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Eur J Clin Pharmacol (1990) 38: S 82-S 88

EuropeanJournalof ~ @ ~

@ Springer-Verlag 1990

The pharmacology of carvedilol


R. R. Ruffolo Jr, M. Gellai, J. R Hieble, R. N. Willette, and A. J. Nichols
Department of Pharmacology, Smith Kline Beecham, p. 1.c., King of Prussia, Pennsylvania,USA

Summary. Carvedilol is a potent antihypertensive agent Carvedilol (Fig. 1) is a potent antihypertensive agent in
with a dual mechanism of action. At relatively low concen- animals (Sponer et al. 1987) and in humans (Eggertsen et
trations it is a competitive [3-adrenoceptor antagonist and al. 1987; Sundberg et al. 1987). Studies on its mechanism of
a vasodilator, whereas at higher concentrations it is also a action indicate that the compound is a [3-adrenoceptor an-
calcium channel antagonist. The antihypertensive activity tagonist and a vasodilator, and both of these activities con-
of carvedilol is characterized by a decrease in peripheral tribute to the antihypertensive response produced by the
vascular resistance, resulting from the vasodilator activity compound. The reduction in blood pressure produced by
of the compound, with no reflex tachycardia, as a result of carvedilol is associated with a decrease in peripheral vas-
[3-adrenoceptor blockade. The antihypertensive activity cular resistance, indicative of arterial vasodilation (Eg-
of carvedilol is associated with an apparent "renal spar- gertsen et al. 1987; Strein et al. 1987; Sundberg et al. 1987),
ing" effect in that the reduction in mean arterial blood and the lack of reflex tachycardia is a consequence of the
pressure does not compromise renal blood flow or urinary [3-adrenoceptor blocking properties of the compound
sodium excretion. Studies on the mechanism of action of (Eggertsen et al. 1987).
carvedilol indicate that the compound is a potent compe-
titive antagonist of [~1-and [32-adrenoceptors with a disso- OH
ciation constant (KB) of 0.9 nM at both ~-adrenoceptor I
O-CH2-CH-CH2-NH-CH2CH20~
subtypes. Carvedilol is also a potent c~l-adrenoceptor an- * >=/
tagonist (KB = 11 nM), which accounts for most, if not all,
of the vasodilating response produced by the compound.
At concentrations above 1 gM, carvedilol is a calcium
channel antagonist. This activity can be demonstrated in H
vivo at doses that represent the higher end of the anti- Fig.L Chemical structure of carvedilol. The asterisk denotes the
hypertensive dose-response curve. Although the calcium- point of asymmetry
channel blocking activity of carvedilol may not contribute
to the antihypertensive activity of the compound, it may
play a prominent role in certain peripheral vascular beds, 200 450

such as the cutaneous circulation, where marked increases I


E c
in blood flow are observed. The data indicate that carve- E
LO0
dilol is an antihypertensive agent that is both a [3-adreno- tn
150
ceptor antagonist and a vasodilator. The vasodilating ac- ffl
cq
tivity of carvedilol results largely from cq-adrenoceptor u- 350
c~
blockade, and its [~-adrenoceptor blocking activity pre- ._o
vents reflex tachycardia. In some regional vascular beds, L- 100
O
such as the cutaneous circulation, the calcium-channel O 300
blocking activity of carvedilol may be responsible for in- "r

creasing the blood flow.


50 i ~ ~ ~ ~,~, ~ , ~J 250
Vehicle 1 10 100
Key words: carvedilol, [~-adrenoceptor antagonist, al- Dose of carvedilol (mg/kg. oral)
adrenoceptor antagonist, vasodilator, calcium channel Fig.2. Dose-response relationship for the antihypertensive and
antagonist, antihypertensive agent chronotropic effects of carvedilol in conscious, spontaneously
hypertensive rats. • Heart rate; [ ] mean aortic pressure
R. R. Ruffolo et al.: The pharmacology of carvedilol S 83
180 180
z 160 I 160
E E
E 140 E 140
(3_ O_
< 120 < 120
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9.0

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-- 14
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I I I I I IEIII[ I I I lillll I I I I I tlllll J I t J~ltJt

Vehicle 1 10 100 Vehicle 1 10 100


Dose of carvedilol (mg/kg, oral) Dose of carvedilot (mg/kg, oral)

Fig.& The effect of carvedilol on cardiac output (CO) and total Fig.& Effects of carvedilol on renal blood flow (RBF) and renal
peripheral resistance (TPR) throughout the entire antihypertensive vascular resistance (RVR) throughout the antihypertensive dose-
dose-response curve in conscious, spontaneously hypertensive rats response curve in conscious, spontaneously hypertensive rats

The mechanism(s) of action responsible for the va- gonists that decrease the heart rate and cardiac output and
sodilator activity of carvedilol has not been completely increase total peripheral vascular resistance (Ruffolo
established, inasmuch as this compound has a variety of 1988).
pharmacologic actions over a wide range of concentra- The effects of carvedilol on renal hemodynamics in
tions (Sponer et al. 1987; Strein et al. 1987). It has been conscious, spontaneously hypertensive rats are presented
proposed that the vasodilation produced by carvedilol re- in Fig. 4. Throughout the antihypertensive dose range for
sults from nonspecific relaxation of vascular smooth carvedilol, renal blood flow remains relatively stable, indi-
muscle, selective cq-adrenoceptor blockade, calcium cating that renal autoregulatol 7 integrity is unaffected by
channel blockade, and/or some combination of these ac- carvedilol. As shown in Fig. 5, sodium excretion does not
tions. In this manuscript we review the pharmacologic ac- change during sustained i. v. infusion of carvedilol, indicat-
tivities of carvedilol in a variety of in vivo and in vitro test ing an important "renal sparing" effect. This is in marked
systems, with emphasis on the mechanism of action of car- contrast to another [3- and C~l-adrenoceptor antagonist,
vedilol as an antihypertensive agent. labetalol, which significantly decreases sodium excretion,

1.2
A n t i h y p e r t e n s i v e activity o f carvedilol

The antihypertensive activity of carvedilol in conscious, a~ 1.0


ED
o
T
spontaneously hypertensive rats is shown in Fig.2. The
dose-dependent reduction in mean arterial blood pres- 'c 0.8
sure produced by carvedilol is not associated with reflex E
activation of sympathetic outflow to the myocardium that ~0.6
leads to tachycardia. In fact, throughout the entire dose- c
response curve for the antihypertensive effect of carvedi- .2
"~ 0.4
1ol, the heart rate remains relatively stable. i_
u
x
The systemic hemodynamic effects of carvedilol are Iii

depicted in Fig. 3 and are consistent with two mechanisms o 0.2


z
of action, namely, [3-adrenoceptor blockade and vasodila-
tion. The reduction in mean arterial blood pressure pro- CarvediloL Labetal01
duced by carvedilol results largely from a vascular effect,
since cardiac output, like the heart rate, remains relatively Fig.5. Effect of sustained i.v. infusion of equieffective antihyper-
tensive doses of carvedilol and labetalolol on sodium excretion in
constant and total peripheral vascular resistance declines conscious, spontaneously hypertensive rats. [ ] Control; ~] sus-
in parallel with blood pressure. This hemodynamic profile tained drug infusion (10 gg kg ~min-~). * Significantly different
of carvedilol is distinct from that of ~3-adrenoceptor anta- from control (P < 0.05)
S 84 R. R. Ruffolo et al.: The pharmacology of carvedilol
120 of Arunlakshana and Schild (1959) gives a Schild regres-
sion with a slope of 1.1, which is not significantly diffe-
rent from the theoretical value of unity, indicating that
lOO o/ -',,,~/" .a.';,t
blockade is competitive in nature (Ruffolo 1982). The pA2
value obtained from the Schild regression is 9.03 + 0.17,
.~ 80 which corresponds to a dissociation constant (KB) of
E 0.9 nM.
60 In pithed, normotensive rats, carvedilol (0.3 mg/kg
i.v.) produces a parallel rightward displacement of the 131-
adrenoceptor-mediated, positive chronotropic response
40 to isoproterenol (data not shown). This dose of carvedilol,
which is associated with a significant reduction in mean ar-
terial blood pressure in spontaneously hypertensive rats,
results in a dose ratio of approximately 100-fold, demon-
/
strating pronounced 131-adrenoceptor blockade.
o 'r?,,,,g.+m'g,,~,,,,,,~,,,,,,,, ,,, ............. ,, ..................
10-10 10-9 10-8 10 -7 10 -6 10 -5 10 -z, 10-3 10-2
I s o p r o t e r e n o l (motar)
~2-Adrenoceptor blockade
Fig.6. The effects of various concentrations of carvedilol on the [~l-
adrenoeeptor-mediated, positive chronotropic response of isopro- Carvedilol produces a concentration-dependent inhibi-
terenol in isolated guinea pig atrium, n = 3-7. Q) Control; • car- tion of the 132-adrenoceptor-mediated relaxation induced
vedilol (3 x 10 9M), [] carvedilol (1 x 10 8 M); • earvedilol by isoproterenol in guinea pig trachea precontracted with
(3 x 10 -s M); A carvedilol (1 x 10 7 M ) ; • carvedilol (3 x 10 7 M)
i gM carbachol (Fig. 7). The antagonism of isoproterenol
by carvedilol is competitive, as evidenced by the concen-
tration-dependent, parallel rightward shifts in the isopro-
terenol concentration-response curves, with no significant
reduction in the maximal response. A Schild regression
based on these data provides a slope of 0.9, which is not sig-
nificantly different from unity, and a pA2 value of
9.03 + 0.12, which corresponds to a KB of 0.9 nM. This value
is identical to that obtained at [31-adrenoceptors and indi-
cates that carvedilol is a relatively nonselective 13-adreno-
ceptor antagonist.
oo_ A0 In the pithed rat, carvedilol (0.3 mg/kg i. v.) significant-
u3
0) ly inhibits the [32-adrenoceptor-mediated vasodilator re-
20 sponse of salbutamol, confirming in vivo the 132-adreno-
ceptor blocking activity observed in vitro. The dose ratio
0 -~e-~,n ,~,,, , .............. obtained at the half-maximal response of salbutamol is
10-8 10 -7 10-6 10 4 10 -~ similar to that observed for 131-adrenoceptors in the pithed
I s o p r o t e r e n o l (molar) rat, indicating that carvedilol does not discriminate be-
Fig.7. The effects of various concentrations of carvedilol on the ~2- tween 131-and 132-adrenoceptors in vivo.
adrenoceptor-mediated bronchodilation produced by isoproterenol
in carbachol-contracted (1 gM) guinea pig trachea, n = 3. Q) Con-
trol; • carvedilol (3 x 10 9 M); [] carvedilol (1 x 10-8 M); • car- (z-Adrenoceptor blockade
vedilol (3 x 10 8M)
oq-Adrenoceptor blockade

thereby leading to sodium retention, which is a common Carvedilol is a potent, competitive antagonist of ~l-
phenomenon among antihypertensive agents. adrenoceptors in vivo and in vitro. In isolated rabbit aorta,
the ~l-adrenoceptor-mediated vasoconstrictor response
to norepinephrine is antagonized in a concentration-de-
[3-Adrenoceptor blocking activity pendent manner by carvedilol, resulting in parallel right-
ward displacements in the norepinephrine concentration-
131-Adrenoceptor blockade response curves, with no change in the maximal response
(Fig. 8). Schild analysis of these data yield a straight line
Carvedilol is a potent antagonist of the 131-adrenoceptor- with a slope of 0.9 and a pA2 of 7.97 + 0.11, which corre-
mediated, positive chronotropic response to isoprotere- sponds to a KB of 11 nM. These results indicate that car-
nol in the guinea pig atrium. As shown in Fig. 6, carvedilol vedilol is approximately 1 order of magnitude less potent
produces concentration-dependent, parallel rightward as an (zl-adrenoceptor antagonist than as a 13-adrenocep-
displacements of the concentration-response curve to iso- tor antagonist.
proterenol, with no significant effect on the maximal chro- At an established antihypertensive dose, carvedilol
notropic response. Analysis of these data by the technique (0.3 mg/kg i.v.) significantly antagonizes the (zl-adreno-
R. R. Ruffolo et al.:The pharmacology of carvedilol S 85

1/.0
"~ 10 0, y___....~O
t3

L-

100 /; E 8O
O
O

80 x-" 60
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0J 40
C
O
cn

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n i i 1111111 r r [111111 i i i [11111

10-7 10-6 10-s 10-~


~ I [ i IIIIHI I I [111111

10 10 10 6 10 5 10 ~ 10-3
Carvedilol (molar)
Norepinephrine (molar) Fig. 9. Concentration-dependent relaxation produced by carvedilol
in potassium-depolarized rat uterus, n = 4
Fig.& Effects of various concentrations of earvedilo] on (z~-adreno-
ceptor-mediated vasoconstriction produced by norepinephrine in
isolated rabbit aorta, n = 3-5. C) Control; • carvedilol (3 x 10-8 M);
[ ] carvedilol (1 × 10 -7 M); • carvedilol (3 x 10 7M) sponse that results from the opening of calcium channels
associated with the cell membrane. Carvedilol produces a
concentration-dependent relaxation of the potassium-
ceptor-mediated vasopressor response to cirazoline in the depolarized rat uterus, with an EDs0 of 7.65 +_0.62 g M
pithed rat (data not shown). These results establish that (Fig. 9). Similar results are also obtained in potassium-
significant oq-adrenoceptor blockade occurs at antihyper- depolarized rabbit aorta (data not shown). Furthermore,
tensive doses of carvedilol in vivo, in spite of the fact that in rabbit aorta incubated in calcium-free buffer and de-
the C~l-adrenoceptor blocking activity of the drug is > 10- polarized with potassium (70 nM), a response to calcium
fold weaker than the corresponding ~3~-and 132-adrenocep- chloride can be observed that is sensitive to inhibition by
tor blockade. calcium channel blockers. At concentrations > 1 ~tM car-
vedilol significantly inhibits the calcium-induced contrac-
tile response in this tissue, with a 10-fold parallel right-
{~2-Adrenoceptorblockade ward displacement of the calcium concentration-response
curve being observed at a 10 ~tM concentration of the drug
Carvedilol inhibits the ~x2-adrenoceptor-mediated vaso- (Fig. 10).
constrictor response of B - H T 920 in the isolated canine The calcium-channel blocking activity of carvedilol
saphenous vein. This effect is noncompetitive, with high has also been demonstrated in vivo. In the pithed rat, the
doses of carvedilol depressing the maximal response to B- direct calcium channel activator, Bay-K-8644, produces a
H T 920, suggesting that the former has a complex action
at the ~2-adrenoceptor and/or its effector system (see
below). Electrophysiologic studies suggest only a weak in-
teraction of carvedilol with cza-adrenoceptors (Seki et al. 2OO
1988).

160
Calcium channel antagonism

120
At concentrations of ~>1 gM, carvedilol inhibits the {z2- E
adrenoceptor-mediated vasoconstrictor response to B-
H T 920 in canine saphenous vein in a noncompetitive 80
manner. Because c~2-adrenoceptor-mediated vasocon- c-
O
striction in this tissue is invariably dependent on the trans- D_
m

location of extracellular calcium (Nichols and Ruffolo 40


1988) and because no compelling evidence exists to sug-
/
gest that carvedilol interacts directly with (z2-adrenocep- 0 /-/o.,.,-r77~4, , ~ r Jr,,r, , , ~,~rr,'.
tors, it was hypothesized that carvedilol may be a calcium 10-5 10-~ 10-3 10 -2
channel blocker at these higher concentrations. Ca 2÷ (molar)
A series of experiments were performed to confirm Fig. 10. Effects of carvedilol on the calcium concentration-response
the hypothesis that carvedilol is a calcium channel anta- curve in potassium-depolarized rabbit aorta previously equilibrated
gonist. Depolarization of the rat uterus by potassium in calcium-free buffer, n = 3. Q) Control; • carvedilol (1 x 10-6 M);
(70 nM) produces a nifedipine-sensitive, contractile re- [ ] carvedilol (1 x 10 5M)
S 86 R. R. Ruffolo et al.: The pharmacology of carvedilol
8O 120
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Fig.ll. Effects of carvedilol and labetalol at equieffective anti- /
hypertensive doses (1 mg/kg i.v.) on mean arterial blood pressure 80
(MAP), heart rate (HR), cutaneous perfusion (CP),and cutaneous
vascular resistance (CVR). [] Labetalol (1 mg/kg, i.v.); [ ] carvedi-
lol (1 mg/kg, i.v.) 60

dose-dependent vasoconstrictor response that is inhibited 40


by calcium channel blockers. At a carvedilol dose of
i mg/kg i.v., which represents the higher portion of the 20 /
antihypertensive dose-response curve, the drug signifi-
cantly inhibits the vasoconstrictor response of Bay-K-
0 ~ 1111111 I I I IHIII I I I ] ]111 I [111111 I I IIIIIII
8644, thereby confirming in vivo that carvedilol is a cal- 10-9 104 10 -? 10-6 10-5 10-~
cium channel blocker. Isoproterenol (molar)
Although carvedilol can indeed block calcium chan-
nels, our studies do not suggest a prominent role for this Fig. 12. a The effects of S ( - )-carvedilol and b R ( + )-carvedilol in
activity in the antihypertensive response of the com- antagonizing the [31-adrenoceptor-mediated,positive chronotropic
pound. Thus, in spontaneously hypertensive rats pre- response of isoproterenol in isolated guinea pig atrium, n = 3.
a Q) Control; • S( - )-carvedilol (1 x 10 -9 M); [ ] S( - )-carvedilol
treated with propranolol and prazosin to block [3- and oq- (3 x 10-9 M); • S(-)-carvedilol (lx 10-8 M). b Q) Control;
adrenoceptors, carvedilol does not produce an additional • R ( + )-carvedilol (1 x 10 8M); [ ] R ( + )-carvedilol (3 x 10-8 M);
reduction in blood pressure, whereas the potent calcium • R ( + )-carvedilol (1 x 10-7 M)
channel antagonist nifedipine does (data not shown). Al-
though the calcium-channel blocking activity of carvedilol
may not play an important role in the antihypertensive re- flow. At doses of carvedilol and labetalol that produce
sponse of the compound, it may be of importance in in- equivalent reductions in mean arterial blood pressure and
creasing the blood flow in specific regional vascular beds heart rate, labetalol significantly reduces cutaneous blood
that do not contribute greatly to total peripheral vascular flow by over 20%, with no change in cutaneous vascular
resistance, such as the cutaneous circulation. resistance (Fig. 11). In marked contrast, carvedilol in-
creases cutaneous blood flow by over 60%, and this effect
results from a dramatic reduction in cutaneous vascular
Cutaneous circulation resistance. Because the cutaneous circulation is highly
sensitive to calcium channel blockers, it is tempting to
To determine whether its calcium-channel blocking activ- speculate that the decrease in cutaneous vascular resis-
ity (or some other as yet unidentified activity) is relevant tance produced by carvedilol but not by labetalol results
to the response to carvedilol, we compared the drug with from calcium channel blockade.
another compound known to possess combined [3- and o~l-
adrenoceptor antagonist properties, labetalol, in the cuta-
neous circulation. The effectiveness of calcium channel Enantiomers of carvediloi
blockers such as nifedipine in the treatment of peripheral
vascular disease in humans (Rodeheffer et al. 1983; Smith Carvedilol possesses one asymmetric carbon atom, giving
and McKendry 1982) suggests the strong involvement of rise to a single pair of enantiomers (Fig. 1). The racemic
extracellular calcium in the regulation of cutaneous blood mixture of carvedilol is being studied clinically. Racemic
R. R. Ruffolo et al.: The pharmacologyof carvedilol S 87

120 carvedilol results predominantly from the S ( - )-enan-


a) tiomer.
In contrast to the marked enantioselectivity observed
100
at [~l-adrenoceptors, S ( - ) - and R ( + )-carvedilol are
equipotent as (zl-adrenoceptor antagonists in rabbit aorta
80 (Fig. 13 A, B), with KB values against norepinephrine of 16
and 14 nM, respectively. Consistent with this observation,
the dose-response curve for the oq-adrenoceptor-medi-
6O ated pressor effect of cirazoline in pithed rats was shifted
6-fold in parallel and to the right with both the S ( - )- and
4O R ( + )-enantiomers of carvedilol (1 mg/kg i.v.).
-g The results demonstrate that the enantiomers of car-
D vedilol show marked stereoselective antagonism of ~1-but
._~
x
20 not oq-adrenoceptors. This represents an unusual instance
E in which enantiomers of an optically active drug differ not
only quantitatively in terms of potency (Ruffolo 1984) but
also qualitatively, in that they possess distinct pharmaco-
c- logic profiles. As such, neither enantiomer alone has the

/! //5¢-
O
o_ 100
tn
same pharmacologic profile as the racemic mixture of car-
00
n/ vedilol used clinically, since only the S ( - )-enantiomer of
carvedilol provides potent [3~-adrenoceptor blocking ac-
80
tivity, whereas both enantiomers contribute equally to the
vasodilation resulting from oq-adrenoceptor blockade. As
60
/ such, the most active enantiomer of carvedilol as a 131-
adrenoceptor antagonist [i.e., S(-)-carvedilol] is not
40
/ simply a 2-fold more potent form of the racemic mixture,
but rather is pharmacologically distinct from the racemic
mixture since the R (+)-enantiomer also contributes to
the oq-adrenoceptor blockade. This unusual phenomenon
20
occurs only rarely and is analogous to the situation that
exists for ( + )-dobutamine and its enantiomers (Ruffolo
IIIIHP I ~llHn I f IIHNt
0 ~
10-8 10-7 10-6 10-s 10-4 10-3 1987).
Norepinephrine (molar)

Fig.13. a The effects of S( - )-carvedilol and b R ( + )-carvedilol Conclusions


on the a,-adrenoceptor-mediated vasoconstrictor response to
norepinephrine in isolated rabbit aorta, n = 3 - 4 , a O Control;
The data accumulated to date indicate that carvedilol is a
O S( - )-carvedilol (1 x 10 7M); [] S( - )-carvedilol (3 x 10-7 M);
• S( - )-carvedilol (1 x 10 6M). b (~) Control; O R ( + )-carvedi- potent competitive antagonist of [~1-, 132-,and oq-adreno-
lol (1 x 10-7 M); [] R( + )-carvedilol (3 x 10-7 M); • R( + )-car- ceptors. In addition, it is a calcium channel blocker at
vedilol (1 x 10 6M) higher concentrations. The vasodilator activity of carvedi-
lol results primarily from ~l-adrenoceptor blockade, with
little or no contribution to the antihypertensive effect
R,S(+)-carvedilol is a competitive antagonist against being derived from calcium channel blockade. However,
131-adrenoceptors (KB = 0.9 nM) and al-adrenoceptors calcium channel blockade by carvedilol may be important
(KB = 11 riM), as described above. The enantiomers of in certain regional vascular beds, such as the cutaneous
carvedilol have also been evaluated as [31- and ~l-adre- circulation, where carvedilol is an extremely potent va-
noceptor antagonists to investigate stereoselectivity. sodilator. Throughout the antihypertensive dose range of
S (-)-Carvedilol is a potent 131-adrenoceptor antagonist carvedilol, reflex tachycardia is not observed, and this
in guinea pig atrium, with a KB of 0.4 nM (Fig. 12A), effect is due largely to the [31-adrenoceptor blocking
which is approximately 2-fold more potent than the property of carvedilol that results predominantly from the
racemic mixture. In contrast, as a 131-adrenoceptor an- S(-)-enantiomer. Although carvedilol is being de-
tagonist R(+)-carvedilol is approximately 100-fold veloped as a racemic mixture of the S ( - )- and R ( + )-en-
weaker than the S ( - )-enantiomer, having a KB of 45 nM antiomers, it is important to emphasize that the pharma-
(Fig. 12B). Accordingly, S ( - )-carvedilol (0.1 mg/kg i.v.) cologic profile of ( + )-carvedilol is not mimicked by either
produced a 25-fold rightward shift in the dose-response of the individual enantiomers, since only the S ( - )-en-
curve for the 131-adrenoceptor-mediated, positive chro- antiomer is a 131-adrenoceptor antagonist, whereas both
notropic effect of isoproterenol in pithed rats, whereas at enantiomers contribute equally to cq-adrenoceptor
a dose 10-fold that above (lmg/kg i.v.), the R ( + ) - blockade. We conclude that carvedilol is a unique anti-
enantiomer had no [31-adrenoceptor blocking activity hypertensive agent with several mechanisms of action, in-
(data not shown). Taken together, these results indicate cluding 13-adrenoceptor blockade and vasodilation. These
that the 131-adrenoceptor blocking activity of racemic combined mechanisms produce a reduction in blood
S 88 R. R. Ruffolo et al.: The pharmacology of carvedilol

pressure that is m e d i a t e d by a decrease in peripheral vas- Ruffolo RR Jr (1988) Cardiovascular adrenoceptors: physiology
cular resistance, with no c o m p e n s a t o r y increase in heart and critical care implications. In: Chernow B (ed) The pharmaco-
logic approach to the critically ill patient. Williams and Wilkins,
rate. Baltimore, pp 166-183
Seki N, NagaoT, Komori K, Suzuki H (1988) Alpha- and beta-
adrenoceptor blocking action of carvedilol in the canine mesen-
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