Quantitative Trait Locus Analysis Find Regions

Hyptertension Normal 120(systolic)/80 (diastolic) Prehypertensive 130-139/85-89 Hypertensive >140/90 increased changes of MI, Stroke Risk Increase: 3x Coronary Heart Disease, 6X Congestive Heart Failure, 7x Stroke Kidneys: Dominant BP controller, renal function altered in every genetic/ experimental model of htn, Requires elevated renal perfection pressure to increase normal Na intake, effective antiHTN drugs promote Na/H20 excretion and shift the pressure natriuetic relationship, impaired renal function requires increased renal perfusion pressure (AP) to restore fluid and electrolye balance, Cross transplant HTN kidney in normal animal causes HTN and vice versa Normal- able to maintain BP at 100mmHg w/ vertical line increase Na input/output Non-salt sensitive ability to maintain vertical line at increased pressure High P to excrete Na Salt-sensitive even higher P to excrete Na, more linear relationship Monogenic Forms of Human Tensions 1. Glucocorticoid-Remidiable Hyperaldosteronism- Autosomal dominant, early HTN. Norm/elevated aldosterone, suppressed rennin activity, Hypokalemia, Alkalosis -Glucocorticoids completely suppress Aldosterone elevation -unequal crossing over between aldosterone synthase/11b hydroxylase chimeric gene Increased Aldosterone on Principle Cells of Late distal tubule/ Cortical collecting duct to increase Na reabsorption/ K secretion, Increase K/H counter transportAlkalosis 2. AME- Apparent Mineralocorticoid Excess- Autosomal Recessive, HTN, Hypokalemia, Alkalosis, Supressed plasma rennin release a. BP lowered by mineral corticoid receptor agonists b. Cortisol/Aldosterone both bind to Mreceptor (11B hydroxysteroid dehydrogenase allows only Aldosterone to be active on Mreceptor by converstion of i. cortisol (active) cortisone (inactive) c. Mutations in 11Bhydroxysteroid dehydrogenase allow cortisol to bind to MB to increase Na reabsorption HTN 3. Liddle Syndrome- Autosomal Dominant, Early HTN, Hypokalemia, Alkalosis, Low Plasma Renin Activity, Low Aldosterone a. Mutations in ENaC result in increased ENaC channels on apical membrane (Na Channel) Increase Na reabsorption, Increase K secretion 4. Barter Syndrome- Autosomal Recessive, Hypotensive, Hypercaliuria, Hypokalemia, Alkalosis, decreased Na reabsorption, decreased ECF volume a. Loss of Function Mutations

i. Na/K/2Cl transporter (thick ascending) ii.ROMK apical K channel iii.CLCNKB basolateral Cl Channel Common forms of Hypertension 1. Essential Hypertension- polygenic, multifactoral (genes/envornement) -Pharmacological alteration of Salt retention in the kidney commonly used for treatment -QTL quantitative trait locus analysis find regions of chromosomes associated w/ trait Animal models overlap with human models for HTN genetics Animal models are used for physiological studies Pharmacological studies Organ studies Salt loading studies Genetic Studies in Models