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Chapter 10. Cardiotonic Agents for the Treatment of Heart Failure
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ANNUAL REPORTS IN MEDICINAL CHEMISTRY-I6
Chapter 10. CARDIOTONIC AGENTS FOR THE TREATMENT OF HEART FAILURE
James A. B r i s t o l and Dale B. Evans, Warner-Lambert
Co.,
Ann Arbor, M I .
Cardiac output i s r e g u l a t e d by t h e i n t i m a t e i n t e g r a t i o n of the c o n t r a c t i l e s t a t e of t h e h e a r t and the dynamics of t h e p e r i p h e r a l circ u l a t o r y system. I n h e a r t f a i l u r e , the fundamental d e f e c t i s an impairment of v e n t r i c u l a r myocardial c o n t r a c t i l i t y , w h i c h r e s u l t s i n an inadequate o u t p u t t o meet the metabolic and c i r c u l a t o r y demands of the body. Subsequent t o depression of t h e c o n t r a c t i l e state of the h e a r t , loading c o n d i t i o n s on the h e a r t become c r i t i c a l determinants of t h e output. E f f e c t i v e pharmacologic therapy of h e a r t f a i l u r e i s brought about e i t h e r by enhancing t h e c o n t r a c t i l e s t a t e of t h e f a i l i n g pump with p o s i t i v e i n o t r o p i c a g e n t s , o r by adjustment of t h e p e r i p h e r a l c i r c u l a t o r y s t a t e w i t h p e r i p h e r a l v a s o d i l a t o r s . The use of a g e n t s which s t i m u l a t e myocard i a l c o n t r a c t i l i t y a r e of major v a l u e i n t h e t r e a t m e n t of h e a r t f a i l u r e . D i g i t a l i s p r e p a r a t i o n s have been t h e s t a n d a r d therapy f o r f a i l u r e and a r e t h e only o r a l l y e f f e c t i v e i n o t r o p i c drugs a v a i l a b l e f o r the treatment of t h i s condition. However, t h e i r c a r d i a c e l e c t r i c a l t o x i c i t y and p e r i p h e r a l v a s c u l a r e f f e c t s make t h e s e a g e n t s less than i d e a l drugs. Sympathomimetic amines a r e t h e o t h e r major c l a s s of c a r d i a c s t i m u l a n t s which a r e used f o r t r e a t m e n t of f a i l u r e . The use of t h e s e a g e n t s i s l i m i t e d because of o r a l i n e f f e c t i v e n e s s , p o s i t i v e c h r o n o t r o p i c a c t i v i t y , arrhythmogenic p r o p e r t i e s , and unwanted p e r i p h e r a l v a s o c o n s t r i c t o r a c t i o n s . P r e s e n t l y , dobutamine (Dobutrex) and dopamine ( I n t r o p i n ) are the predominantly used sympathomimetic agents f o r h e a r t f a i l u r e . S e v e r a l timely review a r t i c l e s have appeared which provide a com rehensive a n a l y s i s of h e a r t f a i l u r e therapy with c a r d i o t o n i c drugs.l-$
Cardiac Glycosides - D i g i t a l i s c o n t i n u e s t o be the p r i n c i p a l pharmacologic therapy of h e a r t f a i l u r e d e s p i t e t h e major l i m i t a t i o n s of t h i s c l a s s of drugs. The c a r d i a c e l e c t r i c a l t o x i c i t y which poses s i g n i f i c a n t hazards t o t h e p a t i e n t and t h e controversy concerning t h e b e n e f i c i a l e f f e c t s of longterm therapy with d i g i t a l i s 8 continue t o c h a l l e n g e the r a t i o n a l use of t h i s c l a s s of a g e n t s i n h e a r t f a i l u r e . S u b s t a n t i a l e f f o r t s have y e t t o c l e a r l y d e f i n e the mechanism of t h e i n o t r o p i c a c t i o n , t o d i f f e r e n t i a t e the mechanisms of e l e c t r i c a l t o x i c i t y and p o s i t i v e i n o t r o p y , and t o c l e a r l y demonstrate long-term b e n e f i t with c h r o n i c use of t h e s e agent^.^-^ Proposed models of t h e d i g i t a l i s r e c e p t o r have been suggested which c o n s i s t of hydrophobic, e l e c t r o s t a t i c , and hydrogen bonding s i t e s with the s t e r o i d , l a c t o n e , and sugar m o i e t i e s of t h e c a r d i o t o n i c s t e r o i d s . Using t h i s model, t h e low potency and genin-like p r o p e r t i e s of actodigen have been r a t i o n a l i z e d t o r e s u l t from binding of t h e a-linked l a c t o n e r i n g t o t h e r e c e p t o r l a c t o n e binding s i t e i n a manner t h a t does not allow t h e s t e r o i d and sugar m o i e t i e s t o bind a s they do i n digoxin.1° Another approach uses the graphic a n a l y t i c a l f e a t u r e s of t h e N I H PROPHET computer system t o model cardenolide-receptor i n t e r a c t i o n s . The probable manner of t h e s e s p e c i f i c r e c e p t o r binding s i t e ( s ) f o r c a r d i a c g l y c o s i d e s has spawned a proposal f o r the e x i s t e n c e of a p u t a t i v e endogenous s u b s t a n c e , "endodigin," which may r e g u l a t e Na,K-ATPase a c t i v i t y . l 2 ASI-222 (L), a s e m i s y n t h e t i c 4-aminosugar c a r d i a c g l y c o s i d e , was compared with the n e u t r a l B-D-galactose analog, ASI-253 (2 ) and
Copyright 0 1981 by Academic Press. Inc. All righls of reproduction in any form meWed.
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d i g i t o x i g e n i n (A); ASI-222 was t h r e e times more potent than 2 and two times more potent than 2 a t i n c r e a s i n g l e f t v e n t r i c u l a r s t r o k e work i n a dog heart-lung p r e p a r a t i o n and had a longer d u r a t i o n of action.13 ASI-222 was t e n times as potent as ASI-253 i n i n h i b i t i n g Na,K-ATPase (ID 0 f o r ASI-222 was 1.3 x l r 7 M and ID50 f o r ASI-253 was 1.15 x lo&). l 4 The t h e r a p e u t i c and t o x i c i n d i c e s ( l e t h a l d o s e / t o x i c dose) of ASI-222, ASI-253, and 3 were compared: t h e t h e r a p e u t i c i n d i c e s were 2.88, 1.65, and 2.27,while the t o x i c i n d i c e s were 1.4, 3.9, and 5.9, r e s p e ~ t i v e 1 y . l ~It was suggested that more than one r e c e p t o r system may account f o r the divergent t o x i c and t h e r a p e u t i c index ranges f o r t h e t h r e e compounds. The e l e c t r o p h y s i o l o g i c a l and i n o t r o p i c e f f e c t s were determined f o r two n a t u r a l l y occurring aminosugar c a r d i a c g l y c o s i d e s , m i t i p h y l l i n e (4) and h o l a r o s i n e B. (5).16 I n t h e guinea pig i s o l a t e d atrium, m i t i p h y l l i n e producez a p o s i t i v e i n o t r o p i c e f f e c t a t c o n c e n t r a t i o n s from 5 to 5 x x gfml, had no p o s i t i v e i n o t r o p i c e f f e c t i n t h e rat h e a r t a t a c o n c e n t r a t i o n of 5 x gfml, and shortened t h e a c t i o n p o t e n t i a l p l a t e a u i n t h e guinea pig perfused h e a r t . Holarosine B produced a maximal p o s i t i v e i n o t r o p i c e f f e c t i n t h e i s o l a t e d guinea p i g atrium a t 5 x g/ml and caused a n e g a t i v e i n o t r o p i c e f f e c t i n t h e perfused rat heart at 5 x g/ml,which was a s s o c i a t e d w i t h an i n c r e a s e i n t h e amplitude and d u r a t i o n of t h e a c t i o n p o t e n t i a l plateau. l6
2:R=
-3:R=
HoQ
58,178 ?:R=
5a,l7a
H2N H;
58,178
om3
(L),
14,15-6-oxido analog of p r o s c i l l a r i d i n showed one-fourth the potency of p r o s c i l l a r i d i n i n producing a p o s i t i v e i n o t r o p i c e f f e c t i n t h e guinea pig atrium and an equi-potent p o s i t i v e i n o t r o p i c e f f e c t i n dogs, while the arrhythmogenic l e t h a l doses were two and f i v e times h i g h e r f o r HOE 040. The amount of HOE 040 absorbed from t h e duodenum of dogs was 72% compared with 14-25% f o r p r o ~ c i l l a r i d i n . ~ ~
(s),
A c o l l e c t i o n of papers concerning m e p r o s c i l l a r i n t h e 4'-meth 1 e t h e r of p r o s c i l l a r i d i n , was published, which compared the two analogs. lii M e p r o s c i l l a r i n is b e t t e r absorbed than p r o s c i l l a r i d i n . l9 I n Friedberg'sclass 111111 h e a r t f a i l u r e p a t i e n t s , a d a i l y maintenance dose of 0.50.75 mg of m e p r o s c i l l a r i n induces a cumulative blood l e v e l of 1-1.5 mg a f t e r 8-10 days, which was s u f f i c i e n t t o e l i m i n a t e h e a r t f a i l u r e . 2 0
Gitoformate (9)was t h e s u b j e c t of a symposium, t h e proceedings of which have been published.21 C l i n i c a l l y , a d m i n i s t r a t i o n of 0.12 =/day of gitoformate and 0.50 mgfday of digoxin t o NYHA-class 1/11 h e a r t f a i l u r e p a t i e n t s r e s u l t e d i n similar p o s i t i v e i n o t r o p i c responses t o each drug. Unlike digoxin, gitoformate did n o t reduce h e a r t rate.22,23 Asclepin (10)has been e v a l u a t e d in v i t r o and i n vivo i n s e v e r a l s p e c i e s . 24 I n cats w i t h p e n t o b a r b i t a l induced c a r d i a c i n s u f f i c i e n c y , a d m i n i s t r a t i o n of 100 Ug/kg of a s c l e p l n e l i c i t e d a 135% increase i n l e f t
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ventricular (LV) dP/dt max compared with a 79% increase with d i g ~ x i n . ~ ~ Helveticosol-3',4'-dinitrate ( 1 1 )26 and the 3',4'-dipropionate (12)were compared: administration of 8 mg of 2 and 2 to healthy volunteers resulted in maximal shortening of systolic time intervals three hours after dosing. There was no difference between the activity of the glycosides and no perceptible cardiac or gastrointestinal side effects.27 The 4-(indolin-5-yl)-2,5-dihydrofuran-2-one, 2,elicited increases in contractile force of 24 and 52% following administration of 1 and 5 mg/kg intravenously to dogs. Interesting1 the corresponding glucoside, 14, produced negative inotropic responses. 54 -
-7:
-8:
R2=a-L-rhamopyranosyl R2=4-0-methyla-L-rhamopyranosyl
R10
-6:Rl=a-L-rhamopyranosyl
R1 n
-9 11 12
I I E l 3 CHO
H
CH3
OCHO
1
NO2
OH
CH20H
H
1
COC3H7
OH
CHZOH
H
14: R = C o O - g l u c o s e II 0
8-Adrenoceptor Stimulants - The positive inotropic action of catecholamines,such as norepinephrine, epinephrine, and isoprotereno1,i.s accompanied by either tachycardia or vasotropic activities,which limit the use of these agents in the treatment of patients with heart failure. More recently, dopamine and dobutamine (15)have been introduced into therapy. These agents are claimed to have a more favorable profile of hemodynamic activity than the classical sympathomimetic amines. However, both dopamine and dobutamine are readily inactivated enzymatically and are These agents have been used effectively in orally ineffe~tive.~~-~l failure associated with myocardial infarction without causing an increase in infarct size.32 Tolerance to the hemodynamic action of dobutamine has been demonstrated in patients receiving 24 hr or four-day infusions.31933 Prenalterol (H 133122 16) is an orally effective cardioselective 8-adrenoceptor agonist .34-38 This agent i s undergoing clinical evaluation in heart f a i l ~ r e . ~ ~Prenalterol -~~ has been shown to have a
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preferential positive inotropic action,as compared to its positive chronotropic a ~ t i o n . ~The ~ ,cardiovascular ~~ effects of prenalterol have been favorably assessed in patients with coronary heart disease or myocardial infarction and left ventricular dysf~nction.~~ is a structural analog of dobutamine. It is not a Butopamine (17) catecholamine and is refractory to the action of catechol-Omethyltransferase. Unpublished data indicate that butopamine has a similar hemodynamic profile to that of dobutamine and that, unlike dobutamine, it is orally effective.47 In congestive heart failure patients, intravenous administration of butopamine produced a positive inotro ic effect; however, positive chronotropic activity was also n ~ t e d . ~ In ~,~~ comparison to previous data from similar studies, the degree of rate increase was greater than that of dobutamine and similar to that of dopamine at equi-effective inotropic doses. X
15: XtOH; Y=H 17: X=H; Y=OH
19; X=H; -
R=(CH2)2NHCOi
b
U
Ibopamine (SB 7505), the diisobutyric ester of N-methyldopamine, is an orally effective ositive inotropic agent in anesthetized dogs and in healthy In humans, doses of 50, 100 and 150 mg of this agent caused dose-related decreases in electromechanical systole and pre-ejection period,which appeared to last for approximately 8 hrs. Insignificant changes were observed in heart rate and arterial blood pressure.
volunteer^.^^
RO 363 (18)is a selective B1-adrenoceptor agonist. In anesthetized cats, this agent had similar potency to isoproterenol as a positive chronotropic a ent but was substantially less potent as a peripheral vasodilator.52 In studies in vitro, RO 363 was approximately one half as potent, but equi-active, to isoproterenol as a positive chronotropic agent in guinea pig right atria and similarly potent but less active as a positive inotropic agent in guinea pig left atria and in ventricular strips from guinea pig, rat, and rabbit.53 ICI 118587 (19)is a new f3-adrenoceptor partial agonist which has been demonstrated to possess cardioselectivity in reserpinized dogs. In these studies, a dose of 3.2 mg/kg, intravenously, was determined to be the ED50 for tachycardia,while at doses up to 3.0 mg/kg, ICI 118587 caused no effect on hind limb perfusion pressure.54 Although positive inotropic action with this agent has not been reported, it is presumed that such activity is intrinsic to this compound. The diacetyl-L-y-glutamyl amide of dopamine, Abbott 47884, administered intravenously to dogs produced a profile similar to subpressor doses of dopamine. A dose of 5 mg/kg produced a prolonged increase in myocardial contractility, heart rate, and renal blood flow.55 The dopamine analogs, (3) and (211, have been reported to produce cardiostimulatory effects similar to do amine (the E isomer was substantially more potent than the 2 isomer). 5E
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A theophylline-dopamine derivative, D 4975 (221, was more active intravenously as a positive inotropic agent than dopamine or dobutamine in anesthetized dogs, and also increased heart rate and blood p r e s ~ u r e . ~ ~ , ~ ~
Two analogs of the 8-adrenoceptor antagonist bufuralol are reported to be 8-adrenoceptor agonists. 59 The 5-hydroxy analog (2) had greater affinity for vascular 8-receptors while the 6-hydroxy derivative (24) had similar affinity for both receptor types.
Amezinium metilsulfate (LU-1631, 25) is a chemically and pharmacologically novel indirect-acting sympathomimetic agent. 6o This agent is an inhibitor of intraneuronal MA0 and also releases norepinephrine from sympathetic nerve terminals. 61 62 This compound increased myocardial contractility, heart rate, and blood pressure in anesthetized animals.63 In healthy human subjects, amezinium was an effective positive inotropic agent. The duration of action following intravenous administration was 90 - 120 min and was approximately 6 hrs following oral admini~tration.~~ This compound is being considered for development as a cardiostimulant drug.47
I
H 3 G N kNJ-(C%)3NH(C112)2 HO
OH
I
CH3 22
23: X=OH; 24: X=H;
OH
CH3SOi CgH5
Y=H
Y-OH 2.2 Phosphodiesterase Inhibitors - Inhibition of the degradation of cyclic AMP by phosphodiesterase (PDE) in the cardiac cell causes an increase in intracellular cyclic AMP levels. This activity has been implicated in the positive inotropic actions of several agents although the interrelationin this ship has not been unequivocally e ~ t a b l i s h e d . ~Interest ~ approach to the development of a cardiotonic has resulted in compounds of potential interest. Buquineran (UK 14275, 26) was previously reviewed.66 A closely related analog, carbazeran (UK 31557, 27) is currently under development as a c a r d i o t ~ n i c . ~ ~ , ~ ~ Phthalazinol (EG-626, 28) increased contractility in guinea pig atrial and ventricular Although this activity was not correlated with PDE inhibitory activity, this relationship was suggested based on previous data.70 Cilostamide (OPC-3689, 291, an antithrombotic agent which inhibits PDE,71 increased myocardial contractility in rabbit and dog hearts. This agent was more potent but less active than IBMX in rabbit ventricular muscle, whereas cilostamide and IBMX had comparable activities in dog ventricular muscle. This difference was ascribed to species differences in basal turnover rates of cyclic AMP.72 Recent studies indicate that the PDE inhibitor APlO inotropic activity and antiarrhythmic activity.73
(2) has
USV 2776 (31) and related dihydro- and tetrahydro-isoquinolines inhibit cardiac cyclic nucleotide PDE, although no demonstration was made of positive inotropic action.74
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One of t h e most promising p o s i t i v e i n o t r o p i c a g e n t s Novel Cardiotonics t o ’ b e s t u d i e d i n r e c e n t years is t h e b i p y r i d y l analog amrinone (Win 40680, 32 ).75s76 I n i s o l a t e d c a t a t r i a and p a p i l l a r y muscles, amrinone (3-1000Tg/ml) caused s i g n i f i c a n t dose-related i n c r e a s e s i n developed t e n s i o n with r e l a t i v e l y smaller changes i n r i g h t a t r i a l rate.77 In t h e a n e s t h e t i z e d dog, a 1 mg/kg intravenous dose of amrinone caused a 75% peak increase i n c a r d i a c c o n t r a c t i l e f o r c e measured by a s t r a i n gauge and a 60% peak i n c r e a s e i n LV dP/dt max. Administration of amrinone o r a l l y a t 10 mg/kg caused a 57% i n c r e a s e i n LV dP/dt max w i t h an o n s e t of 45 minutes and a t o t a l d u r a t i o n of the i n o t r o p i c e f f e c t of more than 5 hours.77 I n pentobarbital-induced h e a r t f a i l u r e i n dogs, amrinone caused an i n c r e a s e i n both c o n t r a c t i l e f o r c e and c a r d i a c output. I n i s o l a t e d blood v e s s e l strips78 and i n the canine i s o l a t e d perfused h i ~ ~ d l i m ba , d~i r~e c t coronary v a s o d i l a t i o n d i s t i n c t from t h a t o c c u r r i n g secondary t o i n o t r o p i c a c t i v i t y was demonstrated f o r amrinone. The mechanism of amrinone’s i n o t r o p i c a c t i o n has been the s u b j e c t of It is not a d i r e c t o r i n d i r e c t 8-adrenoceptor a g o n i s t , does not i n c r e a s e cyclic-AMP, does not i n h i b i t Na,K-ATPase, and does not s t i m u l a t e histamine r e c e p t o r s . 76, 77 Amrinone i n c r e a s e d cont r a c t i l i t y and s t i m u l a t e d i n f l u x of t a u r i n e i n t o the guinea pig but n o t t h e r a t heart.80 S t u d i e s using t h e calcium s e n s i t i v e p r o t e i n aequorin81 and dog e r y t h r o c y t e s 8 2 suggest t h a t amrinone i n c r e a s e s t h e t r a n s p o r t of calcium a c r o s s the sarcolemma, t h u s i n c r e a s i n g i n t r a c e l l u l a r calciuml e v e l s . Other s t u d i e s show t h a t amrinone is a n o n s p e c i f i c r e l a x a n t of smooth muscle, a c t i n g a t m u l t i p l e s i t e s t o decrease the a v a i l a b i l i t y of calcium which may account f o r i t s v a s o d i l a t o r proper tie^.^^
intense investigation.
S e v e r a l c l i n i c a l s t u d i e s i n h e a r t f a i l u r e showed t h a t i n p a t i e n t s r e c e i v i n g concommitant doses of d i g i t a l i s , amrinone e l i c i t e d i n c r e a s e s i n c a r d i a c output, s t r o k e volume, s t r o k e work, and LV dP/dt max,while c a p i l l a r y wedge p r e s s u r e declined. Heart rate remained unchanged,while myocardial oxygen consumption decreased. 84-87 Two of n i n e p a t i e n t s rec e i v i n g amrinone developed s e v e r e but r e v e r s i b l e thrombocytopenia. 88 Experiments i n dogs w i t h experimentally induced ischemia suggest t h a t amrinone and i s o p r o t e r e n o l a r e e q u a l l y d e t r i m e n t a l i n i n c r e a s i n g a c u t e ischemia and myocardial i n j u r y , which may l i m i t the p o t e n t i a l use of amrinone i n h e a r t f a i l u r e p a t i e n t s with a c u t e myocardial ischemia.89 Peak plasma c o n c e n t r a t i o n s of drug occurred between 0.25-3 hours. The mean was 2.94 .21 hours suggesting an o r a l dosage regimen of 4-6 hours The development and pharmacological a c t i v i t y of amrinone h a s been reviewed.91
*
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The carbazole derivative, Win 35020 (331, was shown to be a positive inotropic agent both in vitro and in vivo, causing a dose-related increase in contractile force at 3-100 pgg/ml in the isolated cat papillary muscle preparation, at 0.1-3.0 mglkg intravenously in the anesthetized dog, and at 15-60 mglkg orally in conscious dogs.76 Pretreatment with reserpine resulted in complete elimination of the inotropic response in vitro and a diminution of the response in vivo indicating that the mechanism of action was due to release of n ~ r e p i n e p h r i n e . ~Hemolytic ~ anemia appeared in dogs following oral administration of 33 at 50 mglkg for 50 days.
AR-L 57 (34) and AR-L 115 (35) are novel positive inotropic agents with unknown mechanisms of action. In normal human males, a single intravenous dose of 200 mg of AR-L 57 caused a significant inotropic response of short duration, suggesting utility in the intensive care facility.92 In squid axons, AR-L 57 rapidly and reversibly inhibited the sodium pump in some ways resembling the action of cardiac glycosides; the action was not dependent upon external sodium ions, suggesting a difference in the molecular mode of interaction with the sodium pump.93 AR-L 115 displayed positive inotropic effects in vitro at 10-300 pM and increased LV dP/dt max 12-123% at 0.1-2.0 mg/kg intravenously in the anesthetized dog. Orally, in conscious dogs, AR-L 115 increased LV dp/dt max by 16-92% for 5-12 hours following administration of 2.5-30 mg/kg.94 6-adrenoceptor blockade did not diminish the inotropic effect of AR-L 115 and the therapeutic ratio was shown to be 17 times that of ouabain.95 In patients with "HA-class I I I / I V heart failure, AR-L 115 at 3 mglkg intravenously produced increases in heart rate (18%) cardiac output (21%) and a decrease in arterial pressure (25%). At 200 mg orally t.i.d., AR-L 115 improved cardiac output (31%) and ejection fraction (35%) in patients with congestive cardiomyopathy. The agent did not cause an enhancement of ectopic activity in the heart and did not cause conduction defects.96
(z),
RMI 82,249 0.3-10.0 mglkg intravenously, increased myocardial contractile force and heart rate, and decreased blood pressure in anesthetized dogs. These effects were not blocked by propranol01.~~ RMI 82,249 produced greater hemodynamic effects in dogs with experimentally-induced heart failure than in normal dogs.98* 99
The antiarrhythmic agent, BIIA, 37, produced significant positive inotropic effects in vitro at 0.3-10.0-~01/ll and in vivo in the anesthetized cat at 2.0 mglkg intravenously. Inotropic action is not mediated by a- or B-adrenoceptors. In the guinea pig heart and kidney BIIA inhibits Na,K-ATPase, but unlike the cardiac glycosides this inhibition is competitive with sodium. loo
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Ionophores The ionophore monensin, which preferentially complexes sodium, has undergone study as a cardiotonic agent. In anesthetized dogs, monensin at doses of 5-25 pg/kg produced dose-dependent increases in coronary blood flow and decreased total peripheral resistance, while at doses greater than 25 /kg it increased myocardial contractility and aortic blood pressure. pb2 The combination of low concentrations of ouabain with monensin led to irreversible contracture and irregular responses to electrical stimulation in isolated rabbit left atria. lo3 In anesthetized dogs, the potassium complexing ionophores grisorixin (2 mg/kg) and alborixin (1 mglkg) produced 250 and 320% increases in ventricular contractile force accompanied by ECG disorders similar to those described for hypokalemia. lo4, lo5 In the isolated working rat heart preparation, the calcium complexing ionophore X-537A (Ro-2-2985) increased heart rate and contractility. The increase in heart rate was eliminated by reserpine pretreatment or B-adrenoceptor blockadeawhile the increase in contractility was only partially attenuated, indicating a direct inotropic effect of the ionophore.lO6 Peptides - Three peptides with similar cardiotonic activity have been isolated from the sea anemone: Anthopleuran-A (AP-A) and AP-C have been sequenced, while AP-B has been partially sequenced.lo7 In vitro, AP-A increased force of contractions of isolated cat heart papillary muscles at doses as low as 2 x lo-%.1oa Dantrolene inhibits the positive inotropic effect of AP-A, suggesting that the mechanism of action may be an intracellular translocation of calcium, unlike ouabain or isoproterenol which require increased transmembrane calcium flux. log References A. J. Taggart and D. G. McDevitt, Drugs, 20, 398 (1980). D. Noble Cardiovasc, Res,, 14,495 (1980). C. M. Latners and J. Roberts. Life Sci... 27. 1713 (1980). .'l Akera and T. M. Brody, Pharmacol. Rev., 29, 187 -(1978). D. Jewitt, K. Jennings, and P. Go Jackson, Am. J . Med., 65, 197 (1978). C. L. Skelton, J. Louisana State Med. SOC., 131,109 (1979). Cardiology, 65. Supp. 1 (1980). S. 8. Arnold, R . C. Byrd, W. Meister, K. Melmon, M. D. Cheitlin, J. D. Bristow, W. W. Parmley, and K. Chatterjee, N. Eng. J. Med., 303, 1443 (1980). 9. R . Thomas, L. Brown, J . Boutagy, and A. Gelbart, Circ. Res, Supp.1, 4 6 , 1-167 (1980). 10. R. Thomas, J. Allen, B.J.R. Pitts, and A. Schwartz, Eur. J. Pharmacol., 53, 227 (1979). 11. D. C. Rohrer, D. S. Fullerton,K.Yoshioka, A.H.L. From, and K. Ahmed, "Computer Assisted Drug Design,'' E. 0. Olson and R, E. Christoffersen, Ed., ACS Symposium Series 112, ACS-Washington, p 259, 1979. 12. A. Schwartz and R. J. Adams, Circ. Res. Supp. I, 5, 1-154 (1980). 13. L. S , Cook, R . W. Caldwell, and C. B. Nash, J. Cardiovasc. Pharmacol., 1, 551 (1979). 141 (19787. 14. R. W. Caldwell and C. B. Nash, J. Pharmacol. Exp. Ther., 15. L. S, Cook, R, W. Caldwell, and C. B. Nash, J. Pharmacol. Exp. Ther., 215, 198 (1980). 16. P. Choay, E. Coraboeuf, and E. Deroubaix, Eur. J. Pharmacol., 50, 317 (1978). 17. V. E. Lindner, G. V. Peitzenstein, and H. H. Schone, Arzneim. Forsch., 29, 221 (1979). 18. Arzneim. Forsch., 2. (3a) (1978). 19. M. Raschack, H. Haas, G. Neugebauer, and J. Sipos, Arzneim. Forsch., 28, 495 (1978). 20. H. Pozenel, Arzneim. Forsch., 28, 560 (1978). 21. Drugs Exp. Clin. Res., 5, (3) (1980). 22. L. Deicas, A. L, Barilli, E. Astorri, and G. Bianchi, Drugs Exp. Clin. Res., 5, 207 (1980). 23. E. Ambrosioni, C. Magelli, S. Boschi, L. Paaetti, and B. Magnani, Drugs Exp. Clin. Res., 6, 221 (1980). 24. G. K. Patnaik and B. N. Dhawan, Arzneim. Forsch., 28, 1095 (1978). 25. G. K. Patnaik and E. Kohler, Arzneim. Forsch., 28, 1368 (1978). 26. Drugs Future, 5, 31 (1980). 27. K. 0. Haustein and G. Nowak, Arch. Int. Pharmacodyn. Ther., 239, 270 (1979). 28. P, J, Grossi, J. N, Vallat, A. Boucherle, and J. Simiand, Eur. J. Med. Chem., 15,285 (1980). 29. D. V. Unverferth, R. D. Magorien, R. P. Lewis, and C. V. Lier, Am. Heart J. 100, 622 (1980).
1. 2. 3. 4. 5. 6. 7. 8.
-7
m,
Chap. 10
Cardiotonic Agents
Bristol, Evans
101
30. R. M. Gagnon, L. Fortin, R. Boucher, S . Gilbert, M. Morrisette, S . Present, J. Lemire, and A. David, Chest, 694 (1980). 31. M. Renard and R. Bernard, J. Cardiovasc. Pharmacol., 2, 543 (1980). 32. R. A. Goldstein, E. R. Passamani, and R. Roberts, N. Eng. J. Med., 303,846 (1980). 33. D. V. Unverferth, M. Blanford, R. E. Kates. and C. V. Leier, Am. J. Med., 2, 262 (1980). 34. D.H.T. Scott, G. R. Arthur. R. N. Boyes, and D. B. Scott, Br. J. Clin. Pharmacol., 1, 365 (1979). 35. 0. Ronn. C. Graffner. G. Johnsson. . L. Jordo. P. Lundbore. -, and J. Wikstrand. Eur. J. Clin. Pharmacol. l5,'9 (1979). 58, 425 (1980). 36. K. A. Meurer. R. Lang, V. Hombach. and A. Helber, Klin. Wochenschr., 37. 0. Ronn, E. Fellenius, C. Graffner, G. Johnsson, P . Lundborg, and L. Svensson, Eur. J. Clin. Pharmacol., l7, 81 (1980). 38. T. L. Svendsen, 0. J. Hartling, and J. Trap-Jensen, Eur. J. Clin. Pharmacol., l8, 219 (1980). 39. F. Waagstein, M. Estrada-Yamamoto, C. Reyes, I. Wallentin, and A. Hjalmarson, Circulation, 60, (11). 41 (1979). o ,382 40. D. N. Sharpe, J. E. Douglas, R. Coxon, and B. R. Long, Aust. N. 2. J. Med., l (1980). 41. W. Kupper, K. H. Kuck, F. Sonntag, W. Bleifeld, Circulation, 62 (III), 298 (1980). 42. M. Evenson, N. Awan, K. Needham, and D. T. Mason, Circulation, 62 (III), 127 (1980). 43. A. Tweddel, B. C. Bastian, R. G. Murray, T.D.V. Lawrie, and I. Hutton, Circulation, 62 (III), 299 (1980). 44. E. Carlsson, C. G. Dahlof, A. Hedberg, H. Persson, and B. Trangstrand, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 300, 101 (1977). 45. G. Johnsson, L. Jordo, and P. Lunborg, 0. Ronn, I. Welin-Fogelberg, and J. Wikstrand, Eur. J. Clin. Pharmacol., l3, 163 (1978). 46. I. Hutton, R. G. Murray, R. N. Boyes, A. P. Rae, and W. S. Hillis, Br. Heart J., 9, 134 (1980). 47. Scrip, 524, 11 (1980). 591A (1980). 48. M. J. Thompson and C. V. Leier, Clin. Res., 49. M. J. Thompson, P. Huss, D. V. Unverferth, A. Fasola and C. V. Leier, Clin. Pharmacol. Ther., 2. 324 (1980). 50. C. V. Leier, P. Heban, P. Huss, C. A. Bush, and R. P. Lewis, Circulation, 58, 466 (1978). 51. L. Dei C a s , C. Manca, G. Vasini, M. Mansour, B. Bernardini, and 0. Visioli, Arzneim. Forsch.. 3, 498 (1980). 52. C. Raper, G. A. McPherson, and D. Iakovidis, Eur. J. Pharmacol., 52, 241 (1978). 53. D. Iakovidis, E. Malta, G. A. McPherson, and C. Raper, Br. J. Pharmacol., 68, 677 (1980). 54. J. J. Barlow, 33. G. Main, J. A. Moors, A. Nuttall, and H. M. Snow, Br. J. Pharmacol., 67, 412P (1979). 55. J. J. Kyncl and R. E. Hollinger, Fed. Proc. Fed. Am. SOC. Exp. Biol., 2, 267 (1979). 56. P. W. Erhardt, R. J. Gorczynski and W. G. Anderson, J. Med. Chem.. 2, 907 (1979). 57. P. Anttila, F. W. Dreyer, and E. Westermann, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 297 (II), 128 (1977). 58. D. McCaig and J. R. Parratt, Br. J. Pharmacol.. 67,239 (1979). 59. K. Lovgren, A. Hedberg, and J. L. G. Nilsson, J. Med. Chem., 3,624 (1980). 60. D. Lenka, J. Gries, R. Kretzchmar, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 308, R12 (1979). 61. A. Steppeler and K. Starke, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 314, 13 (1980) 62. A. Steppeler, R . Pfandler, L. Hedler, and K. Starke, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 314, 1 (1980). 63. H. D. Lehmann, J. Schuster, and H. Giertz, Naunyn-Schniedeberg's Arch. Pharmakol. Exp., 308, R16 (1979). 64. K. M. Wilsmann, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 308, R16 (1979). 1 9 7) . 65. G. I. Drummond and D. L. Severson, Circ. Res., 44, 145 ( 66. S . F. Campbell and J. C. Danilewicz, Annual Resports Med. Chem., 13,92 (1978). 67. British Patent 2,000,136. 68. J. h e r . Med. Assoc.. 243, 787 (1980). 69. K. Shigenobu, Y. Iwayama, R. Sakai. and Y. Kasuya, J. Pharm. Dyn., 1,5 4 3 (1980). 97 (1977). 70. K. Adachi and F. Numano, Jap. J. Pharmacol., 1, 71. H . Y. Kohri, K. Kimura, T. Watanabe, T. Kaube, T. Nishi, K. Natagawa, H. Hayashi, and H . Hidaka, Abstracts 7th Internat. Cong. Pharmacol., (Paris), 125 (1978). 72. M. Endoh, K. Satoh. and S . Yamashita, Eur. J. Pharmacol., 66, 43 (1980). 73. A. F. Prigent, G. Nemoz. M. Roche, and H. Pacheo, Arch. Int. Pharmacodyn. Ther., 241, 131 (1979). 74. R. G. Van Inwegen, P. Salaman, V. St. Georgiev, and I. Weinryb, Biochem. Pharmacol., 28, 1307 (1979). 75. Drugs Future, 5 , 245 (1979). 76. A. E. Farah and A. A. Alousi, Life Sci., 22, 1139 (1978). 666 (1979). 77. A. A. Alousi, A. E. Farah, G. Y. Lesher, and C. J. Opalka, Circ. Res., 9,
s,
a,
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- Pharmacodynamic Agents
Comer, Ed.
78. R. W. Millard, G. Dube. G. Grupp, I. Grupp, A. A. Alousi, and A. Schwartz, J. M o l . Cell. Cardiol., 2, 647 (1980). 79. A. A. Alousi and A. Helstosky, Fed. Proc. Fed. Am. SOC. Exp. Biol., 39, 855 (1980). 80. J. Azari and R. J. Huxtable, Eur. J. Pharmacol., 67, 347 (1980). 81. J. P. Morgan, N. K. M. Lee, and J. R. Blinks, Fed. Proc. Fed. Am. SOC. Exp. Biol., 2, 854 (1980). 254 (1980). 82. J. C. Parker and J. R. Harper, J. Clin. Invest., 83. K. D. Meisheri, R. F. Palmer, and C. V. Breemen. Eur. J. Pharmacol., 6 l , 159 (1980). 84. J. R. Benotti. W. Grossman, E. Braunwald, D. D. Davolos, and A. A. Alousi, N. Eng. J. Med., 299, 1373 (1978). 85. T. H. LeJemtel, E. Keung, E. H. Sonnenblick, H. S . Ribner. M. Matsumoto, R. Davis. W. Schwartz, A. A. Alousi, and D. Davolos, Circulation, 2,1098 (1979). 86. T. H. LeJemtel, E. Keung, H. S . Ribner, R. Davis, J. Wexler, M. D. Blaufox, and E. H. Sonnenblick, Am. J. Cardiol., 45, 123 (1980). 87. J. R. Benotti, W. Grossman, E. Braunwald, and B. A. Carabello, Circulation, 62, 28 (1980). 88. J. Wynne, R. F. Malacoff, J. R. Benotti, G. D. Curfman, W. Grossman, B. L. Holman, T. W. Smith, and E. Braunwald, Am. J. Cardiol., 45, 1245 (1980). 89. R. E. Rude, R. A. Kloner, P. R. Maroko, S. Khuri, S. Karaffa, L.W.V. DeBoer, and E. Braunwald, Cardiovasc. Res.. l4, 419 (1980). 90. K. C. Lasseter, D. C. Garg, S. L. Hayes, P. Kullberg, and R. F. Palmer, Clin. Res., 28, 5898 (1980). 91. A. A. Alousi and A. E. Farah, Trends Pharmacol. Sci., 1, 143 (1980). 92. G. G. B e l z , H. Nubling. and A. Zimmer, Eur. J. Clin. Pharmacol., l0, 319 (1976). 93. P. Honerjager, M. Rieter. and P. F. Baker, Mol. Pharmacol., l7, 350 (1980). 94. W. Diederen, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 308, R19 (1979). 95. W. Diederen, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 311. Supp, R38 (1980). 96. J. Thorman, W. Kramer, and M. Schlepper, Circulation, 62 (III), 233 (1980). 97. R. C. Dage, C. P. Hsieh, and N. L. Wiech, Fed. Proc. Fed. Am. SOC. Exp. Biol., 39, 1105 (1980). 98. C. P. Hsieh and R. C. Dage. Fed. Proc. Fed. Am. SOC. Exp. Biol., 39, 1106 (1980). 99. L. E. Roebel, H . C. Cheng, R. W. Lucas, R. J. Hodgeman, 0. K. Reavis, and J. K. Woodward, Pharmacologist, 21, 287 (1980). 100.U. Borchard, A.A.L. Fox, and K. Greeff, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp.312, 187 (1980). o , 101.M. Shlafer, P. Somani, B. C. Pressman, and R. F. Palmer, J. Mol. Cell. Cardiol., l 333 (1978). 102.R. K. Saini, R. K. Heater, P. Somani, and B. C. Pressman, J. Cardiovasc. Pharmacol., 1, 123 (1979). 103.M. Shlafer and P. Kane, J. Pharmacol. Exp. Ther., 214, 567 (1980). 104.N. Moins, P. Gachon, and P. Duchene-Marullaz, J. Cardiovasc. Pharmacol., 1, 659 (1979). 105.P. Gachon and N. Moins, Arzneim. Forsch., 30, 1502 (1980). 106.R. L. Rodgers, J. I. Moore, and K. R. Hornbrook, Can. J. Physiol. Pharmacol. 57, 428 (1979). 107.T. R. Norton, Fed. Proc. Am. SOC. Exp. Biol., 40, 21 (1980). 108.A. Scriabine, C. G. Van Arman, G. Morgan, A. A. Morris, C. P. Bennett, and N. R. Bohidar, J. Cardiovasc. Pharmacol.,,.I 571 (1979). 109.L. E. Bailey, S. Shibata, D. G. Seriguchi, P. E. Dresel, Life Sci., 26, 1061 (1980).
a,
ANNUAL REPORTS IN MEDICINAL CHEMISTRY-I6
Chapter 10. CARDIOTONIC AGENTS FOR THE TREATMENT OF HEART FAILURE
James A. B r i s t o l and Dale B. Evans, Warner-Lambert
Co.,
Ann Arbor, M I .
Cardiac output i s r e g u l a t e d by t h e i n t i m a t e i n t e g r a t i o n of the c o n t r a c t i l e s t a t e of t h e h e a r t and the dynamics of t h e p e r i p h e r a l circ u l a t o r y system. I n h e a r t f a i l u r e , the fundamental d e f e c t i s an impairment of v e n t r i c u l a r myocardial c o n t r a c t i l i t y , w h i c h r e s u l t s i n an inadequate o u t p u t t o meet the metabolic and c i r c u l a t o r y demands of the body. Subsequent t o depression of t h e c o n t r a c t i l e state of the h e a r t , loading c o n d i t i o n s on the h e a r t become c r i t i c a l determinants of t h e output. E f f e c t i v e pharmacologic therapy of h e a r t f a i l u r e i s brought about e i t h e r by enhancing t h e c o n t r a c t i l e s t a t e of t h e f a i l i n g pump with p o s i t i v e i n o t r o p i c a g e n t s , o r by adjustment of t h e p e r i p h e r a l c i r c u l a t o r y s t a t e w i t h p e r i p h e r a l v a s o d i l a t o r s . The use of a g e n t s which s t i m u l a t e myocard i a l c o n t r a c t i l i t y a r e of major v a l u e i n t h e t r e a t m e n t of h e a r t f a i l u r e . D i g i t a l i s p r e p a r a t i o n s have been t h e s t a n d a r d therapy f o r f a i l u r e and a r e t h e only o r a l l y e f f e c t i v e i n o t r o p i c drugs a v a i l a b l e f o r the treatment of t h i s condition. However, t h e i r c a r d i a c e l e c t r i c a l t o x i c i t y and p e r i p h e r a l v a s c u l a r e f f e c t s make t h e s e a g e n t s less than i d e a l drugs. Sympathomimetic amines a r e t h e o t h e r major c l a s s of c a r d i a c s t i m u l a n t s which a r e used f o r t r e a t m e n t of f a i l u r e . The use of t h e s e a g e n t s i s l i m i t e d because of o r a l i n e f f e c t i v e n e s s , p o s i t i v e c h r o n o t r o p i c a c t i v i t y , arrhythmogenic p r o p e r t i e s , and unwanted p e r i p h e r a l v a s o c o n s t r i c t o r a c t i o n s . P r e s e n t l y , dobutamine (Dobutrex) and dopamine ( I n t r o p i n ) are the predominantly used sympathomimetic agents f o r h e a r t f a i l u r e . S e v e r a l timely review a r t i c l e s have appeared which provide a com rehensive a n a l y s i s of h e a r t f a i l u r e therapy with c a r d i o t o n i c drugs.l-$
Cardiac Glycosides - D i g i t a l i s c o n t i n u e s t o be the p r i n c i p a l pharmacologic therapy of h e a r t f a i l u r e d e s p i t e t h e major l i m i t a t i o n s of t h i s c l a s s of drugs. The c a r d i a c e l e c t r i c a l t o x i c i t y which poses s i g n i f i c a n t hazards t o t h e p a t i e n t and t h e controversy concerning t h e b e n e f i c i a l e f f e c t s of longterm therapy with d i g i t a l i s 8 continue t o c h a l l e n g e the r a t i o n a l use of t h i s c l a s s of a g e n t s i n h e a r t f a i l u r e . S u b s t a n t i a l e f f o r t s have y e t t o c l e a r l y d e f i n e the mechanism of t h e i n o t r o p i c a c t i o n , t o d i f f e r e n t i a t e the mechanisms of e l e c t r i c a l t o x i c i t y and p o s i t i v e i n o t r o p y , and t o c l e a r l y demonstrate long-term b e n e f i t with c h r o n i c use of t h e s e agent^.^-^ Proposed models of t h e d i g i t a l i s r e c e p t o r have been suggested which c o n s i s t of hydrophobic, e l e c t r o s t a t i c , and hydrogen bonding s i t e s with the s t e r o i d , l a c t o n e , and sugar m o i e t i e s of t h e c a r d i o t o n i c s t e r o i d s . Using t h i s model, t h e low potency and genin-like p r o p e r t i e s of actodigen have been r a t i o n a l i z e d t o r e s u l t from binding of t h e a-linked l a c t o n e r i n g t o t h e r e c e p t o r l a c t o n e binding s i t e i n a manner t h a t does not allow t h e s t e r o i d and sugar m o i e t i e s t o bind a s they do i n digoxin.1° Another approach uses the graphic a n a l y t i c a l f e a t u r e s of t h e N I H PROPHET computer system t o model cardenolide-receptor i n t e r a c t i o n s . The probable manner of t h e s e s p e c i f i c r e c e p t o r binding s i t e ( s ) f o r c a r d i a c g l y c o s i d e s has spawned a proposal f o r the e x i s t e n c e of a p u t a t i v e endogenous s u b s t a n c e , "endodigin," which may r e g u l a t e Na,K-ATPase a c t i v i t y . l 2 ASI-222 (L), a s e m i s y n t h e t i c 4-aminosugar c a r d i a c g l y c o s i d e , was compared with the n e u t r a l B-D-galactose analog, ASI-253 (2 ) and
Copyright 0 1981 by Academic Press. Inc. All righls of reproduction in any form meWed.
94
S e c t . I1
-
Pharmacodynamic Agents
Comer, Ed.
d i g i t o x i g e n i n (A); ASI-222 was t h r e e times more potent than 2 and two times more potent than 2 a t i n c r e a s i n g l e f t v e n t r i c u l a r s t r o k e work i n a dog heart-lung p r e p a r a t i o n and had a longer d u r a t i o n of action.13 ASI-222 was t e n times as potent as ASI-253 i n i n h i b i t i n g Na,K-ATPase (ID 0 f o r ASI-222 was 1.3 x l r 7 M and ID50 f o r ASI-253 was 1.15 x lo&). l 4 The t h e r a p e u t i c and t o x i c i n d i c e s ( l e t h a l d o s e / t o x i c dose) of ASI-222, ASI-253, and 3 were compared: t h e t h e r a p e u t i c i n d i c e s were 2.88, 1.65, and 2.27,while the t o x i c i n d i c e s were 1.4, 3.9, and 5.9, r e s p e ~ t i v e 1 y . l ~It was suggested that more than one r e c e p t o r system may account f o r the divergent t o x i c and t h e r a p e u t i c index ranges f o r t h e t h r e e compounds. The e l e c t r o p h y s i o l o g i c a l and i n o t r o p i c e f f e c t s were determined f o r two n a t u r a l l y occurring aminosugar c a r d i a c g l y c o s i d e s , m i t i p h y l l i n e (4) and h o l a r o s i n e B. (5).16 I n t h e guinea pig i s o l a t e d atrium, m i t i p h y l l i n e producez a p o s i t i v e i n o t r o p i c e f f e c t a t c o n c e n t r a t i o n s from 5 to 5 x x gfml, had no p o s i t i v e i n o t r o p i c e f f e c t i n t h e rat h e a r t a t a c o n c e n t r a t i o n of 5 x gfml, and shortened t h e a c t i o n p o t e n t i a l p l a t e a u i n t h e guinea pig perfused h e a r t . Holarosine B produced a maximal p o s i t i v e i n o t r o p i c e f f e c t i n t h e i s o l a t e d guinea p i g atrium a t 5 x g/ml and caused a n e g a t i v e i n o t r o p i c e f f e c t i n t h e perfused rat heart at 5 x g/ml,which was a s s o c i a t e d w i t h an i n c r e a s e i n t h e amplitude and d u r a t i o n of t h e a c t i o n p o t e n t i a l plateau. l6
2:R=
-3:R=
HoQ
58,178 ?:R=
5a,l7a
H2N H;
58,178
om3
(L),
14,15-6-oxido analog of p r o s c i l l a r i d i n showed one-fourth the potency of p r o s c i l l a r i d i n i n producing a p o s i t i v e i n o t r o p i c e f f e c t i n t h e guinea pig atrium and an equi-potent p o s i t i v e i n o t r o p i c e f f e c t i n dogs, while the arrhythmogenic l e t h a l doses were two and f i v e times h i g h e r f o r HOE 040. The amount of HOE 040 absorbed from t h e duodenum of dogs was 72% compared with 14-25% f o r p r o ~ c i l l a r i d i n . ~ ~
(s),
A c o l l e c t i o n of papers concerning m e p r o s c i l l a r i n t h e 4'-meth 1 e t h e r of p r o s c i l l a r i d i n , was published, which compared the two analogs. lii M e p r o s c i l l a r i n is b e t t e r absorbed than p r o s c i l l a r i d i n . l9 I n Friedberg'sclass 111111 h e a r t f a i l u r e p a t i e n t s , a d a i l y maintenance dose of 0.50.75 mg of m e p r o s c i l l a r i n induces a cumulative blood l e v e l of 1-1.5 mg a f t e r 8-10 days, which was s u f f i c i e n t t o e l i m i n a t e h e a r t f a i l u r e . 2 0
Gitoformate (9)was t h e s u b j e c t of a symposium, t h e proceedings of which have been published.21 C l i n i c a l l y , a d m i n i s t r a t i o n of 0.12 =/day of gitoformate and 0.50 mgfday of digoxin t o NYHA-class 1/11 h e a r t f a i l u r e p a t i e n t s r e s u l t e d i n similar p o s i t i v e i n o t r o p i c responses t o each drug. Unlike digoxin, gitoformate did n o t reduce h e a r t rate.22,23 Asclepin (10)has been e v a l u a t e d in v i t r o and i n vivo i n s e v e r a l s p e c i e s . 24 I n cats w i t h p e n t o b a r b i t a l induced c a r d i a c i n s u f f i c i e n c y , a d m i n i s t r a t i o n of 100 Ug/kg of a s c l e p l n e l i c i t e d a 135% increase i n l e f t
Chap. 10
Cardiotonic Agents
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95
ventricular (LV) dP/dt max compared with a 79% increase with d i g ~ x i n . ~ ~ Helveticosol-3',4'-dinitrate ( 1 1 )26 and the 3',4'-dipropionate (12)were compared: administration of 8 mg of 2 and 2 to healthy volunteers resulted in maximal shortening of systolic time intervals three hours after dosing. There was no difference between the activity of the glycosides and no perceptible cardiac or gastrointestinal side effects.27 The 4-(indolin-5-yl)-2,5-dihydrofuran-2-one, 2,elicited increases in contractile force of 24 and 52% following administration of 1 and 5 mg/kg intravenously to dogs. Interesting1 the corresponding glucoside, 14, produced negative inotropic responses. 54 -
-7:
-8:
R2=a-L-rhamopyranosyl R2=4-0-methyla-L-rhamopyranosyl
R10
-6:Rl=a-L-rhamopyranosyl
R1 n
-9 11 12
I I E l 3 CHO
H
CH3
OCHO
1
NO2
OH
CH20H
H
1
COC3H7
OH
CHZOH
H
14: R = C o O - g l u c o s e II 0
8-Adrenoceptor Stimulants - The positive inotropic action of catecholamines,such as norepinephrine, epinephrine, and isoprotereno1,i.s accompanied by either tachycardia or vasotropic activities,which limit the use of these agents in the treatment of patients with heart failure. More recently, dopamine and dobutamine (15)have been introduced into therapy. These agents are claimed to have a more favorable profile of hemodynamic activity than the classical sympathomimetic amines. However, both dopamine and dobutamine are readily inactivated enzymatically and are These agents have been used effectively in orally ineffe~tive.~~-~l failure associated with myocardial infarction without causing an increase in infarct size.32 Tolerance to the hemodynamic action of dobutamine has been demonstrated in patients receiving 24 hr or four-day infusions.31933 Prenalterol (H 133122 16) is an orally effective cardioselective 8-adrenoceptor agonist .34-38 This agent i s undergoing clinical evaluation in heart f a i l ~ r e . ~ ~Prenalterol -~~ has been shown to have a
96 -
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Pharmacodynamic Agents
Comer, Ed.
preferential positive inotropic action,as compared to its positive chronotropic a ~ t i o n . ~The ~ ,cardiovascular ~~ effects of prenalterol have been favorably assessed in patients with coronary heart disease or myocardial infarction and left ventricular dysf~nction.~~ is a structural analog of dobutamine. It is not a Butopamine (17) catecholamine and is refractory to the action of catechol-Omethyltransferase. Unpublished data indicate that butopamine has a similar hemodynamic profile to that of dobutamine and that, unlike dobutamine, it is orally effective.47 In congestive heart failure patients, intravenous administration of butopamine produced a positive inotro ic effect; however, positive chronotropic activity was also n ~ t e d . ~ In ~,~~ comparison to previous data from similar studies, the degree of rate increase was greater than that of dobutamine and similar to that of dopamine at equi-effective inotropic doses. X
15: XtOH; Y=H 17: X=H; Y=OH
19; X=H; -
R=(CH2)2NHCOi
b
U
Ibopamine (SB 7505), the diisobutyric ester of N-methyldopamine, is an orally effective ositive inotropic agent in anesthetized dogs and in healthy In humans, doses of 50, 100 and 150 mg of this agent caused dose-related decreases in electromechanical systole and pre-ejection period,which appeared to last for approximately 8 hrs. Insignificant changes were observed in heart rate and arterial blood pressure.
volunteer^.^^
RO 363 (18)is a selective B1-adrenoceptor agonist. In anesthetized cats, this agent had similar potency to isoproterenol as a positive chronotropic a ent but was substantially less potent as a peripheral vasodilator.52 In studies in vitro, RO 363 was approximately one half as potent, but equi-active, to isoproterenol as a positive chronotropic agent in guinea pig right atria and similarly potent but less active as a positive inotropic agent in guinea pig left atria and in ventricular strips from guinea pig, rat, and rabbit.53 ICI 118587 (19)is a new f3-adrenoceptor partial agonist which has been demonstrated to possess cardioselectivity in reserpinized dogs. In these studies, a dose of 3.2 mg/kg, intravenously, was determined to be the ED50 for tachycardia,while at doses up to 3.0 mg/kg, ICI 118587 caused no effect on hind limb perfusion pressure.54 Although positive inotropic action with this agent has not been reported, it is presumed that such activity is intrinsic to this compound. The diacetyl-L-y-glutamyl amide of dopamine, Abbott 47884, administered intravenously to dogs produced a profile similar to subpressor doses of dopamine. A dose of 5 mg/kg produced a prolonged increase in myocardial contractility, heart rate, and renal blood flow.55 The dopamine analogs, (3) and (211, have been reported to produce cardiostimulatory effects similar to do amine (the E isomer was substantially more potent than the 2 isomer). 5E
Chap. 10
Cardiotonic Agents
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97
A theophylline-dopamine derivative, D 4975 (221, was more active intravenously as a positive inotropic agent than dopamine or dobutamine in anesthetized dogs, and also increased heart rate and blood p r e s ~ u r e . ~ ~ , ~ ~
Two analogs of the 8-adrenoceptor antagonist bufuralol are reported to be 8-adrenoceptor agonists. 59 The 5-hydroxy analog (2) had greater affinity for vascular 8-receptors while the 6-hydroxy derivative (24) had similar affinity for both receptor types.
Amezinium metilsulfate (LU-1631, 25) is a chemically and pharmacologically novel indirect-acting sympathomimetic agent. 6o This agent is an inhibitor of intraneuronal MA0 and also releases norepinephrine from sympathetic nerve terminals. 61 62 This compound increased myocardial contractility, heart rate, and blood pressure in anesthetized animals.63 In healthy human subjects, amezinium was an effective positive inotropic agent. The duration of action following intravenous administration was 90 - 120 min and was approximately 6 hrs following oral admini~tration.~~ This compound is being considered for development as a cardiostimulant drug.47
I
H 3 G N kNJ-(C%)3NH(C112)2 HO
OH
I
CH3 22
23: X=OH; 24: X=H;
OH
CH3SOi CgH5
Y=H
Y-OH 2.2 Phosphodiesterase Inhibitors - Inhibition of the degradation of cyclic AMP by phosphodiesterase (PDE) in the cardiac cell causes an increase in intracellular cyclic AMP levels. This activity has been implicated in the positive inotropic actions of several agents although the interrelationin this ship has not been unequivocally e ~ t a b l i s h e d . ~Interest ~ approach to the development of a cardiotonic has resulted in compounds of potential interest. Buquineran (UK 14275, 26) was previously reviewed.66 A closely related analog, carbazeran (UK 31557, 27) is currently under development as a c a r d i o t ~ n i c . ~ ~ , ~ ~ Phthalazinol (EG-626, 28) increased contractility in guinea pig atrial and ventricular Although this activity was not correlated with PDE inhibitory activity, this relationship was suggested based on previous data.70 Cilostamide (OPC-3689, 291, an antithrombotic agent which inhibits PDE,71 increased myocardial contractility in rabbit and dog hearts. This agent was more potent but less active than IBMX in rabbit ventricular muscle, whereas cilostamide and IBMX had comparable activities in dog ventricular muscle. This difference was ascribed to species differences in basal turnover rates of cyclic AMP.72 Recent studies indicate that the PDE inhibitor APlO inotropic activity and antiarrhythmic activity.73
(2) has
USV 2776 (31) and related dihydro- and tetrahydro-isoquinolines inhibit cardiac cyclic nucleotide PDE, although no demonstration was made of positive inotropic action.74
S e c t . I1
98
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Pharmacodynamic Agents
Comer, Ed.
-
One of t h e most promising p o s i t i v e i n o t r o p i c a g e n t s Novel Cardiotonics t o ’ b e s t u d i e d i n r e c e n t years is t h e b i p y r i d y l analog amrinone (Win 40680, 32 ).75s76 I n i s o l a t e d c a t a t r i a and p a p i l l a r y muscles, amrinone (3-1000Tg/ml) caused s i g n i f i c a n t dose-related i n c r e a s e s i n developed t e n s i o n with r e l a t i v e l y smaller changes i n r i g h t a t r i a l rate.77 In t h e a n e s t h e t i z e d dog, a 1 mg/kg intravenous dose of amrinone caused a 75% peak increase i n c a r d i a c c o n t r a c t i l e f o r c e measured by a s t r a i n gauge and a 60% peak i n c r e a s e i n LV dP/dt max. Administration of amrinone o r a l l y a t 10 mg/kg caused a 57% i n c r e a s e i n LV dP/dt max w i t h an o n s e t of 45 minutes and a t o t a l d u r a t i o n of the i n o t r o p i c e f f e c t of more than 5 hours.77 I n pentobarbital-induced h e a r t f a i l u r e i n dogs, amrinone caused an i n c r e a s e i n both c o n t r a c t i l e f o r c e and c a r d i a c output. I n i s o l a t e d blood v e s s e l strips78 and i n the canine i s o l a t e d perfused h i ~ ~ d l i m ba , d~i r~e c t coronary v a s o d i l a t i o n d i s t i n c t from t h a t o c c u r r i n g secondary t o i n o t r o p i c a c t i v i t y was demonstrated f o r amrinone. The mechanism of amrinone’s i n o t r o p i c a c t i o n has been the s u b j e c t of It is not a d i r e c t o r i n d i r e c t 8-adrenoceptor a g o n i s t , does not i n c r e a s e cyclic-AMP, does not i n h i b i t Na,K-ATPase, and does not s t i m u l a t e histamine r e c e p t o r s . 76, 77 Amrinone i n c r e a s e d cont r a c t i l i t y and s t i m u l a t e d i n f l u x of t a u r i n e i n t o the guinea pig but n o t t h e r a t heart.80 S t u d i e s using t h e calcium s e n s i t i v e p r o t e i n aequorin81 and dog e r y t h r o c y t e s 8 2 suggest t h a t amrinone i n c r e a s e s t h e t r a n s p o r t of calcium a c r o s s the sarcolemma, t h u s i n c r e a s i n g i n t r a c e l l u l a r calciuml e v e l s . Other s t u d i e s show t h a t amrinone is a n o n s p e c i f i c r e l a x a n t of smooth muscle, a c t i n g a t m u l t i p l e s i t e s t o decrease the a v a i l a b i l i t y of calcium which may account f o r i t s v a s o d i l a t o r proper tie^.^^
intense investigation.
S e v e r a l c l i n i c a l s t u d i e s i n h e a r t f a i l u r e showed t h a t i n p a t i e n t s r e c e i v i n g concommitant doses of d i g i t a l i s , amrinone e l i c i t e d i n c r e a s e s i n c a r d i a c output, s t r o k e volume, s t r o k e work, and LV dP/dt max,while c a p i l l a r y wedge p r e s s u r e declined. Heart rate remained unchanged,while myocardial oxygen consumption decreased. 84-87 Two of n i n e p a t i e n t s rec e i v i n g amrinone developed s e v e r e but r e v e r s i b l e thrombocytopenia. 88 Experiments i n dogs w i t h experimentally induced ischemia suggest t h a t amrinone and i s o p r o t e r e n o l a r e e q u a l l y d e t r i m e n t a l i n i n c r e a s i n g a c u t e ischemia and myocardial i n j u r y , which may l i m i t the p o t e n t i a l use of amrinone i n h e a r t f a i l u r e p a t i e n t s with a c u t e myocardial ischemia.89 Peak plasma c o n c e n t r a t i o n s of drug occurred between 0.25-3 hours. The mean was 2.94 .21 hours suggesting an o r a l dosage regimen of 4-6 hours The development and pharmacological a c t i v i t y of amrinone h a s been reviewed.91
*
Chap. 10
Cardiotonic Agents
Bristol, Evans
99
The carbazole derivative, Win 35020 (331, was shown to be a positive inotropic agent both in vitro and in vivo, causing a dose-related increase in contractile force at 3-100 pgg/ml in the isolated cat papillary muscle preparation, at 0.1-3.0 mglkg intravenously in the anesthetized dog, and at 15-60 mglkg orally in conscious dogs.76 Pretreatment with reserpine resulted in complete elimination of the inotropic response in vitro and a diminution of the response in vivo indicating that the mechanism of action was due to release of n ~ r e p i n e p h r i n e . ~Hemolytic ~ anemia appeared in dogs following oral administration of 33 at 50 mglkg for 50 days.
AR-L 57 (34) and AR-L 115 (35) are novel positive inotropic agents with unknown mechanisms of action. In normal human males, a single intravenous dose of 200 mg of AR-L 57 caused a significant inotropic response of short duration, suggesting utility in the intensive care facility.92 In squid axons, AR-L 57 rapidly and reversibly inhibited the sodium pump in some ways resembling the action of cardiac glycosides; the action was not dependent upon external sodium ions, suggesting a difference in the molecular mode of interaction with the sodium pump.93 AR-L 115 displayed positive inotropic effects in vitro at 10-300 pM and increased LV dP/dt max 12-123% at 0.1-2.0 mg/kg intravenously in the anesthetized dog. Orally, in conscious dogs, AR-L 115 increased LV dp/dt max by 16-92% for 5-12 hours following administration of 2.5-30 mg/kg.94 6-adrenoceptor blockade did not diminish the inotropic effect of AR-L 115 and the therapeutic ratio was shown to be 17 times that of ouabain.95 In patients with "HA-class I I I / I V heart failure, AR-L 115 at 3 mglkg intravenously produced increases in heart rate (18%) cardiac output (21%) and a decrease in arterial pressure (25%). At 200 mg orally t.i.d., AR-L 115 improved cardiac output (31%) and ejection fraction (35%) in patients with congestive cardiomyopathy. The agent did not cause an enhancement of ectopic activity in the heart and did not cause conduction defects.96
(z),
RMI 82,249 0.3-10.0 mglkg intravenously, increased myocardial contractile force and heart rate, and decreased blood pressure in anesthetized dogs. These effects were not blocked by propranol01.~~ RMI 82,249 produced greater hemodynamic effects in dogs with experimentally-induced heart failure than in normal dogs.98* 99
The antiarrhythmic agent, BIIA, 37, produced significant positive inotropic effects in vitro at 0.3-10.0-~01/ll and in vivo in the anesthetized cat at 2.0 mglkg intravenously. Inotropic action is not mediated by a- or B-adrenoceptors. In the guinea pig heart and kidney BIIA inhibits Na,K-ATPase, but unlike the cardiac glycosides this inhibition is competitive with sodium. loo
100 -
Sect. I1
- Pharmacodynamic Agents
Comer, Ed.
-
Ionophores The ionophore monensin, which preferentially complexes sodium, has undergone study as a cardiotonic agent. In anesthetized dogs, monensin at doses of 5-25 pg/kg produced dose-dependent increases in coronary blood flow and decreased total peripheral resistance, while at doses greater than 25 /kg it increased myocardial contractility and aortic blood pressure. pb2 The combination of low concentrations of ouabain with monensin led to irreversible contracture and irregular responses to electrical stimulation in isolated rabbit left atria. lo3 In anesthetized dogs, the potassium complexing ionophores grisorixin (2 mg/kg) and alborixin (1 mglkg) produced 250 and 320% increases in ventricular contractile force accompanied by ECG disorders similar to those described for hypokalemia. lo4, lo5 In the isolated working rat heart preparation, the calcium complexing ionophore X-537A (Ro-2-2985) increased heart rate and contractility. The increase in heart rate was eliminated by reserpine pretreatment or B-adrenoceptor blockadeawhile the increase in contractility was only partially attenuated, indicating a direct inotropic effect of the ionophore.lO6 Peptides - Three peptides with similar cardiotonic activity have been isolated from the sea anemone: Anthopleuran-A (AP-A) and AP-C have been sequenced, while AP-B has been partially sequenced.lo7 In vitro, AP-A increased force of contractions of isolated cat heart papillary muscles at doses as low as 2 x lo-%.1oa Dantrolene inhibits the positive inotropic effect of AP-A, suggesting that the mechanism of action may be an intracellular translocation of calcium, unlike ouabain or isoproterenol which require increased transmembrane calcium flux. log References A. J. Taggart and D. G. McDevitt, Drugs, 20, 398 (1980). D. Noble Cardiovasc, Res,, 14,495 (1980). C. M. Latners and J. Roberts. Life Sci... 27. 1713 (1980). .'l Akera and T. M. Brody, Pharmacol. Rev., 29, 187 -(1978). D. Jewitt, K. Jennings, and P. Go Jackson, Am. J . Med., 65, 197 (1978). C. L. Skelton, J. Louisana State Med. SOC., 131,109 (1979). Cardiology, 65. Supp. 1 (1980). S. 8. Arnold, R . C. Byrd, W. Meister, K. Melmon, M. D. Cheitlin, J. D. Bristow, W. W. Parmley, and K. Chatterjee, N. Eng. J. Med., 303, 1443 (1980). 9. R . Thomas, L. Brown, J . Boutagy, and A. Gelbart, Circ. Res, Supp.1, 4 6 , 1-167 (1980). 10. R. Thomas, J. Allen, B.J.R. Pitts, and A. Schwartz, Eur. J. Pharmacol., 53, 227 (1979). 11. D. C. Rohrer, D. S. Fullerton,K.Yoshioka, A.H.L. From, and K. Ahmed, "Computer Assisted Drug Design,'' E. 0. Olson and R, E. Christoffersen, Ed., ACS Symposium Series 112, ACS-Washington, p 259, 1979. 12. A. Schwartz and R. J. Adams, Circ. Res. Supp. I, 5, 1-154 (1980). 13. L. S , Cook, R . W. Caldwell, and C. B. Nash, J. Cardiovasc. Pharmacol., 1, 551 (1979). 141 (19787. 14. R. W. Caldwell and C. B. Nash, J. Pharmacol. Exp. Ther., 15. L. S, Cook, R, W. Caldwell, and C. B. Nash, J. Pharmacol. Exp. Ther., 215, 198 (1980). 16. P. Choay, E. Coraboeuf, and E. Deroubaix, Eur. J. Pharmacol., 50, 317 (1978). 17. V. E. Lindner, G. V. Peitzenstein, and H. H. Schone, Arzneim. Forsch., 29, 221 (1979). 18. Arzneim. Forsch., 2. (3a) (1978). 19. M. Raschack, H. Haas, G. Neugebauer, and J. Sipos, Arzneim. Forsch., 28, 495 (1978). 20. H. Pozenel, Arzneim. Forsch., 28, 560 (1978). 21. Drugs Exp. Clin. Res., 5, (3) (1980). 22. L. Deicas, A. L, Barilli, E. Astorri, and G. Bianchi, Drugs Exp. Clin. Res., 5, 207 (1980). 23. E. Ambrosioni, C. Magelli, S. Boschi, L. Paaetti, and B. Magnani, Drugs Exp. Clin. Res., 6, 221 (1980). 24. G. K. Patnaik and B. N. Dhawan, Arzneim. Forsch., 28, 1095 (1978). 25. G. K. Patnaik and E. Kohler, Arzneim. Forsch., 28, 1368 (1978). 26. Drugs Future, 5, 31 (1980). 27. K. 0. Haustein and G. Nowak, Arch. Int. Pharmacodyn. Ther., 239, 270 (1979). 28. P, J, Grossi, J. N, Vallat, A. Boucherle, and J. Simiand, Eur. J. Med. Chem., 15,285 (1980). 29. D. V. Unverferth, R. D. Magorien, R. P. Lewis, and C. V. Lier, Am. Heart J. 100, 622 (1980).
1. 2. 3. 4. 5. 6. 7. 8.
-7
m,
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30. R. M. Gagnon, L. Fortin, R. Boucher, S . Gilbert, M. Morrisette, S . Present, J. Lemire, and A. David, Chest, 694 (1980). 31. M. Renard and R. Bernard, J. Cardiovasc. Pharmacol., 2, 543 (1980). 32. R. A. Goldstein, E. R. Passamani, and R. Roberts, N. Eng. J. Med., 303,846 (1980). 33. D. V. Unverferth, M. Blanford, R. E. Kates. and C. V. Leier, Am. J. Med., 2, 262 (1980). 34. D.H.T. Scott, G. R. Arthur. R. N. Boyes, and D. B. Scott, Br. J. Clin. Pharmacol., 1, 365 (1979). 35. 0. Ronn. C. Graffner. G. Johnsson. . L. Jordo. P. Lundbore. -, and J. Wikstrand. Eur. J. Clin. Pharmacol. l5,'9 (1979). 58, 425 (1980). 36. K. A. Meurer. R. Lang, V. Hombach. and A. Helber, Klin. Wochenschr., 37. 0. Ronn, E. Fellenius, C. Graffner, G. Johnsson, P . Lundborg, and L. Svensson, Eur. J. Clin. Pharmacol., l7, 81 (1980). 38. T. L. Svendsen, 0. J. Hartling, and J. Trap-Jensen, Eur. J. Clin. Pharmacol., l8, 219 (1980). 39. F. Waagstein, M. Estrada-Yamamoto, C. Reyes, I. Wallentin, and A. Hjalmarson, Circulation, 60, (11). 41 (1979). o ,382 40. D. N. Sharpe, J. E. Douglas, R. Coxon, and B. R. Long, Aust. N. 2. J. Med., l (1980). 41. W. Kupper, K. H. Kuck, F. Sonntag, W. Bleifeld, Circulation, 62 (III), 298 (1980). 42. M. Evenson, N. Awan, K. Needham, and D. T. Mason, Circulation, 62 (III), 127 (1980). 43. A. Tweddel, B. C. Bastian, R. G. Murray, T.D.V. Lawrie, and I. Hutton, Circulation, 62 (III), 299 (1980). 44. E. Carlsson, C. G. Dahlof, A. Hedberg, H. Persson, and B. Trangstrand, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 300, 101 (1977). 45. G. Johnsson, L. Jordo, and P. Lunborg, 0. Ronn, I. Welin-Fogelberg, and J. Wikstrand, Eur. J. Clin. Pharmacol., l3, 163 (1978). 46. I. Hutton, R. G. Murray, R. N. Boyes, A. P. Rae, and W. S. Hillis, Br. Heart J., 9, 134 (1980). 47. Scrip, 524, 11 (1980). 591A (1980). 48. M. J. Thompson and C. V. Leier, Clin. Res., 49. M. J. Thompson, P. Huss, D. V. Unverferth, A. Fasola and C. V. Leier, Clin. Pharmacol. Ther., 2. 324 (1980). 50. C. V. Leier, P. Heban, P. Huss, C. A. Bush, and R. P. Lewis, Circulation, 58, 466 (1978). 51. L. Dei C a s , C. Manca, G. Vasini, M. Mansour, B. Bernardini, and 0. Visioli, Arzneim. Forsch.. 3, 498 (1980). 52. C. Raper, G. A. McPherson, and D. Iakovidis, Eur. J. Pharmacol., 52, 241 (1978). 53. D. Iakovidis, E. Malta, G. A. McPherson, and C. Raper, Br. J. Pharmacol., 68, 677 (1980). 54. J. J. Barlow, 33. G. Main, J. A. Moors, A. Nuttall, and H. M. Snow, Br. J. Pharmacol., 67, 412P (1979). 55. J. J. Kyncl and R. E. Hollinger, Fed. Proc. Fed. Am. SOC. Exp. Biol., 2, 267 (1979). 56. P. W. Erhardt, R. J. Gorczynski and W. G. Anderson, J. Med. Chem.. 2, 907 (1979). 57. P. Anttila, F. W. Dreyer, and E. Westermann, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 297 (II), 128 (1977). 58. D. McCaig and J. R. Parratt, Br. J. Pharmacol.. 67,239 (1979). 59. K. Lovgren, A. Hedberg, and J. L. G. Nilsson, J. Med. Chem., 3,624 (1980). 60. D. Lenka, J. Gries, R. Kretzchmar, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 308, R12 (1979). 61. A. Steppeler and K. Starke, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 314, 13 (1980) 62. A. Steppeler, R . Pfandler, L. Hedler, and K. Starke, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 314, 1 (1980). 63. H. D. Lehmann, J. Schuster, and H. Giertz, Naunyn-Schniedeberg's Arch. Pharmakol. Exp., 308, R16 (1979). 64. K. M. Wilsmann, Naunyn-Schmiedeberg's Arch. Pharmakol. Exp., 308, R16 (1979). 1 9 7) . 65. G. I. Drummond and D. L. Severson, Circ. Res., 44, 145 ( 66. S . F. Campbell and J. C. Danilewicz, Annual Resports Med. Chem., 13,92 (1978). 67. British Patent 2,000,136. 68. J. h e r . Med. Assoc.. 243, 787 (1980). 69. K. Shigenobu, Y. Iwayama, R. Sakai. and Y. Kasuya, J. Pharm. Dyn., 1,5 4 3 (1980). 97 (1977). 70. K. Adachi and F. Numano, Jap. J. Pharmacol., 1, 71. H . Y. Kohri, K. Kimura, T. Watanabe, T. Kaube, T. Nishi, K. Natagawa, H. Hayashi, and H . Hidaka, Abstracts 7th Internat. Cong. Pharmacol., (Paris), 125 (1978). 72. M. Endoh, K. Satoh. and S . Yamashita, Eur. J. Pharmacol., 66, 43 (1980). 73. A. F. Prigent, G. Nemoz. M. Roche, and H. Pacheo, Arch. Int. Pharmacodyn. Ther., 241, 131 (1979). 74. R. G. Van Inwegen, P. Salaman, V. St. Georgiev, and I. Weinryb, Biochem. Pharmacol., 28, 1307 (1979). 75. Drugs Future, 5 , 245 (1979). 76. A. E. Farah and A. A. Alousi, Life Sci., 22, 1139 (1978). 666 (1979). 77. A. A. Alousi, A. E. Farah, G. Y. Lesher, and C. J. Opalka, Circ. Res., 9,
s,
a,
102
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- Pharmacodynamic Agents
Comer, Ed.
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