Adrenergic Receptor Subtypes continued:  Three subtypes of β-adrenergic receptors have been described:  β₁, β₂, and β₃.⁹

• Activation of these receptors by agonist ligands cause activation of the stimulatory G protein, G_s, (as noted earlier, certain G proteins are inhibitory). G_s increases adenylyl cyclase catalytic activity which results in elevation of intracellular cAMP.

• Higher levels of cAMP in turn promote phosphorylation of various proteins; the phosphorylation step changes protein function and thus is an important regulatory step.

• cAMP is the primary second messenger system for the β-adrenergic receptor system and activation of the receptor system can cause, via cAMP, numerous tissue-specific effects.

   

  

   

  →β₁-Adrenergic Receptors←

   

  • One example is activation of glycogen phosphorylase in the liver secondary to β-adrenergic receptor induced [cAMP] elevation ([  ] refers to molar concentration).

  • In the kidney, β₁-adrenergic receptor stimulation results in increased renin release; whereas, β₁-cardiac adrenergic receptor stimulation increases both contractility and heart rate (positive inotropism and positive chronotropism respectively).

    • The positive chronotropic effect occurs because of the change in the slope of phase 4 spontaneous depolarization at sinoatrial nodal pacemaker cells.

    • The positive inotropic effect of adrenergic agonists occurs due to increased phosphorylation of Ca²⁺ ion channels.

      • In addition to enhanced sarcolemmal Ca²⁺-channel phosphorylation, β₁-adrenergic activation also phosphorylates an important regulatory protein of the cardiac muscle Ca²⁺ calcium channel, phospholamban.⁴⁰

      • Phospholamban, when acted on by protein kinase A, an effects stimulated by cAMP secondary to β₁-adrenergic receptor activation, becomes phosphorylated and then exhibits a reduced ability to inhibit a sarcoplasmic reticulum calcium pump (SERCA2).

      • Therefore, the phosphorylated phospholamban increases activity of this Ca²⁺ pump, consequence of which is to both reduce free Ca²⁺ (this favors cardiac muscle relaxation in diastole) and increase the amount of Ca²⁺ calcium released from sarcolemmal stores with the next action potential.⁴⁰

        • This latter action results in the positive inotropic effect observed following phospholamban phosphorylation. (More detailed studies of the phospholamban phosphorylation pattern indicate three protein kinase-dependent phosphorylation sites:

          • (1) the cAMP-dependent protein kinase just described phosphorylates a serine amino acid residue,

          • (2) a Ca²⁺/calmodulin-dependent protein kinase catalyzes a phosphorylation reaction at a threonine amino acid residue and

          • (3) protein kinase C catalyzes phosphorylation of a distinct serine amino acid residue. These phosphorylation reactions all appear to stimulate initial rates of sarcoplasmic reticulum Ca²⁺-transport.⁴⁰

        • Dephosphorylation of phospholamban is catalyzed by a cardiac sarcoplasmic reticulum-associated type 1 protein phosphatase, which is also controlled by cAMP-dependent phosphorylation of its inhibitor protein.⁴⁰

        • Phospholamban Pentamer⁴¹

        • With respect to possible clinical correlation, heart failure (CHF, congestive heart failure) is a disease associated with abnormal intracellular Ca²⁺-"handling." Specifically, cardiac relaxation and rapid reduction of cytosolic [Ca²⁺] by SERCA2 appear impaired with a resulting increase in diastolic [Ca²⁺]. Such an increase, by reducing cardiac sarcoplasmic reticulum stores, reduces Ca²⁺ availability for subsequent cardiac contractions. Possible clinical therapeutic approaches might involve altering phospholamban or SERCA2 protein expression levels or disruption of the phospholamban-SERCA2 complex.⁴⁰

         

    • The combination of β₁-adrenergic receptor mediated increases in both heart rate and contractility (positive inotropism) results in an increase in cardiac output.

    • Changes in conduction velocity at the atrioventricular (AV) node are also mediated by β₁ receptors: ⁹

      • (1) Activation of these receptors increases conduction velocity by increasing Ca²⁺-channel conductance. Depolarization of AV nodal cells is especially sensitive to Ca²⁺ because in this specialized cardiac tissue Ca²⁺ as opposed to Na+ provides the primary inward, depolarizing current.

      • (2) Therefore, by contrast, blockers or antagonists that act at β₁-receptors decrease conduction through the AV node.

        • Short-acting β-receptor antagonists, such as esmolol, ( β₁-receptor selective)  may be helpful in rapid, short-term management of high ventricular following rates in the setting of supraventricular arrhythmias (e.g. atrial fibrillation).

        • Lead II (2) ECG tracing of supraventricular tachycardia (heart rate about 150/min)  in a 40 year old male⁴⁵

          • Esmolol (Brevibloc): β₁-adrenergic receptor Antagonist

    • The recognition that β₁-receptors promote increases in both heart rate and myocardial contractility presents opportunities for pharmacological management of several cardiovascular disorders, including hypertension and angina.⁹ 

      • A reduction in blood pressure would be expected with β-adrenergic receptor antagonism because heart rate and force of contraction decrease.

      • Angina is a clinical symptom associated with an imbalance between myocardial oxygen requirements and oxygen availability.

      • If oxygen availability is limited by suboptimal coronary perfusion secondary, for example, to coronary atherosclerosis, one option is to decrease myocardial oxygen demand, by decreasing myocardial contractility.

    • Myocardial oxygen extraction is about 70% at rest (dog model).^{42, 42a} Therefore, increased myocardial oxygen consumption must be accompanied by an increase in coronary blood flow, since there is limited additional oxygen extraction possible.

    • The relationship between coronary blood flow and myocardial oxygen consumption is approximately linear.⁴²

      • The Relationship of Coronary Flow to Oxygen Usage (Dog Model)⁴³

      • Anatomical overview: large epicardial branches of the left and right coronary arteries undergo additional branching.

        • Epicardial (surface) Coronary Vessels⁴⁴

      • The smaller branches enter the myocardium and right angles and then divide into many more arteries and arterioles. The smaller structures support a very dense capillary network, with approximately one capillary for each cardiac fiber.⁴²

      • Transmural (across the myocardial wall) blood flow distribution in accordance with moment to moment oxygen supply versus local demand change is supported by control of subendocardial and subepicardial vessel tone.⁴²

        • Vasoactive substances released by coronary vascular endothelium provide circulatory regulation.

        • For example, a number of factors including pulsatile flow and hypoxia stimulate release of the coronary vasodilator prostacyclin.

          • Prostacyclin (Epoprosterol), an eicosanoid

        • Hypoxia and shear stress are two factors that increase production and release of nitric oxide (N-O) by increasing catalytic activity of nitric oxide synthase (NOS). By this mechanism, coronary vasodilatation occur secondary to N-O-dependent cGMP (cyclic GMP) mechanisms.⁴²

        • Endothelium also elaborates vasoconstrictors such as the endothelins, thromboxane A2, and angiotensin in response to several exogenous and endogenous factors.⁴²  

          • Thromboxane A2

        • Pathophysiological changes associated with coronary vascular disease can induce abnormalities between these vasodilator and vasoconstrictor effects. For example, a reduction in N-O release with a concurrent increase in endothelin synthesis.

          • Endothelins in addition to being vasoconstrictive also promote platelet adhesion which may increase thrombosis risk and cause smooth muscle proliferation.⁴²