PHA 622

M.T. Piascik

G-Protein Coupled Receptor Systems

A Drug Targets 


Additional Recommended Reading and References;


Jahangir, A. And Terzic, A. ; Katp channel therapeutics at the bedside. J. Mol. Cel. Cardio., 39; 99-112. 2005.


Murad, F. ; Nitric Oxide and cyclic GMP in cell signaling and drug development. New Engl. J. Med., 355; 2003-2011, 2006.



The student should be able to explain or describe;

1.         The effects of dopamine, dobutamine and PDE-inhibitors on the heart and blood vessels and the therapeutic uses of these drugs.


2.         The pharmacologic actions and therapeutic uses of beta and alpha adrenergic receptor antagonists.


3.         The physiologic processes regulated by angiotensin II receptors and effects of ACE -inhibitors, AT1-receptor antagonists on the heart and blood vessels as well as the therapeutic uses of these drugs.


4.         The regulation of vascular function by cGMP and the pharmacologic action of drugs that increase smooth muscle cGMP levels.


5.         The actions of K+-channel openers on vascular smooth muscle.


Key drugs or drug classes


Alpha-adrenergic receptor blockers

AT1-receptor blockers

Beta-adrenergic receptor blockers




K+-channel openers


Organic nitrates





Beta1 Agonists


Dopamine-An illustration of the actions of a drug  that activates multiple receptors


Dopamine has a complex pharmacology.  It can activate at least 4 different receptors: the  beta1, dopamine1 (DA1),  alpha1 and alpha2DA1 receptors exist in the renal vascular bed.  Activation of these receptors produces a decrease in renal vascular resistance and an increase in renal blood flow.  Activation of the beta1 receptor increases the force of myocardial contraction. Dopamine has a very unusual action on the heart in that it selectively increases the force of myocardial contraction without a significant effect on heart rate.  However, high doses of dopamine, like all catecholamines which activate the beta1 system, can induce rhythm disturbances.





Dobutamine-An illustration of the differential properties of isomers


The effects of dobutamine on the cardiovascular system are summarized below:


  1)   Activates myocardial beta1 receptors to increase the force of myocardial contraction.


  2)   Little effect on heart rate at therapeutic doses - high doses can induce arrhythmias.


            3)   Causes a small decrease in blood pressure and TPR.


            4)   Does not activate dopamine receptors.


It is interesting to note that dobutamine used clinically is a racemic mixture of (+) and (-) isomers.  These individual isomers have different pharmacologic properties:


            1)  (+) Dobutamine is a beta1 and beta2 agonist.


            2)  (-) Dobutamine is an alpha1 agonist.


            3)  The observed clinical profile is due to a combination of these pharmacological effects.


The use of isomers as a single drug product is very common.  Most isomeric pairs have the same activity.  Dobutamine is an unusual example of a pair of isomers that have distinctly different activities.


Actions of Dobutamine and Dopamine in Heart Failure


Both dobutamine and dopamine have  the potential for improving the negative circulatory events associated with heart failure. For example, by increasing the force of myocardial contraction, cardiac output could increase.  In addition, dopamine by  inducing renal vasodilation (via DA1 receptors), can increase renal blood flow  and urine output. 


Maladaptive Responses in Heart Failure

The excess stimulation of myocardial beta1 and alpha1 receptors promotes several maladaptive changes including activation of hypertrophic growth and generation of reactive oxygen species.  In addition, the excess stimulation of myocardial beta1 receptors caused by the increase in sympathetic tone actually promotes the desensitization and down regulation of these receptors.




Milrinone and Inamrinone

These compounds are orally active inhibitors of cAMP phosphodiesterase.  This enzyme breaks down cAMP thus terminating its actions.  The cardiovascular effects of increasing intracellular cAMP are similar to those seen following activation of beta1 and beta2 receptors.  PDE inhibitors were designed to replace cardiac glycosides as orally active positive inotropic agents for the treatment of congestive heart failure.  These PDE inhibitors were shown to increase cardiac output and decrease peripheral vascular resistance. However, clinical trials showed oral dosing with these agents were not effective in decreasing the morbidity and mortality in heart failure.  These drugs are second line agents reserved for the intravenous treatment of decompensated heart failure.


Cardiovascular Actions


        1)         There are isoforms of  cAMP phosphodiesterase.  Inamrinone and milrinone inhibit the cAMP    phosphodiesterase isoform (PDE III) that is present in the heart and blood vessels.


        2)         Inhibition of cardiac PDE results in an increased force of contraction and cardiac output.


        3)         Inhibition of vascular PDE produces vasodilation and a decrease in peripheral vascular resistance.


        4)         These agents have the potential to induce arrhythmias.


        5)         Tolerance does not develop to the cardiovascular actions of PDE inhibitors.



1)         These drugs are competitive antagonists of the beta adrenergic receptor.


2)         The beta blockers used in clinical therapeutics are either selective for the beta1 receptor or nonselective beta1 and beta2 antagonists.


Propranolol - the Prototype Beta Blocker


         1)     Propranolol is a nonselective beta blocker.  Atenolol is an example of a selective beta1 receptor blocker.



Cardiovascular Effects and Clinical Uses of the Beta Blockers


The beta1-adrenergic receptor associated with the heart increases the force and rate of myocardial contraction.  Beta antagonists block the ability of the sympathetic nervous system to increase the contractile force and the rate of contraction.  The release of renin from the kidney is also regulated by the beta1-receptor.  By blocking renin secretion beta1 blockers reduce the formation and hence the biological activity of angiotensin II.  Beta1-receptor antagonists decrease blood pressure.  While the mechanism underlying this effect is not completely understood, it certainly involves  a decrease in cardiac output and heart rate as well as decreasing angiotensin II levels.  This reduction in blood pressure makes the beta blockers useful in the treatment of hypertension.  Beta blockers are also useful in treating ischemic heart disease.  This is because two major determinants of myocardial oxygen consumption are the force and rate of myocardial contraction which are diminished by this class of drugs.   Beta blockers are given following a myocardial infarction to prevent reinfarction.  Certain arrhythmias are due to excess stimulation of the beta1-receptors.  Thus beta blockers are useful in treating supraventricular tachyarrhythmias. There are many indications for beta blockers unrelated to cardiovascular therapeutics.




Prazosin and analogs(doxazosin, terazosin, trimazosin) - Selective, competitive antagonists

Tamsulosin- Selective, competitive antagonist

Phentolamine-Nonselective, competitive antagonist

Phenoxybenzamine-Irreversible receptor antagonist


Effects of Prazosin and Analogs on the Cardiovascular System:



Prazosin and analogs are selective alpha1-receptor blockers used to treat hypertension. These agents have similar cardiovascular actions, differing only in  pharmacokinetic parameters.  Doxazosin, trimazosin and terazosin are more widely used than prazosin.


           1)         These agents relax the smooth muscle associated with arteries and veins.


           2)         This results in a decrease in systemic arterial blood pressure due to a decrease in  peripheral vascular resistance and venous return.


           3)         The reduction in arterial blood pressure does not result in a significant increase in heart rate.



Many  ACE inhibitors have been developed.  Captopril was the first agent developed and hence is the prototype.  Enalapril is a prodrug that is de-esterified by plasma esterases to enalaprilat.  Most of the ACIs are activated in this fashion.



            Benazepril - Metabolized to benazeprilat


            Enalapril - Metabolized to enalaprilat

            Fosinopril - Metabolized to fosinoprilat


            Moexipril- Metabolized to moexiprilat        

            Quinapril - Metabolized to quinaprilat

            Ramipril - Metabolized to ramiprilat

            Trandolapril-Metabolized to tandolaprilat

            Perindopril - metabolized to perindoprilat




Effects on the Cardiovascular System


        1)         ACE inhibitors decrease circulating levels of angiotensin II and aldosterone.


        2)         These agents decrease peripheral vascular resistance.


        3)         Despite this fall in peripheral resistance, there is little effect on heart rate.


        4)         Angiotensin II (acting at the AT1-receptor) is a stimulus for cardiac remodeling and hypertrophic growth.  ACE inhibitors block these deleterious effects.


        5)         In addition to heart failure, ACE inhibitors are also widely used to treat hypertension.


        6)         While there are many ACE-inhibitor products available, their mechanisms of action are the same.  The differences are in the requirement of activation and/or duration of action and plasma half life.


Status in Cardiovascular Medicine


        1)         ACE-inhibitors are first line medications in the treatment of heart failure.  Numerous clinical trials have shown that these drugs decrease the risk of death, improve outcomes and decrease symptoms of patients with heart failure. 


        2)         ACE-inhibitors have been shown to be effective in reducing morbidity and mortality in patients following myocardial infarction.


        3)         ACE-inhibitors are also drugs of first choice in the treatment of hypertension and are especially useful in patients with co-existing heart failure or post MI.





        1)         Many of the effects of angiotensin II are a result of interaction at angiotensin1 receptor (AT1), typical G-protein coupled receptors.


        2)         By blocking AT1 receptors, angiotensin II receptor antagonists directly block the ability of angiotensin II to stimulate vascular smooth muscle contraction, aldosterone release, cardiac remodeling  and hypertrophic growth.


        3)         Losartan, Irbesartan, Eprosartan, Candesartan, Telmisartan and Valsartan are antagonists at AT1 receptors.


        4)         The binding of Irbesartan, Candesartan and Valsartan is such that they do not readily dissociate from the receptor.  However, they do not covalently modify the receptor.  Therefore, antagonism with these compounds is not overcome with increasing amounts of angiotensin II.  The reason for these binding kinetics is not clear.  However, the insurmountable antagonist has advantages if the physiologic concentration of angiotensin II increases.


        5)         Like ACE inhibitors, AT1 receptor antagonists are effective for the chronic treatment of congestive heart failure.  They are also widely used to treat hypertension.  There is evidence that these agents increase survival following myocardial infarction.



Status in Cardiovascular Medicine                                          


        1)         AT1 receptor antagonists are effective in the treatment of heart failure.   Clinical trials have shown that these drugs decrease the risk, improve outcomes and decrease symptoms of patients with heart failure. 


        2)         Similarly, AT1 receptor antagonists are alternatives to ACE-inhibitors in reducing morbidity and mortality in patients following myocardial infarction.


        3)         AT1 receptor antagonists are also first line agents in the treatment of hypertension


        4)         There is no evidence that AT1 receptor antagonists are superior to  ACE-inhibitors. Therefore, the drugs should be considered as alternative choices in treating cardiovascular disease.


cGMP Dependent Vascular Mechanisms






Drugs that work through cGMP-dependent mechanisms


1. Organic nitrates- ischemic heart disease

2. Hydralazine- hypertension and congestive heart failure

3. Nitroprussde- hypertension and congestive heart failure


Potassium Channel Openers



The Treatment of Hypertension

The goal of therapy is not the reduction in blood pressure per se. Rather, it is to decrease the end organ damage and subsequent pathophysiology that occurs with sustained, untreated elevated blood pressure. Another goal of therapy is to minimize the number of drugs prescribed as well as the times that drugs have to be taken. Hypertension is a unique clinical problem because it is an asymptomatic disease. Therefore, if therapy with antihypertensive drugs causes unpleasant side effects, patient compliance could be reduced. A good source for this material is The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7). This report can be found at:

Elevated blood pressure is the most common chronic illness in the United States, affecting more than 50 million people. There are differences in the prevalence of this disease which are based on age, race, sex and socioeconomic status. Guidelines for the classification of hypertension are as follows:

Untreated hypertension leads to end-organ damage and death. Reduction of blood pressure is associated with a decrease in the morbidity and mortality of other cardiovascular diseases such as stroke, congestive heart failure, left ventricular hypertrophy and renal failure, as well as an increase in the quality of life. In addition to pharmacologic means to lower blood pressure, life-style modifications can also decrease blood pressure. These would include weight reduction, smoking cessation, decreases in alcohol consumption and an increase in regular exercise.



Potential Sites of Action for Antihypertensive Drugs

Blood pressure = Cardiac Output x TPR

Cardiac output = Stroke Volume x Heart Rate

Blood pressure = (Stroke volume x Heart rate) x Total peripheral vascular resistance

Classes of Antihypertensive Drugs

These tables are not intended to be all inclusive but rather to give you an idea of number of drug classes and combination products available to treat hypertension.


Classes of Antihypertensive Drugs

These tables are not intended to be all inclusive but rather to give you an idea of number of drug classes and combination products available to treat hypertension.