abbreviations

AA: arachidonic acid

ACTH: corticotropin (previously adrenocorticotropic hormone)

ADH: antidiuretic hormone

AIP: aldosterone-induced protein

Aldo: aldosterone

Ang: angiotensin

ANP: atrial natriuretic peptide

ATL: ascending thin limb

AVP: arginine vasopressin

BL: basolateral membrane

BNP: brain natriuretic peptide

CA: carbonic anhydrase

cGMP: cyclic guanosine monophosphate

CHF: congestive heart failure

CNGC: cyclic nucleotide-gated cation channel

CNP: C-type natriuretic peptide

CNT: connecting tubule

COX: cyclooxygenase

DAG: diacyglycerol

DCT: distal convoluted tubule

DDAVP: 1-deamino-8-D-AVP (desmopressin)

DI: diabetes insipidus

DTL: descending thin limb

ECFV: extracellular fluid volume

ENaC: epithelial Na+ channel

ENCC1 or TSC: the absorptive Na+-Cl symporter

ENCC2, NKCC2, or BSC1: the absorptive Na+-K+-2Cl

ENCC3, NKCC1, or BSC2: the secretory symporter

FDA: Food and Drug Administration

FF: filtration fraction

GFR: glomerular filtration rate

GPCR: G protein–coupled receptor

GTP: guanosine triphosphate

HCTZ: hydrochlorothiazide

HDL: high-density lipoprotein

HSD: 11-β-hydroxysteroid dehydrogenase

IMCD: inner medullary collecting duct

IP3: inositol trisphosphate

LDL: low-density lipoprotein

LM: luminal membrane

LOX: lipoxygenase

LT: leukotriene

MR: mineralocorticoid receptor

MRA: mineralocorticoid receptor antagonist

mRNA: messenger RNA

NP: natriuretic peptide

NPA: asparagine-proline-alanine

NPR_: natriuretic peptide receptor _ (e.g., NPRA, B, or C)

NSAID: nonsteroidal anti-inflammatory drug

OAT: organic anion transporter

PA: phosphatidic acid

PG: prostaglandin

PK_: protein kinase _ (e.g. PKA, PKB, PKG)

PL_: phospholipase _ (e.g., PLC, PLD)

PTH: parathyroid hormone

PVN: paraventricular nucleus

RAAS: renin-angiotensin-aldosterone system

RAS: renin-angiotensin system

RBF: renal blood flow

SGK-1: serum ...

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