The regulation of blood pressure and fluid homeostasis in the body occurs thorough an endocrine pathway called the renin angiotensin (RAS) pathway. This is a multistep pathway in which two step conversion of angiotensinogen to angiotensin I by rennin and subsequent conversion of angiotensin I to angiotensin II by angiotensin converting enzyme (ACE) occurs (Fig 1a). The RAS involves a number of peptides, receptors and enzymes partake in this highly regulated system. The angiotensin II, however, is the key biological player of this pathway. Uncontrolled activation and improper regulation of the RAS pathway leads to hypertension, organ failure and eventually death. Antihypertensive drugs work by inhibiting the synthesis of angiotensin II or its downstream activation following binding to its receptor. The pathways targeted by the anti-hypertensive agents’ include inhibition of formation of angiotensin I by renin, inhibition of ACE that converts the angiotensin I to II and competitive inhibition of the angiotensin II receptor binding1.
The concluding step of the renin-angiotensin pathway involves binding of angiotensin II to its receptor angiotensin II (AT) receptor which results in activation of the receptors. The two clinically important angiotensin II receptor are types 1 and 2. The key effectors of manifestation of angiotensin II activity is the AT1 receptor. These inhibitors were developed to minimize some of the side effects presented by the ACE inhibitors. The activation of the AT1 receptor results in vasoconstriction, sodium and water retention, aldosterone synthesis, release of vasopressin etc2(Fig 1b). The AT1 receptor antagonists are competitive inhibitors of the substrate angiotensin II. The receptor antagonists exhibit high affinity for the receptor and as a result dissociate very slowly from the receptor. The IC50 values for the inhibitors are in the range of 2-20 nmol/L3. The AT1 receptor antagonists induce relaxation and dilation of the blood vessels and enhance the release of sodium and water through the urine. They also inhibit the release of vasopressin aldosterone resulting in lowering of hypertension. The angiotensin receptor antagonists are used specifically in treatment of hypertension, congestive heart failure and diabetic nephropathy4. Losartan, irbesartan, olmesartan are some of the commonly used angiotensin II receptor antagonists.
Calcium channel blockers inhibit or ‘block’ the entry of calcium through the voltage dependent membrane channels into the cell. As a result, they are also known as calcium entry blockers. The various available blockers target the L-type channels (large, long lasting) and elicit antihypertensive effect5 (Fig 2a). The L channels exist in skeletal; cardiac and smooth muscles and are responsible for vessel contraction of cardiovascular system. The concentration of calcium outside the cell is usually much higher than the intracellular concentration. Following activation of an upstream pathway, membrane depolarization occurs which results in influx of Ca2+ into the cells by the membrane potential dependent channel6. The calcium channels bind to the transmembrane subunit of the channel .The selective physiological effect of many calcium antagonists stem from their ‘use dependence’. This simply means that inhibitors block the calcium channels in the cells where they are most active5. The calcium channel blockers inhibit the L-type channels in vascular tissues and induce relaxation of vascular smooth muscle and lower cardiac contractility (fig 2b). This ability is associated with their antihypertensive and antianginal effects. Some of the commonly used calcium blockers include Verapamil, Diltiazem, Amlodipine and Nifedipine.
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Fig 1 Renin Angiotensin Aldosterone System.
Fig 1(a) Renin Angiotensin Pathway, indicating inhibitors’ site of blockade. (Burnier, 2000)
Fig 1 (b). Competitive inhibition of AT1 by the inhibitor. (www.medmovie.com)
Fig 2 (a) Voltage gated L-type Ca2+ channel
Fig 2(b) Mode of action of Calcium channel blocker