Arterial dilation reduces afterload on the failing ventricle and leads to an increase in stroke volume and ejection fraction, as well as increases organ perfusion. The cardiostimulatory and vasodilatory actions of PDE3 inhibitors make them suitable for treating heart failure. Finally, NO acting through cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation. Therefore, inhibitors cGMP-dependent phosphodiesterase, by increasing intracellular cGMP, enhance smooth muscle relaxation and vasodilation, and cause penile erection. NO also activates K + channels, which leads to hyperpolarization and relaxation. Increased intracellular cGMP inhibits calcium entry into the cell, decreasing intracellular calcium concentrations and causing smooth muscle relaxation ( click here for details). This enzyme breaks down cGMP that forms in response to increased nitric oxide (NO). The type 5 isoform of this enzyme (PDE5) is found in the corpus cavernosum of the penis and in vascular smooth muscle. There is a second isoenyme form of PDE in vascular smooth muscle that is a cGMP-dependent phosphodiesterase. General Pharmacology of cGMP-Dependent Phosphodiesterase Inhibitors (PDE5) However, only cilostazol (see below) is used for this purpose in the treatment of intermittant claudication (ischemic leg pain associated with leg movement). PDE3 inhibitors also decrease platelet aggregation by increasing platelet cAMP. Because of the dual cardiac and vascular effects of these compounds, they are sometimes referred to as "inodilators." Other actions At normal therapeutic doses, PDE3 inhibitors such as milrinone have a greater vascular than cardiac effect, so that arterial pressure is lowered in the presence of augmented cardiac output. Because cardiac output increases and systemic vascular resistance decreases, the change in arterial pressure depends on the relative effects of the PDE inhibitor on the heart versus the vasculature. The cardiac and vascular effects of cAMP-dependent PDE inhibitors cause cardiac stimulation, which increases cardiac output, and reduced systemic vascular resistance, which lowers arterial pressure. Decreased pulmonary capillary wedge pressure.Increased stroke volume and ejection fraction.Therefore, inhibition of this enzyme increases intracellular cAMP, which further inhibits myosin light chain kinase, producing less contractile force (i.e., promoting relaxation).ĬAMP-dependent PDE (type3) Inhibitors Systemic Circulation Like the heart, the cAMP is broken down by a cAMP-dependent PDE (PDE3). The reason for this is that cAMP normally inhibits myosin light chain kinase, the enzyme that phosphorylates smooth muscle myosin, causing contraction. Unlike cardiac muscle, increased cAMP in smooth muscle causes relaxation. Beta 2-adrenoceptor agonists such as epinephrine stimulate the Gs-protein and the formation of cAMP ( click here for details). Blood vesselsĬyclic-AMP also plays an important role in regulating the contraction of vascular smooth muscle. ![]() PDE3 inhibitors can be thought of as a backdoor approach to cardiac stimulation, whereas β-agonists go through the front door to produce the same cardiac effects. This increases cardiac inotropy, chronotropy and dromotropy. Inhibition of this enzyme prevents cAMP breakdown and increases its intracellular concentration. The isoform of this enzyme that is targeted by currently used clinical drugs is the type 3 form (PDE3). Cyclic-AMP is broken down by an enzyme called cAMP-dependent phosphodiesterase (PDE). ![]() Increased cAMP, through its coupling with other intracellular messengers, increases contractility (inotropy), heart rate (chronotropy) and conduction velocity (dromotropy). This activates adenylyl cyclase to form cAMP from ATP. These catecholamines bind primarily to beta 1-adrenoceptors in the heart that are coupled to Gs-proteins. Activation of the sympathetic nervous system releases the neurotransmitter norepinephrine and increases circulating catecholamines (epinephrine and norepinephrine). Intracellular concentrations of cAMP play an important second messenger role in regulating cardiac muscle contraction. General Pharmacology of cAMP-Dependent Phosphodiesterase Inhibitors (PDE3) Heart
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