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Cyclic AMP-dependent and independent positive inotropic effects of phenylephrine
Gen. Pharmac. Vol. 13. pp. 369 to 374, 1982
0306-3623/82/050369-06~[03.00,0 Copyright © 1982PergamonPress Ltd
Printed in Great Britain.All rights reserved
MINIREVIEW CYCLIC A M P - D E P E N D E N T A N D I N D E P E N D E N T POSITIVE INOTROPIC EFFECTS OF PHENYLEPHRINE* ARU~ G. TAHILIANI,SUBHASHC. VERMA,~ and JOlly H. MCNEILL Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C., Canada V6T lW5 (Received 23 March 1982)
The concept that catecholamines may exert their effects through two distinct mechanisms (Ahlquist, 1948) has proved to be extremely useful in the understanding of the effects of adrenergic agonists. Since that time, a considerable amount of work has been directed towards a better understanding of these effects. With the advent of newer and more specific agonists and antagonists, the ~t-and fl-receptors mediating the adrenergic effects have been subclassifled either as ~t or ~1 and fll or f12 (Lands et al., 1967: 1967a; Starke, 1977: Starke & Docherty, 1980). The positive inotropic and chronotropic effects produced by adrenergic agonists have long been associated with fl- adrenoceptors (Moran & Perkins, 1958; Black et al., 1964). However, more recent evidence suggests that zt- adrenoceptors also exist in the myocardium and that stimulation of these receptors may result in positive inotropic effects (Wenzel & Su, 1966: Gorier. 1967. 1968; Benfey & Varma. 1967: Mugelli et al., 1976). However, the question of the role of myocardial :t-adrenoceptors in mediating the inotropic effects of sympathomimetic agents has been land still is) a matter of controversy. The effects of phenylephrine, an adrenergic amine with predominant activity on ~-adrenoceptors (Ahlquist & Levy. 1959) have been studied extensively on the heart and the drug has often been used as an experimental tool to demonstrate the presence of myocardial :t-receptors (Nakashima et al., 1971; Schumann et al., 1974: Verma & McNeill, 1976: Wagner & Brodde, 1978). Ahhough it is widely speculated that the cardiac effects of phenylephrine are mediated via x-receptors, there still exists an element of doubt. This is because phenylephrinc has been shown to elevate cyclic AMP levels in myocardial tissues of guinea-pigs (McNeill & Verma. 1973). rats (Osnes & Oye. 1975) and rabbits (Endoh et al., 1976) and cyclic AMP elevation is essentially a [ L and not an z~-adrenoceptor function (Murad et al., 1962: Brinbaumer et al.. 1974: Kaumann et al., 1978: Martinez & McNeill, 1977a}. This * Work from our laboratory cited in this article was supported by grants from MRC (Canada} and the Can. Heart Fdn. ~.. Dr. S. C. Verma was the Professor and Chairman of the Department of Pharmacology, k. M. College of Pharmacy, Ahmedabad. India. Deceased, July 1981.
review summarizes the positive inotropic effects of phenylephrine in various preparations and the probable mechanisms by which these effects may be mediated. Studies demonstrating the cardiac effects of phenylephrine are shown in Table I. CYCLIC AMP-INDEPENDENT POSITIVE INOTROPIC EFFECTS OF PHENYLEPHRINE The positive inotropic effect of phenylephrine is known to be antagonized by ~-adrenoceptor antagonists. In the presence of phenoxybenzamine, a parallel shift of the concentration-response curve of phenylephrine to the right has been demonstrated (Benfey, 1973: Kunos & Nickerson, 1977). The shift is accompanied by a suppression of the maximum (Benfey, 1973). However, phentolamine appears to shift the curve to the right without affecting the maximum suggesting a competitive type of antagonism (Verma & McNeill, 1976: Martinez & McNeill, 1977; Wagner & Brodde, 1978: Bruckner, 1978). On the other hand, there are a few examples where the phenylephrineinduced increase in cardiac contractility was not affected by the aforementioned antagonists. These include the spontaneously beating rabbit atria (Yoo & Lee, 1970) and perfused isolated hearts from rats (Weston, 1971). A solution to this apparent discrepancy was suggested by Wagner et al. (1977) who found that the ~-adrenergic positive inotropic response was critically dependent on the frequency of stimulation. The antagonist effect of phentolamine is evident in preparations driven at about I Hz and is lost when the driving frequency is increased to more than 2.5 Hz (Schumann et al., 1974: Endoh & Schumann, 1975: Mugelli et al.. 1976). In spontaneously beating rat right atria, phentolamine failed to block the phenylephrine-induced responses (Bennett & Kemp, 1978k which supports the suggestion of Wagner et ul. (1977). A rational conclusion that can be drawn from these studies is that the mechanisms of action involved at varying frequencies are different. Frequency dependency of phentolamine antagonism has been observed with adrenaline (Mugelli et al., 1976): methoxamine (Endoh & Schumann. 1975) and other x-adrenergic agonists. At concentrations greater than 10,uM, the effects of phenylephrine were found to be antagonized by
369
3-',0
ARt N G. TAHn IANI ct ~11.
laLblc I. Studic~, shov, ing it positixc inolrorqc elgect of phcn.,.lcphrinc m i,,olatcd cardiac prcpiir:itior~, Irom cilllcrcnl
species i"issuc
.";pecics Guinea-pig
Lefl ulrJa Ventricle
Rabbit
Right ,it ria Pa pilkir.', inuscle Perfused heart Left atria
Rat
Ventricular strip Right atria l'apillar> muscle Pcrfuscd heart l.eft atriu
( "dl
('hicken
Dog 'o',s
(
Vcntricular strip Right atria l)apillar.,, muscle Perfused heart Papillar} muscle Ventricul,lr strip Atrial strip Papillar~ muscle Perfuscd heart Vei3trJcul,lr trahcculac Right atrial strip
Reference Gorier. 1967. 1968: Wagner ct a/.. 1977 I.edda eta/.. 1975; Wugner & Brodde. 197S: Sl'Jibaltaict ,ll., 19SO: l.edda uta/.. It)SO McNcill <'t a/.. 1972 Shibata cta/.. 1980; Sanches-('hapula. 1981 McNeill & Verma. 1973: Verma & McNeill. 1976 Ilcnl;e,, & Varma. 1967; 13enfey. 1971. 1973: Wagner & Rcinhardt. 1974: Benfe>. 1977 Broode uta/.. I978; Stlibata t't a/.. 19,gO l.eong & Benfe~,. I968; McNeill et el.. 1972: Shibata et al.. 1980 I{ndoh & Schumann. 1974: Schumann & Endoh. 1976; Shibala ut o/.. 1980 Starke. 19-/2; Wagner t't a/.. 1974:Ftqimott) et al.. 1976 Nakashima et o/.. 1971: Kunos & Nickcrson. 1977; Martm¢.," & McNcill. 1977 Wen.~el & Su. 1966: Wagner & Ilrodde. 197,R; Shihata uta/.. 10~0 ,Martincz & McNclll. 1977: Bennett & Kemp. 197,R: Shibula ut a/.. 19St) ()snes t': ,tl.. 1976; 197,R; Shibal,i ct a/.. 1980 Wcshm 1971: Osncs 1976; ()sties el a/.. 197S Bruckner et o/.. 1978: Wagner & Broddc. 197S Schmidl cta/., lg,~t} Wngncr & Brodde. 197S Wagner& Broddc. 1978 Benfe~ & ('arolin. 1971 K:ib¢la uta/.. 1969 Bruckncr. 197~: Bruckncr & SchtHl. 19S(I Schumann ct all.. 1978
fl-receptor antagonists (Brodde et el. 1948). Effects produced by' lower concentrations of phenylephrme were skox~ n to be insensitive to fl-receptor antagonists IBrodde et al.. 1948). This suggests thal the amine mediates its effects through :~-adrenoceptors up to concentrations of a b o u t 10 HM while higher concentrations probably involve both, ~- and /t-adrenoceptors. l h e r e is some evidence that temperature ITIti\ tilter the responses to phcnxlcphrme. On lo\~ering the temperature, tin increase in the inotropic potcne~ of phcnylcphrine has been reported m rat ~entricular strips and rat left atria (Brodde & ,Schumann. 197S~. Ito\~exer. Martinez & McNeill [1977p and Bcnl'ex (1977) did not obscrxe an ~, stick ch;.inge m the r:.il Icfl atriu. ()n the other hand. ~ h e n the temperature ~\as increased from 37 to 42 ('. Endoh et al. (1975l observed a decrease in the :,-adrenoceptor medJuted inotrope. \\hercas the fl-adrencrgic response of phen>lephrinc ~ l s not altered signilicantl 5. Apparentl> under some conditions lke :~-cldrenergic conaponcnl Js 1]-1oi,,2 sensitJ\e nt elevtited telnperalurcs. Net another factor lhdt seems to pla 5 a role in the adrcnergic responses is thai of the thyroid slate. While the fl-adrcncrgic response is believed to be enha,lced by hyperthyroidism and decreased in hypothyroid state (Nakashima et al.. 1971: Young & McNeilI, 1974: Hartley & McNeill. 1976) the opposite appears to hold true for the > a d r e n e r g i c responses. l h e > a d r e n e r g i c positb, e inotropic effect ~ a s mcreased m hypoth.,,roid stales (Nakashima et al.. 1971: Kuruos ct o/.. 1974; Kunos. 1977: Simpson & McNeill, 1980) while a decrease was observed m ks perthyroid animals (Kunos. 1977). These restllts indicate that the sensitivity of > a d r e n o c e p t o r s is increased m hypoth3roidism. K u n o s (1977) D u n d an incrcase of binding
of L~HJphenoxyhenzamine to intact left atria of h~poth.',roid rats and suggested that a change in the n u m b e r of binding sites may be responsible for a change in tile response. Ciaraldi & Marinelti (1977), using r~H]dihydroergoeryptine found that though the n u m b e r of :~- and //-receptors decreased m h~pothyroid rat ventricular membranes, the aflhfit.', and binding sites of both increased. Scholz (198()} suggested that the selecti,,e increase of the ~-adrenergic c o m p o n e n t may be due to changes beyond the receptor level. The rcsults discussed thus far provide evidence that phenylephrine stimulates :~-adrenoceptors and that stimulation of these receptors produces inolropic eft'cots. It appears reasonable to aSStLmc thal the e',entual mechanism through which these effects arc mediated invol',es calcium. This ma} be an increase m the intracellukir concentration of calcium ions interacting with the contractile proteins..,%hernati,,ely, the ellects ma~ resuh from changes in the sensitivity of the contractile protems for c a l c i u m I)-6(R). a calcium ~,low channel blocker, depresses the positive motropic ell'cot of phcnylephrine (Endoh e t a / . . 1975: l.edda ut a/.. 1975). The effects of phen}lephrine ma 5. thus he interpreted sis a result of altered calcium llt, x through the m.',ocardial membrane, probably tin enhstncemenl of the inv, ard ealcit,m current. In ventricular trtlbeculae of cattle depolarized with 22 mM K - , Bruckncr & Scholz 11980)observed a phenylephrine-indLLccd increase m contraction as v,,ell sis the slo~s imvard current ,a,hich ~verc inhibited by phentolamme. l.edda c t a / . {1980i studied the effects of phenylephrinc in guinea pig ~cntriclc strips m ~hich the ftlst sodium ch;.u3nels ~sere inacti\'ilted b\ 22 m M K ' .
In
contrast to the above sttidies, they found that the dectrical and mechanical responses to the anline were
Cardiac effects of phenylephrine
371 PHENYLEPHRINE
NEURONE 7
Jr", "
:
•"~
/
.
/-t
1~
Na + ATP
?
-- PHENYLEPHRINE
Conditions under which the positive inotropic effect of phenylephrine through respective receptors 0s most prominent. Alpha adrenergic Lower dose Lower frequency Hypothyroid state
Beta
adrenergic
.Higher dose Higher frequency Hyperthyroid s t a t e
Fig. 1. Schematic representation of the mechanism of the phenylephrine-induced positive inotropic effec. Phenylephrine may activate zc- or fl- adrenergic receptors directly or indirectly through the release of norepinephrine (NE). blocked by fl-. and not :c- antagonists. Similar results have been reported by Sanchez-Chapula [1981) in the guinea pig papillary muscle. Moreover. methoxamine was unable to restore the slow current in these studies. The proposal that ~-adrenoceptors may' be involved with an increa~ in calcium flux (Miura et aL, 1978) does not seem to be consistent with these data. W a g n c r & Schumann (1979) reduced the calcium ion concentration from 2.5 to 1.25 mM and observed a decrease in the affinity of the inotropic :~-adrenoceptors for phenylephrine. This suggests that :~-adrenergic effects are dependent not only on the trans-sarcolemmal calcium influx (Endoh et al., 1975a) but also on the extraccllular calcium ion concentration. Figure 1 illustrates the probable mechanisms through v.,hich phenylcphrine may act and the conditions under ~hich the receptor actions are most prominently seen. From the discussion so far, the precise mechanism of action of :~-adrenoceptors appears to be largely unknown. An involvement of calcium in the responses appears to be definite, but conflicting results do not yield a clear picture (Fig. 2). An attempt to explain the mechanism of 7-adrenoceptor action on the basis of Na" + K" ATPase activity has been made. Posner et a/. (1976l found that low concentrations of catecholamines inhibit +ZK uptake in dog Purkinje fibres. They suggested that the =-adrcnoceptor-induccd positive inotropic effect is due to the inhibition of N a ' + K" ATPase. However, Schmitz et al. (1980) did not detect any significant inhibition of (8t'Rb + K ' F u p t a k e , a measure of Na+ + K ÷ ATPase activity, in intact cat papillary muscles in the presence of phenylephrine though an increase in the contractility was seen.
> z / CP
_
"q 5
.......
Fig. 2. A hypothetical scheme of events following the stimulation of adrenergic receptors by phenylephrine. An increase in calcium influx which may be due to cyclic AMP (I) or inhibition of N a ' . K--ATPase (21 results in an increase in intracellular calcium• The elevated levels of intracellular calcium may also be due to release of calcium from the sarcoplasmic reticulum (SRJ (3) by cyclic AMP. Calcium then binds with contractile proteins I('P) leading to contraction. ~-Receptor stimulation may enhance the binding of calcium to the CP (4j or may increase the sensitivity of these proteins to calcium 15). CYCLIC AMP AND PHENYLEPHRINE-INDI.CED POSI'I+IV[ INOTROPIC RESPONSES It is now generally accepted that cyclic A M P is involved as a mediator in the inotropic response to adrenergic amines (Oye et al., 1964; Drummond et al., 1966: Kukovetz & Pooh, 1972: McNcill & Verma, 1973: Keely & Corbin, 1977). However. a lack of correlation between cyclic AM P and contractile force has also been reported (Oye & Langslet. 1972: Benfcy et al.. 1973; Osnes et al. 1973). A lack of correlation does not necessarily eliminate cyclic A M P as a mediator of responses, but only suggests the possible involvement of other mechanisms. On the other hand. elevation of cyclic A M P during increased myocardial contraction does not necessarily mean that the inotropic effects of all adrenergic amines arc mediated via cyclic AMP. Phenylephrine has been reported to increase cardiac contractility and cyclic A M P levels in isolated guinea pig and rat hearts (McNeill & Verma, 1973: Drummond & Hemmings, 1973: Keely et al., 1978), rabbit papillary muscle (Endoh et a/., 19761 and rat atria (Martinez & McNeill, 1977). The elevation of cyclic A M P levels was not affected by the presence of :~-adrenoceptor antagonists in most studies {Verma & McNeill, 1976; Wagner & Brodde, 1978). On the other hand, /,C-blocking agents were effective in preventing the cyclic A M P elevation [Osnes, 1976: Verma & McNeill, 1976: Bruckner et al., 19781. This supports the hypothesis that phenylephrinc posmsses
3"r2
ARUN G. TAHILIANI et al.
/f-agonistic activity in addition to its :~-adrenoceptor stimulant effects. Other data indicate that pretreatment ~ilh reserpine abolishes the phenylcphrineinduced elevation in cyclic A M P in rat atria and perfused hearts, suggesting that the elc~.ation in cyclic A M P ma~ be through a release of endogemms catecholamincs IVerma & McNeill. 1976: Martincz & McNeill. 19771 II"ig. II. A phentohtmine sensitive increase in cyclic A M P has been observed in a fe',~ studies. Phentolaminc ~as found to bc effective m preventing the c~clic A M P elevation m perfused rabbit hearts driven electrical b tl"ujimoto eta/.. 19761. A similar effect ~as reported b3 Kunos et al., 11976) in electricalh driven left atria from h~pothyroid rats. Hov~cvcr. phen.,,Icphrine failed to elevate c3clic A M P levels in quiescent atria suggesting that the phentolaminc-scnsitivc elevation of cyclic A M P requires mechanical activity. Kunos et al. ( 1 9 7 6 ) h a v e suggested that the elevation of cyclic A M P may be a resuh of events leading to inotropy rather than their cause i.e. :~-receptor stimulation. Simpson & McNeill ( 19801. ho,,vcver, were unable to conlirm an :~-mcdiated increase in cyclic A M P in rat atria. Osncs & (.')yc (19751 have suggested that the inotropic ctl'cct of phenylephrine may bc a result of a localizcd or minute accumulation of cyclic A M P or at slightly incrcascd rate of turnover of the nucleotidc. These changes may not bc detected by measuring total tissue content of c3clic AMP. A potential drawback of this suggestion is that in the case of h3pothyroidism, where the :~-adrenergic response is incrcascd. phcnylephrinc produccd an increase in cardiac contractility, but did not clcvatc cyclic A M P levels IOsncs. 1976). For the suggestion to hold. cyclic A M P should have been elevated. Further. in the prcscnce of phosphodiestcrase inhibiting agents, the positive inotropic response ~.as not potentiated [Schumann et al., 1974: Broddc et al.. 1978: Martincz & McNcill. 1977). In the presence of pindolol, phcnylephrinc failed to elevate c)clic AMF' in the presence of papaverine (Broddc eta/.. 1978). Thus. phcnylephrinc is capablc of elevating cyclic A M P lcvcls in cardiac tissues. "fhc elevation appears to be through /]-adrcnoccptor stimulation and the resulting events arc illustrated in Fig. 2.
SUMMARY
To summarize, a large number of studies indicate that the effects of phenylephrinc on ca:diac contractilit} arc mediated through 7-adrcnoceptors. although not exclusively. There are an equally large number of reports indicating some /1-adrenoccptor stimulant effects of phenylephrinc. Of the latter, some are based o n the finding of antagonism by //-receptor antagonists and some on the fact that phenylcphrine is capable of elevating cyclic AM P levels, which is primarily a [L. and not :~-adrcnoceptor effect. Although it is nov, widely accepted that phenylephrinc elevates cyclic A M P levels, the contribution and significance of the elevated nuclcotidc lcvels to the ovcrall positive inotropy of phcnylcphrine appears to bc small. :~-Adrenoceptors may be mvolved with calcium. a h h o u g h the precise interaction between calcium and the :z-adrcnoceptor is not clear. Finally. the adrcn-
ergic elti~cts seem to depend on the experimental and physiological conditions including calcium ion concentration, thyroid state and driving frcqucnc3.
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dependence of alpha adrenoceptor mcdiated positive inotropic effect in guinea pig heart. Eur. J. Pharmac. M), 215-220. MURAl) F., Cttl Y.-M. & SuIIn:RLANI) E. W. (1962) Adcnyl cyclase III. The effect of catecholamincs and choline esters on thc formation of adcnosine 3'.5' -phosphate b~ preparations from cardiac muscle and liver. J. hiol. Chem. 237, 1233-1238. NAKASIIIMA M.. MAI!DA K., SIKI'JA A. & HA(its() Y. (19711 Effcct of hypothyroid st~itus on myocardiz, l responses to s~mpathomimetic drugs. Jap..J. Pharmac. 21,819 825. OSNt.S J. B. (1976) Positive inotropic effect ',sithout cyclic AMP elcwltion after 2-adrcncrgic stimulation of perfused hearts from hypothyroid rvts. Acta pharmac, to.L (Kbh) 39, 232 240. OSNES J. B., CHRISIOI:H!RSEN T. & (9",~ 1. (1973J Mechanism of inotropic effect of catecholamines as rcxealed from experiments of the perfused rat heart. Acta ph.wiol. wand. (suppl) 396, 6. OSNES J. B. & (,)El: 1. (1975) Relationship bet~.een cyclic A M P metabolism and inotropic response of isolated rat hearts to phenylephrinc and other adrcncrgic amines. Adv. c)xlic Nucleotide Rex. 5, 415 433. ()YE I.. Bt;I('HI:R R. W., MORGAN H. E. & SI"I'ttERLANI) E. W. (1964) Epinephrine and cyclic Y.5'-AMP levels in v, orking rat hcarts. Fedn Proc. Fedn Am. Sots exp. Biol. 23, 562. f ) w 1. & LANGSLt!TA. (1972) The role of cyclic AMP in the inotropic response to isoprenaline and glucagon. Adv. cyclic Nucleotide Res. I, 291 300. POSNER P.. FARRAR E. L. & EAMBERI C. R. [1976) Inhibitory effects of catecholamines in canine cardiac Purkinje fibres. Am. J. Physiol. 231, 1415-1420. SANCIItiz-CIIAPULA J. (1981) Multiple effects of putative :~-adrcnoceptor agonists on the electrical and mechanical activity of guinea-pig papillary muscle. Naunyn-Schmiedeherg's Archs Pharmac. 316, 108 111. S([IMITZ W.. S(tIOI.Z H. & WERI)AN K. (1980) Evidence against a role of (Na' + K ' } ATPasc in the alphaadrcnoccptor mcdiatcd positivc inotropic effect of phenylephrine. Experientia 36, 1313-1315. SC'Hot,z H. (19801 Effects of beta- and alpha adrenoceptor agonists and adrenergic transmitter relcasing agents on the mcchanical activity of the heart. In llandhook o! Experimental Pharmacology Vol. 54/1: Adrenergic Activators and Inhibitors, Part ! (Edited by SZEKERES 1,.) pp 694-708. Springer, Berlin. S('Ht;MANN H. J., ENDOH M. & WAGNER, J. (1974) Positive inotropic effects of phcnylephrine in the isolated rabbit papillary muscle mediatcd by z~- and /~-adrenoceptors. Naunyn-Sehmiedhergs Arch~ Pharmac. 284, 133 143. SCIIIMANN H. J.. WAGNER J.. KNORR A.. Rlin)l:MlilSll:R J., SADON~ V. & SCHRAMSt G. (1978) Demonstration in human atrial preparation of ~-adrenoceptors mediating positive inotropic effects. Naun.vn Schmiedhergx Archs Pharmac. 302, 333- 336. S~MPSON W. W. & McNEILL J. It. (1980J The effect of adrcnergic agonists on the cyclic AMP levels in atria from euthyroid and hypothyroid rats. Rex. connnun. Chem. Path. Pharamc. 29, 487 497. STARKE K. (1977) Regulation of noradrenaline release by prcsynaptic receptor systems. Ret'. Physiol. Bioehem. Pharmac. 77, 1-124. STARKt! K. & I)Ot'HERTY J. R. (1980) Recent developments in 2-adrenoccptor research. ,1. Cardiot'a,w. Pharmae. 2 (suppl. 3) $269-$286.
3"4 VI:p,~.|.', S. ('. & M ( N , n . t . J .
ARt'N G, TAttll.l.XX;I ('t al.
|1. {1976) Biochemical and mechanical ell'cots of phen.~lephrine on the heart. Eu,'..1. Phormac. 36, 447 450. W.X(iXlR J.. KN()RR A. & S('ltt M..XNN H. J. 11977) On the presence of myocardial alpha-adrenoceptors in the atrium of guinea pig. Arch. Pharmac. "l'~ic. 3, 83 92. W..X(;XJ:R .1. & BRODDI O. -E. 119781 On the presence and distribution of alpha-adrcnoccptors m the heart of various species. Natmcn S('hmiedlwr#~ .lr('hs Pharma('. 3112, 239 254. W..x(,xJ~ J. & S(nt:xtAxx H. J. 119791 Different mechanisms underlying the stimulation of myocardial :,- and l¢-adrenoceptors. L!li' Sci. 24, 2045 2052. W ~ x z l l D. G. & St' J. L. (19661 Interactions bet~een s~m-
pathonlimetic ainincs and blocking agents on the rat ventricular sIfip..-lr(h.~ int. Pharm(wodrn. Ill&'. 161), 379-389. WlS[()N m. U. 11971) Effects of isoprenahne and phen',lephrine on energy-rich phosphate c o m p o u n d s and glucose-6-phosphate in smooth and cardiac muscle. Br. ,I. Pharmac. ,.13, 593 603. Y ( ~ (% S. & Llil: W. ('. (1970i Blockade of the cardiac action of phen~,lephrine by bretylium or c o c a i n e . . / . Plu*rm(a'. evp. Ther. 172, 274 2~1. 'lot:y(, B. A. & M('NNI.L J. H. 119741 The effect of noradrenaline and tyramine on cardiac contractility, cyclic A M P and phosphor}lase in normal and hyperthyroid rats. ('a~l. ,I. Physiol. Pharmac. 52, 375 383.
0306-3623/82/050369-06~[03.00,0 Copyright © 1982PergamonPress Ltd
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MINIREVIEW CYCLIC A M P - D E P E N D E N T A N D I N D E P E N D E N T POSITIVE INOTROPIC EFFECTS OF PHENYLEPHRINE* ARU~ G. TAHILIANI,SUBHASHC. VERMA,~ and JOlly H. MCNEILL Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C., Canada V6T lW5 (Received 23 March 1982)
The concept that catecholamines may exert their effects through two distinct mechanisms (Ahlquist, 1948) has proved to be extremely useful in the understanding of the effects of adrenergic agonists. Since that time, a considerable amount of work has been directed towards a better understanding of these effects. With the advent of newer and more specific agonists and antagonists, the ~t-and fl-receptors mediating the adrenergic effects have been subclassifled either as ~t or ~1 and fll or f12 (Lands et al., 1967: 1967a; Starke, 1977: Starke & Docherty, 1980). The positive inotropic and chronotropic effects produced by adrenergic agonists have long been associated with fl- adrenoceptors (Moran & Perkins, 1958; Black et al., 1964). However, more recent evidence suggests that zt- adrenoceptors also exist in the myocardium and that stimulation of these receptors may result in positive inotropic effects (Wenzel & Su, 1966: Gorier. 1967. 1968; Benfey & Varma. 1967: Mugelli et al., 1976). However, the question of the role of myocardial :t-adrenoceptors in mediating the inotropic effects of sympathomimetic agents has been land still is) a matter of controversy. The effects of phenylephrine, an adrenergic amine with predominant activity on ~-adrenoceptors (Ahlquist & Levy. 1959) have been studied extensively on the heart and the drug has often been used as an experimental tool to demonstrate the presence of myocardial :t-receptors (Nakashima et al., 1971; Schumann et al., 1974: Verma & McNeill, 1976: Wagner & Brodde, 1978). Ahhough it is widely speculated that the cardiac effects of phenylephrine are mediated via x-receptors, there still exists an element of doubt. This is because phenylephrinc has been shown to elevate cyclic AMP levels in myocardial tissues of guinea-pigs (McNeill & Verma. 1973). rats (Osnes & Oye. 1975) and rabbits (Endoh et al., 1976) and cyclic AMP elevation is essentially a [ L and not an z~-adrenoceptor function (Murad et al., 1962: Brinbaumer et al.. 1974: Kaumann et al., 1978: Martinez & McNeill, 1977a}. This * Work from our laboratory cited in this article was supported by grants from MRC (Canada} and the Can. Heart Fdn. ~.. Dr. S. C. Verma was the Professor and Chairman of the Department of Pharmacology, k. M. College of Pharmacy, Ahmedabad. India. Deceased, July 1981.
review summarizes the positive inotropic effects of phenylephrine in various preparations and the probable mechanisms by which these effects may be mediated. Studies demonstrating the cardiac effects of phenylephrine are shown in Table I. CYCLIC AMP-INDEPENDENT POSITIVE INOTROPIC EFFECTS OF PHENYLEPHRINE The positive inotropic effect of phenylephrine is known to be antagonized by ~-adrenoceptor antagonists. In the presence of phenoxybenzamine, a parallel shift of the concentration-response curve of phenylephrine to the right has been demonstrated (Benfey, 1973: Kunos & Nickerson, 1977). The shift is accompanied by a suppression of the maximum (Benfey, 1973). However, phentolamine appears to shift the curve to the right without affecting the maximum suggesting a competitive type of antagonism (Verma & McNeill, 1976: Martinez & McNeill, 1977; Wagner & Brodde, 1978: Bruckner, 1978). On the other hand, there are a few examples where the phenylephrineinduced increase in cardiac contractility was not affected by the aforementioned antagonists. These include the spontaneously beating rabbit atria (Yoo & Lee, 1970) and perfused isolated hearts from rats (Weston, 1971). A solution to this apparent discrepancy was suggested by Wagner et al. (1977) who found that the ~-adrenergic positive inotropic response was critically dependent on the frequency of stimulation. The antagonist effect of phentolamine is evident in preparations driven at about I Hz and is lost when the driving frequency is increased to more than 2.5 Hz (Schumann et al., 1974: Endoh & Schumann, 1975: Mugelli et al.. 1976). In spontaneously beating rat right atria, phentolamine failed to block the phenylephrine-induced responses (Bennett & Kemp, 1978k which supports the suggestion of Wagner et ul. (1977). A rational conclusion that can be drawn from these studies is that the mechanisms of action involved at varying frequencies are different. Frequency dependency of phentolamine antagonism has been observed with adrenaline (Mugelli et al., 1976): methoxamine (Endoh & Schumann. 1975) and other x-adrenergic agonists. At concentrations greater than 10,uM, the effects of phenylephrine were found to be antagonized by
369
3-',0
ARt N G. TAHn IANI ct ~11.
laLblc I. Studic~, shov, ing it positixc inolrorqc elgect of phcn.,.lcphrinc m i,,olatcd cardiac prcpiir:itior~, Irom cilllcrcnl
species i"issuc
.";pecics Guinea-pig
Lefl ulrJa Ventricle
Rabbit
Right ,it ria Pa pilkir.', inuscle Perfused heart Left atria
Rat
Ventricular strip Right atria l'apillar> muscle Pcrfuscd heart l.eft atriu
( "dl
('hicken
Dog 'o',s
(
Vcntricular strip Right atria l)apillar.,, muscle Perfused heart Papillar} muscle Ventricul,lr strip Atrial strip Papillar~ muscle Perfuscd heart Vei3trJcul,lr trahcculac Right atrial strip
Reference Gorier. 1967. 1968: Wagner ct a/.. 1977 I.edda eta/.. 1975; Wugner & Brodde. 197S: Sl'Jibaltaict ,ll., 19SO: l.edda uta/.. It)SO McNcill <'t a/.. 1972 Shibata cta/.. 1980; Sanches-('hapula. 1981 McNeill & Verma. 1973: Verma & McNeill. 1976 Ilcnl;e,, & Varma. 1967; 13enfey. 1971. 1973: Wagner & Rcinhardt. 1974: Benfe>. 1977 Broode uta/.. I978; Stlibata t't a/.. 19,gO l.eong & Benfe~,. I968; McNeill et el.. 1972: Shibata et al.. 1980 I{ndoh & Schumann. 1974: Schumann & Endoh. 1976; Shibala ut o/.. 1980 Starke. 19-/2; Wagner t't a/.. 1974:Ftqimott) et al.. 1976 Nakashima et o/.. 1971: Kunos & Nickcrson. 1977; Martm¢.," & McNcill. 1977 Wen.~el & Su. 1966: Wagner & Ilrodde. 197,R; Shihata uta/.. 10~0 ,Martincz & McNclll. 1977: Bennett & Kemp. 197,R: Shibula ut a/.. 19St) ()snes t': ,tl.. 1976; 197,R; Shibal,i ct a/.. 1980 Wcshm 1971: Osncs 1976; ()sties el a/.. 197S Bruckner et o/.. 1978: Wagner & Broddc. 197S Schmidl cta/., lg,~t} Wngncr & Brodde. 197S Wagner& Broddc. 1978 Benfe~ & ('arolin. 1971 K:ib¢la uta/.. 1969 Bruckncr. 197~: Bruckncr & SchtHl. 19S(I Schumann ct all.. 1978
fl-receptor antagonists (Brodde et el. 1948). Effects produced by' lower concentrations of phenylephrme were skox~ n to be insensitive to fl-receptor antagonists IBrodde et al.. 1948). This suggests thal the amine mediates its effects through :~-adrenoceptors up to concentrations of a b o u t 10 HM while higher concentrations probably involve both, ~- and /t-adrenoceptors. l h e r e is some evidence that temperature ITIti\ tilter the responses to phcnxlcphrme. On lo\~ering the temperature, tin increase in the inotropic potcne~ of phcnylcphrine has been reported m rat ~entricular strips and rat left atria (Brodde & ,Schumann. 197S~. Ito\~exer. Martinez & McNeill [1977p and Bcnl'ex (1977) did not obscrxe an ~, stick ch;.inge m the r:.il Icfl atriu. ()n the other hand. ~ h e n the temperature ~\as increased from 37 to 42 ('. Endoh et al. (1975l observed a decrease in the :,-adrenoceptor medJuted inotrope. \\hercas the fl-adrencrgic response of phen>lephrinc ~ l s not altered signilicantl 5. Apparentl> under some conditions lke :~-cldrenergic conaponcnl Js 1]-1oi,,2 sensitJ\e nt elevtited telnperalurcs. Net another factor lhdt seems to pla 5 a role in the adrcnergic responses is thai of the thyroid slate. While the fl-adrcncrgic response is believed to be enha,lced by hyperthyroidism and decreased in hypothyroid state (Nakashima et al.. 1971: Young & McNeilI, 1974: Hartley & McNeill. 1976) the opposite appears to hold true for the > a d r e n e r g i c responses. l h e > a d r e n e r g i c positb, e inotropic effect ~ a s mcreased m hypoth.,,roid stales (Nakashima et al.. 1971: Kuruos ct o/.. 1974; Kunos. 1977: Simpson & McNeill, 1980) while a decrease was observed m ks perthyroid animals (Kunos. 1977). These restllts indicate that the sensitivity of > a d r e n o c e p t o r s is increased m hypoth3roidism. K u n o s (1977) D u n d an incrcase of binding
of L~HJphenoxyhenzamine to intact left atria of h~poth.',roid rats and suggested that a change in the n u m b e r of binding sites may be responsible for a change in tile response. Ciaraldi & Marinelti (1977), using r~H]dihydroergoeryptine found that though the n u m b e r of :~- and //-receptors decreased m h~pothyroid rat ventricular membranes, the aflhfit.', and binding sites of both increased. Scholz (198()} suggested that the selecti,,e increase of the ~-adrenergic c o m p o n e n t may be due to changes beyond the receptor level. The rcsults discussed thus far provide evidence that phenylephrine stimulates :~-adrenoceptors and that stimulation of these receptors produces inolropic eft'cots. It appears reasonable to aSStLmc thal the e',entual mechanism through which these effects arc mediated invol',es calcium. This ma} be an increase m the intracellukir concentration of calcium ions interacting with the contractile proteins..,%hernati,,ely, the ellects ma~ resuh from changes in the sensitivity of the contractile protems for c a l c i u m I)-6(R). a calcium ~,low channel blocker, depresses the positive motropic ell'cot of phcnylephrine (Endoh e t a / . . 1975: l.edda ut a/.. 1975). The effects of phen}lephrine ma 5. thus he interpreted sis a result of altered calcium llt, x through the m.',ocardial membrane, probably tin enhstncemenl of the inv, ard ealcit,m current. In ventricular trtlbeculae of cattle depolarized with 22 mM K - , Bruckncr & Scholz 11980)observed a phenylephrine-indLLccd increase m contraction as v,,ell sis the slo~s imvard current ,a,hich ~verc inhibited by phentolamme. l.edda c t a / . {1980i studied the effects of phenylephrinc in guinea pig ~cntriclc strips m ~hich the ftlst sodium ch;.u3nels ~sere inacti\'ilted b\ 22 m M K ' .
In
contrast to the above sttidies, they found that the dectrical and mechanical responses to the anline were
Cardiac effects of phenylephrine
371 PHENYLEPHRINE
NEURONE 7
Jr", "
:
•"~
/
.
/-t
1~
Na + ATP
?
-- PHENYLEPHRINE
Conditions under which the positive inotropic effect of phenylephrine through respective receptors 0s most prominent. Alpha adrenergic Lower dose Lower frequency Hypothyroid state
Beta
adrenergic
.Higher dose Higher frequency Hyperthyroid s t a t e
Fig. 1. Schematic representation of the mechanism of the phenylephrine-induced positive inotropic effec. Phenylephrine may activate zc- or fl- adrenergic receptors directly or indirectly through the release of norepinephrine (NE). blocked by fl-. and not :c- antagonists. Similar results have been reported by Sanchez-Chapula [1981) in the guinea pig papillary muscle. Moreover. methoxamine was unable to restore the slow current in these studies. The proposal that ~-adrenoceptors may' be involved with an increa~ in calcium flux (Miura et aL, 1978) does not seem to be consistent with these data. W a g n c r & Schumann (1979) reduced the calcium ion concentration from 2.5 to 1.25 mM and observed a decrease in the affinity of the inotropic :~-adrenoceptors for phenylephrine. This suggests that :~-adrenergic effects are dependent not only on the trans-sarcolemmal calcium influx (Endoh et al., 1975a) but also on the extraccllular calcium ion concentration. Figure 1 illustrates the probable mechanisms through v.,hich phenylcphrine may act and the conditions under ~hich the receptor actions are most prominently seen. From the discussion so far, the precise mechanism of action of :~-adrenoceptors appears to be largely unknown. An involvement of calcium in the responses appears to be definite, but conflicting results do not yield a clear picture (Fig. 2). An attempt to explain the mechanism of 7-adrenoceptor action on the basis of Na" + K" ATPase activity has been made. Posner et a/. (1976l found that low concentrations of catecholamines inhibit +ZK uptake in dog Purkinje fibres. They suggested that the =-adrcnoceptor-induccd positive inotropic effect is due to the inhibition of N a ' + K" ATPase. However, Schmitz et al. (1980) did not detect any significant inhibition of (8t'Rb + K ' F u p t a k e , a measure of Na+ + K ÷ ATPase activity, in intact cat papillary muscles in the presence of phenylephrine though an increase in the contractility was seen.
> z / CP
_
"q 5
.......
Fig. 2. A hypothetical scheme of events following the stimulation of adrenergic receptors by phenylephrine. An increase in calcium influx which may be due to cyclic AMP (I) or inhibition of N a ' . K--ATPase (21 results in an increase in intracellular calcium• The elevated levels of intracellular calcium may also be due to release of calcium from the sarcoplasmic reticulum (SRJ (3) by cyclic AMP. Calcium then binds with contractile proteins I('P) leading to contraction. ~-Receptor stimulation may enhance the binding of calcium to the CP (4j or may increase the sensitivity of these proteins to calcium 15). CYCLIC AMP AND PHENYLEPHRINE-INDI.CED POSI'I+IV[ INOTROPIC RESPONSES It is now generally accepted that cyclic A M P is involved as a mediator in the inotropic response to adrenergic amines (Oye et al., 1964; Drummond et al., 1966: Kukovetz & Pooh, 1972: McNcill & Verma, 1973: Keely & Corbin, 1977). However. a lack of correlation between cyclic AM P and contractile force has also been reported (Oye & Langslet. 1972: Benfcy et al.. 1973; Osnes et al. 1973). A lack of correlation does not necessarily eliminate cyclic A M P as a mediator of responses, but only suggests the possible involvement of other mechanisms. On the other hand. elevation of cyclic A M P during increased myocardial contraction does not necessarily mean that the inotropic effects of all adrenergic amines arc mediated via cyclic AMP. Phenylephrine has been reported to increase cardiac contractility and cyclic A M P levels in isolated guinea pig and rat hearts (McNeill & Verma, 1973: Drummond & Hemmings, 1973: Keely et al., 1978), rabbit papillary muscle (Endoh et a/., 19761 and rat atria (Martinez & McNeill, 1977). The elevation of cyclic A M P levels was not affected by the presence of :~-adrenoceptor antagonists in most studies {Verma & McNeill, 1976; Wagner & Brodde, 1978). On the other hand, /,C-blocking agents were effective in preventing the cyclic A M P elevation [Osnes, 1976: Verma & McNeill, 1976: Bruckner et al., 19781. This supports the hypothesis that phenylephrinc posmsses
3"r2
ARUN G. TAHILIANI et al.
/f-agonistic activity in addition to its :~-adrenoceptor stimulant effects. Other data indicate that pretreatment ~ilh reserpine abolishes the phenylcphrineinduced elevation in cyclic A M P in rat atria and perfused hearts, suggesting that the elc~.ation in cyclic A M P ma~ be through a release of endogemms catecholamincs IVerma & McNeill. 1976: Martincz & McNeill. 19771 II"ig. II. A phentohtmine sensitive increase in cyclic A M P has been observed in a fe',~ studies. Phentolaminc ~as found to bc effective m preventing the c~clic A M P elevation m perfused rabbit hearts driven electrical b tl"ujimoto eta/.. 19761. A similar effect ~as reported b3 Kunos et al., 11976) in electricalh driven left atria from h~pothyroid rats. Hov~cvcr. phen.,,Icphrine failed to elevate c3clic A M P levels in quiescent atria suggesting that the phentolaminc-scnsitivc elevation of cyclic A M P requires mechanical activity. Kunos et al. ( 1 9 7 6 ) h a v e suggested that the elevation of cyclic A M P may be a resuh of events leading to inotropy rather than their cause i.e. :~-receptor stimulation. Simpson & McNeill ( 19801. ho,,vcver, were unable to conlirm an :~-mcdiated increase in cyclic A M P in rat atria. Osncs & (.')yc (19751 have suggested that the inotropic ctl'cct of phenylephrine may bc a result of a localizcd or minute accumulation of cyclic A M P or at slightly incrcascd rate of turnover of the nucleotidc. These changes may not bc detected by measuring total tissue content of c3clic AMP. A potential drawback of this suggestion is that in the case of h3pothyroidism, where the :~-adrenergic response is incrcascd. phcnylephrinc produccd an increase in cardiac contractility, but did not clcvatc cyclic A M P levels IOsncs. 1976). For the suggestion to hold. cyclic A M P should have been elevated. Further. in the prcscnce of phosphodiestcrase inhibiting agents, the positive inotropic response ~.as not potentiated [Schumann et al., 1974: Broddc et al.. 1978: Martincz & McNcill. 1977). In the presence of pindolol, phcnylephrinc failed to elevate c)clic AMF' in the presence of papaverine (Broddc eta/.. 1978). Thus. phcnylephrinc is capablc of elevating cyclic A M P lcvcls in cardiac tissues. "fhc elevation appears to be through /]-adrcnoccptor stimulation and the resulting events arc illustrated in Fig. 2.
SUMMARY
To summarize, a large number of studies indicate that the effects of phenylephrinc on ca:diac contractilit} arc mediated through 7-adrcnoceptors. although not exclusively. There are an equally large number of reports indicating some /1-adrenoccptor stimulant effects of phenylephrinc. Of the latter, some are based o n the finding of antagonism by //-receptor antagonists and some on the fact that phenylcphrine is capable of elevating cyclic AM P levels, which is primarily a [L. and not :~-adrcnoceptor effect. Although it is nov, widely accepted that phenylephrinc elevates cyclic A M P levels, the contribution and significance of the elevated nuclcotidc lcvels to the ovcrall positive inotropy of phcnylcphrine appears to bc small. :~-Adrenoceptors may be mvolved with calcium. a h h o u g h the precise interaction between calcium and the :z-adrcnoceptor is not clear. Finally. the adrcn-
ergic elti~cts seem to depend on the experimental and physiological conditions including calcium ion concentration, thyroid state and driving frcqucnc3.
REFI".REN('F;S AHI.QtISI R. P. (1948) A study of the adrenotropic receptors. Anr J. Ph.wiol. 153, 586 6(X). Aln.Oulsr R. P. & l.j:v', B. (1959) Adrcnergic receptive mechanism of canine ileum. J. Pharnlac. 127. 146 149. Bt.xH!Y B. G. 11973) Characterization of :t-adrenoceptors in the myocardium Br..I. Pharmac. 48, 132 138. BENHiY B. G'. (19771 Cardiac adrenoceptors of low temperature and the adrenoceptor interconversion h3pothcsis. Ill'. J. Pharnzac. 61, 167 173. BIN'/vv B. G. & VaR~.I,,, 1). R. (19671 Interactions of s,,mpathomirnetic drugs, propranolo] and phcntolamine on atrial refractor', period and contractility. Br. J. Pharnm¢. 30,603 611. BExHi'r B. (i.. Kt xos G. & NI('KI:RSON M. (19731 :~-Adrenoceptor mediuted effect of catecholamines on cardiac contractility not assoc(ated v, ith increased myocardial cyclic AMP accumulation. IX Int. ('onq. Biochenfi.~H'v. Stockholm 1973. Abstracts. p. 354. BI xlNI:I I T. & Kit,n, A. 119781 Lack of e~idence for a lemperature-mcdiated change of adrcnoccptor type in the rat heart. Naun~n-Schmicdeht,rq.~ -Irchs Pharma¢. 301, 217 222. BIRNBA( MI!R L.. [)(tin. S. L. & KAt:MANN A..I. 11't74) Receptors and acceptors: A necessary distinction m hormone binding studies...hh, cyclic .Vuch,otidc Rc~. 4, 239 281. BI.A( K J. W.. ('R(I\VInER A. 1"., Sn.~,XKSR. G.. SMJln L. H. & DOR',;HtJRSl A. ('. (19641A new adrcnerglc beta receptor antagonist. Lancet I, 1080 11)81. BRODI)t! O. 1"i.. MOI¢)MI'R,~,S.. [{',IDOtl M. & S¢ nt"~la~,',, If. ,I. (19481 Lack of correlation betv,een the positl',e inotropit effect evoked b.', ~-adrcnoceptor stimulation and the levels of cyclic AMP and for cylic GMP in thc isolated ventricle ,;trip of the rabbit J. moh,c. Ceil. (',rdi,I. 10. 2O7 219. BRt('KNI.R R. (19781 The positive inotropic ell'cuts of phen3 lephrine in bovine c,lrdiac muscle. ,\'amUn S~ hmicdt'her~l~ :lrch.s Pharmac. 302. (suppl.) R31. Bm ('KXl R R. & Scnol z H. (19801 Eflizcts of phcnylephrmc in the pleseno2 of propallolol on slow potentials it) nlammalian ',enu'ictflar fibres. Naun.xn-Sctmlicdct~er~t~ ..lrchs I'harmac. 31 l, R37. ('I,'~RAII)I F. & MAR[NI i't/ (L V. 119771 lhyroxine and prop',hhiouracil effects m t i t , 011 alpha and beta adrenergic receptors itl rat heart. 13ioch('m. hioph~. Re,. (oremira. 74, 984 991. I)RI:MMONI) (j. I.. [)tNc.,,x I.. & ItlRIZMAN E. (19661 Efli:ct of epinephrine on phosphor,,lasc b kinase in perfused rat hearts..I, biol. Chcnr 241, 5899 591)3. [)Rt MMONI)a . I. & [h.MMIN(iS S. J. (19731 Role of uden',late c',clasc-c,,clic AM P in cardiac aclions of adrencrgic amines. In Rt.ccllt ~ldl(ltR'('.S ill Stl,lh'~ oil ({D'ditlu S t r l , -
tm'c and Metabolism. Vol. 3. (l!ditcd b', DUaIIA N. SJ pp 213 222. Uni~.ersily Park Press. Baltimore. Exl)on M. & S~ln",lay>; tl. J. 119751 I-requcnc3 dependence of the positive inotropic ell'cot of mcthoxaname and naphzolinc mediated b~, alpha adrenoceptors m the isolated rabbit papillar3 muscle..\mmln-S¢hmit'dhcr~l~ .,lmh~ t'harmac. 287. 377 379. [NI)(lll M.. WA(iNI R J. & S ( I n MANN H..I. 11975) Inllucnce of temperature o n Ihe positi;c motropic e(l;,.zct5mediated by ):- and //-adrcnoccptors m the isolated rabbit pap(11ill'}
ii111scle..Vaunyn-S~hmiedchcrq~ .Irch~
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