Date of download: 9/18/2016 From: The Cardiomyopathy of Overload: An Unnatural Growth Response in the Hypertrophied Heart Ann Intern Med. 1994;121(5): doi: / Converting enzyme inhibitors decrease the formation of angiotensin II and the breakdown of bradykinin.II323322Decreased levels of angiotensin II (A ), by blunting the cascade shown at the left of the figure, inhibit the production of two intracellular messengers: inositol 1,4,5-trisphosphate (InsP ) and diacylglycerol (DAG). Because the former releases calcium (Ca +) from internal stores, decreased InsP production in smooth muscle cells has a vasodilator effect. Inhibition of the cascade initiated by angiotensin II also decreases the production of the mitogen DAG, so that converting enzyme inhibitors can inhibit cell growth. Inhibition of bradykinin breakdown has even more complex effects, shown at the right of the figure. Increased bradykinin levels lead to the production of InsP and DAG. However, because the net effect of increased bradykinin is vasodilation, the calcium released by the bradykinin cascade appears to favor the production of several vasodilator molecules; these include nitric oxide (produced when an increase in cytosolic calcium activates nitric oxide synthase) and the eicosanoids, prostaglandin E and prostacyclin (released when calcium activates the lipolytic enzyme phospholipase A [PLA]). Bradykinin also activates adenylyl cyclase, which increases the production of yet another vasodilator molecule, cyclic adenosine monophosphate (cAMP). The nitric oxide formed by the bradykinin cascade appears also to have important growth-inhibitory effects. Together, these effects account for the ability of the converting enzyme inhibitors to unload the heart by decreasing peripheral resistance (afterload), and to exert growth-inhibitory effects. The latter, by slowing the progression of maladaptive hypertrophy, may play a role in the ability of the converting enzyme inhibitors to prolong survival in patients with heart failure. G protein = guanine nucleotide-binding coupling proteins; PKC = protein kinase C; and PLC = phospholipase C. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

Date of download: 9/18/2016 From: The Cardiomyopathy of Overload: An Unnatural Growth Response in the Hypertrophied Heart Ann Intern Med. 1994;121(5): doi: / Overall growth patterns in the proliferating myocytes of the embryonic heart, the terminally differentiated myocytes of the normal adult heart, and the maladaptively hypertrophied myocytes of the failing heart.Left.Right.In the embryonic heart, growth factors stimulate synthesis of fetal-specific gene products that, because protein synthesis is matched to active cell cycling, lead to normal cell division. Center. Withdrawal of growth factors and binding of myogenic factors to the E box in the terminally differentiated cells of the normal adult heart slows protein synthesis, inhibits the cell cycle, and favors the synthesis of adult muscle-specific gene products. Overloading of the adult heart initiates an immediate-early gene response that reactivates growth factor stimulation; this, in turn, accelerates protein synthesis and favors the expression of fetal muscle-specific gene products. However, because the cell cycle remains blocked, the overloaded heart undergoes an unnatural growth response. One consequence of this response is accelerated myocardial cell death, which may be partly caused by the ability of some of the activated growth factors not only to stimulate protein synthesis but also to cause programmed cell death (apoptosis). Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians