screening of antihypertensive agents

Download Screening of antihypertensive agents

Post on 18-Dec-2014




3 download

Embed Size (px)




  • 1.
  • 2. What is Hypertension
    • High blood pressure: blood forced through the arteries at an increased rate.
    • It is measured as two numbers, e.g. 120/80 mmHg. Normal blood pressure is below this value.
      • The first number is the systolic blood pressure. This is the maximum pressure in the arteries when heart contracts/beats.
      • The second number is the diastolic blood pressure. This is the minimum pressure in the arteries when heart is at rest between beats.
    • Until it becomes extreme, there are no symptoms. Hence, it is called the Silent Killer.
    • Severe hypertension may cause headache, sleepiness, confusion or coma.
  • 3.
  • 4.
    • ACE Inhibition in rat
    • Goldbalt Hypertension
    • Chronic renal hypertension in rats
    • Tail cuff method
    • Salt- sensitive Dahl Rats
    • Renin inhibition in Monkeys
    • Chronic renal hypertension in Dogs .
    • Antihypertensive and vasodilator action in rats.
  • 5.
    • IN VITRO & EX-vivo models
    • Monocrotaline Induced Pulmonary Hyperyension
    • ACE Inhibition in GUENIA PIG illeum
    • 1 Sympatholytic Activity in GUENIA PIG Atria
    Inactive Angiotensin -I Active Angiotensin -II ACE
  • 7.
    • Male Sprague- Dawley rats (200-225gm) are selected..
    • They are anaesthetised with 60mg/kg of phenobarbitone sodium i.v.
    • The intubated trachea is artificially respirated with 30strokes/min and a stroke volume of 6-8ml.
    • The right artery is cannulated for recording the pressure.
    • The jujular vein is cannulated for i.v. test injection.
    • The B.P is diminished by the administration of 5mg/kg of pentolinium i.p.
    • Atropine(40g/kg) is also injected i.m to inhibit the mucous secretion.
    • Now 310ng/kg of Ang I is injected i.v. in 0.1ml saline.
    • The injection is repeated in 5min interval until an identical pressure is attained.
  • 8.
    • The test drug is administered at a dose of 10mg/kg intravenously or 25mg/kg intradeudenally.
    • Again Ang I is injected as the similar dose above.
    • The diminution of the pressure after the administration of potent ACE inhibitors is compared .
  • 9. In vivo models GOLDBALT HYPERTENSION (2 Kidney 1 Clip Method)
    • Ischemia of kidney Blood pressure
    • METHOD: Renin- Angiotensin Mechanism
    • Clamping of renal artery for 4hr and reopening
    • Accumulated renin is released
  • 10.
    • Sprague Dawley Rats (300gm) are anesthetized Hexobarbital sodium (100mg/kg) Intra peritonially.
    • Cannulate the trachea for respiration and the Jugular vein for test compound administration.
    • A transducer is connected to the carotid artery for recording the pressure.
    • A PVC coated clip is placed in the left hilum of the kidney by fixing with the back muscle for 3.5 - 4hr.
    • Pentolinium is administered for ganglionic blockache.
    • Relaese the clip and record the rise in B.P.
    • Administer the test drug througfh I.V. and moniter the pressure continuously.
    • Increase in B.P after releasing the clip and reduction after the drug administration is determined.
    • Compare using percentage values
  • 11. CHRONIC RENAL HYPERTENSION (1 Kidney- I -Clip Method)
    • Sprague Dawley Rats (200 - 300gm) are anesthetized Phenobarbitone sodium (100mg/kg) Intra peritonially.
    • A flank parallel incision is made in the left lumbar area.
    • Renal artery is dissected, cleaned and U shaped silver clip is slipped around near the aorta.
    • The internal gap b/w the clip is adjusted to 0.25 0.38 nm.
    • The right kidney is removed after tying off the renal pedicel.
    • After 4-5 weeks the B.P is measured and the animals are divided into groups of different doses.
    • Test drug is administered for 3 days
    • Pressure before and after drug administration(3min) are recorded.
    • Percent reduction in pressure is calculated and compare to the Std.
  • 12. TAIL CUFF METHOD (Blood Pressure in Conscious rats)
    • Method without any surgical procedure, Similar to sphygomanometry in humans (systolic pressure).
    • Widely used to evaluate the antihypertensive drugs in experimently induced animals.
    • Charles River male rats(300-350g) are anaesthetized using I.P injection of 0.8ml of 4% of chloral hydrate.
    • Both the kidneys are exposed, hypertension is induced by placing a silver clip on both renal arteries.(0.2mm dm & 4mm l)
    • After 5 to 6 weeks operated animals attain renal hypertension with systolic B.P of 170 to 200mmHg.
    • A tubular inflatable cuff is placed around the base of tail and a Pizo- electric pulse detector is positioned distal to the cuff.
  • 13.
    • The cuff is inflated to approximately 300mmHg.
    • As the pressure in the cuff is released slowly, the systolic pressure is detected and recorded in the poly graph.
    • Test substance is administered intra peritonially for alternative days in three times.
    • Decrease in the systolic pressure is determined by the following steps.
      • Day 1: Predose & 2hr postdrug
      • Day 3: Predose & 2hr postdrug
      • Day5: Predose , 2hr post drug & 4hr postdrug
    • These rats Develop severe fatal hypertension when fed high salt
    • diets, whereas salt resistance rats cant.
    • Sprague Dawley Rats (250 - 300gm) are used in this study.
    • Drinking water is replaced with 8% NaCl soln. high salt diet is prepared by mixing salt with regular diet.
    • The animals are fed with the above diet and saline.
    • The test group rats are administered the drug orally for 1 month.
    • Blood pressure changes are recorded.
    • After the experiment the animals (both cntrl & test) are sacrificed.
    • The hearts are isolated, the mass, weight of LV & RV is compared and measured.
    • Upon salt feeding animals B.P rises steeply (up to 36%).
    • The ability of the drug to reverse these changes is studied.
    • Cardiac failure occurs at 4 to 5 months of age in thse kind of rats.
    • Male Sprague- Dawley rats (200-225gm) are selected..
    • They are anaesthetised with 60mg/kg of phenobarbitone sodium i.v.
    • One carotid artery is cannulated & connected with a Statham transducer and the B.P is recorded in a polygraph.
    • Both the jujular veins are cannulated to administer the test drug.
    • Pentolinium (10mg/kg) is injected to block the ganglionic activity.
    • Atleast 5 animals are used for the evaluation of test drug.
    • In 10 min interval doses of 0.5,1.0, and 2g/kg of angiotensin II are injected to establish the dose response curves.
    • After 10 min a continuous infusion is started of the Ang II blocker in a dose of 10g/kg/ 0.1ml/ml.