Exam 1 n6280.docx

Exam 1 Kidney, Salt and Water - Body water \~60% (can be measured by heavy H2O deuterium oxide) - Falls w/ age (bc muscle holds a lot of water and muscle mass dec w/ age) - Males have more body water bc more muscle - 70kg person has \~42L of water - 25L in...

Exam 1 Kidney, Salt and Water - Body water \~60% (can be measured by heavy H2O deuterium oxide) - Falls w/ age (bc muscle holds a lot of water and muscle mass dec w/ age) - Males have more body water bc more muscle - 70kg person has \~42L of water - 25L intracellular (65%ish) - 17L extracellular (35%ish) - 3L plasma, 8L interstitial, 5L connective tissue and bone - Third spacing can occur (edema, pleuritis, ascites, etc) which is unproductive water - \*\*BP = CO x TPR (TPR = radius of vessels) - Want to keep the ratio of ICF to ECF right which usually involves movement of salt - Regulated by sensors (like baroreceptors, osmoreceptors) that bring signals back to medulla to make decisions about how to regulate water - In fluid overload, GFR increases to make you pee more - RAAS system activated in hypoperfusion of kidney to conserve water and Na  - Moles / equivalents - 1 equivalent = 1 mole, 1 mEq = 1/1,000^th^ of an equivalent - For univalent molecules (+1 charge like Na, K, Cl or HCO3), 1mEq = 1 mmol - For bivalent molecules (+2 charge like Ca, Mg, CO4), 1mEq = 2mmol - Na is the major cation in the plasma, Cl and bicarb are the major anions - Plasma osmolality is majorly determined by Na concentration - Osmolar gap - OG = measured osmolality -- calculated osmolality - With an expanded osmolar gap, the cell will shrink because water is pulled from the cell - Things like alcohol intoxication increase the osmolar gap which would cause cell shrinkage - Measured reports everything in the blood, like if there are aldehydes from alcohol - Regulation of blood volume - When baroreceptor firing goes down, it activates the SNS - The concentration of vasopressin inc in higher osmolality and this stimulates thirst when osmolality gets above 285ish - Vasopressin inc in hemorrhage too - ADH (vasopressin) is causes more reabsorption of water in the distal tubule then released and binds w/ vasopressin receptors w/ Gs stim proteins transcription factors make more aquaporins more water pumped back into blood volume - This also requires salt in the capillary to pull water via the Na/K pump (done by aldosterone to make more Na/K pumps) - Kidney regulation of water and salt - Kf \~ permeability - Pg -- BP - Pb -- bowman capsule pressure - Pi g -- oncotic pressure in glomerulus (lessens filtration) - Pi b -- bowman's capsule oncotic pressure - Renal perfusion is the major determinant of GFR, so anything that changes volume or salt in ECF determines kidneys decision to excrete more or not - Factors affecting GFR - Most important regulator of GFR = blood volume / renal BF - When renal BF / blood vol inc = GFR inc and extra fluid excreted (and vice versa) - Control done by sympathetics, macula densa, metabolism, renin / ang and myogenic responses - GFR mirrors blood flow as you work in the normal BP range, there is constant renal BF and urine output - Hypotension, urine output goes WAY down - Hypertension -- not as steep of a decline in renal fxn as w/ hypotension, but you pee a lot of fluid out and more Na is pushed into Bowman's capsule than normotension - Autoregulation relative consistency of GFR and RBF between MAP of 80-170 (done via myogenic mechanism and tubuloglomerular feedback) - SNS stim -- significant in reducing GFR in severe acute disturbances in arterial BP (like brain ischemia, severe hemorrhage or hypotn) - Myogenic vasoconstriction and dilation dictates flow to kidney (high pressure ultimately causes constriction of the afferent arteriole bc of high stretch) - Tubuloglomerular feedback - Each nephron can regulate its own GFR and is controlled by the juxtaglomerular (JGA) cells - Controlled by glomerulus, macula densa and specialized JGA cells that produce and release renin - Macula densa sits at the end of the distal tubule and senses Na in the tubule great proximity to afferent arteriole that have JGA cells and SNS nerves - Figure: Renal artery clipped (pressure to kidney falls) less flow macula densa sense less salt renin inc bc lack of perfusion less fluid loss bc retention of Na and H2O can trigger HTN crisis - Afferent constriction and efferent dilation dec GFR and vice versa - Macula densa cells inc activity of Na/K pump which inc adenosine (bc of dephosphorylation of ATP so when all 3 phosphates have been cleaved, adenosine is left) which causes contraction of afferent arterioles and induces relaxation of efferent arterioles - Low GFR JGA cells produce renin ANG I ANG II (contracts efferent arteriole maintaining GFR) - High BP high GFR inc Na sensing on macula densa constriction of afferent arteriole (direct, not myogenic bc of high Na sensing d/t adenosine) - Macula densa release adenosine smooth muscle cells have adenosine type I receptors these receptors inhibit cAMP formation inhibition of adenyl cyclase formation which would constrict smooth muscle (bc cAMP usually dilates) AND works thru Gq proteins which inc intracellular Ca to contract smooth muscle and all working to constrict the afferent arteriole  - Macula densa have Na/Cl/K pumps pushing Na into cell which exits thru Na/K pump into blood (requires ATP); HTN causes an ATP-ADP gradient and when its working so fast, you're left w/ adenosine - Cross-talk bt macula densa and JGA cells is the other part of regulation - JGA cells secrete renin when they are triggered (precursor to RAAS); transcription factors go up or down to regulate renin which can be turned on by cAMP - Loss of Na d/t HTN inc Na/K pump speed more adenosine made adenosine goes to smooth muscle and JGA cells stim of adenosine I receptor (Gi protein) inhibition of adenyl cyclase less cAMP dec renin secretion constriction of afferent arteriole - Sympathetic nerve stim + catecholamines stim beta receptors on JGA cell (Gs receptor) inc adenyl cyclase and cAMP inc renin synthesis - Prostaglandins can also drip out the macula densa cells stim prostaglandin Gs receptors inc cAMP more renin - Low Na upregulation of nitric oxide in macula rensin inc formation of prostaglandin then back to the previous bullet (combo of JGA and SNS) - High Na inhinits prosta synthesis which inhibits renin formation - When the macula densa works really hard, ATP can leak out of the cell which stim purine receptors (P2YR Gq protein) inc Ca in the JGA cell inhibits renin - ANG II can also inhibit renin via Gq protein and high Ca - Na and BP - High Na usually inc BP and only \~1% of filtered Na is actually excreted - When there is a reduced nephron \#, high Na can inc BP bc it is isn't excreted as much - Salt sen vs salt insen HTN - As arterial pressure inc, the urinary Na excretion should inc (HTN high Na excretion bc high GFR) - Called pressure naturesis - W/ HTN, it takes more pressure to get the same amt of Na excretion (eventually adds to HTN bc retention of Na = inc in blood volume bc of water retention) - Salt sensitive vs salt insensitive HTN - Na insen HTN parallel shift is usually d/t dec renal BP that dec GFR which inc renin (can be a problem w/ prerenal vessels) - Na sen HTN has 3 main causes: - Dec kidney mass dec renal BF dec GFR lower renin - Dec capillary filtration can be from infections causing leakiness, WBC action, inflammation - Inc distal and collecting tubule reabsorption - BOTH VERSIONS make the pt less able to excrete Na at a given pressure - BP and obesity - Compression of vessels to kidney less RBF renin released bc sensed hypoperfusion Na reabsorption bc high aldosterone ECF expansion bc of physical compression of the kidney macula densa sense high Na afferent arteriole constriction bc high Na high GFR - Other mechanisms of renal issues and HTN  Other hormones - Aldosterone -- directly controls Na handling - Secretion is controlled by ANGIIand acts on the distal tubule / collecting duct via intracellular (steroid) receptors to inc Na reabsorb and K excretion - Loss of aldosterone secretion d/t adrenalectomy or addison's disease - Tremendous loss of Na by kidneys w/ a reduction in plasma Na conc severe vol depletion and hypotn - Aldosterone makes more Na/K pumps on blood vessel side to push more Na into blood vessel water follows thru aquaporins which is a massive vol expander - Naturetic peptide - ANP / BNP regulate excretion of Na during vol overload - Atrial muscle cells release ANP in response to stretch (inc preload) - Ventricular myocardium release BNP in response to overload - ANP / BNP act on kidney to promote naturesis (rise in Na excretion) and dec Na reabsorption by the collecting duct, promote vasodilation and inc GFR - "Brake for Na reabs", antithesis of aldosterone - ANP released by RA d/t stretch and BNP released when LV is stretch all d/t expanded plasma vol - Both cause dec Na abs to promote peeing off more fluid to reduce volume - Inhibitory on ANGII and works against RAAS and vasodilates - Urodilatin, uroguanylin and guanylin - For urodilatin to be released, distal and collecting tubule cells identify inc circulating vol, similar structure to ANP / BNP INHIBIT Na reabs, vasodilation - Uroguanylin + guanylin for these to be released, cells in intestines respond to NaCl ingestion to INHIBIT Na, Cl and water reabsorption (responds based on diet) - SUMMARY - Increased Na reabsorption RAAS, aldosterone - Decreased Na reabsorption ANP / BNP, urodilatin, uroguanylin, guanylin - Diuretic agents - Drugs that alter the osmolality of urinary filtrate and oppose reabsorption of water, rsulting in an inc in urine vol - Osmotic diuretics inc osmolality of filtrate causing more water to remain in the tubule which is excreted - ACEIs inhibit the formation of ANGII and aldosterone - Loop diuretics block the Na/K/Cl pumps in the ascending loop of henle - Thiazide diuretics block Na reabsorption - K distribution - K is usually secreted in the cortical collecting duct and can exceed the K that was diltered in the first place - You secrete lots of K w/ inc aldosterone (bc Na/K ATPase pump), high dietary intake, high ANP / BNP dec K secretion - Anything that inc Na reabsorption inc K secretion - Shift K to outside of cells dec ECF pH, dig, hypoxia, hyperosmolality, hemolysis, infection, ischemia, trauma - H+ and K go in opposite directions, so more H+ inside cell = higher K outside cell - W/ impaired blood flow which causes acidosis, the H+ will go into the cell bc it builds up outside so it goes down its gradient in exchange for K - Shift K inside cells inc ECF pH, insulin, epi - Epi metabolically activates the Na/K pump, glucose uptake into cells w/ insulin also fuels ATP pump - Na/K pump pushes K into cells w/ use of enzyme Na/K ATPase; if this enzyme is inhibited, hyperK can result - A dec in ECF pH (inc in ECF H+) tends to produce a rise in ECF K bc passive exchange of extracellular H+ for intracellular K across the membrane - Insulin promotes the uptake of K by skeletal muscle and liver cells and is a result of stim of cell membrane Na/K ATPase pumps - Epi inc K uptake by cells mediated by beta 2 receptors - Hyperosmolality raises K by causing cells to shrink and raises ICF (bc less volume) which causes K to go out to ECF down gradient - Tissue trauma, infection, ischemia, hemolysis and severe exercise cause release of K from cells bc RBCs are destroyed which leaks K into the ECF from lysis - Ca distribution - About 60% of filtered Ca is reabsorbed in the proximal convoluted tubule, 1/3 is reabsorbed by Ca channels and a Na/Ca exchanger (by changing Na concentration in distal tubule, you facilitate Ca/Na exchange by pushing Na out and pulling Ca back in) - Reabsorption continues along distal convoluted tubule and is inc by thiazide diuretics (inhibit the Na-Cl cotransporter which causes a fall in ICF Na which promotes the Na/Ca exchanger and inc Ca reabsorption) - Thiazide diuretics can be prescribed for hypercalciuria or kidney stone (nephrolithiasis) - PTH is the primary hormonal regulator of Ca excretion Ca reabsorption is inc when PTH is high - PTH inc Ca reabs in the thick ascending limb, distal convulted tubule and connecting tubule - Mg distribution - About 25% of Mg filtered by glomerulus is reabsorbed in the proximal tubule, but loop of Henle is great at reabsorbing Mg - Reabsorption of Mg is passive mainly and Mg can fit thru tight junctions - Phosphate distribution - Phosphate reabs is transport-max limited meaning the amt of phosphate filtered usually exceeds the max reabsorption capacity of the tubules bc P and Na are reabs together - If more P is ingested than is needed, the kidney excretes more - PTH helps control this it decreases transport-max which inc P excretion - Response to PTH is fast and involves endocytosis of Na/P cortansporters - Fibroblast growth factor 23 inhibits tubular P reabs and elevated plasma levels cause hypoP which can cause rickets or osteomalacia - Patients w/ CKD often have hyperP bc when GFR falls the filtered P load is diminished and the tubules reabs P - High P can cause crystals when it binds w/ Ca which can cause atherosclerosis type crystals in the vessels - Kidney and anesthesia - Anesthesia causes reversible dec in RBF, GFR, urinary flow and Na excretion and are mediated by autonomic and hormonal responses to surgery and anesthesia - Volatile agents dec renal vascular resistance and sevo might lead to compound A formation at low flows nephrotoxic compound in rats - Opioids and prop exhibit minor if any effects on kidney when used alone, ketamine may preserve renal fxn during hemorrhagic hypovolemia Blood vessels - Peripheral circulation is a circuit all flow thru lungs, variation in regional flow, inc flow in active tissues, maintained flow to vital organs, limited change to systemic flow - Difference in resistance in arterioles changes local perfusion - Flow = vol of blood thry organ, tissue or vessel at a given time (mL / min) - Perfusion = flow per given vol or mass of tissue (mL / min / g) - Pressure = force of blood exerted on vessel wall (mmHg) - GI and kidney flow is variable as opposed to heart and brain which is not, skeletal muscle takes the most blood flow during exercise - When area goes up, velocity goes down of flow speed of blood going by a given tissue slows down to allow for diffusion (time-dependent) - L heart R heart = pressure difference - Arterioles have the biggest pressure drop off bc blood loses pulsatile nature and becomes a continuous flow - 60% of blood sits in veins at rest bc of compliance bt arteries and veins; veins have more volume per pressure bc they are more compliant than arteries (veins can constrict bc they have smooth muscle, but less than arteries) - Vessels have laminar flow in the center and then the flow slows down on the sides and has more turbulent flow bc of blood sheering on the side of the vessel - Vessel structure - Inside is the endothelial lining (interna), next is the media which is the muscle, then the externa which is connective tissue, nerves and vasovasorum (blood vessels supplying the vessels) - Arterioles have lots of smooth muscle, capillaries have none - Components of ECM \-\-\-\-\-\-\-\-\-\-\-\-- - Capillaries - Smallest vessels single layer of endothelial cells w/ small lumen meant to exchange materials and are in close proximity to cells - Can be continuous, fenestrated or sinusoid - VEGF is a growth factor that can sprout more capillaries - Vessel control of BP -  - Calculation of MAP = Pd + (Ps -- Pd) / 3 (Pd = diastolic, Ps = systolic) - Determinants of resistance - MAP = L side, CVP = RA - SVR = (MAP -- CVP) x 80 / CO (which is usually 5-6L) - Blood viscosity - "Thickness" of blood resulting from RBCs and albumin - Directly proportional to resistance, inversely proportional to flow - Around 40-45% Hct, viscocity goes up quick - Vessel length - Distance blood must travel: longer distance = more friction - Longer vessel = greater resistance - Longer vessel = lower flow - Vessel organization - Our vessels are organized into "lanes" like multi-lane highways, where each branch has its own resistance - Pressure is inversely related to the \# conduits and flow is determined by paracrine local factors, SNS / PSNS, neural factors - Smooth muscle contraction of vessels - No visible sarcomeres, but operates by a sliding filament mechanism - Alpha 1 stim constricts these muscles - No t-tubules, SR close to plasma membrane, no troponin present and regulation is done via myosin filaments - Primary regulatory mechanism is MLCK - Ca binds to smooth muscle cell from L-type Ca channel or SR intracellular Ca binds to calmodulin (like an uber) shuttles Ca to contractile apparatus (actin-myosin) Ca + calmodulin activates MLCK phosphorylation myosin head cocks and cross bridges to contract muscle - Relaxation is done via dephosphorylation of myosin done by the enzyme phosphatase - Phosphatase is activated by cAMP and cGMP, which is activated by bradykinin, NO and prostaglandin - Alpha 1 adrenergic receptor mechanisms of vasoconstriction - Norepi binds to the alpha1 receptor (likes alpha \> beta) Gq protein activation activation of L type Ca channels (inc intracellular Ca) activated PLC (phospholipase C) PLC splits PIP2 forming DAG and IP3 IP3 releases Ca from intracellular stores in ER (so more intracellular Ca) inc intracellular Ca leads to contraction via MLCK mechanism - Norepi alpha \> beta - Epi beta \> alpha - Endothelin is the most potent vasoconstrictor, ANG II 2^nd^ most potent - On the other side of the pathway, GEF can be activated leads to Rho stim and Rho kinase stim which inhibits PP1M caldesmon (which normally inhibits actin-myosin interaction) is phosphorylated vasoconstriction - Calponin inhibits the ATPase - Anything that LOWERS phosphorylation is dilatory - MLCK phosphorylation and force development - Smooth muscle can maintain force for a while without weakening but myosin light chain phosphorylation declines during this time which is called the latch state - Control of flow - Autoregulation -- tissue can regulate its own flow - Myogenic control -- if pressure w/in a vessel is suddenly inc, the vessel responds by constricting and relaxation at low flow - Metabolic control - CO2, H+, K+ and lactic acid - Vasoactive chemicals like histamine, prostaglandins and bradykinin (all dilators) - Angiogenesis -- VEGF (stimmed by exercise bc low ATP in the tissues) - Local hypoxia causes dilation for tissues in everything except lungs (HPV) - Vasodilators -- bradykinin, histamine, beta 2 stim, ANP, prostacyclin, NO - Prostacyclin comes from arachidonic acid which stims cAMP (stims phosphatase) to vasodilate - L arginine acted on by iNOS makes NO turns on cGMP activates phosphatases vasodilation - NO turned on by inflammation, blood flow sheering across endothelial cells, nitroglycerine (direct NO donor to smooth musc to directly turn on cGMP to dilate) - Anything that inc cAMP / cGMP dilates - Bradykinin stimmed by inflammation and clotting binds to bradykinin receptors on endothelial cell inc NO release NO drips out and goes to smooth musc cell cGMP made shut down kinases and activates phosphatases dilation - Bradykinin also leads to prostacyclin to inc cAMP dilation - Hyperemia and NO - Hyperemia = excess flow - If you have a BP cuff that releases, there is a huge surge of flow which can cause sheer stress w/ lots of flow hitting vessel wall - Exercise causes more blood flow to working muscle - Neural control - Vasomotor center in medulla SNS stim constricts most vessels EXCEPT DILATES the skeletal and cardiac muscle - Regulated by baroreceptors, chemoreflex and medullary ischemic reflex - Stretch stims baroreceptor firing - HTN more baroreceptor firing inhibitory element activated turn on PSNS (vessels done have PSNS endings, but heart does) reduced HR to compensate lower SV - For vessel response, reduce SNS tone to dilate - Arterial baroreceptors - Activation of baroreceptor (high pressure) NTS tract active talks to NA and RVLM NA is the main PSNS outflow neurons from the brainstem PSNS activity to the heart (vagal activity) - NTS ALSO lessens activity of SNS outflow (mediated thru RVLM) drain into preganglionic SNS tone to blunt this less SNS activity going to heart and more SNS to veins to dilate less preload lower pressure - SNS has nerve endings in veins and arterioles, PSNS can inhibit SNS activity thru Raffy nucleus but no PSNS endings to vasculature - Baroreflex - Autonomic, - feedback mechanism in response to BP = baroreceptors - Inhibit SNS in cardiac and vasomotor center, excites vagal fiber - Effects -- reduced HR, reduce CO, vasodilation and reduces BP - This reflex is initiated when baroreceptors are stretched - Some nerve endings release Ach and PSNS has a lot of Ach releasing around the heart - SNS in presynaptic nerves release Ach activates postsynaptic nerves release norepi from lateral horn in thoracic region - feedback (dilation, reduce BP, CO, HR) - Low BP lower baroreceptor firing reduce PSNS (shut down flow to NA) and turn on SNS SNS goes to arterioles to induce vasoconstriction and inc TPVR inc in BP - SNS can also inc venous tone and blood volume to inc venous pressure (pressure in veins before RA -- can be central in thorax or peripheral in veins) this tries to inc venous return to the heart as a while to bring up SV, CO and BP - For changes in position: sitting standing blood to legs leg veins have higher pressure lower SV, CO and BP less baroreceptor firing reduce PSNS activity and higher SNS activity inc BP, SV, constriction, RAAS later to expand volume (+/-) - Chemoreflex - Autonomic response to chemical changes chemoreceptors, low pH, low O2, high CO2 - Primary role is to adjust respiration (higher MV), secondary -- vasoconstriction, inc perfusion - Things that trigger chemoreflexes are considered stressful like acidosis, hypoxia, hypercarbia - Systemically, these factors are constrictors, locally, they're dilators - Medullar ischemic reflex - Cardiac & vasomotor centers inc HR and contraction, widespread vasoconstriction - Ischemic brain (stressful) will sacrifice BF everywhere else to perfuse the brain as much as possible major SNS response to inc HR, BP, SV to try to get blood to brain - Cushing's reflex -- HTN, bradycardia, irregular respirations (Cheyenne Stokes) - Like ischemic brain but causes inc in ICP which can push on microvascular tissue in the brain - In order of occurrence: baroreceptors, chemoreceptors, brain ischemia response, RAAS - The body will do what it can to keep BP the same, but when there is no change in BP, there either has to be a change in CO or resistance - Hypertension - Mortality inc w/ systolic or diastolic HTN - As pts age, so do their vessels -- stiffer, less compliant - R side of figure: when an older person has a stiffer aorta, the stiff aorta fights the flow which causes the pressure wave to deflext back to the heart which augments systolic BP which drives up afterload = heart works harder - Younger pt does not have this issue - Thoughts about initiation of HTN - Defect of vascular smooth muscle w/ abnormal reactivity (inc vascular resistance) - Defect of renal Na excretion body fluid vol inc, inc BP - Inflammation and insulin resistance can perpetuate HTN and worsen atherosclerosis - Potentially treatable causes of HTN CKD, renovascular disease, endocrine (aldosterone excess, pheochromocytoma, cortisol excess) - Renal fxn & BP - Dec BP inc renal SNS activity (bc baroreceptor reflex) inc renal arteriolar vasoconstriction dec GFR inc renin release ANG II inc aldosterone inc renal Na reabs inc renal fluid reabs dec urinary output inc in BP - In HTN, it takes a higher pressure to excrete the same amt of urine and Na Special Circulation - CO and venous return: venous return CVP (IVC, SVC all into RA; preload) CO - Peripheral venous compartment pressure \~7, CVP \~2, so delta Pressure of \~5 driving flow - R graph: at a normal CO, CVP is \~2 and CO is around 5L/min, but w/ inc ionotrophy w/ a normal fxn curve, CVP will dec and CO will inc slightly  - High CO2, high Oe, high NO, high lactate, high CO, cerebral autoregulation, PSNS and high SNS activity all inc cerebral blood flow - Cerebral perfusion is maintained in a BP range of 60-160, pressures higher than 160 can cause the BBB to become leaky - Cerebral vessels are dilated by: high CO2, low pH, low O2, prostaglandins, NO, warmth, dec hct - Volatile anesthetics inc CBF, but uncouple BF metabolism interrelationship - Coronary BF - When in systole, the heart is compressing the coronaries, so the heart muscle is not perfused during systole, in diastole when the heart is relaxed, the coronaries are perfused and the heart muscle is oxygenated - Tachycardia = impaired coronary perfusion - W/ a HF patient, when they exercise their coronaries can paradoxically constrict worsening perfusion d/t endothelial damage - Skeletal muscle -- when you exercise, you need dilation to have BF to feed the muscle (SNS activity is inc during exercise and dilates the vessels to skeletal and cardiac muscle) - SNS constricts in vessels w/ alpha receptors usually, but skeletal muscle has less alpha than beta (lots of these) so NE ends up dilating the vessels bc of beta activity - Coronary vasculature also has lots of beta 2 receptors - SNS dilates coronary and skeletal muscle vessels - Cardiac and skeletal muscle vessels do not have PSNS endings, but Ach can interact w/ muscarinic receptors which can cause relaxation / dilation of these muscles and when skeletal muscle contracts a lot, adenosine is released, which is a dilator - Other dilators: NO, prostaglandins, adenosine, ATP, K, H+, inc CO2, low O2, osmolality - Shock - Hypovolemic (hemorrhage), cardiogenic, distributive (most common -- septic, anaphylactic, neurogenic) & obstructive (PE, tamponade, tension pneumo) - Hemorrhagic shock - \>2pints of blood loss (causing loss of pressure) - Adaptive response -- inc activation of baroreceptor reflexes (bc low baroreceptor firing) inc HR & CO, vasoconstriction (inc SVR); activation of chemoreceptors (more minor) - Inc renin release