0022.3565/78/2072-0311$02.OO/O
`Tiia
`JoURNAl.
`OF
`PHARMACOLOGY
`© 1978 by The American
`Copyright
`
`THERAPEuI’Ics
`EXPSRIMENTAL
`AND
`Society
`for Pharmacology
`and
`Experimental
`
`Therapeutics
`
`Vol
`Printed
`
`No.
`(cid:1)7,
`in U.S(cid:1)4.
`
`2
`
`Selectivity
`Isomers
`Tracheal
`
`and Steric
`Isolated
`on
`Muscles
`
`Effects
`Rabbit
`
`of M etop rolol
`Atria,
`Arteries
`
`and
`
`NOBORU
`MIVAZAKI
`
`Department
`Accepted
`
`TODA,
`
`SHIGEHIRO
`
`HAVASHI,
`
`YOSHIO
`
`HATANO,
`
`HIDEKI
`
`OKUNISHI
`
`and MIZUO
`
`of Pharmacology.
`
`Shiga
`
`University
`
`of Medical
`
`Sciences,
`
`Seta, Ohtsu
`
`520-21.
`
`Japan
`
`for publication June 5, 1978
`
`ABSTRACT
`Toda,
`Noboru,
`HidekI
`tano,
`Selectivity
`and
`mers
`on isolated
`cheal
`muscles.
`311-319,
`1978.
`
`Ha-
`Yoshlo
`Hayashi,
`Shlgehlro
`Miyazaki:
`and
`Mlzuo
`Okunlshl
`effects
`of metoprolol
`iso-
`steric
`atria,
`arteries
`and
`tra-
`rabbit
`J. Pharmacol.
`Exp.
`Ther.
`207:
`
`iso-
`
`of
`responses
`inotropic
`and
`Chronotropic
`atria
`to isoproterenol
`and
`left
`right
`lated
`rabbit
`and also the relaxation
`induced
`by isoproterenol
`of
`tracheal
`muscles
`contracted
`with
`acetylcho-
`line were
`antagonized
`by
`(-)-metoprolol
`to a
`the
`greater
`extent
`than
`response
`to isoprotere-
`nol of pulmonary
`arterial
`strips
`contracted
`with
`prostaglandin
`F20. The
`pA2 of
`(-)-metoprolol
`in
`right
`and left atria,
`tracheal
`strips
`and pulmonary
`arteries
`were
`7.81,
`7.79,
`7.29
`and
`6.50,
`spectively.
`The
`pA2
`values
`of
`propranolol
`these
`preparations
`were
`not appreciably
`ent.
`In contrast,
`the response
`of
`isolated
`
`re-
`in
`
`differ-
`guinea-
`
`sen-
`more
`was much
`to isoproterenol
`atria
`pig
`aortic
`and
`tracheal
`than
`to metoprolol
`sitive
`and
`6.25
`being
`7.93,
`the
`pA2
`values
`strips,
`tracheal
`respectively.
`In rabbit
`atria
`and
`6.79,
`(-)-metroprolol
`was
`270
`to 380
`times
`muscles,
`more
`potent
`than
`(+)-metoprolol
`in attenuating
`the
`response
`to
`isoproterenol,
`while
`in rabbit
`arteries,
`the former
`was
`approximately
`20 to 30
`of
`times
`the activity
`of
`the latter.
`(-)-Metroprolol
`attenuated
`the isoproterenol-induced
`relaxation
`of
`rabbit
`and
`dog
`coronary
`arteries
`to a greater
`extent
`than
`the
`relaxation
`of
`rabbit
`pulmonary
`pA2 values
`in the
`and mesenteric
`arteries,
`the
`former
`arteries
`being
`almost
`identical
`with
`the
`values
`in rabbit
`atria.
`It may
`be concluded
`that
`beta
`antagonists
`of
`to
`susceptibility
`selective
`beta
`adrenoceptors
`of
`tracheal
`smooth
`muscles
`from different
`species
`differs;
`thus,
`organ-
`the
`selective
`action
`of
`the antagonists
`in dif-
`varies
`ferent
`species.
`Beta-adrenoceptors
`rabbit
`in
`and
`coronary
`arteries
`appear
`to be beta1.
`
`dog
`
`and
`
`of sympatho-
`a series
`of
`potency
`relative
`The
`stimulation,
`fatty
`cardiac
`for
`amines
`mimetic
`vaso-
`bronchodilatation
`mobilization,
`acid
`can
`be
`responses
`and
`differs,
`these
`depression
`coefficients
`groups
`following
`classified
`into
`two
`activities.
`of
`correlation
`between
`the
`relative
`al.
`Lands
`(1967)
`thus
`suggested
`that
`have
`et
`receptors
`beta1
`are
`differentiated
`as
`and
`beta
`is the
`selective
`Practolol
`beta1-
`first
`block-
`introduced
`which
`antagonizes
`agent
`the
`car-
`induced
`catecholamines
`to
`stimulation
`
`beta2.
`ing
`diac
`
`by
`
`Received
`
`for
`
`publication
`
`December
`
`27,
`
`1977.
`
`than
`
`extent
`a greater
`and
`vasodilatation
`Barrett
`et
`al.,
`1968).
`also
`been
`demonstrated
`oselective
`action
`studies,
`however,
`in situ
`in
`alyzed
`airway
`smooth
`different
`species,
`heart
`have
`been
`either
`on
`airway
`the
`from
`same
`species.
`The
`present
`
`relaxation
`muscle
`and
`Shanks,
`1968;
`has
`metoprolol
`such
`a cardi-
`et
`1973).
`In most
`(Ablad
`has
`cardioselectivity
`been
`an-
`in vitro
`(heart,
`preparations
`or
`from
`vasculature)
`muscle
`and
`beta
`the
`on
`or
`blocking
`actions
`actions
`compared
`the
`muscles
`vasculatures
`
`tracheal
`(Dunlop
`Recently,
`to
`
`possess
`al.,
`
`with
`or
`on
`
`study
`
`was
`
`thus
`
`undertaken
`
`to
`
`311
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1033-1
`IPR2016-00379
`
`

`
`312
`
`Todaetal.
`
`Vol. 207
`
`selectivity
`the
`investigate
`on
`(-)-metoprolol
`tions
`of
`and
`atria,
`tracheal
`muscle
`of
`potencies
`to
`determine
`relative
`these
`preparations,
`(±)-metoprolol
`in
`compare
`antagonism
`by
`(-)-metoprolol
`the
`response
`of
`coronary,
`pulmonary
`to
`enteric
`strips
`isoproterenol.
`arterial
`blocking
`actions
`of metoprolol
`were
`pared
`isolated
`rabbit
`and
`guinea-pig
`rations.
`
`of
`beta
`isolated
`arteries
`
`ac-
`blocking
`left
`right
`and
`from
`rabbits
`and
`(-)-,
`(+)-
`to
`and
`of
`
`and
`
`also
`
`mes-
`Beta
`com-
`prepa-
`
`the
`
`in
`
`Methods
`
`of both
`ether
`
`1.7 to 2.3 kg,
`weighing
`sexes,
`rabbits
`Albino
`anesthesia,
`the
`Under
`were
`used.
`animals
`were
`The
`heart,
`from carotid
`arteries.
`by bleeding
`sacrificed
`mesenteric
`artery
`superior
`pulmonary
`trachea,
`and
`node-right
`removed.
`The
`sinoatrial
`were
`rapidly
`artery
`and
`the
`atrial
`preparation
`left
`preparation
`were
`atrial
`prepared.
`Tracheal
`strips,
`approximately
`20 mm
`length,
`were
`prepared following the method
`described
`by Ak#{231}asu(1959)
`with minor
`modifications.
`Ventral
`interventricular
`branches
`of
`the
`left
`coronary
`artery
`heart.
`were
`isolated
`from the
`The
`coronary
`artery
`and
`the
`distal
`portion
`and mesenteric
`arter-
`of pulmonary
`the
`lengths
`of which
`ies were
`helically
`cut
`into
`strips,
`20 mm
`approximately
`were
`(Furchgott,
`1960).
`The
`right
`and
`left
`atrial
`preparations,
`tracheal
`muscle
`prep-
`and
`strips
`vertically
`fixed
`be-
`arations
`arterial
`tween
`the
`of
`20 ml
`hooks
`in
`capacity,
`muscle
`containing
`nutrient
`solution
`aerated
`a mix-
`the
`with
`and
`5% CO2. Hooks
`anchoring
`the
`95% 02
`ture
`of
`upper
`prejiarations
`were
`connected
`to the
`end
`of
`the
`lever
`of a force-displacement
`transducer
`(Sanei
`Sokki
`Co., Tokyo,
`Japan).
`the
`lower
`end
`of
`left
`Hooks
`fixing
`were
`(Ni-
`atria
`connected
`to
`electronic
`stimulator
`
`in
`
`were
`bath
`
`an
`
`for
`to
`
`of
`
`solution
`The
`Japan).
`Tokyo,
`Co.,
`Kogyo
`honkoden
`with
`0.5#{176}Cfor
`30
`at
`was maintained
`experiments
`±
`tracheal
`0.5#{176}Cfor
`with
`alma
`and
`at 37 ±
`experiments
`adequate
`These
`were
`and
`arterial
`strips.
`temperatures
`or
`longer.
`responses
`5 hr
`to
`obtain
`reproducible
`g for
`right
`adjusted
`0.3
`was
`The
`resting
`tension
`0.7 g for
`tracheal
`strips,
`1.0 g for
`atria,
`3 g for
`left
`atria,
`arteries
`0.5 g for
`cor-
`and
`mesenteric
`and
`pulmonary
`onary
`arteries,
`these
`values
`except
`value
`for
`right
`the
`atria
`optimal
`for
`inducing
`the maximum
`con-
`being
`traction.
`Constituents
`the
`solution
`were
`as
`follows
`(millimolar
`concentrations):
`Na(cid:1),
`162.1; K(cid:1),
`5.4; Ca(cid:1) (cid:1),
`2.2; Mg(cid:1) (cid:1),
`1.0; C1,
`159.0; HC03,
`14.9;
`and
`dextrose,
`5.6. The
`pH of
`7.2 to 7.3. Preparations
`the
`solution
`was
`90 to
`in control
`120 mm
`were
`allowed
`equilibrate
`for
`to
`fluids,during
`which
`time
`the
`solutions
`were
`replaced
`every
`10 to
`15 mm.
`re-
`relaxations
`and
`Isometric
`contractions
`Sokki
`corded
`an
`(Sanei
`oscillograph
`inkwriting
`electrically
`driven
`were
`Co.).
`atrial
`preparations
`Left
`supramaximum
`by a train
`of 3 msec
`square pulses
`of
`intensity
`(2-3 mA,
`5 times
`threshold)
`applied
`frequency
`of
`60/mis
`(Toda,
`Dose-response
`1969).
`the
`isoproterenol
`were
`obtained
`by
`adding
`of
`curves
`in cumulative
`concen-
`to bathing media
`amine
`directly
`trations.
`The
`were
`dose-response
`curves
`reproducible
`second series
`of
`in the preparations
`after
`experiments
`used;
`second
`curve
`was
`therefore,
`dose-response
`taken
`as
`a control.
`Tracheal,
`pulmonary
`arterial
`and
`mesenteric
`arterial
`preparations
`had
`been
`contracted
`with
`acetylcholine
`(5 x
`10(cid:1)(cid:1)-(cid:1)0(cid:1)
`M),
`prostaglandin
`x
`(F(cid:1)
`(3 x
`M)
`and
`phenylephrine
`(10-(cid:1)-8
`107_106
`re-
`iO(cid:1)(cid:1) M),
`respectively,
`before
`isoproterenol-induced
`contrac-
`laxations
`were
`obtained.
`The
`magnitude
`tions
`45 to 60% of
`the maximum
`contrac-
`attained
`was
`relaxations
`tion.
`At
`the
`of
`experiments,
`maximum
`were
`obtained
`by
`the
`addition
`of
`iO(cid:1) M papaverine,
`and
`isoproterenol-induced
`relaxations
`relative
`to those
`
`on
`
`the
`
`end
`
`were
`
`at
`
`a
`
`of
`
`TABLE
`values
`Mean
`muscles
`tracheal
`N. number
`of preparations
`log (dose
`ratio
`1) vs.
`-
`
`1
`pA
`
`of
`
`of metoprolol
`
`Isomers
`
`and (±)-propranolol
`
`In Isolated
`
`rabbit
`
`atrla,
`
`arteries
`
`and
`
`used. Figures
`concentrations
`
`-log
`
`In parentheses
`of antagonist,
`
`values
`of mean
`ranges
`indicate
`pA, values were
`calculated
`
`± S.E. Slope,
`from this
`plot.
`
`slope
`
`of
`
`the
`
`plot
`
`(-)
`
`- Metoprolol
`
`(+)
`
`- Metoprolol
`
`(±)
`
`- Propranolol
`
`Prepar-
`ations
`
`N
`
`pA,
`
`Slope
`
`N
`
`pA,
`
`Slope
`
`,
`
`pA,
`
`Slope
`
`Rightatrium
`Leftatrium
`Coronary
`artery
`Pulmonary
`artery
`Mesentenc
`artery
`Trachea
`
`22
`7
`5
`
`8
`
`7
`
`11
`
`7.81
`7.79
`7.60
`(7.45-7.84)
`6.50
`(6.40-6.62)
`6.18
`(6.03-6.42)
`7.29
`(7.19-7.40)
`
`-1.09
`-1.12
`-1.03
`
`-1.13
`
`-0.95
`
`-0.93
`
`c
`ra
`
`nc
`0
`
`1
`1.0
`1.6
`
`21
`
`43
`
`3.3
`
`N
`
`12
`5
`
`11
`
`6
`
`14
`
`5.23
`5.36
`
`4.99
`(4.89-5.12)
`4.86
`(4.66-5.22)
`4.82
`(4.73-4.94)
`
`-1.24
`-1.04
`
`-0.94
`
`-0.88
`
`-0.90
`
`Iso-
`meric
`ratIo”
`
`380
`270
`
`32
`
`21
`
`5
`
`5
`
`Conc.
`ratio’
`
`8.66
`
`-0.96
`
`1
`
`9.21
`(9.10-9.35)
`
`-1.20
`
`0.3
`
`296
`
`10
`
`8.00
`(7.92-8.09)
`
`-0.97
`
`4.3
`
`a concentration
`Antilog
`((pA,
`
`antilog
`ratio:
`(-)-isomer)
`
`of
`
`[(pA, of (-)-metoprolol
`(+)-isomer)J.
`of
`(pA,
`
`-
`
`in right
`
`atria)
`
`-
`
`(pA,
`
`of
`
`(-)-metoprolol
`
`in other
`
`preparations)).
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1033-2
`IPR2016-00379
`
`(cid:1)
`

`
`1978
`
`Selective
`
`Beta
`
`Blocking
`
`Action
`
`of Metoprolol
`
`313
`
`atria
`Rabbit
`O ControL
`Si-)-MP
`L(cid:1)-)-MP
`X t--MP
`
`(22)
`10-8M
`5X10-8M
`2X10-7M
`
`(13)
`(13)
`(10)
`
`atria
`Rabbit
`(12)
`O Control
`#{149}H#{247}MP5X1O-6M(6)
`t(cid:1)i+(cid:1)-MP2X10-5M
`(6)
`X t+ MP 10-4M
`
`(8)
`
`Conc.
`
`of
`
`ISO
`
`(M)
`
`CHi
`
`CH3
`
`100r
`
`50(cid:1)
`
`a)
`
`0 0 0 C a
`
`)
`In
`0a)
`
`UC
`
`0
`
`OH
`
`Conc.
`
`of
`
`ISO
`
`(M)
`
`I
`
`a)
`
`0 0 0 C a
`
`)
`
`a)
`
`UC
`
`C
`
`CH3O-CH2-CH2
`
`O-CH2-CH-CHz-NH(cid:1)CH(cid:1)(cid:1)
`*
`
`of
`
`±
`
`±
`
`Fig.
`by
`1. Modification
`(-)-
`Vertical
`to isoproterenol.
`atria
`the
`atrial
`of
`Mean
`values
`used.
`and
`2 x
`1 O(cid:1) M)-treated
`1 0(cid:1)
`± 9 beats/mm
`(N =
`109
`(+)-metoprolol
`control
`and
`115
`± 7 beats/mm
`12),
`-
`figure).
`The maximum
`(for
`right
`and
`(-)-metroprolol(105,
`in control
`93
`± 5 beats/mm
`(N -
`13),
`103
`figure),
`and
`those
`in control
`and
`(N = 12),
`91
`± 14
`beats/mm
`8).
`respectively
`(for
`right
`figure).
`
`rabbit
`isolated
`of
`response
`chronotropic
`positive
`the
`(+)-metoprolol
`and
`number
`of preparations
`indicate
`the
`Figures
`in parentheses
`S.E.M.
`represent
`bars
`5 x
`the
`addition
`of
`the
`amine
`in control
`and
`(-)-metoprolol
`(1 0(cid:1).
`before
`rate
`were
`9 beats/mm
`(N = 13),
`preparations
`110
`6 beats/mm
`(N
`22),
`110
`±
`and
`10
`beats/mm
`(N = 10),
`respectively
`(for
`left
`figure),
`those
`in
`and
`102
`13)
`±
`1 O(cid:1)”
`and
`1 O(cid:1)
`110
`1 0(cid:1),
`2 x
`x
`(5
`7 beats/mm
`M)-treated
`preparations
`were
`(N
`±
`10 beats/mm
`(N = 6) and
`96
`= 8),
`respectively
`6),
`101
`(N =
`8 beats/mm
`(N
`±
`induced
`by isoproterenol
`was
`taken
`as
`mean
`absolute
`values
`rate
`increase
`100%;
`and
`2 x
`io(cid:1)(cid:1)
`M)-treated
`atria were
`94
`5 beats/mm
`(N = 22),
`5 X iO(cid:1)
`±
`(N
`13)
`and
`85
`± 8 beats/mm
`(N = 10),
`respectively
`(for
`left
`± 7 beats/mm
`104
`(5
`1 O(cid:1),
`2 x
`1 O-(cid:1)
`and
`1 0(cid:1)
`M)-treated
`atna
`were
`± 12
`(+)-metoprolol
`x
`beats/mm
`(N = 6),
`101
`12 beats/mm
`(N = 6) and
`9 beats/mm
`(N =
`105
`±
`±
`The
`chemical
`structure
`of metoprolol
`is demonstrated.
`‘Asymmetrical
`carbon.
`
`right
`
`induced
`the
`text.
`blocking
`proterenol
`from
`the
`(ED5O)
`of
`blocking
`Only
`two
`same
`atrial
`were
`obtained
`1)
`against
`ratio
`
`-
`
`and
`in figures
`by
`presented
`are
`papaverine
`30 mm to
`been
`had
`Preparations
`for
`exposed
`of
`iso-
`the
`agents
`before
`curve
`dose-response
`was
`estimated
`The
`pA2 value
`was
`obtained.
`concentrations
`effective
`ratio
`of median
`and
`absence
`in the
`presence
`isoproterenol
`Schild,
`(Arunlakshana
`and
`1959).
`agents
`blocking
`agents
`could
`be
`used
`of
`doses
`preparations;
`therefore,
`mean
`pA2
`values
`by
`plotting
`mean
`values
`log
`(dose
`log doses
`of
`antagonists.
`
`Atrial
`helical
`tic
`(350-400
`tricular
`(8-15
`fixed
`tension
`strips
`coronary
`contracted
`guinea-pig
`
`aor-
`and
`strips
`muscle
`tracheal
`preparations,
`pigs
`from guinea
`also
`obtained
`were
`strips
`of ventral
`interven-
`Helical
`strips
`g b.wt.).
`left
`the
`coronary
`from dogs
`of
`branches
`artery
`prepared.
`The
`preparations
`were
`were
`kg b.wt.)
`as described
`above.
`The
`resting
`media
`in bathing
`to 0.2 g for atria,
`0.3 g for
`tracheal
`was
`adjusted
`guinea-pig
`aortic
`strips
`and
`dog
`and
`1.5 g for
`arterial
`strips.
`Tracheal
`preparations
`were
`with
`histamine
`(3
`and
`106_105
`aortic
`strips
`dog
`arterial
`were
`
`x
`
`and
`
`M),
`strips
`
`in
`
`of
`
`of
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1033-3
`IPR2016-00379
`
`

`
`314
`
`Todaetal.
`
`prostaglandin
`agents
`
`F(cid:1)
`produced
`
`with
`contracted
`stimulating
`These
`contraction.
`maximum
`as mean
`expressed
`results
`are
`The
`were made
`the
`results
`Comparisons
`of
`were
`dent’s
`D(-)-,
`test.
`Drugs
`t
`used
`(±)-propranolol
`metoprolol
`hydrochloride,
`ride,
`(±)-isoproterenol hydrochloride,
`F(cid:1),
`acetylcholine
`chloride,
`histamine
`and
`phenylephrine
`hydrochloride.
`
`i0(cid:1)7 M).
`x
`(2-8
`40 to 60% of
`the
`
`values
`using
`D(+)-
`
`± S.E.M.
`the
`Stu-
`and
`D(±)-
`hydrochlo-
`prostaglandin
`dihydrochloride
`
`Results
`
`10(cid:1)
`and
`
`on
`and
`and
`
`of
`
`to
`
`of metoprolol
`addition
`
`Effects
`The
`atria.
`concentrations
`in
`slowed
`the
`decrease
`± 1 and
`from
`the
`the
`values
`±
`2 beats/min
`predrug
`rate
`
`of
`rate:
`
`atrial
`response
`in
`3 beats/mm
`10 ±
`predrug
`rate
`with
`the
`(N
`114
`
`rabbit
`isolated
`(+)-metoprolol
`(-)-
`M slightly
`i0(cid:1)
`iO(cid:1)5
`the
`rate
`of
`values
`mean
`were
`(-)-isomer
`the
`respectively,
`= 6),
`(N
`and
`±8
`beats/mm,
`111
`of
`were
`3 ± 1 and
`(+)-isomer
`= 5),
`respectively,
`from
`13 beats/mm.
`The
`
`±
`
`the
`lower
`
`of
`
`Vol. 207
`
`failed
`
`to
`
`alter
`
`the
`
`of metoprolol
`
`response
`to the
`right
`
`of
`curve
`by
`treatment
`
`iso-
`
`concentrations
`atrial
`rate.
`The
`dose-chronotropic
`shifted
`proterenol
`was
`30 mm with
`(-)-metoprolol
`for
`by
`higher
`than
`i0-(cid:1) M and
`5 x
`M (fig.
`1). Average
`(+)-metoprolol
`(±)-
`
`7.53
`
`than
`(-)-
`
`10-6
`
`of
`to
`up
`contractile
`of
`a
`rate
`at
`by metoprolol
`M in
`a
`i0-(cid:1)
`attenuations
`
`7.81,
`were
`(±)-Propranolol
`potent
`
`the
`
`terenol
`1).
`(table
`times more
`The
`additon
`concentrations
`nificantly
`electrically
`attenuated
`i0(cid:1)
`and
`average
`20.6
`and
`2.3
`7.8
`±
`predrug
`the
`from
`attenuations
`the
`and
`7.3 ± 1.2 and
`24.0
`
`2.8%
`±
`contraction
`the
`with
`± 2.1% (N
`
`concentrations
`in
`(+)-metoprolol
`of
`pA2
`values
`(-)-,
`isopro-
`of
`against
`ED5O
`and
`5.23,
`respectively
`was
`approximately
`(-)-metoprolol.
`in
`and
`(+)-metoprolol
`sig-
`alter
`M failed
`to
`force
`of
`left
`atria
`driven
`60/min.
`The
`force
`was
`in
`concentrations
`of
`dose-dependent
`the
`with
`(N
`
`above
`
`10
`
`manner:
`were
`
`(-)-isomer
`= 5),
`respectively,
`of
`2.39
`0.19
`(+)-isomer
`were
`= 3),
`respectively,
`
`±
`
`g,
`
`5
`
`6
`
`C0a 5
`
`,
`
`pulmonary
`Rabbit
`O ControL
`(10)
`SI+)-MP2X1O--SM
`1(cid:1)f*-Mp1O-4M
`X (+)-PAP5X10-4M
`
`art.
`
`(6)
`
`(6)
`
`(6)
`
`x
`
`10-8
`
`i(cid:1)-(cid:1)
`
`io-6io-5
`
`C I
`
`i#{248}-(cid:1)
`
`(MP) of the
`(+)-metoprolol
`pulmonary
`rabbit
`by (-)-
`2. Modification
`FIg.
`response
`relaxing
`and
`induced
`relaxations
`F20. Maximum
`with
`prostaglandmn
`contracted
`were
`strips
`The
`to isoproterenol.
`1 0(cid:1)
`5 x
`(1 O(cid:1),
`and
`(-)-metoprolol
`values
`in control
`mean
`absolute
`100%;
`as
`taken
`papaverine
`599
`193 mg
`(N = 8),
`153 mg
`(N = 10),
`686
`1 0”
`mg
`171
`523
`were
`preparations
`M)-treated
`±
`±
`±
`(2
`in control
`and
`(+)-metoprolol
`respectively
`(for
`left
`figure),
`and
`those
`219 mg
`(N = 6),
`and
`656
`±
`preparations
`were
`855
`148 mg (N = 10),
`980
`305 mg (N = 6), 911
`1 O(cid:1)
`and
`5 x
`1 O(cid:1) M)-treated
`±
`±
`mg
`(N = 6) and
`855
`211 mg (N = 6),
`respectively
`(for
`right
`figure).
`±
`
`Conc.
`
`of
`
`ISO
`
`(M)
`
`of
`
`arterial
`by
`
`strips
`1 O(cid:1) M
`and
`2 x
`(N = 9)
`x
`1 O(cid:1),
`± 252
`
`pulmonary
`Rabbit
`O Control
`(10)
`SF-(cid:1)-MP1O-6M
`L(cid:1)I-)-MP5X10-6M
`X I-)-MP
`2X10-5M
`
`(8)
`
`art.
`
`(9)
`(6)
`
`0
`
`50
`
`C0 0Kaa
`
`)
`
`i(cid:1)-(cid:1)
`
`iO-8
`
`i(cid:1)-(cid:1)
`
`10-6
`
`i(cid:1)-(cid:1)
`
`Conc.
`
`of
`
`ISO
`
`(M)
`
`were
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1033-4
`IPR2016-00379
`
`

`
`1978
`
`Slective
`
`Beta Blocking
`
`Action
`
`of Metoprolol
`
`315
`
`trachea
`Rabbit
`O Control
`(15)
`#{149}(cid:1)4-MP10-8M
`(13)
`t(cid:1)i-l-MP5X10-8M
`2X10-7M (13)
`X (--MP
`#{163}i--MP 10-6M (11)
`V.-’-MP5X1O-6M
`(6)
`
`(6)
`
`trachea
`Rabbit
`O Control
`(15)
`#{149}I*MP5X10-6M
`LS144-MP2X1O-SM
`X Fs)-MP
`10-4M
`Af’4-MP5X1O-4M
`
`(11)
`(12)
`(10)
`(4)
`
`0r
`
`C 0a
`
`C0aKa5
`
`,
`
`10-810-7
`
`i#{248}-6i(cid:1)5iO-4’
`
`Conc.
`
`of
`
`ISO
`
`(M)
`
`10
`
`1o-(cid:1)
`
`10-6
`
`(cid:1)-5
`
`io-4
`
`Conc.
`
`of
`
`ISO
`
`(M)
`
`3. Modification
`FIg.
`The
`isoproterenol.
`were
`taken
`as
`100%;
`5 x
`1 0(cid:1)
`M)-treated
`389
`± 38 mg
`(N -
`those
`in control
`and
`51 mg (N -
`15),
`±
`(N =
`4),
`respectively
`
`±
`
`(+)-metoprolol
`and
`by
`(-)-
`contracted
`with
`were
`strips
`absolute
`values
`mean
`preparatmons
`were
`416
`13).
`353
`35 mg
`(N =
`(+)-metoprolol
`(5
`x 10-6,
`328
`34 mg (N =
`11),
`±
`(for
`right
`figure).
`
`339
`
`(MP)
`acetylcholmne.
`in control
`and
`41 mg (N =
`±
`and
`309
`11)
`2 x
`1 O(cid:1),
`49 mg
`±
`
`of
`
`relaxing
`the
`Maximum
`(-)-metoprolol
`15),
`329
`43 mg
`±
`1 O(cid:1)
`and
`(N =
`
`of
`response
`induced
`relaxations
`5 x
`1 0(cid:1),
`(1 0-s,
`30 mg (N =
`6), 413
`±
`(N =
`6),
`respectively
`5 x
`1 O(cid:1) M)-treated
`299
`41 mg (N =
`±
`
`strips
`tracheal
`rabbit
`by 1 O(cid:1) M papaverine
`x
`1 O(cid:1),
`2
`106
`43 mg (N =
`±
`left
`fi9ure),
`(for
`preparations
`were
`10)
`and
`±
`
`to
`
`and
`13),
`and
`449
`21 mg
`
`388
`
`12),
`
`±
`1.60
`contraction
`predrug
`the
`from
`sufficient
`current
`intensity
`minimum
`The
`contractions
`(0.58
`± 0.07 mA,
`atrial
`elicit
`not
`influenced
`(-)-metoprolol
`up
`was
`of
`four
`out
`preparations
`nor
`M in
`two
`metoprolol
`in
`of
`two
`preparations.
`functional
`refractory
`period
`obtained
`by
`ing
`the
`stimulus
`stepwise
`frequency
`affected
`by metoprolol
`concentrations
`than
`M but
`was
`prolonged
`M (-)-
`(+)-metoprolol.
`Mean
`values
`minimum
`interstimulus
`interval
`to
`obtain
`equal
`magnitude
`of
`contractions
`in
`response
`all
`stimuli
`before
`and
`after
`with
`treatment
`±42
`385
`and
`were
`354±52
`msec
`(-)-isomer
`before
`those
`4),
`respectively,
`and
`and
`=
`were
`the
`treatment
`with
`(+)-isomer
`342
`respectively.
`and
`381
`57 msec
`3),
`(N
`±
`positive
`inotropic
`effect
`of
`isoproterenol
`with
`significantly
`attenuated
`treatment
`was
`(-)-metoprolol
`concentrations
`of
`10_8 M or
`
`and
`p(cid:1),
`were
`
`by
`
`(+)-metoprolol
`values
`of
`7.79,
`
`(-)-,
`and
`
`7.34
`
`5 x 10_6 M.
`above
`(+)-meto-
`and
`(±)-
`5.36,
`respectively
`
`(ta-
`
`higher
`Avearge
`prolol
`ble
`
`1).
`isolated
`of metoprolol
`Effects
`of pulmonary
`strips
`Helically
`cut
`arteries.
`were
`neither
`mesenteric
`arteries
`superior
`and
`(±)-metoprolol
`nor
`tracted
`relaxed
`by
`(-)-
`M.
`prostaglandin
`In
`in concentrations
`to
`i0(cid:1)
`up
`metoprolol
`F(cid:1)-contracted
`strips,
`arterial
`i05
`M produced
`a slight contraction.
`pulmonary
`arteries
`contracted
`In
`taglandin
`x
`F(cid:1)(3
`10_7_10_6
`M),
`in
`isoproterenol
`concentrations
`i(i(cid:1)
`to
`10_6 M caused
`a dose-related
`mm
`Treatment
`for
`30
`with
`(10_6_2
`10-’
`M)
`shifted
`curve
`isoproterenol
`to
`dependent
`manner,
`whereas
`(+)-isomer
`were
`relaxations
`terenol
`significantly
`attenuated
`
`on
`
`the
`
`x
`
`of
`
`rabbit
`and
`con-
`
`above
`
`pros-
`of
`from
`n.
`
`dose-
`M
`
`with
`addition
`the
`ranging
`relaxatk
`(-)-metoprok.l
`dose-response
`right
`in
`a
`only
`at
`iO(cid:1)
`induced
`by
`isopro-
`(fig.
`2). Average
`
`the
`
`by
`four
`out
`
`in
`slightly
`
`i0(cid:1)
`
`and
`
`of
`
`0.26
`
`g.
`to
`
`=6)
`iO-(cid:1)
`
`N
`to
`by
`
`(+)-
`The
`increas-
`was
`not
`lower
`i0(cid:1)
`the
`the
`to
`the
`
`at
`
`of
`
`(N
`after
`63
`±
`
`The
`
`=
`
`by
`
`in
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1033-5
`IPR2016-00379
`
`

`
`316
`
`Todaetal.
`
`Vol. 207
`
`(-)-,
`4.99,
`obtained
`and
`
`(+)-metoprolol
`and
`(±)-
`(table
`respectively
`in mesenteric
`(+)-isomers
`(±)-Propranolol
`more
`potent
`the
`response
`
`were
`1). Similar
`arteries:
`pA2
`were
`6.18
`and
`was
`approxi-
`(-)-meto-
`than
`of pulmonary
`
`arteries,
`was
`
`the
`shifted
`The
`
`dose-
`
`to
`pA2
`(7.60)
`(ta-
`dog
`
`in
`
`with
`values
`
`did
`
`were
`
`(5
`acetylcholine
`relaxation
`of
`the
`concentra-
`these
`in-
`relaxation
`and
`9.8
`± 2.6
`and
`the
`values
`and
`40.5
`2.7
`±
`lower
`concentra-
`alter
`tracheal
`
`x
`
`±
`
`the
`
`contracted
`strips
`cheal
`average
`M):
`10_7_10_6
`in
`(-)-metoprolol
`by
`induced
`maximum
`to
`the
`relative
`tions
`M papaverine
`by
`iO(cid:1)
`duced
`± 4.3% (N =
`6),
`respectively,
`35.7
`(+)-metoprolol
`were
`11.3
`with
`3.4% (N = 4),
`respectively.
`The
`tions
`of metoprolol
`not
`muscle
`tension.
`Isoproterenol
`lated
`relaxations
`with
`acetylcholine.
`isoproterenol
`ment
`with
`5
`x
`i0(cid:1)
`above
`(-)-,
`
`M)
`
`in
`
`elicited
`(10-(cid:1)-10-’
`tracheal
`strips
`of
`The
`dose-response
`right
`shifted
`to
`the
`was
`(-)-metoprolol
`concentrations
`M or
`higher
`by
`(+)-metoprolol
`and
`of
`10-’ M (fig.
`3). Average
`pA2
`values
`and
`(+)-metoprolol
`were
`7.29,7.19 and
`
`dose-re-
`contracted
`curve
`by
`treat-
`
`of
`
`of
`
`2 x
`(±)-
`
`rabbit
`
`in
`
`tra-
`
`a)
`a
`
`0 C a
`
`)
`
`IA
`
`UC
`
`of
`values
`pA2
`and
`6.50,6.32
`were
`results
`of
`values
`(-)-
`respectively.
`4.86,
`times
`2000
`mately
`in attenuating
`prolol
`to
`isoproterenol.
`arteries
`isolated
`rabbit
`In
`of
`curve
`response
`by
`5 x
`the
`right
`10(cid:1)
`appreciably
`value
`was
`and
`than
`in
`pulmonary
`were
`ble
`1). PA2
`values
`rabbit
`(7.81,
`9)
`and
`N
`Effects
`of metoprolol
`tracheal
`strips.
`The
`concentrations
`10-’
`
`=
`
`of
`
`addition
`and
`
`i0(cid:1)
`
`coronary
`isoproterenol
`M (-)-metoprolol.
`greater
`in coronary
`mesenteric
`arteries
`almost
`identical
`coronary
`arteries.
`on
`isolated
`of metoprolol
`M relaxed
`
`G.P-Atria
`(12)
`O
`ControL
`(5)
`Sl-4-MP5X1O-8M
`I(cid:1).--MP
`2X10-7M (11)
`X(cid:1)-i-MP1O-6M
`(8)
`
`100r
`
`G.P-Trachea
`O Control
`(11)
`(4)
`Si-e-MP2X1O-7M
`L(cid:1)-,-MP10-6M
`(4)
`(7)
`X I-)-MP 5X10-6M
`A(cid:1)--MP
`2X10-5M (8)
`
`0
`
`C0 0 a
`
`)
`
`io-9
`
`io-8
`
`i(cid:1)-(cid:1)
`
`iO-6
`
`io-(cid:1)
`
`10-10
`
`iO-8i0-7i0-6i0-5
`
`Conc.
`
`of
`
`ISO
`
`(M)
`
`Conc.
`
`of
`
`ISO
`
`(M)
`
`of
`
`and
`405
`
`(MP)
`4. Modification
`FIg.
`(-)-metoprolol
`by
`histamine.
`with
`contracted
`were
`Tracheal
`strips
`in control
`absolute
`values
`as
`100%;
`mean
`123 mg (N =
`11),
`728
`tracheas
`were
`±
`106 mg
`(N =
`8),
`respectively
`549
`7)
`and
`±
`x
`in control
`and metoprolol
`isoproterenol
`(N -
`(N =
`12),
`4 beats/mm
`beats/mm
`142
`±
`8),
`respectively
`(for
`figure).
`The maximum
`right
`mean
`absolute
`values
`in control
`and metoprolol
`12),
`128
`5 beats/mm
`(N =
`beats/mm
`(N =
`±
`8),
`respectively.
`
`(5
`
`±
`(for
`1 0(cid:1),
`5),
`
`of guinea-pig
`responses
`relaxations
`Maximum
`(2
`x
`1 0(cid:1),
`metoprolol
`135 mg (N =
`4),
`left
`figure).
`Mean
`2 x
`1 0(cid:1)
`and
`129
`8 beats/mm
`±
`rate
`increase
`induced
`(5
`x
`x
`1 0(cid:1),
`1 O(cid:1)
`2
`5),
`122
`5 beats/mm
`±
`
`433
`values
`106
`
`atria
`induced
`1 0-6,
`±
`
`and
`by
`5 x
`94 mg
`of
`the
`M)-treated
`and
`(N =
`11)
`by
`isoproterenol
`and
`M)-treated
`10-6
`and
`120
`(N =
`11)
`
`to isoproterenol.
`strips
`tracheal
`1 O(cid:1) M papaverine
`were
`taken
`10-6
`and
`2
`x
`M)-treated
`(N =
`4),
`664
`163 mg
`(N =
`atrial
`rate
`before
`the
`addition
`of
`preparations
`were
`128
`7
`±
`120
`8 beats/mm
`(N =
`±
`was
`taken
`100%;
`atria were
`126
`±
`4 beats/mm
`(N -
`
`1 0(cid:1)
`±
`
`as
`
`4
`
`±
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1033-6
`IPR2016-00379
`
`

`
`1978
`
`Selective
`
`Beta
`
`Blocking
`
`Action
`
`of Metoprolol
`
`317
`
`of
`
`(-)-metoprolol
`muscles
`isolated
`
`in atria,
`from
`
`2
`TABLE
`values
`Mean
`pA2
`and tracheal
`aortae
`pigs
`guinea
`in parentheses
`used. Figures
`N, number
`of preparations
`In aortic
`strips,
`range of mean value ± SE.
`indicate
`the
`of
`isoproterenol
`were obtained
`curves
`in
`dose-response
`control media and
`(N = 3) or
`in the presence
`of 2 x 10-f
`10(cid:1) M metoprolol
`(N = 3);
`from mean values
`of
`the two
`ratios
`the pA(cid:1) value was obtained.
`dose
`
`(-)
`
`- Metoprolol
`
`Prepara-
`tions
`
`Atrium
`Aorta
`Trachea
`
`N
`
`12
`3
`9
`
`pA,
`
`7.93
`6.79
`6.25
`(6.13-6.42)
`
`Slope
`
`-0.89
`-1.02
`-1.07
`
`Conc.
`ratio”
`
`1
`14
`48
`
`a Concentration
`other
`preparations)).
`
`respectively
`4.82,
`approximately
`loL
`
`ratio,
`
`antilog
`
`((pA5
`
`in atria)
`
`(pA,
`
`in
`
`-
`
`(table
`twice
`
`as
`
`(±)-Propranolol
`1).
`potent
`as
`(-)-metopro-
`
`was
`
`of
`
`(3
`
`by
`
`differ
`
`atria
`
`of
`
`Effects
`(-)-metoprolol
`and
`tracheal
`aortae
`atria,
`(-)-metoprolol
`of
`values
`pA2
`did
`not
`strips
`tracheal
`of
`(-)-metroprolol
`onisms
`on
`guinea-pig
`terenol
`were
`compared.
`muscles
`isoproter-
`of
`effect
`positive
`chronotropic
`The
`significantly
`atria was
`on
`enol
`guinea-pig
`treatment
`with
`iO-(cid:1) M (-)-metoprolol.
`by
`duced
`strips
`contracted
`with
`prostaglandin
`In
`aortic
`F(cid:1),
`the
`isoproterenol-induced
`relaxation
`was
`2 x
`by
`(-)-metoprolol
`above
`iO(cid:1)
`tenuated
`The
`dose-response
`curve
`isoproterenol
`guinea-pig
`tracheal
`strips
`contracted
`x
`tamine
`10_(cid:1)-.10(cid:1)
`M)
`was
`shifted
`right
`10_6 M (-)-metoprolol
`(fig.
`average
`pA2
`value
`of
`(-)-metoprolol
`(7.93) was
`markedly
`greater
`than
`aortae
`(6.79)
`and
`tracheal
`strips
`
`guinea-pig
`on
`muscles.
`in rabbit
`appreciably,
`actions
`tracheal
`
`to
`and
`
`of
`
`Since
`and
`antag-
`isopro-
`smooth
`
`atria
`
`re-
`
`in
`2).
`
`at-
`M.
`in the
`his-
`the
`The
`atria
`
`with
`to
`4).
`in
`values
`(table
`
`the
`(6.25)
`
`Discussion
`
`study
`present
`The
`the
`attenuated
`atria
`rabbit
`than
`extent
`of pulmonary
`propranolol
`while
`receptor
`beta
`results
`obtained
`those
`identical
`with
`including
`humans
`pigs
`(present
`study;
`
`lot
`lated
`greater
`relaxation
`strips,
`selective
`These
`not
`are
`species,
`guinea
`
`(-)-metopro-
`that
`revealed
`isoproterenol
`on
`effect
`of
`and
`tracheal
`muscles
`the
`isoproterenol-induced
`arterial
`and mesenteric
`such
`failed
`to
`show
`tissues.
`blockade
`in these
`in
`rabbit
`preparations
`obtained
`from
`(Harms,
`1976)
`Harms,
`1976),
`
`iso-
`to
`
`a
`
`a
`
`other
`and
`in that
`
`and
`
`is
`
`20
`in
`
`adrenoceptors
`beta
`to metoprolol
`practolol,
`similar
`
`et
`guinea
`and
`
`in
`al.,
`
`Patil,
`for
`
`has
`
`al.,
`1972;
`of
`
`7.4
`
`the
`In
`
`doses
`
`receptors
`of
`isoprotere-
`much
`less
`than
`asthma
`al.,
`These
`findings
`1975).
`beta
`ad-
`difference
`(hu-
`exist
`may
`muscles
`the
`and
`rabbit)
`pig
`vs.
`beta
`agents
`blocking
`of
`an
`assumption
`Such
`on
`the
`basis
`that
`of practolol
`activity
`times
`greater
`650
`is only
`16 times
`muscles
`(Bristow
`
`et
`(Ablad
`species
`the
`tracheal
`guinea
`action
`species.
`evidence
`the
`beta
`blocking
`the
`atria is approximately
`in
`aortae
`in
`tracheal
`
`that
`
`of
`
`and
`
`different
`by
`
`that
`
`in
`
`but
`
`in
`suf-
`in-
`
`of
`
`more
`markedly
`cardiac
`are
`beta
`recep-
`tracheal
`than
`sensitive
`beta1
`a
`known
`selective
`With
`tors.
`cardioselective
`blockade
`antagonist,
`dogs
`(Levy
`Wilkenfeld,
`and
`been
`observed
`et
`1975),
`cats
`(Apperley
`1969;
`Daly
`pigs
`(Baird
`and
`Linnell,
`1976)
`and
`1971).
`The
`pA2
`values
`Buckner
`guinea-pig
`atrial
`and
`tracheal
`(-)-metoprolol
`beta
`obtained
`in
`the
`present
`adrenoceptors
`respectively)
`are
`in reason-
`6.25,
`study
`(7.93
`and
`of
`the
`values
`(±)-metopro-
`with
`able
`agreement
`and
`(7.43
`6.06,
`respec-
`in literatures
`lol
`reported
`6.3,
`and
`quoted
`from
`tively,
`by Harms,
`1976;
`to Harms
`(1976),
`the
`Harms’
`paper).
`According
`trachea
`seem
`to
`be
`fairly
`guinea-pig
`atrium
`and
`good
`models
`for
`study
`of
`cardioselectivity
`human
`tissues.
`fact,
`metoprolol
`in
`beta
`ficient
`to
`suppress
`cardiac
`bibited
`the
`bronchodilator
`effect
`in
`not
`patients
`with
`propranolol
`indicate
`renoceptors
`man,
`cat
`organ-selective
`varies
`in
`is
`supported
`KB values,
`in rabbit
`activity
`than
`the
`than
`greater
`et
`al.,
`1970).
`potentiates
`hydrocortisone
`with
`Treatment
`inotropic
`effect
`chronotropic
`and
`positive
`the
`of
`isoproterenol
`effect
`the
`also
`and
`vasodilating
`due
`possibly
`1969; Kaumann,
`1972),
`(Kalsner,
`an
`interference
`with
`extraneuronal
`uptake
`Salt,
`(Iversen and
`1970).
`Preliminary
`using
`rabbit
`atria and mesenteric
`arterial
`treated
`with
`hydrocortisone
`indicated
`organ
`selectivity
`of metoprolol
`was
`appre-
`ciably.
`and
`preparations
`rabbit
`In
`atria, tracheal
`effective
`always
`more
`(-)-metoprolol
`was
`teries,
`than
`of
`isoproterenol
`in antagonizing
`action
`the
`that
`demonstrated
`the
`(+)-isomer.
`has
`been
`It
`potent
`times
`more
`to
`(-)-propranolol
`is 60
`100
`the
`chronotropic
`(+)-isomer
`than
`the
`in blocking
`of
`anesthetized
`and
`vasodepressor
`response
`and
`dogs,
`cats
`(Howe
`Shanks,
`1966)
`isoproterenol
`and
`Cullum,
`1968)
`to
`(Barrett
`the
`chronotropic
`response
`isolated
`rabbit
`of
`to
`isoproterenol
`(Whitsitt
`and
`Lucchesi,
`times
`(-)-Sotalol
`to
`30
`more
`active
`the
`(+)-isomer
`attenuating
`the
`inotropic
`
`the
`
`study
`strips
`
`the
`
`that
`altered
`
`not
`
`to
`
`ar-
`
`rats
`and
`atria
`1967).
`than
`re-
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1033-7
`IPR2016-00379
`
`

`
`318
`
`Todaetal.
`
`Vol. 207
`
`properties
`ToxicoL
`E. AND
`
`macological
`Acts
`Pharmacol.
`B., CARLSSON,
`Arn(cid:1)AD,
`two
`of
`new
`carclioselective
`107-119,
`12:
`onists.
`Life
`Sci.
`Ax#{231}(cid:1).su,A.: The
`physiologic
`tics
`of
`the
`tracheal
`muscle.
`122:
`201-207,
`1959.
`G. H., D(cid:1)ux,
`APPERLEY,
`of
`
`of metoprolol
`animals
`in
`36:
`7-23,
`1975.
`suppi.
`EK, L: Pharmacological
`beta-receptor
`adrenergic
`1973.
`characteris-
`pharmacologic
`mt.
`Pharmacodyn.
`Th#{233}r.
`
`and
`
`man.
`
`studies
`antag-
`
`and
`Arch.
`
`M.
`
`J.
`
`AND
`
`LEVY,
`
`G. P.: Selectivity
`
`and
`
`on bronchial,
`anesthetized
`
`the
`
`skel-
`cat.
`
`antagonists
`muscle
`in
`235-246,
`1976.
`Some
`H.
`0.:
`SCHILD,
`J. PharmacoL
`Brit.
`
`quantitative
`14:
`48-58,
`
`and
`
`spouse
`nol
`
`of
`(Levy,
`
`isolated
`1968).
`
`of
`
`to
`study,
`
`isoprotere-
`the
`
`po-
`
`to
`
`atna
`left
`rabbit
`In
`the
`present
`was
`to
`(+)-metoprolol
`ratio
`tency
`300
`(-)-
`380 in
`preparations,
`and
`tracheal
`rabbit
`atnai
`pulmonary
`to
`20
`30
`in
`was
`the
`ratio
`while
`difference
`A significant
`mesenteric
`arteries.
`of
`propranolol,
`tween
`stereoselectivities
`and
`on
`atrial
`olol,
`practolol
`or
`beta
`been
`also
`cyte
`has
`adrenoceptors
`al.,
`et
`It may
`1977).
`strated
`(Harms
`concluded
`that
`beta-adrenoceptors
`atria
`and
`tracheal
`differ from
`muscles
`arterial
`smooth
`muscles,
`with
`respect
`that
`interacts
`with
`the
`beta-hydroxy
`the
`long
`side
`chain
`of metoproloL
`sufficient
`Metoprolol
`in
`concentrations
`of
`rabbit
`tenuate
`significantly
`the
`relaxation
`isoproterenol
`by
`onary
`arterial
`induced
`of pulmonary
`failed
`to
`inhibit
`response
`value
`of
`(-)-meto-
`mesenteric
`arteries.
`The
`pA2
`prolol
`rabbit
`coronary
`arteries
`was
`approxi-
`in
`mately
`same
`as
`the
`values
`dog
`coronary
`the
`in
`arteries
`also
`in
`rabbit
`left
`right
`atria.
`and
`and
`Similar
`selective
`antagonism
`practolol
`has
`by
`et al.,
`been
`demonstrated
`in isolated
`(Baron
`dog
`1972)
`and
`pig
`arteries
`(Drew
`and
`Levy,
`coronary
`1972;
`however,
`other
`authors
`1973);
`Johansson,
`have
`come
`to
`conclusion
`with
`isolated
`opposite
`al.,
`pig
`coronary
`(Bayer
`1974).
`arteries
`rabbit
`The
`rate
`and
`contractility
`isolated
`atria
`and
`tone
`of
`tracheal
`and
`pulmonary
`the
`arterial
`were
`not
`altered
`(-)-meto-
`muscles
`by
`in
`prolol
`concentrations
`sufficient
`attenuate
`to
`significantly
`the
`of
`isoproterenol
`action
`(10’-10(cid:1)
`M). With
`high
`concentrations
`very
`(10(cid:1)’(cid:1) M or higher),
`both
`and
`(+)-metoprolol
`(-)-
`slightly
`attenuated
`the
`contractile
`force,
`slowed
`the
`atrial
`rate
`relaxed
`the
`tracheal
`muscle
`and
`contracted
`with
`acetylcholine.
`In
`anesthetized,
`reserpine-treated
`cats,
`metoprolol
`produces
`those
`effect
`in
`doses
`above
`far
`cardiodepressant
`et
`al.,
`beta
`eliciting
`cardiac
`blockade
`(Ablad
`observed
`that
`1973).
`These
`findings
`suggest
`the
`block-
`the
`with
`not
`associated
`changes
`are
`action.
`depressant
`ing
`action
`but
`with
`a direct
`In
`cardiac
`and
`tracheal
`muscles,
`a membrane-
`stabilizing
`action
`of metoprolol
`if
`any,
`slight.
`
`nifenalol
`
`strips
`the
`
`to
`
`et
`of
`
`and
`be-
`alpren-
`adipo-
`demon-
`thus
`rabbit
`those
`the
`group
`
`be
`
`in
`site
`in
`
`in
`
`to
`
`at-
`cor-
`
`and
`
`a
`
`beta
`
`is,
`
`only
`
`Acknowledgments
`
`(+)-
`(-)-,
`by Ciba-Geigy
`
`and
`
`(±)-metoprolol
`(Japan)
`Ltd.
`
`References
`
`hydrochloride
`
`were
`
`provided
`
`K. 0.,
`B., BORG,
`ABLAD,
`CAELSSON,
`T. AND
`MALMFORS,
`REGARDH,
`
`E., EK, L,
`C.-G.: A survey
`
`JOHNSBON,
`of
`the
`
`G.,
`phar-
`
`of
`
`Circ.
`
`(cid:1)-adrenoceptor
`agonists
`and
`et.al,
`cardiac
`vascular
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`57:
`Brit.
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`ARUNLARSHANA,
`AND
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`of
`drug
`antagonists.
`1959.
`J. R. C. AND
`of(cid:1)-adren-
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`J.: The
`LINNELL,
`BAHW,
`in vitro
`cardioselectivity
`and
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`blocking
`oceptor
`1972.
`24:
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`Pharmacol.
`J. Pharm.
`in vivo.
`SPEDEN,
`R. N. AND
`BAN0N,
`G. D.,
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`coronary
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`skeletal
`muscle
`arteries.
`receptors
`in
`nergic
`J. Physiol.
`223:
`878-881,
`1972.
`Amer.
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`A. F., DUNLOP,
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`L H.: Cardio-selective
`G. AND
`SMrnI,
`Schmiedeberg’s
`Arch.
`PharmacoL
`A. M. AND CULLUM, V.A.:
`BAluus’r,
`of
`the
`optical
`of propranolol
`isomers
`J. Pharmacol.
`cardiac
`Brit.
`arrhythmias.
`BAYER,
`B.-L,
`P. AND
`MEie’rz,
`FORSTER,
`in coronary
`adrenoceptors
`of
`the
`58-65,
`29:
`1974.
`Pharmacol.
`T. R. AND
`M.,
`SHERROD,
`BRISTOw,
`drug
`receptor
`beta
`interactions
`and
`aorta,
`stomach
`trachea.
`1970.
`52-61,
`C. K. AND
`BUCKNER,
`PATIL,
`XVI.
`Beta
`drugs.
`adrenergic
`trachea.
`J.
`and
`Pharmacol.
`DALY, M. J., FL0OK,
`J. J. AND
`antagonists
`$-adrenoceptor
`responses
`to
`chodilator
`J. Pharmacol.
`dog.
`Brit.
`DREw,
`G. M. AND
`LEVY,
`nary
`vascular
`/3-adrenoceptor
`46:
`348-350,
`1972.
`D. AND
`SIIANICs,
`DUNLOP,
`beta
`oceptive
`receptors
`1968.
`201-218,
`R F.:
`strips
`Spirally-cut
`FuRCHoOrr,
`of arterial
`studies
`vitro
`of
`responses
`ods Med.
`Res.
`8:177-186,
`1960.
`H. H.:
`Isoproterenol
`antagonism
`HARMS,
`agents:
`blocking
`beta
`adrenergic
`receptor
`cardiac
`and
`study
`of human
`and
`guinea-pig
`J.
`PharmacoL
`Exp.
`adrenergic
`receptors.
`329-335,
`1976.
`J.: Differentiation
`H. H., ZAAGSMA,
`J. AND
`DE VENTE,
`HAluss,
`and adipose
`of
`f(cid:1)-adrenoceptors
`in right
`atrium,
`diaphragm
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