THE SURFACES OF CELLS IN VARIOUS ORGANS and tissues have receptor sites. Hormones and other chemicals act at their respective receptor sites to bring about a particular action in the cell. Adrenaline and noradrenaline are called catecholamines and are released from sympathetic nerve endings and as hormones from the adrenal glands. They have their major actions on receptor sites called beta-receptors. Stimulation of the sympathetic–adrenal system during danger or severe stress, for example, causes an outpouring of adrenaline and noradrenaline into the blood circulation and at nerve endings.

Catecholamines (adrenaline and noradrenaline) are stimulants and cause an increase in the force of contraction of the heart increasing heart rate, blood pressure, and blood sugar. An outpouring of catecholamines is necessary to prepare the body for a fight-or-flight response. Therefore, we need this surge of adrenaline if we have to flee from a charging bull. Although adrenaline and noradrenaline have positive effects, in excess they can cause overcharging of the cardiovascular system, which can precipitate ventricular fibrillation.

It is well documented that during a heart attack large quantities of noradrenaline are released into the heart muscle, which can precipitate abnormal heart rhythms, particularly, ventricular fibrillation. Adrenaline causes an increase in heart rate and an increase in blood pressure, thus causing the heart to work harder. Because a coronary artery is blocked during a heart attack, the increased work with less available oxygen causes further damage to the heart muscle and increases the size of the muscle damage, causing a larger heart attack.

Beta-blocking drugs were originally discovered by Sir James Black of Imperial Chemical Industries. Since the introduction of the prototype, propranolol, for the management of hypertension in 1964, more than 12 betablocking drugs have become available. Beta-adrenergic blocking drugs have become the cornerstone of cardiac drug therapy.

BETA-RECEPTORS

By definition, beta-blockers block beta-receptors. Structurally they resemble the catecholamines (adrenaline and noradrenaline) and block the action of these catecholamines at their receptor sites. The beta-receptors are situated on the cell membrane and are believed to be a part of the adenyl cyclase system. An agonist acting on its receptor site activates adenyl cyclase to produce cyclic adenosine-5-monophosphate, which is believed to be the intracellular messenger of beta stimulation. There are two types of beta-receptors, beta-1 and beta-2.

Beta-1 Receptors
The beta-1 receptors are present mainly in the heart, renin-secreting tissues of the kidney, parts of the eye responsible for the production of aqueous humor, and to a limited degree in bronchial tissue of the lung. Beta-1-adrenergic receptors regulate heart rate and myocardial contractility, but in situations of stress with the provocation of epinephrine release stimulation of cardiac beta-2 receptors contribute to additional increases in heart rate and contractility.

Beta-2 Receptors
These are predominant in the bronchial tissues of the lung, vascular smooth muscle, insulin-secreting tissues of pancreas, gastrointestinal tract, and to a limited degree in the heart and coronary arteries. None of these tissues exclusively contains one subgroup of receptor. The population density of receptors decreases with age. In addition, the beta-receptor population is not static, and during long-term therapy with beta-adrenergic blocking agents the number of receptors is increased. The heart contains beta-1 and beta-2-adrenergic receptors in the proportion 70:30. In heart failure, cardiac beta-1 receptors are reduced in number and population.

MECHANISM OF ACTION

Blockade of cardiac beta-1 receptors causes a decrease in heart rate, myocardial contractility, and velocity of cardiac contraction. Beta-blockers cause the heart muscle to work less, thus requiring less oxygen; in time of oxygen lack, such as during a heart attack or severe angina, this action can be life-saving. Because of the reduction in the oxygen requirement of the heart muscle, the beta-blocking drugs are effective in preventing the chest pain of angina pectoris. Because patients with angina have a high risk of developing a heart attack over ensuing years, beta-blockers are important for both pain and prevention. An increase in adrenaline such as that produced during stress or vigorous exercise causes an increase in (1) the number and stickiness of blood platelets, (2) clotting factor VIII (the hemophilic factor), and (3) the viscosity of the blood. Beta-blockers block some harmful effects of
adrenaline.

Beta-blockers have antiarrhythmic effects; they depress phase 4 diastolic depolarization and are effective in abolishing arrhythmias caused by increased catecholamines. This action is particularly important in patients with ischemic heart disease. The electrical impulse traffic through the AV node in reduced with beta-blockers and the rate of conduction is slowed. This important action slows the heart rate in patients with rapid heart rates caused by atrial fibrillation. There is also a favorable effect on ventricular arrhythmias, particularly those induced by increased sympathetic activity observed in patients with oxygen lack to the myocardium because of obstructive coronary artery disease. Blockade of beta-1 receptors reduces activity of the renin–angiotensin system in the kidney by reducing renin released from the juxtaglomerular cells; this action causes some lowering of blood pressure.

Pierre-Yves et al. have shown that patients with stable coronary artery disease exhibit much higher exercise releases of atrial and ventricular natriuretic peptides (ANP and BNP) when they are treated with beta-blockers these authors postulated that increased secretion of potent vasodilating and natriuretic agents constituted a mechanism for protecting diseased hearts against stress.

SALUTARY EFFECTS

Beta-blockers have been shown to prevent fatal and nonfatal heart attacks and sudden cardiac death.  A decrease in heart rate increases the diastolic interval during which the coronary arteries are filled with blood. The coronary arteries are squeezed during systole and blood flow is restricted. Thus beta-blockers increase oxygen supply to the myocardium. This major beneficial effect has not been given prominence by workers in the field. Beta-blockers decrease the force and velocity of cardiac contraction and decrease the heart rate pressure product (RPP). This action decreases myocardial oxygen demand and is important in the relief of angina.

It is interesting to note the good effect of beta-blockers on the arterial system. The thousands of miles of arteries are constantly under pressure from the pulsatile force and velocity of blood as well as blood pressure. The decrease in cardiac ejection velocity and a decrease in hemodynamic stress on the arterial wall, especially at the branching of arteries, may decrease the atherosclerotic process and plaque rupture. Atherosclerosis is commonly seen where arteries divide. Beta-blockers reduce blood pressure as well as the force and velocity of blood flow at these dividing points of mechanical stress and provide some protection from vessel wall injury. This favorable effect is of paramount importance in patients with high blood pressure. Mechanical injury from the velocity and force of blood is the prime cause of vessel wall injury, which leads to atherosclerosis, dissection of the plaques of atheroma and subsequent thrombosis, as well as rupture of an aneurysm (see the chapter Aneurysm).

A decrease in the fatal arrhythmias, an increase in ventricular fibrillation threshold, and amelioration of ventricular and supraventricular arrhythmias have been documented with beta-blockers. They decrease early morning platelet aggregation and arrhythmias induced by catecholamines. By doing this, they decrease the early morning peak incidence of heart attack and sudden death.

INDICATIONS

Angina
Beta-blockers are first-line therapy for the management of stable angina. They have been shown to be more effective than oral nitrates and calcium antagonists. They reduce the recurrence of chest pain in more than 66% of patients. Many patients with angina manifest little pain, but they may have several episodes of ischemia during the day or night.These episodes can be adequately suppressed by the use of beta-blocking drugs. In patients with unstable angina these drugs are used immediately with aspirin when the patient arrives in the emergency room.

Acute Myocardial Infarction
Beta-blockers are strongly recommended as therapy for acute myocardial infarction and are administered within minutes of arrival in the emergency room to virtually all patients who present with acute chest pain believed to be caused by a heart attack. As soon as an ECG confirms the diagnosis, an aspirin, a beta-blocker, and a thrombolytic agent are administered. In patients with acute myocardial infarction beta-blockers have been shown to prevent cardiac death and reduce infarct size. In these patients, beta-blockers are often continued for several years.

Hypertension
Beta-blockers and diuretics remain first-line agents for the management of virtually all patients with hypertension. Beta-blockers are the drugs of choice in younger and older white patients. Contrary to the opinion of some experts, beta-blockers have been proven effective in older white patients. Beta-blockers are particularly indicated in all individuals with hypertension and concomitant coronary artery disease, diabetes, or dyslipidemia. They are indicated for hypertension in younger African-Americans; they appear to be less effective in older patients of African origin. Beta blockers are also indicated in hypertensive patients with mild-tomoderate heart failure.

Arrhythmias
Atrial fibrillation is the most commonsustained arrhythmia observed in clinical practice and is a common disorder observed worldwide. Beta-blockers remain the mainstay of therapy to control the rapid heart rate in these patients. These agents have replaced digoxin, except in patients with severe heart failure. In a few patients paroxysmal attacks may be prevented. Ventricular premature beats, particularly those caused by coronary artery disease and mitral valve prolapse, are another type of arrhythmia. Nonsustained ventricular tachycardia may respond to beta-blockers in patients with coronary artery disease and repetitive ventricular fibrillation caused by electrocution.

Heart Failure
The harmful effects of overactivation of the sympathetic nervous system in heart failure are ameliorated significantly by beta-blockers. The judicious use of titrated doses of beta-adrenergic blockers has been shown to improve quality of life, recurrence of heart failure, and mortality in patients with various grades of heart failure. The COPERNICUS study involved 2289 patients with severe heart failure and ejection fractions of less than 20%. The treatment drug carvedilol caused significant reductions in mortality and hospitalization for heart failure. The COMET study randomized 1511 patients with chronic heart failure (ejection fraction less than 35%) to treatment with carvedilol and 1518 to metoprolol. Follow up at 58 months showed all-cause mortality to be 34% for carvedilol and 40% for metoprolol, p¼0.0017.

Elective Percutaneous Coronary Intervention
Elective percutaneous coronary intervention (PCI) involving balloon angioplasty and intracoronary stent implantation is now done in many centers worldwide for the management of coronary artery disease. All patients undergoing PCI are administered beta-blocking drugs that are continued indefinitely. A clinical trial has shown that beta-blocker therapy is associated with a marked longterm survival benefit among patients undergoing successful PCI. Beta-blocker therapy has been shown to be associated with a reduction from 6 to 3.9% at one year (P¼0.0014).

Dissecting Aneurysm
A dissecting aneurysm of the aorta is a life-threatening condition resulting in death in greater than 75% of patients. A beta-adrenergic blocking agent is the drug of choice to reduce aortic pressure which decreases the rate of dissection. A beta-blocker is often combined with nitroprusside to lower blood pressure, but even when the systolic blood pressures is as low as 110 mmHg, a betablocker is still indicated to reduce cardiac ejection velocity and thus the aortic pressure.

Mitral Regurgitation and Mitral Stenosis
Recent clinical trials with carvedilol in patients with mitral regurgitation have documented improvement in geometry of the left ventricle. In mitral regurgitation (a leaky valve), blood flows backward through the widely opened valve that should be shut and flows from the left ventricle into the left atrium. The left ventricle becomes enlarged and finally weakens causing heart failure. In an animal study of mitral regurgitation, the ACE inhibitor, lisinopril, reduced pre- and afterload, but its effect on the left ventricular contractility was insignificant. Atenolol, when added to lisinopril, achieved a maximum hemodynamic benefit and also restored left ventricular contractility. Moderateto-severe mitral regurgitation is an extremely difficult condition to manage; the timing for surgery in patients with severe disease is often a dilemma. Any cardioactive agent that causes amelioration of the disease process is a welcome addition to the drug armamentarium. Beta-blockers are the cornerstone of treatment for pregnant patients with moderate-to-severe mitral stenosis. These agents slow the heart rate which allows filling of the left ventricle and prevents life-threatening pulmonary edema. In mitral stenosis the mitral valve opening is stenosed or tight, and blood flow from the left atrium is restricted. This flow is further decreased when the heart rate is fast. Patients with mitral valve prolapse and bothersome palpitations respond favorably to betablockers.

Hypertrophic Cardiomyopathy
Although medical treatment with beta-blockers does not cause a decrease in mortality, symptoms are often significantly
relieved with a beta-blocking agent.

Perioperative Mortality
Beta-blockers have been shown to decrease morbidity and mortality in patients undergoing coronary artery bypass surgery and in cardiac patients undergoing other types of surgery. Beta-adrenergic blockade allows safer induction of anesthesia and prevents the hypertensive response to endotracheal intubation. These agents reduce the occurrence of arrhythmias in the intra- and postoperative periods. Both atenolol and bisoprolol have been shown in randomized clinical trials to reduce morbidity and mortality when given perioperatively and for one week postoperatively.

Marfan Syndrome
This disease often causes dilatation of the ascending aorta, which results in aortic dissection. Prophylactic betaadrenergic blockade slows the rate of aortic dilation and retards the development of aortic complications.

Diabetic Patients
Death in the majority of patients with type 2 diabetes is caused by cardiovascular disease. Both fatal and nonfatal and sudden heart attacks are common in diabetics. Unfortunately, the usual optimal treatment of diabetes with insulin or oral agents does not significantly prevent cardiovascular complications. Beta-adrenergic blockers are usually considered by experts to be relatively contraindicated in diabetics, particularly those with dyslipidemias. This expert advice is illogical. These are the only cardioactive agents along with aspirin that could protect the heart from serious events and dyslipidemia can be controlled with statins.. Also, beta-blockers appear to have a renoprotective effect. In the SOLVD heart failure study, surprisingly in contrast to the ACE inhibitor enalapril, beta-blockers were renoprotective in both the ACE inhibitor and the placebo groups. See the later discussion of the UKPDS beneficial results in diabetics treated with a beta-blocker in Section V.D.

Other Indications
Prolonged QT interval syndromes may cause syncope or sudden death and beta-blockers provide some benefit in these patients. An electrical storm in the heart may precipitate multiple episodes of ventricular tachycardia or ventricular fibrillation and repetitive ventricular fibrillation resistant to therapy. The beneficial effect of the betablocker propranolol on recurrent ventricular fibrillation caused by electrocution was documented in 1970s, but little attention was given to this report. Recent studies have documented the role of beta-blockers in electrical storms and today propranolol is used for the management of repetitive ventricular fibrillation resistant to defibrillation.

CLINICAL TRIALS
Clinical trials have documented that beta-blockers significantly prevent death in patients who are given the drug from the first week of the heart attack and for an additional two years.

Norwegian Postinfarction Timolol Trial
This hallmark clinical trial was the first to document the life-saving effects of beta-blockers in patients following a heart attack (see Fig. 2). In this superbly well-conducted Norwegian study, 1884 patients were randomized to two groups. The first group of 942 patients was started on a beta-blocker, timolol, 7 days after a heart attack. The other group received a placebo. At the end of two years, the treated group had a 35% reduction in heart death, 28% reduction in new heart attack, and 67% reduction in sudden death ( p<0.001). The impressive results were observed in smokers and nonsmokers; they were published in 198.

The American Beta-Blocker Heart Attack Trial
The Beta-Blocker Heart Attack Trial (BHAT) gave similar if not just as impressive results. In 16,400 randomized patients, propranolol, 120–240 mg, administered to patients 14 days after myocardial infarction and followed for 2 years showed a significant 26% reduction in mortality rate. Propranolol was not effective in smokers, however, because of the interactions in the liver; cigarette smoking lowers the blood levels of propranolol and decreases cardioprotective effects.

The CAPRICORN Study
In this recent, large multicenter study, patients from 1 to 21 days after acute myocardial infarction and ejection fraction less than 40% were randomized. The control group received optimal medical therapy including the use of ACE inhibitors. The treated group received carvedilol 6.25 mg increased progressively to 25 mg twice daily. Carvedilol caused a significant 23% reduction in all-cause mortality in patients observed for 2.5 years; the mortality was 116, (12%) in the treated versus 151 (15%) in the placebo group. The absolute reduction in risk was 2.3%. Forty-three patients need to be treated for one year to save one life. This reduction is virtually the same as that observed in a meta-analysis of three ACE inhibitor trials. Most important, the reduction observed with carvedilol is in addition to those of ACE inhibitors alone.

The UKPDS Results
The UKPDS results confirm that in type 2 diabetes, betablockers significantly reduced all-cause mortality, risk for heart attack, stroke, and importantly peripheral vascular disease as well as microvascular disease. Over a follow up of nine years the change in albuminuria and serum creatinine was the same in both the ACE inhibitor (captopril), and the beta-blocker groups.

Implications
Beta-blockers and aspirin are proven by studies to prevent death from heart attack. About 450,000 heart attack patients survive to leave hospitals in the United States and Canada annually, and about 100,000 of these patients will have another heart attack in the following year. Betablockers can prevent a heart attack in approximately 20% (30,000) of these patients and prevent death in about 25%. Yet these cardioprotective drugs that can prolong life are not advocated and prescribed by many internists and family physicians because of the rare incidence of impotence and fatigue. Many practitioners continue to use newer agents, particularly, calcium antagonists, nitrates, and other agents that have not been shown to prolong life in randomized clinical trials.

ADVERSE EFFECTS AND CAUTIONS

Beta-blockers are safe cardioactive agents if the warnings and contraindications are followed. They are not advisable in patients with severe class IV heart failure. They are indicated, however, in class I–III heart failure. Class IV patients who have been stabilized and are no longer decompensated can be started on very small doses of carvedilol (3.5 mg). Beta-blockers are contraindicated in patients with bronchial asthma and in patients with severe chronic obstructive pulmonary disease including emphysema. Patients with mild chronic bronchitis may be given a cardioselective beta-1 agent and may require supplemental salbutamol. Other contraindications include:
1. Complete heart block and varying grades of heart block
2. Severe bradycardia less than 48 beats per minute
3. Allergic rhinitis
4. Insulin-dependent diabetics who are prone to hypoglycemia
5. Raynaud’s phenomenon

Adverse side effects of beta-blockers include tiredness and fatigue in about 10% of patients, erectile dysfunction in about 10%, precipitation of heart failure in patients with poor left ventricular function, slowing of the heart rate causing bradycardia less than 50 beats per minute, depression in less than 5%, very cold extremities in less than 10%, and vivid dreams. Switching to a hydrophilic drug excreted by the kidney may decrease vivid dreams.

CLASSIFICATION

Cardioselectivity indicates that the drug chiefly blocks beta-1 receptors in the heart and partially spares beta-2 receptors in the lungs and blood vessels. Large doses of all betablocking agents block beta-2 receptors, thus, cardioselective drugs are not cardiospecific. Bisoprolol is more
cardioselective than metoprolol or atenolol. The classification into cardioselective and nonselective is important, but oversimplified.

SUBTLE DIFFERENCES AND RESEARCH IMPLICATIONS

The subtle differences that exist among the available betablocking drugs are often overlooked. Cardioselective agents are safer than nonselective beta-blockers in diabetic patients and in those with mild-to-moderate chronic obstructive pulmonary disease. This information appears to be well known worldwide. Agents with beta-agonist activity (intrinsic sympathomimetic activity, ISA) are not cardioprotective, e.g., pindolol, and should become obsolete. Of the cardioselective agents only metoprolol has been shown in randomized clinical trials to significantly reduce coronary heart disease mortality and events. Bisoprolol has not been tried in trials of infarction patients but was beneficial in heart failure trials. Atenolol, a popular cardioselective agent, is used worldwide but has never been tested in a randomized trial of post myocardial infarction patients or in patients with left ventricular dysfunction or heart failure. It should not be assumed that this agent has similar cardioprotective properties as metoprolol, carvedilol, propranolol, bisoprolol, and timolol.

Of the cardioselective agents only bisoprolol and metoprolol have been shown to decrease cardiac mortality. Both of these drugs have lipophilic properties. Lipophilicity allows a high concentration of drug in the brain. This appears to block sympathetic discharge in the hypothalamus and elevate central vagal tone to a greater extent than water-soluble, hydrophilic agents. This may relate to the prevention of sudden cardiac death. Abal et al., in a rabbit model, showed that ‘‘although both metoprolol (lipophilic) and atenolol (hydrophilic) caused equal beta blockade, only metoprolol caused a reduction in sudden cardiac death.’’ It appears that this information has not reached clinicians or researchers. In addition, only carvedilol, metoprolol, timolol, and propranolol — all lipophilic agents — have been shown to reduce mortality and morbidity in postinfarction patients. Atenolol is nonlipophilic and probably provides less cardioprotection than proven agents. It has not been adequately tested in randomized trials. Sotalol and oxprenolol, both nonlipophilic, have been tested in randomized clinical trials and have not been shown to significantly reduce mortality or morbidity. Oxprenolol has some betaagonist activity that negates cardioprotection.

Both nonselectivity and lipophilicity may provide cardioprotection. It is possible that cardioselective agents are not as cardioprotective as beta-1 and beta-2 blocking agents. Large, randomized clinical trials in the post myocardial infarction patients with long-term follow up have only been carried out with the nonselective agents timolol, propranolol, and recently with carvedilol. Each agent proved beneficial in reducing cardiac mortality and morbidity. The cardioselective metoprolol reduced mortality and morbidity in a postinfarction trial but follow up was three months. Metoprolol was also successful in a heart failure trial (MERIT). The cardioselective bisoprolol reduced mortality and morbidity in a heart failure trial (CIBIS II), but this agent is partially lipophilic. Atenolol was used in an early acute myocardial infarction trial and the result was only modestly significant. The methodology
was unsound in this trial; patients were admitted 4, 6, and 12 hours post infarction, so this was not a genuine trial of a beta-blocker during the first few hours of infarction. Unfortunately atenolol is the beta-blocking drug most often used in antihypertensive trials comparing beta-blockers with diuretics, calcium antagonists, and ACE inhibitors. A nonselective, lipophilic drug such as carvedilol that is proven effective in postinfarction patients and in patients with severe heart failure should be tested in hypertensive patients. The cardioselective agent bisoprolol has lipophilic properties and also deserves testing in hypertensive trials.

Beta blockade causes a mild increase in serum potassium because of blockade of the beta-2-mediated epinephrine activation of the Na Kþ ATPase pump which transports potassium from extracellular fluid into the cells. During stress, serum potassium has been observed to decrease 1.0 mEq/L; this can be prevented by blockade of beta-2 receptors. Nonselective beta-blockers are superior to selective agents in preventing fluctuations of serum potassium concentration during stress and possibly during acute myocardial infarction. It may also be more cardioprotective than cardioselective agents.

Carvedilol has important differences from atenolol, metoprolol, and other beta-blockers. This lipophilic, beta-1, beta-2 blocking agent is a very mild alpha-1 blocker and causes arteriolar dilatation. Antioxidant and antiproliferative properties have also been noted. Carvedilol also lowers plasma endothelin levels.

INDIVIDUAL BETA-BLOCKERS

Acebutolol
This relatively cardioselective, partially hydrophilic and lipophilic agent possesses mild beta-agonist activity. A dosage of 200–300 mg twice daily is given for hypertension. Because of the presence of beta-agonist activity, this drug is not indicated for the management of angina or myocardial infarction.

Atenolol
This beta-1 cardioselective agent is water-soluble, hydrophilic, and eliminated by the kidneys. It has a low side effect profile and is therefore widely used. As outlined above, the drug has not been shown to decrease mortality in randomized trials. A dosage of 25–50 mg once daily is given, but a dose of 75 mg is required in some patients with angina or hypertension.

Bisoprolol
This agent is highly beta-1 selective and is more cardioselective than metoprolol and atenolol. It is 50% lipophilic and metabolized in the liver. The water-soluble, hydrophilic component is excreted by the kidneys. The concentration of unchanged bisoprolol in rat brain is lower than that of metoprolol or propranolol, but higher than that of atenolol after dosing. This agent has a low side effect profile. A dosage of 5–10 mg once daily, and a maximum of 15 mg daily is recommended.

Carvedilol
This noncardioselective agent is a beta-1, beta-2 receptor blocker with very mild alpha-1 vasodilating activity. A recent randomized trial has shown the drug to be effective in reducing mortality in patients with acute myocardial infarction with an ejection fraction of less than 40%. In a large, randomized trial the drug significantly decreased mortality and morbidity in patients with moderate and severe heart failure. Patients are given a dosage of 3.125 mg daily for heart failure, titrated slowly over weeks to 12.5–25 mg twice daily. For hypertension the dosage is 12.5 mg then 25 mg, if necessary, with a maximum of 50 mg daily.

Metoprolol
This beta-1 cardioselective agent has been used extensively. It is commonly used in the management of angina, hypertension, and heart failure; clinical trials have shown the drug to be effective in reducing morbidity and mortality in patients with a moderate degree of heart failure. Metoprolol is commonly prescribed to reduce the rapid heart rate in patients with atrial fibrillation, but other beta-blockers have similar effects.

Nebivolol
Nebivolol is a new, highly selective beta-1 receptor antagonist with antioxidant properties that has been shown to cause vasodilatation in humans. This agent reverses endothelial dysfunction in hypertensive patients. It appears that the drug causes vasodilatation through an endothelial beta-2-adrenergic receptor mediated nitric oxide production. Nitric oxide formed in arteries causes salutary vasodilatation. The vascular release of superoxide is increased in atherosclerotic arteries and oxygen can inactivate nitric oxide; oxidative inactivation of nitric oxide is a cause of endothelial dysfunction. Cominacini et al. has shown that nebivolol increases nitric oxide by also decreasing its oxidative inactivation.

Others
Other agents include the well known propranolol, but its efficacy is questionable and should become obsolete for the management of hypertension, angina, and following myocardial infarction, because the other agents described above cause less adverse effects. Sotalol is indicated mainly for the management of some patients with paroxysmal atrial fibrillation to maintain sinus rhythm.