Blood Pressure, Renal Control, and Hypertension PDF

BLOOD PRESSURE, RENAL CONTROL and HYPERTENSION OBJECTIVES: To Comprehence the role of various body - systems to control blood pressure changes (short and long term). To know the role of sympathetic nervous system, RAA renin angiotensin aldosterone) system , ADH and ANP in the regulation of blood...

BLOOD PRESSURE, RENAL CONTROL and HYPERTENSION OBJECTIVES: To Comprehence the role of various body - systems to control blood pressure changes (short and long term). To know the role of sympathetic nervous system, RAA renin angiotensin aldosterone) system , ADH and ANP in the regulation of blood pressure. To know the definition of hypertension and its types. To know the main groups of drugs used to treat hypertension and apply how these drugs act. Blood pressure is regulated by both long and short term regulation. Short-term regulation: Short term regulation of blood pressure comes from the baroreceptor reflex. The baroreceptors are found in the carotid sinus and the aortic arch and will respond to stretch stimulus. If there is an increase in arterial pressure and these sensors are stretched, there is information feedback to the medulla via afferent pathways (glossopharyngeal and vagus nerve) which sends effecter impulses to the heart (negative chronotropy and inotropy) and the blood vessels (vasodilatation), reducing cardiac output and TPR (total peripheral resistance). THE BARORECEPTOR REFLEX WORKS WELL FOR ACUTE CHANGES IN BLOOD PRESSURE AND PRODUCES RAPID RESPONSES YET DOES NOT CONTROL SUSTAINED INCREASES. There are four neurohormonal factors controlling blood pressure. These factors all work in part by controlling sodium balance and ECF volume -Renin-angiotensin-aldosterone system -Sympathetic nervous system -Antidiuretic hormone (ADH) -Atrial Natriuretic Peptide (ANP) The baroreceptor reflex works well to control acute changed in BP. It produces a rapid response, but does not control sustained increases as the threshold for baroreceptor firing resets. A 5-10% drop in blood pressure causes low-pressure baroreceptors in the atria and pulmonary vasculature to send signals to the brainstem via the vagus nerve. This activity modulates both sympathetic nerve outflow, secretion of the ADH and reduction of ANP release. A 5-150% change in blood pressure causes high-pressure baroreceptors (carotid sinus/aortic arch) to send impulses via the vagus and glossopharyngeal nerves. A decrease in blood pressure will increase sympathetic nerve activity and the secretion of ADH. Sympathetic nervous system Vasoconstriction by α1-adrenoceptors Inc. force/rate of heart contraction β1-adrenoceptors Decreased Renal Blood flow Decreased GFR and Na+ excretion Activates Na/H exchanger in PCT Stimulates renin release from juxtaglomerular cells Increased Angiotensin II/Aldosterone levels Actions of ADH Addition of Aquaporin to Collecting Duct Reabsorption of water Forms concentrated urine Release stimulated by increases in plasma osmolarity or severe hypovolemia Thick Ascending Limb Stimulates apical Na/K/Cl co-transporter Less Na+ moves out into the medulla, reduced osmotic gradient for water to exit the lumen into the peritubular capillaries from the thin descending limb Atrial Natriuretic Peptide (ANP) Acts in the opposite direction to the others Synthesised and stored in atrial myocytes Promotes Na+ excretion Vasodilation of afferent arteriole High BP Stretch Atrial Cells increase release of ANP increased Na+ excretion, volume decreases, BP decrease Low BP Atrial Cells less stretched reduced release of ANP reduced Na+ excretion, volume increases, BP increases ANP Inhibits Na+ reabsorption along the nephron Prostaglandins Prostaglandins are vasodilators. Locally acting prostaglandins (mainly PGE2) enhance glomerular filtration and reduce Na+ reabsorption. They therefore may have an important protective function by acting as a buffer to excessive vasoconstriction by the sympathetic nervous system and the RAAS. EFFECT OF NSAIDs Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) inhibit the cyclo-oxygenase (COX) pathway that is involved in the formation of prostaglandins. As prostaglandins help to maintain renal blood flow and GFR in the presence of vasoconstrictors, if NSAIDs are administered when renal perfusion is compromised (e.g. in renal disease) GFR can be further decreased, leading to acute renal failure. In heart failure or hypertensive patients, NSAIDs can exacerbate the condition by increasing NaCl and water retention. The renin-angiotensin system Reduced perfusion pressure in the kidney detected by baroreceptors in the afferent arteriole, causes the release of renin from the granular cells of the juxtaglomerular apparatus. Decreased NaCl Concentration at the Macula Densa cells (Due to low perfusion and therefore low GFR) causes Sympathetic stimulation to the JGA. This also increases the release of renin. Also causes Macula Densa cells to release Prostaglandins( Afferent Vasodilation) Renin cleaves Angiotensinogen to Angiotensin I, which is in turn cleaved by Angiotensin Converting Enzyme (ACE) to form the active hormone Angiotensin II. Angiotensin II There are two types of Angiotensin II receptors, AT1 and AT2. They are both G- protein coupled receptors. Angiotensin II’s main actions are via the AT1 receptor Actions of Angiotensin II Vasoconstriction Works on vascular smooth muscle cells, increases TPR thus BP Vasoconstriction of afferent and efferent arteriole Stimulates the adrenal cortex to synthesise and release Aldosterone Aldosterone stimulates Na+ and water reabsorption It stimulate Sympathetic Activity. It stimulates the thirst mechanism. Stimulates ADH release at hypothalamus. Breaks down Bradykinin (Bradykinin is a vasodilator) -The renin-angiotensin system can be inhibited at various points along the biochemical cascade. Several drugs have been developed for clinical use, including ACE inhibitors, which prevent the generation of angiotensin II, and angiotensin (AT1) receptor antagonists, which block the action of angiotensin II. -The action of aldosterone can be inhibited directly by the aldosterone antagonist spironolactone that has a diuretic effect. These drugs are used for the treatment of hypertension and heart failure. Summary of Angiotensin II and its actions: Angiontensin II is a potent vasoconstrictor acting on vascular smooth muscle. In addition, it simulates the adrenal cortex to synthesise and release aldosterone. It acts on the nervous system both centrally and peripherally to enhancing sympathetic nerve activity. AII acts directly on the kidney to increase renal tubule sodium ion reabsorption and it stimulates the thirst mechanism. Increase myocardial demand and atherosclerosis lead to ischemic heart disease like angina and MI Hypertension can be defined as a sustained increase in blood pressure ( systole more or equal to 140 and/or diastole more or equal to 90 mmhg) and two classes exist: Essential and secondary hypertension Hypertension is a sustained increase in blood pressure. In around 95% of cases, the cause is unknown. This is known as Essential Hypertension. Genetic and environmental factors may both be involved and the pathogenesis is unclear. Where a cause can be defined, hypertension is referred to as secondary hypertension. Here it is important to treat the primary cause. Examples include: Renovascular disease Chronic Renal Disease Hyper-aldosteronism Cushing’s syndrome Renovascular Disease Renovascular Disease is caused by an occlusion of the renal artery, causing a fall in perfusion pressure in that kidney. Decreased perfusion leads to that kidney releasing renin and activating RAAS. will then take place at the other kidney. Vasoconstriction and Na+ reyension Adrenal Causes -Conn’s Syndrome Aldosterone secreting adenoma lead to Hypertension and hypokalaemia -Cushing’s Syndrome : Excess cortisol and at high concentrations acts on aldosterone receptors. Lead to Na+ and water retention -Pheochromocytoma : Tumour of the adrenal medulla secretes noradrenaline and adrenaline Hypertension is important as it can be asymptomatic yet can have unknown damaging effects. Treating secondary hypertension involves treating the underlying cause yet treating essential hypertension requires other targets of action. This means affecting the stroke volume, heart rate, or TPR (as BP = CO x TPR): Treatment of Hypertension -ACE Inhibitors : Prevent the production of Angiotensin II from Angiotensin -Angiotensin II receptor antagonists -Thiazide Diuretics : Inhibit NaCC co-transporter on apical membrane of DCT. May cause hypokalaemia (more K+ lost in urine) -Vasodilators -Ca2+ channel blockers, reduce Ca2+ entry into smooth muscle cells -α1 receptor blockers, reduce sympathetic tone -Beta Blockers : Block β1-receptors in the heart. Reduces heart rate and contractility Non-pharmacological approaches to the treatment of hypertension include diet, exercise, reduced Na+ intake, reduced alcohol intake. Q3 What is the effect of hydrostatic pressure across the capillary walls on glomerular filtration ? SS4.4 By what two mechanisms do ACE inhibitors lower blood pressure?