Vasculoprotective Effect of Novel

3rd Generation Beta Blocker for

Kidney, Brain, and Heart

Hasyim Kasim
Divisi Ginjal Hipertensi Departemen
Penyakit Dalam FKUH
Cnemu 2018
 The endothelium: a functional organ
• Endothelium is in fact a metabolically active
organ, playing a crucial role in the
maintenance of vascular homeostasis by
releasing a variety of vasoactive factors that
can either dilate or constrict the blood vessels,
anti-thrombotic and anti-proliferative effects
• Endothelial changes exhibit pro-inflammatory,
pro-oxidant, proliferative, pro-coagulation and
pro-vascular adhesion features
Madau M, CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 4, May 2012
Endothelial activation and dysfunction,
with progression to atherosclerosis

Atherosclerosis with Target Organ Damage :

Brain, Heart, Kidney, Vascular
Madau M, CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 4, May 2012
 ROLE OF NITRIC OXIDE (NO)
• The most critical of the substances released by
endothelium is nitric oxide (NO)
• NO not only produces vasodilatation, but it
also participates in various processes that are
beneficial to the vasculature such as reduction
of vascular smooth muscle cell migration and
growth , platelet aggregation and thrombosis ,
monocyte and macrophage adhesion and
inflammation
Chhabra, Internet Journal of Medical Update, Vol. 4, No. 1, January 2009
Factors contributing to vascular changes
associated with hypertension

Cameron AC et al. Drugs.2016;5:3

Cameron AC et al. Drugs.2016;5:3.
Endothelial dysfunction in hypertension
 Anti-hypertensive Drugs

• Diuretic
• Beta-blocker
• Calcium channel blocker
• ACE-inhibitor
• Angiotensin Receptor Blocker
• Renin-inhibitor

• Alpha-1 adrenoreceptor blocker

• Central Symphatolytic

Cameron AC et al. Drugs.2016;5:3.

Activation of subtypes of β-Adrenergic Receptors

Mason et al. J Cardiovasc Pharmacol. 2009;2(54):123-128.

Suggested main reasons for the lack of cardiovascular protection
provided by (older) β-blockers

▪ Suboptimal antihypertensive effects

▪ Unfavourable haemodynamics
▪ Reduced compliance due to many adverse effects
▪ Unfavourable metabolic effects (lipid and glucose
metabolism)

Kim CH et al. Heart Asia. 2016;8:22-26

 Classification and properties β-blockers

Third generation : Vasodilating β-blockers

Ling LH, Oh VMS. Heart Asia.2016;8:28-29.

J Clin. Hypertens. 2015;1(17).
 Nebivolol
eNOS stimulating
ROS scavenging effects effects

Antioxidant
effect ▪Reduction of cardiac
output Vasodilator
effect
▪Increase smooth muscle relaxation
Reduced Target
▪Central nervous
effects
system
▪Decrease smooth muscle proliferation

▪Decrease platelet agregation

Organ Damage
▪Renin-angiotensin-
aldosteron system
▪Decrease monocyte and platelet inhibition
adhesion
▪Reduction of plasma
▪Decrease inflammation
volume

Prevention and retarding Blood Pressure

of atherosclerosis reduction
Effects of nebivolol on the main organs involved in blood
pressure regulation.

A meta-analysis including almost 19 000 patients concluded

that beta-blocker therapy was associated with a 42% reduction
in heart failure, a 29% reduction in stroke risk, and a 7%
reduction in coronary heart disease in hypertensive patients
(Psaty et al 1997)

Maffei A and Lembo G. Ther Adv Cardiovasc Dis. 2009; 3(4): 317-327
Mechanisms of Action of Nebivolol in the Cardiovascular System

Toblli et al. Vasc. Health Risk Manag.2012;8:151-160

The Composite endpoint combining acute myocardial infarction (AMI)
or sudden cardiac death (SCD)

Chomchol M, Banderly M, Goldbourt U. Nephrol Dial Transplant.

2008; 23:2274-2279
 Double problems for renal disease:
Angiotensin II and sympathetic activity
Primary Renal Disease
Nephron Loss
GFR

Sympathetic Activity ↑ ↑ RAS Activity

Renal NO synthase ↓
ADMA, AGEs
Homocysteine ↑
Dyslipidemia
Oxidative stress

VSM cell proliferation

Glomerular Hypertension

Podocyte Loss
Proteinuria

Mesangial proliferation

Tubulo-intestitial damage

Fibrogenesis/renal scarring

J Am Soc Nephrol 15: 524–537, 2004

 Causes and consequences of
sympathetic activation in CKD
CAUSE CENTRAL INTEGRATION CONSEQUENCE

Afferent
Renin ischemia signals
Adenosine Growth (LVH)
Arrhythmias
NO Ischemia
RAAS Sympathetic Heart failure
activity
Integration
Growth
Contributing factors: Vasoconstriction
Obesity Atherosclerosis
Leptin Arterial compliance
Smoking
Hypercapnia
Hypercholesterolemia Sodium retention
Oxidative stress Hypervolemia
Inflammation RAAS activation
Endothelial factors Aggravation of Proteinuria
hypertension Glomerulosclerosis

J Am Soc Nephrol 20: 933–939, 2009. doi: 10.1681/ASN.2008040402

Treatment with beta-blockers improved cardiovascular and all-cause mortality
in patients with CKD and chronic systolic heart failure
 Summary
Beta-blockers are important agents in
cardiovascular medicine, proving critically
important in the management of hypertension and
heart failure and in reducing cardiovascular risk.

Nebivolol's vasodilating effect, its anti-

atherosclerotic effect, and its positive effects on
arterial compliance suggest that it may provide
more cardiovascular benefits than traditional beta-
blockers
Terima kasih