Autonomic pharmacology

β-Adrenergic Receptor Antagonists

Cardiovascular effects associated with ß antagonist administration continued:

Rhythm and automaticity:^152,240
- ß-adrenergic receptor blockers influence cardiac rhythm and automaticity.¹⁵²
  - Automaticity is a property of cardiac tissue that exhibits an unstable resting membrane potential.
    - The membrane potential decreases (moves towards threshold) until an action potential is triggered.
    - Normally action potential generation is determined by those cells of the cardiac conduction system exhibiting diastolic depolarization with steepest slope, typically cells in the sinoatrial node (pacemaker cells).
      - Phase 4 depolarization: Cardiac Pacemaker Electrophysiology²⁴¹
    - However, other cells both within the specialized cardiac conduction system and nonspecialized myocardial cells also exhibit this property.
    - Cells not associated with the specialized conducting system may, especially under conditions of myocardial injury and ischemia, depolarize, reach threshold and produce an action potential.
    - This condition may predisposes to arrhythmia.
  - ß-receptor blockade would tend to decrease automaticity in that sympathomimetic amines e.g. norepinephrine inherently increase phase 4 (diastolic) depolarization.
    - If increased automaticity is secondary to inadequate myocardial oxygen availability compared to demand, decreased heart rate that may be associated with ß-receptor antagonism may decrease automaticity.
    - High heart rate (tachycardia), driven by increased sympathetic activity and/or increased circulating catecholamines, would likely be decreased following administration of ß-adrenergic receptor blockers.
  - Effects on cardiac rhythm and automaticity associated with the ß receptor were typically analyzed with respect to the ß₁-adrenergic receptor subtype.¹⁵²
    - However, ß₂ receptors appear important in heart rate regulation.
    - The additional ß-receptor subtype, ß₃ also present in myocardial tissue, may have some role in myocardial physiology, although the effect remains to be elaborated.
    - Myocardial electrophysiological/rhythm effects of ß-receptor blockers include:
      - reduced heart rate (sinus rate)
      - decreased atrial and AV nodal conduction velocity
      - reduced spontaneous depolarization rates at ectopic pacemakers (pacemakers associated with e.g. regions of myocardial ischemia), and
      - prolonged AV nodal functional refractory time.¹⁵²
  - Some effects of ß-adrenergic receptor antagonists may be dissociated from ß-receptor blockade, probably at higher drug concentrations.¹⁵²
    - One example is the "quinidine-like" or membrane-stabilizing property of ß-receptor antagonist.
    - At typical dosing levels, ß-receptor blockade is likely more prominent than "quinidine-like" effects.
      - Propranolol is typically available as a racemate, mixture of both d- and l-rotary stereoisomers.²⁴⁰
        
        The l-isomer is much more potent in causing ß-adrenergic receptor antagonism compared to the d-isomer.
        
        The two isomers however appear equal potent as local anesthetics.
        
        Comparison between d- and d,l-propranolol with respect to efficacy in suppression of ventricular ectopic depolarizations indicated effectiveness of d-propranolol by means of an non-ß-mediated activity.
        
        Propranolol thus may suppress ventricular arrhythmias under some circumstances by both ß and non-ß-receptor mediated antagonism.²⁴⁰

Antihypertensive Activity:

ß-adrenergic receptor antagonists are used clinically as antihypertensive medications.¹⁵²

However, mechanisms thatexplain this antihypertensive action remain to be fully elucidated.

For example, ß-adrenergic receptor blockers have limited effects in reducing blood pressure in normal subjects; however, in patients with hypertension, these drugs are effective in decreasing blood pressure.

Some agents (e.g. propranolol) appear especially efficacious if hypertension is associated with elevated plasma renin, although other agents are effective in hypertensive patients with low plasma renin.

Renin Dimer²⁴²

Renin Dimer: 3D ribbon representation
Renin release from the juxtoglomerular system is under sympathetic control with release promoted by ß₁ receptor activation, an effect inhibited by ß-adrenergic receptor antagonists.

Renin-Angiotensin-Aldosterone Axis²⁴³

Renin circulates in the blood stream and catalyzes converstion of angiotensinogen secreted from the liver to angiotensin I. Angiotensin I is subsequently converted to angiotensin II, a vasoactive (vasoconstriction) peptide by Angiotensin Converting Enzyme (ACE).²⁴⁴

However, pindolol is an example of a ß-adrenergic receptor blocker with no effect on plasma renin enzymatic activity.

Other possibilities concerning mechanisms for ß-adrenergic receptor blocker-mediated antihypertensive actions include activity at presynaptic ß-receptors.¹⁵²
- The expected action of ß-antagonists at the site would be to decrease norepinephrine release; however, this possible effect has not been demonstrated to be central to ß-adrenergic agonist antihypertensive actions.
- An important observation is that prolonged administration of ß-adrenergic receptor blockers is associated with the progressive decrease in peripheral vascular resistance.
  - This effect on vascular resistance is also associated with reduced cardiac output.
  - Decreased vascular resistance appears central to explaining the mechanism of ß-blockers; however, the mechanism of this effect remains to be elucidated.
    - Finally, a central site for ß-adrenergic antagonists, a CNS site, has been suggested as contributing to antihypertensive effects, although this model has not been validated.

As discussed earlier, certain ß-adrenergic receptor blockers have additional effects that influence their ability as antihypertensive drugs.¹⁵²

These effects have to do with vasodilator activity, grouped into six possible mechanisms.¹⁵²
- These mechanisms include:
- These differing mechanisms appear to:
  - reduce afterload
  - enhance peripheral blood flow and
  - promote hypotensive responses.
- Additionally, some ß-blockers (nebivolol, celiprolol) cause vasodilatation, thus decreasing preload.

ß-adrenergic receptor blockers with "additional effects"^152,245

→Enhanced nitric oxide (NO) synthesis←
ß-adrenergic receptor antagonist	Structure
Nebivolol (Bystolic)
Carteolol (Cartrol)
Celiprolol (Cardem)
Bopindolol
Nipradilol

ß-adrenergic receptor blockers with "additional effects"^152,245

→ß₂-adrenergic receptor agonist activity←
ß-adrenergic receptor antagonist	Structure
Carteolol (Cartrol)
Celiprolol (Cardem)
Bopindolol

ß-adrenergic receptor blockers with "additional effects"^152,245

→Inhibition of Ca²⁺ entry←
ß-adrenergic receptor antagonist	Structure
Betaxolol (Kerlone)
Carvedilol (Coreg)
Bevantolol

ß-adrenergic receptor blockers with "additional effects"^152,245

→α₁-adrenoceptor antagonist activity←
ß-adrenergic receptor antagonist	Structure
Labetalol (Normodyne)
Carvedilol (Coreg)
Bucindolol
Bevantolol
Nipradilol

ß-adrenergic receptor blockers with "additional effects"^152,245

→Increases K⁺ channel conductance (channel opening)←
ß-adrenergic receptor antagonist	Structure
Tilisolol (Selecal)

ß-adrenergic receptor blockers with "additional effects"^152,245

→Antioxidant activity←
ß-adrenergic receptor antagonist	Structure
Carvedilol (Coreg)

Celiprolol (Cardem)²⁴⁵:

Celiprolol is classified as ß₁-adrenergic antagonist which also exhibits α₂-adrenergic receptor blockade.

Additional receptor antagonism has been noted for celiprolol at postjunctional α₁-adrenergic receptors (weak) and at prejunctional α₂-adrenergic receptor sites as well.

Mechanisms that might explain celiprolol-mediated vasodilatation include:

ß₂-adrenergic receptor activation at vascular smooth muscle sites
elaboration of endothelial nitric oxide (N-O), and

atrial natriuretic peptide (ANP) release.

Natriuretic peptide precursor A²⁴⁶

Atrial natriuretic peptide (ANP) is structurally characterized as a peptide (28 amino acids) with a 17-amino acid ring in the center. ANP is related both to BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide). Atrial cardiac myocytes are responsible for producing, storing and releasing ANP. Factors that promote release include atrial stretch and other signals including exercise, hypercalemia, or caloric restriction. Atrial natriuretic peptide receptors been identified and designated NPR1, NPR2 and NPR3, the first two of which involve guanylyl cyclase coupling. Most physiological effects associated with ANP involve increasing cyclic GMP levels.^{247,248,249,250}

In both healthy individuals in hypertensive patients, celiprolol administered either by the IV or oral routes of administration, reduced peripheral vascular resistance and increased regional blood flow.
- Vasodilation was thought mediated by activation of ß₂-adrenergic receptors.
- In healthy individuals, renal blood flow was enhanced by celiprolol; a similar effect was noted in individuals with chronic glomerulonephritis.
In a number of experimental preparations (e.g. anesthetized dog heart, perfused rat kidney) vasodilatation mediated by celiprolol can occur independent of α-blockade or ß₂-adrenergic receptor activation.
- The mechanism in these examples involve endothelial cell nitric oxide (N-O) elaboration.
  - Released N-O increases cyclic GMP levels in smooth muscle.
  - Another mechanism that promotes both N-O synthesis and release involves ß-adrenergic receptor activation.
    - This mechanism for increasing N-O levels appears dependent on the particular experimental system examined.
Lastly, celiprolol reduces plasma atrial natriuretic peptide (ANP) in healthy volunteers while increasing ANP secretion in hypertensive patients.

Nebivolol (Bystolic):²⁴⁵
- Nebivolol is classified as a selective ß₁ adrenergic antagonist.
  - D-nebivolol exhibits the selective ß₁ antagonist effect; however, the L-isomer is responsible for vasodilatation.¹⁸³
    - Nebivolol (Bystolic) is available as the racemate (50% D- & 50% L isomer).
  - Hemodynamic actions of nebivolol because of vasodilating effects (described below) are different from classical, pure ß-adrenergic antagonists.
    - The classical agents (older) likely cause an increase in peripheral vascular resistance; however, peripheral vascular resistance is lowered by nebivolol.
      - Nebivolol is metabolized to active metabolites. Nebivolol half-life is about 10-12 hours.¹⁸³
- Vasodilator effects associated with nebivolol may depend on elaboration of endothelial nitric oxide (N-O).
- In experimental preparations involving coronary and carotid arteries (canine), arterial relaxation appeared endothelium-dependent.
  - This relaxing effect was eliminated by nitric oxide synthase (NOS) inhibitors and methylene blue which inhibits the enzyme guanylyl cyclase.
    - However, vascular smooth muscle relaxation was not prevented by the non-selective ß-receptor antagonist propranolol, an observation which suggested the absence of a ß-receptor-dependent mechanism.
- In patients with essential hypertension, nebivolol administration appeared to increase both stimulated and constitutive (basal) N-O.
- Nebivolol (Bystolic), because of its selective ß₁-adrenergic receptor antagonism and its ability to promote endothelial N-O release, has been studied for management of hypertension and heart failure.²³⁹
  - Some investigations suggest that long-term treatment with nebivolol enhances left ventricular function, increases exercise capacity, and provides improvement with respect to the clinical endpoints of death and cardiovascular-related hospital admissions for patients exhibiting stable heart failure.
  - Nebivolol is an example of one of the few ß-adrenergic antagonists studied primarily in elderly patients.²³⁹

Nipradilol:²⁴⁵

Nipradilol is categorized as a nonselective ß-adrenergic receptor antagonist which also exhibits vasodilating and α₁-adrenergic receptor blocking activity.
Nipradilol contains a NO₂ radical as does nitroglycerin.

The NO₂ radical in the vasodilating drugs Nipradilol and Nitroglycerin

Nipradilol (NO₂ radical circled)	Nitroglycerin (NO₂ radicals circled)

In experimental preparations coronary arteries (isolated canine vessels) exhibit vasorelaxation after nipradilol administration.²⁴⁵
- Also, nipradilol can be demonstrated to dilate rat mesenteric arterioles in vivo.
- Both nipradilol and nitroglycerin can cause retinal arteries and retinal arteriolar dose-dependent vasodilation, with nipradilol exhibiting about 25% the potency of nitroglycerin.
  - The mechanism of vascular dilation may depend on activation of a guanylyl cyclase (soluble enzyme) resulting in increased cyclic GMP production. Vascular actions probably in part depend on nitric oxide (N-O) elaboration from the molecule itself.
- In a rat portal hypertension model (secondary to portal vein stenosis), nipradilol decreased portal pressure to a greater extent than the nonselective, classical ß-adrenergic receptor antagonist propranolol.
  - Nipradilol reduced portal blood flow without changing portocollateral resistance; by contrast, propranolol reduced portal blood flow but increase resistance.
    - The more efficacious effect of nipradilol in this portal hypertension model compared to propranolol may rest on the drug's venodilator effects on portalcollateral vessels.
    - Comparable conclusions were noted in conscious and unrestrained rats based on two models of portal hypertension as well as in cirrhotic rats.
- In a different model, one that analyzes ocular blood flow, topical nipradilol application decreased ophthalmic vascular resistance, increased ocular blood flow and reduced intraocular pressure.
  - These results were obtained both in a rabbit model and in healthy volunteers.
- The overall pharmacological effects appeared due to both adrenergic receptor antagonism (ß/α) and nitric oxide release.²⁵¹
  - Increased levels of nitric oxide following nipradilol administration may be the sum of two components:
    - The first component is an increase in N-O production and cGMP elevation, as noted above.
      - Increased N-O production is due to an up regulation of the enzyme responsible for N-O synthesis, nitric oxide synthase (NOS).
    - The second component would be a direct N-O release from the molecule itself.
- In the case of endothelial cells and smooth muscle cells, the direct effect (N-O release from the molecule) appears of limited importance.²⁵¹
  - By contrast, this direct mechanism is the principal one observed in both ciliary artery and kidney, as N-O increased even when activity of the N-O synthesizing enzyme, NOS, was inhibited. N-O release from propranolol probably requires facilitation by a reductase enzyme, such as glutathione S-transferase (GST).
- In an experimental system involving human coronary arterial smooth muscle cells, nipradilol was observed to release N-O in the presence of the cells with denitration catalyzed by a reductase contributing to propranolol-mediated N-O release.²⁵¹

Nitric Oxide Signaling Pathway²⁵²

"In this University of Virginia program, Ferid Murad, winner of the 1998 Nobel Prize in physiology, discusses his research into nitric oxide, some of its many biological effects, and its application in drug development for numerous diseases. He and two other researchers earned their 1998 Nobel Prize for discoveries during the 1980s concerning nitric oxide as a signaling molecule in the cardiovascular system, and how the molecule serves to relax blood vessels. The work initiated a new chapter in several areas of biomedical research and initiated new therapies for the treatment and diagnosis of heart disease and other serious inflammatory diseases."²⁵²

Carvedilol (Coreg):²⁴⁵
- Carvedilol (Coreg) is categorized as a nonselective ß-adrenergic receptor antagonist which also exhibits vasodilatory properties as well as some abilities to block -adrenergic receptors.
  - Carvedilol does not exhibit intrinsic sympathomimetic pharmacological actions.
  - By oral and IV administration carvedilol increased forearm blood flow in hypertensive patients.²⁴⁵
- In brain homogenate preparations (rat brain), addition of carvedilol was protected with respect to Fe²⁺ (iron)-mediated α-tocopherol depletion; moreover, since propranolol, celiprolol, and labetalol did not exhibit any effect in the system, carvedilol probably exhibits more notable antioxidant properties compared to other commonly administered ß-adrenergic receptor antagonists.²⁴⁵
  - Carvedilol: Pharmacological properties associated with different molecular regions²⁵³
  - The free radical scavenging property of carvedilol was also noted in human neutrophil preparations.
  - Reduction in oxidative stress in patients with heart failure and hypertension was also found following carvedilol administration.
  - In spontaneously hypertensive rats, endothelial dysfunction appears prevented by carvedilol, presumably by antioxidant properties.
    - The mechanism of this effect may be a reduction in both N-O inactivation and an increase in N-O production by nitric oxide synthase (NOS).
- Carvedilol, comparable to labetalol, is administered as a mixture of isomers, i.e. as a racemate.¹⁸³
  - The S(-) isomer exhibits nonselective ß-adrenergic receptor antagonism; however, both S(-) and R(+) isomers are comparable in α adrenergic receptor antagonism potency.
    - Isomers likely exhibit different elimination half-lives since their hepatic metabolism exhibit stereoselectivity.¹⁸³
    - Carvedilol, when incubated in a rat liver microsomal metabolizing system (rat liver microsomes), four oxidative metabolites were formed:²⁵³
      - 1-hydroxycarvedilol
      - 8-hydroxycarvedilol
      - 4'-hydroxycarvedilol, and
      - O-desmethylcarvedilol.
    - The major products for both enantiomers used as a substrate were 1-hydroxycarvedilol and 8-hydroxycarvedilol.
      - The S/R enantiomeric metabolic ratios for intrinsic clearance for : 1-hydroxycarvedilol, 8-hydroxycarvedilol, 4'-hydroxycarvedilol, and O-desmethylcarvedilol were 0.4, 1.99, 0.77, and 2.71 respectively, demonstrating stereospecific oxidation in this system.
        
        Differences between 1-hydroxycarvedilol and 8-hydroxycarvedilol reflect enantiomeric dependent differences in affinities and/or rate constant with respect to the microsomal metabolizing enzyme isoform. In this case the most likely cytochrome P450 isoform for both enantiomers is CYP2D1.²⁵³
- Carvedilol administration decreases mortality in individuals with heart failure and may be particularly clinically useful for patients who exhibit heart failure in combination with hypertension.

Carteolol (Cartrol):²⁴⁵

Carteolol (Cartrol) is categorized as a nonselective ß-adrenergic receptor antagonist that also exhibits ß₁, ß₂, ß₃ adrenergic receptor agonism.

Hypotensive activity of carteolol (also for pindolol) may occur through a decrease in peripheral vascular resistance due to the intrinsic ß-sympathomimetic activity of the drug.
In experimental preparation utilizing isolated dog coronary artery rings, carteolol increased constitutive or basal release of relaxing factors from femoral artery endothelium.
- This action was abolished by indomethacin, a finding that suggested a role for vasodilator prostaglandins in this observation.
- Additional findings in experimental systems suggested that carteolol enhanced clonidine-mediated vasodilation through an N-O, nitric oxide, mechanism.

With topical application, carteolol enhanced intraocular microcirculatory blood flow and was associated with vasodilatation in both normal individuals and in patients with open angle glaucoma.

Carteolol topical application increased diameter of human optic nerve head surface vessels. The optic nerve head a.k.a. optic disc defines the location where ganglion cell axons exit the eye to form the optic nerve. This region describes a physiological blind spot.
Diagram of the human eye²⁵⁴

Schematic diagram of the human eye

Retinography²⁵⁵

"Self made ophtalmogram of the retina of the right eye. It shows the optic disc as a bright area on the right (nasal side) where blood vessels converge. The spot to the left (temporal side) of the centre is the macula. The grey, more diffuse spot in the centre is a shadow artifact."

Carteolol and timolol both apparently can increase flow velocity in the central retinal artery. (See reference 245 for more details).

Carteolol (Ocupress) in the ophthalmological setting has pharmacological activity similar to other topical ß-adrenergic receptor antagonists used in glaucoma treatment.

Betaxolol (Kerlone):²⁴⁵
- Betaxolol (Kerlone) is categorized as a selective ß₁-adrenergic receptor antagonist that also exhibits vasodilator activity.
  - Betaxolol does not, however, possess intrinsic sympathomimetic action.
- Using the model system of perfused porcine ciliary arteries, betaxolol directly increased arterial diameter more notably than that observed with timolol.
  - In another in vitro test system, utilizing the bovine retinal microcirculatory system, retinal arteriolar and venular diameter was increased following betaxolol administration.
  - Vasodilation observed in perfused pig and human retinal arterioles was noted following both betaxolol administration or nimodipine administration, the latter agent is a L-type Ca²⁺ channel antagonist.
    - Interaction between betaxolol and L-type Ca²⁺ channels was also described in rat cortical membrane preparations. In other experimental systems, betaxolol also appears to interact with the Na+ channel, thus inhibiting Na⁺ inward currents.
- Ocular Effects:
  - Betaxolol administration, in both healthy individuals and in those with glaucoma, causes increased ocular and retrobulbar blood flow.
  - Clinically, betaxolol decreases intraocular pressure by diminishing aqueous humor production.
- Betaxolol may be used in hypertension management and has an investigational, unlabeled use in management of coronary vascular disease.

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Renin Dimer²⁴²

Renin Dimer: 3D ribbon representation