Pharmacology And Therapeutics

GPCRs are involved in cardiovascular regulation in numerous ways. At least 55 types of GPCRs are known to directly mediate neuronal and endocrine regulation of cardiac and vascular responses, and many more influence cardiovascular functions indirectly, via primary effects on the neuronal, endocrine, and metabolic regulatory mechanisms that control various aspects of the functioning of cardiac and vascular cells and tissues. These receptors are widely expressed in different cell types of the heart and blood vessels, where they mediate the actions of a variety of hormones growth factors, neurotransmitters, biologically active peptides, and local mediators, and are consequently involved in the regulation of numerous cellular processes and physiological functions. This review is focused mainly on direct receptor-mediated control of myocardial functions and constriction and relaxation responses of the vascular walls.

In addition to such short-term regulation, cardiac and vascular GPCRs also participate in long-term regulation of cardiovascular functions through effects on the development and plasticity of the heart and blood vessels. Figure 4.1 presents a summary of GPCR expression patterns in blood vessel walls, the heart, and the kidneys — tissues that represent the most important direct effectors in cardiovascular physiology, pathology, and therapeutics. Subtype-specific functions have been identified for many genetically defined receptor subtypes, but several pharmacologically defined receptor responses still await clarification of the roles played by different receptor subtypes.

Splice variants also exist for some GPCRs, such as a1A-adrenoceptors' and type 1 angiotensin II (AT1) receptors2, and their existence further complicates this issue. Closely related receptor subtypes may have very different anatomical distribution patterns and opposing functional effects in the cardiovascular system. In addition to the receptor types shown in Figure 4.1, GPCRs in the central nervous system (such as a2-adrenoceptors that regulate the sympathetic nervous system), GPCRs located in endocrine organs (through regulation, for example, of renin release) and receptors involved in metabolic regulation exert profound effects on cardiovascular health and disease and may constitute therapeutic targets. The important roles that some types of GPCRs have in cardiovascular diseases through effects mediated by receptors located on blood cells (e.g., many types of prostanoid receptors) or acting via enzymatic mechanisms (e.g., thrombin receptors) will not be discussed here.

As of today, GPCRs constitute important drug targets in cardiovascular therapeutics. Table 4.1 lists examples of clinically important drugs used to treat cardiovascular diseases [derived from the Anatomical Therapeutic Chemical (ATC) Classification System of the World Health Organization]. The examples were chosen to represent different therapeutic indications and different target GPCRs and mechanisms of action. Most current therapeutically employed drugs are directly targeted

Smooth muscle


Adrenoceptors (oi^b/u,)

Adenosine (A^)

Angiotensin (AT,)

Adrenoceptors (a^ß^)

Endothelin (ETJ

Angiotensin (AT2)

Dopamine (DJ


Serotonin (5-HT1B,1Ivlullwn)

Chemokine (CCR,«)

Vasopressin (V,)

Dopamine (D2-like)

Adenosine (A^,)

Endothelin (ETB)

Adrenoceptors (a^,^, ß2)

Histamine (H1M)

Ajför Angiotensin (AT2)

Muscarinic (M2)



«¡1 Ml Bradykinin (B,/B,)

Purinergic (P2Ym)

X^k^^j^T/ Chemokine (CCR,,,, CXCRJ

Serotonin (S-HT^^)

^Jjc—Histamine (Him3)


Muscarinic (MJ

Nerve endings

Neuropeptide Y (Yiai5)

Adrenergic (almc)


Serotonin (5-HTmlD„„)

Purinergic (P2Y,is)

Adenosine (A,)


Dopamine (D;-likc)

Muscarinic (M2)

Neuropeptide Y (YM)

Purinergic (P2Y,)


Autonomic nervous svstem

Adrenoceptors (ß,)

Angiotensin (AT,)

rn Adenosine (A,)

Adrenoceptors (oj^mc)

~y Angiotensin (AT,)

Muscarinic (Mj)

T \ Muscarinic (MJ

Neuropeptide Y (Yj)

Adrenoceptors (a,MB,ßM)

ü |VHjp Angiotensin (ATJ

' \\ \| Dopamine (D,)

Ij^v \ J Endothelin (ETA/B)

Histamine (HI(J)


Serotonin (5-HT4)

Adenosine (A,aA) Adrenoceptors (ct2A/2a2c) Angiotensin (AT2) Neuropeptide Y(Yj) Prostanoid Vasopressin (V,)

Reabsorption Angiotensin (AT,)

Adrenoceptors (a^^) Dopamine Vasopressin (V2)

FIGURE 4.1 Locations of therapeutically relevant types of GPCRs in the blood vessel walls, heart, and kidneys. Targets of clinically approved drugs are shown in bold. Note that receptor subtype distributions have not been indicated for all receptor classes (e.g., prostanoid receptors and somatostatin receptors) with complex and incompletely known expression patterns.


Examples of Clinically Approved Drugs Targeted to GPCRs Grouped by ATC Codes of the World Health Organization





Indications and Notes

Muscarinic acetylcholine Atropine

Adrenoceptors Adrenoceptors

-Adrenoceptors ß-Adrenoceptors


Dj dopamine and adrenoceptors D[ dopamine


«¡-Adrenoceptors a2-Adrenoceptors

Norepinephrine Epinephrine

Phenylephrine Isoprenaline






A03BA — Belladonna Alkaloids

Antagonist Elimination of parasympathetic tone

C01CA — Adrenergic and Dopaminergic Agents

Agonist Vasoconstriction (a1: a2) and cardiac stimulation (ß[)

Agonist Vasoconstriction (o^, a2), vasodilatation (ß2), and cardiac stimulation (ßj)

Agonist Vasoconstriction

Agonist Positive inotropic and chronotropic effects on the myocardium

Agonist Positive inotropic and chronotropic effects on the myocardium

Agonist Vasodilatation (Dj); improved renal function

Agonist Vasodilatation (D[)

C01E — Other Cardiac Preparations

Agonist Reduced chronotropy and dromotropy (A[), and vasodilatation (A2a, A2b, A3)

C02A - Centrally Acting Antiadrenergic Agents

Agonist Sympatholysis

Clonidine; guanfacine; Agonist Sympatholysis moxonidine; rilmenidine

Bradycardia; cardiac arrest

Rarely used in clinical settings

Used in cardiac arrest and anaphylactic shock; also used as vasoconstrictor combined with local anesthetic


Not subtype selective

Cardiogenic shock

In high concentrations, vasoconstriction

Hypertensive crisis

Supraventricular tachyarrhythmia; also used as a diagnostic agent to induce coronary vasodilatation

Hypertension; metabolized to a-methylnorepinephrine


«¡-Adrenoceptors Prazosin; doxazosin

5-HT2a Ketanserin

ETa, ETb endothelin Bosentan

(3-Adrenoceptors (3rAdrenoceptors a- and (3-Adrenoceptors

ATj angiotensin

V[ vasopressin

5-HT, aradrenoceptors 5-HT1r serotonin

C02C — Peripherally Acting Antiadrenergic Agents

Antagonist Vasodilatation

C02K — Other Antihypertensives

Antagonist Vasodilatation

Antagonist Vasodilatation

N02C — Antimigraine Preparations

Partial agonists Vasoconstriction and vasodilatation or antagonists Agonist Vasoconstriction


Hypertension Pulmonary hypertension

Hypertension; arrhythmia; ischemic heart disease; chronic heart failure Hypertension; arrhythmia; ischemic heart disease; chronic heart failure Hypertension; chronic heart failure

Hypertension; chronic heart failure; portal hypertension

Upper gastrointestinal bleeding; vasoconstrictor combined with local anesthetic

Acute migraine attacks Migraine

Propranol; timolol; pindolol Acebutolol; metoprolol; atenolol; Celiprolol Labetalol; Carvedilol

Losartan; valsartan

C07A — Beta Blocking Agents

Antagonist Reduction of cardiac output and workload

Antagonist Reduction of cardiac output and workload

Antagonist Reduction of cardiac output and workload;


C09C — Angiotensin II Antagonists

Antagonist Vasodilatation

H01BA — Vasopressin and Analogs

Vasopressin; felypressin Agonist Vasoconstriction

Ergot alkaloids Sumatriptan; naratriptan;


Source: Data extracted from World Health Organization's Anatomical Therapeutic Chemical Classification System provided online by (

to their corresponding receptors, activating them as agonists or blocking their activity as antagonists. The therapeutic response is often a direct consequence of the drug effect, e.g., relaxation or contraction of vascular smooth muscle cells or alteration of the excitability of cardiac myocytes. More indirect ways of influencing receptor activities or cellular functions may soon emerge as alternative approaches to exert pharmacological control of cardiovascular functions. Regulation of receptor responsiveness through regulation of GPCR kinase (GRK) activity is one such recently proposed mechanism.3

Modulation of gene expression through GPCR-linked second messenger pathways represents another promising new approach. Some drugs already in wide clinical use, such as p-adrenoceptor and AT1 receptor antagonists, produce very important therapeutic effects that are mediated by GPCR-dependent signaling cascades involved in cell proliferation, apoptosis, and tissue remodeling. One drug may actually target several cellular mechanisms through the widespread involvement of its receptors in functions critical for cardiovascular pathophysiology and therapeutics. Antagonists of AT1 receptors exemplify this phenomenon (see Smit et al.).4 The most important functions mediated by AT1 receptors include vasoconstriction, induction of the production and release of aldosterone, renal reabsorption of sodium, cardiac cellular growth, proliferation of vascular smooth muscle, increased activity of the sympathetic nervous system, stimulation of vasopressin release, and inhibition of renin release from the kidney. AT1 receptor antagonists inhibit the interaction of angiotensin II with its AT1 receptor, and have proven therapeutic efficacy based on synergism between these mechanisms in many forms of arterial hypertension and chronic heart failure.

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