Bristow, Michael R.

Larrabee, Patti

Minobe, Wayne

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25OA ABSTRACTS JACC Voll. 17, No. 2 February 1991:25QA 
all F, West Concourse 
Clinical Pharmacology- 
MECHANISH OF ACTION OF CARVEDILOL IN HUMAN VBNTRICULAP. 
MYOCARDIUH. Wavne Minobg, Patti Larrabee, Michael R. 
Bristow. University of Utah, Salt Lake City, UT 
Caruedilol (C) is a new B-blocker/vasodilator that is 
undergoing clinical trial for heart failure treatment. 
Data from animal screens suggest that C is a non- 
selective g-blocking agent with vasodilator properties 
due to a-blockade. Because of species differences in 
animals vs human adrenergic receptor pharmacology, we 
have characterized the B- and a-blocking activity of C 
in preparations derived from nonfailing (NF) and failing 
(F) human ventricles and compared the results to the 
selective & blocking agent metoprolol (H) and the 
nonselective B blocker/vasodilator bucindolol (8). 
Results of radioligand-cold ligand competition curves 
(CC) performed in crude myocardial membranes with and 
without 3x10’?4 Gpp(NH)p (G) were: (values r SEM) 
6 ret CC: CUPJ~ IC,,.nH IC,,,nM Ka,nM K,,nM 1 alKI ,nM 
F C 
l..DiGlm i.falQp 
-72 12.2 135* . I . 
(69/31 n-10 2.04 28.9 +79 22.3 2102 k5.2 
B,/B,) H .58 3311 1107 11.9 3711 - 
n-5 k-10 +920 5767 f3.1 +203 
B .81 11.0 44.8* 5.4 - 249 
n-4 2.11 23.3 318.6 22.2 f125 
NF 
(84/16) :=A 
.90 14.2 24.1 7.5 - - 
2.02 +5.0 212.2 a.5 - - 
1) For C the B, receptor affinity (KH) is 
2.5 times > and the B,/B, selectivity ratio is 6 times 
< H. 2) As does 8, C exhibits an “agonist” binding site 
modulated by guanine nucleotides that does not confer 
ISA. 3) The a1 blocking activity of C is 23 fold > that 
of 8, and approaches the B, blocking activity of C. The 
selective B1 and a1 blocking properties of C presumably 
ex,lain why this agent is extremely well tolerated in 
subjects with advanced heart failure. 
EVIDENCE FOR PHOSPHODIESTERASE INHIBITORY ACTIVITY OF 
OPC 8490 IN THE FAILING HUMAN HEART. , 
Wayne Minobe, Matthew A. Movsesian, Judith Krall, 
George Peeters, Yutaka Eki, Michael R. Bristow. 
University of Utah, Salt Lake City, UT 
OPC 8490 is a water soluble quinolinone derivative 
whose properties in animei systems include positive 
inotropic effects and prolongation of action potential. 
Various mechanisms of action for the positive inotropic 
response of the quinolinones have been suggested, 
including K+ and/or Na’ channel activity and CAMP 
phosphodiesterase (CAMP PDE) inhibition, In the 
present study OPC 8490 effects on 1) CAMP PDE III: 2) 
inotropic response in right ventricular trabeculae 
(RVT) in the presence (n-17) and absence of forskolin 
(n-18); and 3) RVT action potential were assessed in 
preparations taken from failing humar <.Garts (FHH). The 
drug inhibited CAMP PDE in a concentration-dependent 
manner with an I& of 12.0 @; the IC,, for the CAMP 
PDE inhibitor enoximone was 3.6 pM. OPC 8490 at 10s8 to 
10-k produced a marginal increase in isometric sys- 
tolic tension in RVT. After administration of a 
minimally effective dose of forskolln to elevate 
intracellular CAMP levels the inotropic response to OPC 
8490 was markedlv ootentiated as shown in the figure. 
““1 indicating PDE inhibitio; 1; 
RVT OPC 8490 induced an act ion 
potential prolongation ,by 
71+3%, with an EC,, of 9.3 &M. 
Conclusions: The positive ino- 
tropic effect of OPC 8490 in 
FHH is due at least in part to 
CAMP PDE inhibition; the con- 
tribution of action potential 
prolongation to the inotropic 
effects remains to be determined. 
XAMOTEROL 
HEART. 
HA8 AGONIST ACTIVITY IN END-STAGE FAILING HUNAN 
Patricia Larrabee, Wary M. Wollmering, 
Michael R. BrisLow. University of Utah, Salt Lake City, 
Utah. 
Xamoterol (X) is a B-adrenoceptor partial agonist with an 
intrinsic activity of approximately 0.4 in model systems. 
X has been reported to improve left ventricular 
performance in patients with mild to moderate heart 
failure, but in severe heart failure (SHF) X has been 
associated with increased mortalie:r. Since data on the 
hemodynamic effects of X in SHF are limited and since it 
has been proposed that X acts solely as a B-blocking 
agent in SHF, we investigated the B-agonistic activity of 
X in preparations derived from the hearts of patients 
with SHF. In crude myocardial membranes derived from 7 
end-stage failing ventricles (receptor density = 28.3 
fmol/mg, decreased by 68%) removed at the time of 
transplantation X competed with 12’[I)ICYP for two 
classes of binding sites. The b was 31.7 + 11.5 nM and 
the KL was 5847 2 2041 nM, indicating 184 fold selctivity 
for B1 vs B2 receptors. At a dose range of lO-B to 10” M 
X alone did not increase force of contraction in L%olated 
right ventricular trabeculae (n-lo), in agreement with a 
previous report. However, in the presence of a minimally 
effective dose of forskolin (EDlo) to augment adenylate 
cyclase catalytic activity, X induced a 1.7 folj increase 
in isometric systolic tension (pc.05) with an ED,, of 8.1 
r&l (n-15); the maximum response was 26.4 
produced by the full agonist isoproterenol. 
CONCLUSION: X can act as a B1 selective partial agonist 
in end-stage failing human heart. 
HEMQDYNAMIC RESI’ONSES TO INTRACORONARY INFUSION OF 
CALCITONIN GENE-RELATED PEPTIDE IN PATIENTS WITH CONGESTMZ 
HEARTFAILURE 
Serge Adnot, Pascal Merle& Christophe 
Eenvenutl, Said Sediame’, Alain Castalgne. Henri Mondor’s Hospital, 
Creteil, 94010, FRANCE. 
Calcitonin Gene-Related peptide (CGRP) has been shown to affect 
coronary vascular tone and cardiac function in experimental studies. We 
studied the hemodynamic responses to intracoronary infusion of CGRP 
in 9 patients with an idiopathic dilated cardiomyopathy (LVEF=2lfgS 
%I). Right (Swan-Ganz) and left catheterizations (Microtip Milk 
catheter) were performed to determine: CI: I.min-l.m-2; LVEDP: 
mmHg; peak positive LV dP/dt (mmHg.s-1); mean arterial pressure 
(MAPxnmHg) and systemic vascular resistance SVR: mmHg.min. l-l). 
Coronary sinus blood flow: mlmin- 1 (Cq) was assessed by continuous 
thermodilution technique (Webster catheter) and coronary vascular 
resistance (CR) was then calculated (mmHg.min.ml-1). CGRP was 
infused into the left main coronary artery at incremental infusion rates 
of 15 (I), 50 (2). 150 (3) and 600 (4) pmol/min. Mean results are 
expressed on table. B= baseline; HR= heart rate: bpm; SO2= coronary 
sinus oxygen saturation(%) 
‘pc.05 HR MAP LVEDP Cl SW +dP/dt Cq so2 CR 
B 87 87 18.3 2.1 36 710 107 26 0.78 
: 
87 88 18.7 2.15 36 709 114 27 0.75 
85 88 18.3 2.14 35 714 118 29 0.76 
: 
92 80’ 15+ 2.67’ 27’ 729 124* 37. 0.601 
loo, 72 * 11. 3.1” 20, 788 134L 400 0.53” 
At the two intracoronary lowest doses of CGRP no systemic effect 
occurred and no effect on cardiac function and coronary hemodynamics 
were observed. The two highest doses induced systemic and coronary 
vasodilation but no change of peak positive LV dP/dr. These results 
suggest that CGRP has a role in the modulation of vascular tone but 
does not affect cardiac contractility. 


Mechanism of action of carvedilol in human ventricular myocardium 

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Mechanism of action of carvedilol in human ventricular myocardium

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