Blockade of the Sympathetic

System in Hypertension & Heart

Failure

Haralambos Gavras

Professor of Medicine

Introduction

• Central sympatholytic agents are the oldest anti-

HTN drugs ( reserpine, methyldopa, clonidine ).

• Beta-AR blockers are now well established in

the treatment of HTN and HF.

• Recently two new approaches were introduced:

• Sympathetic denervation via renal nerve

ablation

• Selective blockade of the alpha 2B-AR subtype.

Grimson, Ann Surg 1941

Surgical Sympathectomy

Peet, Am J Surg 1948

BP control was maintained long-term

Adverse effects of splanchnicectomy

Thoracic duct injuries

Atelectasia

Orthostatic hypotension and tachycardia

Palpitations

Breathlessness

Anhidrosis

Cold hands

Intestinal disturbances

Loss of ejaculation

Sexual dissatisfaction

Papademetriou/Dumas, Am J Cardiol 2010

Renal Sympathetic Nerves as Therapeutic Target

• Arise from T10-L1• Follow the renal artery to the kidney• Primarily lie within the adventitia

Vessel Lumen

Media

Adventitia

Renal Nerves

Results: Blood Pressure Reduction: Simplicity-1

-14 -21 -22 -24 -27-10 -10 -11 -11 -17

-50

-40

-30

-20

-10

0

10

1 month(n=41)

3 months(n=39)

6 months(n=26)

9 months(n=20)

12 months(n=9)

MeanChange in

Blood Pressure(mmHg)

Presented with 95% Confidence

Intervals

Systolic

Diastolic

* P<0.001

** P=0.02

*

* **

* * * *

* *

*

87% had a reduction

in SBP ≥ 10 mmHg

Significant, Sustained BP ResponseExpanded series

92% of patients have BP ↓

-20 -24 -25 -24 -25 -33-10 -11 -11 -11 -15 -15

-50

-40

-30

-20

-10

0

10

1 M(n=138)

3 M(n=106)

6 M(n=82)

12 M(n=63)

18 M(n=32)

24 M(n=17)

Systolic

Diastolic

BP change(mmHg)

Schlaich et al. European Society of Hypertension. 2010.

Approach

• Use of genetically engineered mice with

deletion of each one of the α2AR subtypes.

• Use of renoprival model of hypertension to

assess their roles in regulation of

cardiovascular function and sympathetic

outflow in response to salt loading.

Indirectly Measured Mean Blood Pressure

α2A +/+

α2A -/-

α2B +/+

α2B +/-

α2C +/+

α2C -/-

Conclusions

• Absence of α2A AR (leaving unopposed α2B AR activity) is associated with higher baseline BP and a more severe and rapid salt induced hypertension.

• Adequate expression of α2B AR is a prerequisite for development of salt induced hypertension.

• Because of the possibility that salt induced hypertension is partly a function of sodium reabsorption due to renal α2 AR, experiments were repeated in anephric mice.

Role of the α2B AR subtype in acute

hypertensive response to hypertonic

saline infusion(I)

• Mice were initially subjected to right

nephrectomy.

– right iliac artery was catheterized for direct

pressure measurements

– right iliac vein was catheterized for saline infusion

• The following day the left kidney was removed.

Role of the α2B AR subtype in acute

hypertensive response to hypertonic

saline infusion

• Arterial catheter was connected for direct

blood pressure measurements

• Venous catheter was connected to a

Harvard infusion pump containing 4%

saline.

– Total volume infused over 2 hours was 0.4ml

– 10% blood volume increase

Mean arterial pressure during a 2 hour hypertonic saline

infusion in anephric mice: WT vs KO mice

Conclusions

• Absence of fully functional α2B AR renders animals unable to raise BP in response to acute salt loading.

• Absence of α2A AR or α2C AR does not alter hypertensive response to acute salt overload in KO compared to WT animals.

• Taken together, the acute and chronic experiments suggest that central α2AAR attenuate and α2B ARaccentuate hypertensive response to salt loading, whereas α2C seems hemodynamically neutral.

Gene treatment to block the expression

of the α2B adrenergic receptor in the

CNS

• Proposed Hypothesis:

– if the central α2B adrenergic receptor is

responsible for salt induced

hypertension, blocking its expression in the

CNS should prevent BP rise.

– confirm that α2B AR has a similar role in other

species.

Inhibition of α2AR using Recombinant

AAV-delivered Antisense in

Hypertensive Rats

• Aim: Prolonged reversal of established salt

dependant hypertension in rats by using a

recombinant Adeno Associated Virus

vector for delivery of α2B AR AS-DNA.

Inhibition of α2B AR using

Recombinant AAV-delivered Antisense

in Hypertensive Rats

• Wistar rats were subjected to subtotal nephrectomy and dietary salt loading.

• 2x1010 particles in a volume of 10-15µL Lipofectamine injected stereotaxically into the left lateral ventricle at a rate of 0.167µl/min, over 1-1.5hours.

Scrambled-ODN treated rat

Antisense-ODN treated rat

Pressure Recording Post Injection

Conclusion

• Injection of AS-ODN against the α2BAR in

the CNS produces attenuation of blood

pressure rise.

– Translational inhibition of α2B AR centrally

prevents blood pressure rise.

Summary

• An intact fully functional α2B AR is necessary

for the development of hypertension due to

salt loading .

• When unopposed as in the case of

α2A AR KO mice it causes a hypertensive and

hyperadrenergic state even at baseline.

Summary

• The central presynaptic α2A AR is

sympathoinhibitory

• The central presynaptic α2B AR is

sympathoexcitatory