P-Adrenergic activity

The properties of -adrenoceptor blockers that contribute to antiarrhythmic effects are antagonism of neural/humoral P-adrenergic activity, and antagonism of catecholamine-mediated electrophysiological properties, ie, increase refractory period and decrease in the rate of diastoHc depolarization, ie, decrease automaticity and slow atrioventricular conduction (1,2). 

Norepinephrine is a potent a-adrenergic agent with less pronounced P-adrenergic activity. Doses of 0.01 to 3 mcg/kg per minute can reliably increase blood pressure with small changes in heart rate or cardiac index. Norepinephrine is a more potent agent than dopamine in refractory septic shock.24,27-28... 

Dopamine is a a- and P-adrenergic agent with dopaminergic activity Low doses of dopamine (1 to 5 mcg/kg per minute) maintain renal perfusion, higher doses (greater than 5 mcg/kg per minute) exhibit a- and P-adrenergic activity and are frequently utilized to support blood pressure and to improve cardiac function. Low doses of dopamine should not be used for renal protection as part of the treatment of severe sepsis.24,27-28... 

Skeletal muscle cells lack glucagon receptors. Hormonal control of glycogen degradation is achieved by epinephrine via P-adrenergic activation of adenylate cyclase, resulting in enhanced cytoplasmic cyclic AMP levels. Neural activation of skeletal muscle cells considerably increases the cytoplasmic Ca level. Cyclic AMP and Ca " act in a synergistic fashion to fully express the activity of glycogen phosphorylase in the process described above (Devlin, 1992). 

The drug exhibits a direct-acting sympathomimetic agent having predominantly P-adrenergic activity plus a selective action on the P2-receptors (i.e., (P2-agonist). This is, therefore, recommended for the treatment of severe and acute forms of bronchospasm via IM, IV, sub-cutaneous routes. 

The ability of receptors to couple to G-proteins and initiate GTPase activity may also be independent of ligand. Thus, specific mutations in a- and P-adrenergic receptors have led to receptors that mediate agonist-independent activation of adenylyl cyclase (69,70). These mutations presumably mimic the conformational state of the ligand-activated receptor when they are activated conventionally by ligands. 

Figure 13.3 G protein-mediated activation of adenylate cyclase by hormone binding. Hormone binding on the extracellular side of a receptor such as the P adrenergic receptor activates a G protein on the cytoplasmic ATP side. The activated form of the G protein...

The general picture of muscle contraction in the heart resembles that of skeletal muscle. Cardiac muscle, like skeletal muscle, is striated and uses the actin-myosin-tropomyosin-troponin system described above. Unlike skeletal muscle, cardiac muscle exhibits intrinsic rhyth-micity, and individual myocytes communicate with each other because of its syncytial nature. The T tubular system is more developed in cardiac muscle, whereas the sarcoplasmic reticulum is less extensive and consequently the intracellular supply of Ca for contraction is less. Cardiac muscle thus relies on extracellular Ca for contraction if isolated cardiac muscle is deprived of Ca, it ceases to beat within approximately 1 minute, whereas skeletal muscle can continue to contract without an extraceUular source of Ca +. Cyclic AMP plays a more prominent role in cardiac than in skeletal muscle. It modulates intracellular levels of Ca through the activation of protein kinases these enzymes phosphorylate various transport proteins in the sarcolemma and sarcoplasmic reticulum and also in the troponin-tropomyosin regulatory complex, affecting intracellular levels of Ca or responses to it. There is a rough correlation between the phosphorylation of Tpl and the increased contraction of cardiac muscle induced by catecholamines. This may account for the inotropic effects (increased contractility) of P-adrenergic compounds on the heart. Some differences among skeletal, cardiac, and smooth muscle are summarized in... 

Another mechanism to maintain CO when contractility is low is to increase heart rate. This is achieved through sympathetic nervous system (SNS) activation and the agonist effect of norepinephrine on P-adrenergic receptors in the heart. Sympathetic activation also enhances contractility by increasing cytosolic calcium concentrations. SV is relatively fixed in HF, thus HR becomes the major determinant of CO. Although this mechanism increases CO acutely, the chronotropic and inotropic responses to sympathetic activation increase myocardial oxygen demand, worsen underlying ischemia, contribute to proarrhythmia, and further impair both systolic and diastolic function. 

As noted above, phenylethanolamines are usually p-adrenergic agonists, whereas phenylpropanolamines show antagonist activity. A small series of phenyl-ethanolamine blockers is, however, known. When the haloatom of u)-bromo-5,6,7,8-tetrahydro-2-acetonaphth-one (36) is displaced with isopropylamine and the... 

The answer is d. (Katzung, p 130J Epinephrine has a positive ionotropic and chronotropic effect on the heart because of its pradrenergic activity It also has a-adrenergic activity that causes vasoconstriction in the vascular beds. These actions result in a rise in systolic blood pressure. Epinephrine also has p2-adrenergic activity, which causes vasodilation in skeletal muscle. Because of this latter effect, total peripheral resistance can fall, resulting in a drop in diastolic pressure, particularly at low doses of epinephrine. 

Esmolol hydrochloride is a competitive p-adrenergic receptor antagonist it is selective for pT adrenoceptors. In contrast to pindolol, esmolol has little intrinsic sympathomimetic activity, and it differs from propranolol in that it lacks membrane stabilizing activity Of all of the p-adrenergic blocking drugs, this compound has the shortest duration of action because it is an ester, it is hydrolyzed rapidly by plasma esterases and must be used by the intravenous route Esmolol is approved only for the treatment of supraventricular arrhythmias... 

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