Anonymous
08-08-2004, 10:35 PM
There was a little confusion about this in our last chat, so I thought I'd put up some info on Angiotensin II.
AT II receptors
Two main subtypes of angiotensin II receptors have been described. These are referred to as AT1 and AT2. The pharmacological effects of angiotensin II are primarily mediated by the AT1 receptor.
Angiotensin elevates blood pressure directly and indirectly. Activation of receptors in blood vessel smooth muscle cells causes vasoconstriction and increases in peripheral resistance. Sodium and water are reabsorbed by the direct action of angiotensin II on AT1 receptors in the cells of the proximal tubules. Adding to the resulting volume overload, angiotensin II stimulates vasopressin release and initiates the thirst reflex.8 In addition, it causes the adrenal cortex to increase the production and secretion of aldosterone, which in turn, causes sodium retention and secretion of potassium and hydrogen ions.
Another effect of angiotensin II that has attracted a good deal of recent attention is cardiovascular remodeling (redistribution of mass). One mechanism for this involves an increase in blood volume and peripheral resistance resulting in increased cardiac workload. This can lead to cardiac hypertrophy, fibrosis, thickening of the intimal surface of the blood vessel wall, and increased wall-to-lumen ratio in the blood vessels. In addition, angiotensin II stimulates proliferation and hypertrophy of cardiac myocytes through its action on AT1 receptors in these cells.9 Smooth muscle growth and migration is stimulated, resulting in synthesis of extracellular matrix protein by fibroblasts.10 These changes may contribute to the cardiac sequelae associated with hypertension.
http://www.allergy-consult.com/secure/textbookarticles/Primary_Care_Book/images/88_figure1.gif
ACE inhibitors
ACE inhibitors lower the blood pressure by several mechanisms. First, they block the conversion of angiotensin I to angiotensin II by the competitive inhibition of ACE. A second mechanism for blood pressure reduction with ACE inhibitors involves impeding the degradation of bradykinin and substance P, which, in turn, stimulates prostaglandin biosynthesis. ACE is identical to kininase II, which is responsible for degrading bradykinin. By blocking ACE, the ACE inhibitors also are increasing bradykinin levels. Bradykinin is a potent vasodilator and may be a significant contributor to the efficacy of ACE inhibitors.
Unfortunately, bradykinin and substance P also may be partially responsible for the side effects seen with ACE inhibitor use, including cough.
The Angiotensin II Receptor Blockers (ARBs)
Since all known pressor effects of angiotensin II are mediated through the AT1 receptor, a medication that blocked these receptors would theoretically share therapeutic effects of the ACE inhibitors. Losartan, the first orally administered angiotensin II type 1 receptor blocker, became available in 1995.
ARBs lower blood pressure by interfering with the action of angiotensin II, blockading the AT1 receptor site. This obstructs the action of angiotensin II regardless of its site or mechanism of production. ARBs do not interfere with ACE; therefore, they do not result in increased bradykinin or substance P. They have no effect on glomerular filtration rate, triglycerides, total or HDL cholesterol, or fasting glucose concentrations.
http://www.allergy-consult.com/secure/textbookarticles/Primary_Care_Book/images/88_figure3.gif
Treatment with ARBs has a number of beneficial effects. By blocking the AT1 receptor site, ARBs decrease all of angiotensin II’s known effects, including slow and fast pressor responses, sympathetic nervous system stimulation, CNS effects including thirst, release of adrenal catecholamines, secretion of aldosterone, direct and indirect effects on the kidneys, and growth-promoting actions.
http://www.allergy-consult.com/secure/textbookarticles/Primary_Care_Book/images/88_table2.gif
ref: PC Textbook
AT II receptors
Two main subtypes of angiotensin II receptors have been described. These are referred to as AT1 and AT2. The pharmacological effects of angiotensin II are primarily mediated by the AT1 receptor.
Angiotensin elevates blood pressure directly and indirectly. Activation of receptors in blood vessel smooth muscle cells causes vasoconstriction and increases in peripheral resistance. Sodium and water are reabsorbed by the direct action of angiotensin II on AT1 receptors in the cells of the proximal tubules. Adding to the resulting volume overload, angiotensin II stimulates vasopressin release and initiates the thirst reflex.8 In addition, it causes the adrenal cortex to increase the production and secretion of aldosterone, which in turn, causes sodium retention and secretion of potassium and hydrogen ions.
Another effect of angiotensin II that has attracted a good deal of recent attention is cardiovascular remodeling (redistribution of mass). One mechanism for this involves an increase in blood volume and peripheral resistance resulting in increased cardiac workload. This can lead to cardiac hypertrophy, fibrosis, thickening of the intimal surface of the blood vessel wall, and increased wall-to-lumen ratio in the blood vessels. In addition, angiotensin II stimulates proliferation and hypertrophy of cardiac myocytes through its action on AT1 receptors in these cells.9 Smooth muscle growth and migration is stimulated, resulting in synthesis of extracellular matrix protein by fibroblasts.10 These changes may contribute to the cardiac sequelae associated with hypertension.
http://www.allergy-consult.com/secure/textbookarticles/Primary_Care_Book/images/88_figure1.gif
ACE inhibitors
ACE inhibitors lower the blood pressure by several mechanisms. First, they block the conversion of angiotensin I to angiotensin II by the competitive inhibition of ACE. A second mechanism for blood pressure reduction with ACE inhibitors involves impeding the degradation of bradykinin and substance P, which, in turn, stimulates prostaglandin biosynthesis. ACE is identical to kininase II, which is responsible for degrading bradykinin. By blocking ACE, the ACE inhibitors also are increasing bradykinin levels. Bradykinin is a potent vasodilator and may be a significant contributor to the efficacy of ACE inhibitors.
Unfortunately, bradykinin and substance P also may be partially responsible for the side effects seen with ACE inhibitor use, including cough.
The Angiotensin II Receptor Blockers (ARBs)
Since all known pressor effects of angiotensin II are mediated through the AT1 receptor, a medication that blocked these receptors would theoretically share therapeutic effects of the ACE inhibitors. Losartan, the first orally administered angiotensin II type 1 receptor blocker, became available in 1995.
ARBs lower blood pressure by interfering with the action of angiotensin II, blockading the AT1 receptor site. This obstructs the action of angiotensin II regardless of its site or mechanism of production. ARBs do not interfere with ACE; therefore, they do not result in increased bradykinin or substance P. They have no effect on glomerular filtration rate, triglycerides, total or HDL cholesterol, or fasting glucose concentrations.
http://www.allergy-consult.com/secure/textbookarticles/Primary_Care_Book/images/88_figure3.gif
Treatment with ARBs has a number of beneficial effects. By blocking the AT1 receptor site, ARBs decrease all of angiotensin II’s known effects, including slow and fast pressor responses, sympathetic nervous system stimulation, CNS effects including thirst, release of adrenal catecholamines, secretion of aldosterone, direct and indirect effects on the kidneys, and growth-promoting actions.
http://www.allergy-consult.com/secure/textbookarticles/Primary_Care_Book/images/88_table2.gif
ref: PC Textbook