東北大学機関リポジトリTOUR

Special Lecture 1 : The finding, development and progress of potassium channel openers

著者 柳澤 輝行

The finding, development and progress of

potassium channel openers.

Teruyuki YANAGISAWA, MD, PhD

Dept. Mol. Pharmacol.,

Tohoku Univ. Sch. Grad. Med.

The 87

_{Annual Meeting of The}

Japanese Pharmacological Society

Sendai, 20140319, 10:45-11:45

☑

The author has no conflict of interest

to disclose with respect to this

The development of nicorandil (SG-75)

The development of nicorandil (SG-75) was started under

the concept “a nitrate-like antianginal drug without

hypotensive side effect”. During the studies to explore the

mechanism of action of nicorandil, it has been revealed that

nicorandil opens potassium (K

_{) channel and that}

ATP-sensitive K

_{channels (K}

ATP

) are the target molecules, which

are also opened by other K

_{channel openers (KCO) as}

antihypertensives. Although the clinical results related with

pure KCOs for hypertension have been failed, nicorandil

which is a hybrid of nitrate and KCO has been successful as a

drug for angina pectoris, acute myocardial infarction and

acute heart failure. We have also suggested that nicorandil

will be effective in managing pulmonary arterial

hypertension. The KCOs targeting other than K

are

expected to be novel therapeutic agents to control pain or

epilepsy, including many pathological situations.

K

+

channel openers (K

_ATP

COs)

•

Historical points of view

•

Why they are not successful for the

antihypertensive agents?

•

Vasospastic angina

•

Hyperpolarization-relaxation coupling

•

Progress of new types KCOs

minoxidil, LP 805 Pyrimidine: O N N _{N H} 2 H₂N N trichogen Benzopyran: Cromakalim O H N C O C H ₃ C H ₃ N O * _*

K

+

channel openers

nicorandil

3 N NH S O Cl CH 2 Benzothiadiazine: diazoxide "Nonspecific KCO" Hypertricosis as a side effect

cf. ischemic preconditioning;

pharmacological

The development of nicorandil (SG-75)

•

Blood-perfused cardiac preparations in

Tohoku University

•

The serendipity to find K

opening activity

Dr. Sakai, K

(Born in Ishinomaki)

The Development of nicorandil

Blood

pressure

(mmHg)

Coronary

blood flow

(ml/min)

Heart rate

Nicorandil

Nicorandil

(SG-75):

coronary resistance↓

Intraduodenal administration of nicorandil (3mg/kg) ≒ intravenous injection (0.3mg/kg)

Taira N, Satoh K, Yanagisawa T et al. Clin Exp Pharmacol Physiol 1979;6:301-16. SEM in parentheses, n=5. : P＜0.05,

Nicorandil

(SG-75):

coronary resistance↓

≒ intravenous injection (0.3mg/kg)

Taira N, Satoh K, Yanagisawa T et al. Clin Exp Pharmacol Physiol 1979;6:301-16. SEM in parentheses, n=5. : P＜0.05,

a.v.: arterio-venous; AV: atrioventricular

Distribution of cardiac output & O

consumption

in organs at rest

Organs Blood flow (mL/min) O2 consumption

(/100g) (Whole) (%) Brain Heart Liver Kidney Sk. muscle Skin Others Total (mL/min) (%)

In heart, the tissue O

partition pressure is low,

thus the organ is under relatively hypoxic condition.

K

channels are seemed to be easily opened in heart.

Isolated blood-perfused cardiac preparations

Increase in coronary blood flow,

Very llittle effect on sinoatrial (SA) rate

RA

RV

IVC

SVC SA node

Constant perfusion pressure

Injection, i. a.

SG-75

Nicorandil

Conduction system

AV node

Ventricle

SA node AV node Bundle branch His B. Purkinje f. Slow response Ca2+ _channel

Vent. Septum

N-Sch. Arch. Pharmacol. 1975:290:107-12.

Nifedipine vs. nicorandil on AV conduction time

No effect on AV conduction, furthermore

Arterial blood

Extra. potential

Force of contraction

Nicorandil 1mg, i.a.

Acute ischemia causes a so-called

current of injury????

The concept of

K

_ATP

channel opening

in ischemic/hypoxic cells.

The effect of on APD of cardiac muscle.

（

Ischemia-induced arrhythmia）

(Intra-arterial nicorandil-induced V.F.)

Acute ischemia causes a current of injury

ischemia involving the outer ventricular layer (transmural or epicardial injury)

Lead V4

at rest

exercise

There is 0.3 mV of

horizontal ST-segment depression

,

indicating a positive test for ischemia.

1 mV 1 sec P Q R S T

Electrode

Acute ischemia causes ST changes

K_ATP opened Subendocardium

Epicardium

Conduction

http://ir.library.tohoku.ac.jp/re/bitstream/10097/40205/1/ YANAGISAWA-Teruyuki-01-09-0012.pdf

Ischemic arrhythmias in the light of K

Reentry

→VT, VF

SG-75-induced VT & VF in experiments with

blood-perfused canine preparations

We have given clinicians the caution of the risk of

intracoronary administration of nicorandil.

Fortunately, there has been no report related

accidents

(Am J Cardiol 1989;63:18J-24J)

・

Cromakalim and pinacidil, nonnitrate KCO, have

essentially the same cardiovascular profile as nicorandil in

isolated, blood-perfused canine heart preparations.

1) The property of nicorandil as a resistive vessel dilator highly

selective for vasculature originates in its mechanism of action as a K-channel activator.

2) The non-unanimous effect of nicorandil on venous return is a result of the opposing actions as a capacitive (action as a nitrate) and a

resistive vessel dilator.

3) Nicorandil, with its hybrid nature, is advantageous over specific K-channel activators and classic nitrates in therapeutic implications.

Selectivity spectra for coronary blood flow vs. cardiac variables

Am J Cardiol. 1987;59(3):24B-29B

Canine atrial muscle comparison with ACh

Canine atrial muscle comparison with ACh

SG-75 increases P

_K

Effect of SG-75 on membrane potentials of a

spontaneously firing canine Purkinje fiber

10

M SG-75

10

M SG-75

10

M SG-75

Control

Slow response in 27 mM K

20 msec

20 mV

Hyperpolarization

Shorten APD

【Conclusion-1】

Findings in blood-perfused cardiac prep.

•

SG-75 increases coronary blood flow.

•

No effect on AV conduction

•

Induction of ventricular fibrillation in high dose

•

Shorten QT interval

•

Shorten APD of ventricular muscle

The mechanism is not Ca

channel blockade.

K

+

channel openers (K

_ATP

COs)

•

Historical points of view

•

Why they are not successful for the

antihypertensive agents?

•

Vasospastic angina

•

Hyperpolarization-relaxation coupling

•

Progress of new types KCOs

Treatment of

vasospastic angina

Vm（mV） －55 －90 K+ _channel Ca2+ _channel Vascular sm.m.tone Vascular diameter K＋ channel opener hyperpolarization －75 －40 rested Ca2＋ depolarization K＋ open Hyperpolarization-relaxation coupling K＋ K＋ K ＋ K＋ K＋ Ca2＋ Ca2＋Ca2＋Ca2＋ Ca2＋ close close open

Hypertension, spasm, agonists

Dissociation of

[Ca

_]

i

& Force of contraction

Repolarization

vs.

Inhibition of Ca influx

-10mV

-55mV

[Ca

2+

]

i

-Fc relation;

Vm

Repolarization & Ca sensitivity

Membrane potential (mV)

C

hange

s i

n

C

a

sens

iti

vi

ty

(%

)

RhoK distribution

Relationship

between [Ca

_]

and force of

contraction

induced by

serotonin ( 10

M) in the absence

(

○

) and presence

of levcromakalim

( 10

_M,

_●

_{) or}

nicardipine (

).

[Ca

]

(%)

c

F

o

rce (

%)

Ca sensitivity

↓

by a KCO

C

o n t r o l

F

u r a - 2

r

a t i o

0

. 6

0

. 5

F

o r c e

(

m N )

0

3

U

4 6 6 1 9

C

a f f e i n e

C

r

o

m

a

k

a

l

i

m

1

0

M

0

C a

Naunyn-Schmied. Arch. Pharmacol. 1992;346:691-700. Biochem. Biophys. Res. Commun. 1992;187:1517-22. K+ _{channel opener inhibits IP}

3 generation & Ca2+ release from SR by

Activation of phospholipase C by the agonist U46619 is inhibited by cromakalim-induced hyperpolarization in porcine coronary artery. （in the absence of [Ca2+_]

o）

Hyperpolarization

Molecular signal mechanisms of

relaxation

of

vascular smooth muscle via Hyperpolarization

Hyperpolarization

Hyperpolarization

Hyperpolarization

K

_ATP

K

_ca

K

_ir

Nicorandil, Nitroglycerin

↓

NO→cGMP→G kinase

Hyperpolarization decreases Ca sensitivity

Hyperpolarization Hyperpolarization

K

_ATP

K

_ca

K

_ir

KCO

Nicorandil

Nitroglycerin

EDHF

as NK hybrid

In the presence of nitroglycerin,

Dissociation of

[Ca

_]

& Fc

Ca

2+

desensitization

Ca

2+

sensitization

Pathogenic mechanisms in coronary artery spasm.

Circulation 2011;124:1774-82

Hyperpolarization:

【Conclusion-2】

Coronary artery spasm mechanisms.

Ca

sensitivity in vasc. sm. m. is

increased

or

decreased

by

depolarization

or

hyperpolarization

,

respectively.

The concept of hyperpolarization-relaxation

coupling via. KCO or EDHF is very important,

since we have precisely known the molecular

mechanisms of vasospasm.

K

+

channel openers (K

_ATP

COs)

•

Historical points of view

•

Why they are not successful for the

antihypertensive agents?

•

Vasospastic angina

•

Hyperpolarization-relaxation coupling

【Appendix】

The future of K

_ATP

COs & other type of KCOs

•

Organ perfusion preservation of organ transplant

•

Pulmonary arterial hypertension; Sahara M et al.

PLoS One. 2012;7(3):e33367. doi: 10.1371/

journal.pone.0033367.

•

Advanced diabetic nephropathy; Tanabe K et al.

Am J Physiol Renal Physiol. 2012;302:F1151-60.

K_ATP BK_Ca, IK_Ca Kv ～100 pS, ～10 pS ～10 pS ～100 pS, ～60 pS -90 -80 -70 -60 -50

Vm

(mV)

Single channel conductance

Open channel number in vascular sm. m. cell E _{K =}

Folia Pharmacol. Jpn. 1995;106:157-69.

Anticonvulsant, Analgesic

•

Ezogabine (Retigabine ): KCNQ/Kv7 opener,

anticonvulsant.

•

Flupirtine: the same mechanism , non-opioid

analgesic, muscle relaxant and anticonvulsant.

Thank you for your attention!