1
ABSTRACTS B?wxNGaPlnE pfJIxmmAHpERyINm- IucyPariei, MI) tiD. C!omWQ DcmaldC.qyler,m)r Childrm'sHa3pitall4sdicalCenter,Bcetcm,Msss. Bandingofthepllmmry arteryhasprovedeffective indecreasing excesspulnmaqblocdflavandprevsnting ~lopmntofpulnmxy~iarincriticallyill infIantS.lheN6wEzng1andBghIalInfantCardiacPrcgram expWisncewithtMspzxmdWe (7/68-6/72) has beenre- vimed.Basoverallmrtality forbaiingin 206Mants is36%krluding64eerlydeathsandlOlateare~.The latterincludes&ceewhoeqiredduringcormcti~sur- gery.Infantswithventricularssptaldefect(88)~ sentthelxgmtgroup~mrtalityanmg48tithsinple defectswas 8% aapamdto 42%amxq 4Owifhass~ated lesicns.mallinf~~~ty~~~o~~ whenthsd~isintemqted (45 vs. 3l%).prcbably reflecting sicker andycunger patient~Transpktimswithatrialsepte&nyhavea ~mcrrtaLitythanthagrcupwithout (38vs.47%).Sig- nifioanthpmmmntinnnrtality~ultswhenthefi~ uresarecorxectsdforIcwbiMmqhtandseriousass~ ciatedammlies,particularlymmgthoeetithandocar dialaWhicndefect@!ms).m3lImu.ityforbanding mmginfan~withessentially rnrcprrectablelesiarsis 49% (range l2-80%) withvhkually all deaths occmrhg early.Althaqhthemortalityfigurmfortheto~grmp arehighamlleadonetoahatanpleterxmxhcmata earlierage,fornmtofthelesiasitshculdbeborne inmind&atpllhmaq arterybandingis ~~~ti==d=df~ahast stilt. thsally . andpcst~ative lImMgm&manyofthepatients suc~fullyplliah3draayb3ccmcandidatesfor caxmc&Rsurgezy. THE ROLE OF ALPHAADRENERGIC RECEPTORS IN MEDIATING POSI- TIVE INOTROPIC EFFECTS IN VENTRICULAR MYOCAPDIUM William W. Parmley, MD,FACC; Babeth Rabinowitz, MD, Leonard Chuck, BA, Cedars-Sinai Medical Center, Los Angeles, California. It has been traditionally assumed that there are no alpha adrenergic receptors of importance in left ventricular myocardium. In order to evaluate this assumption, dose response curves to alpha agonists and antagonists were obtained in isolated cat papillary muscles studied in vitro. Methoxamine (n=6) produced a 30 and 45% increase in contractile force at doses of lo-5 and lo-4M. These effects were unchanged following beta adrenergic blockade with 10-6~ propranolol, but were totally abolished by alpha adrenergic blockade with 10w6M phentolamine or ergotamine. Phenylephrine produced the following in- creases in contractile force: 10% at 10_7M, 30% at lo-6M and 60% at lo-5M (n=B). These effects were not altered by 10e6M propranolol although they were reduced by at least half with alpha blockade by lo-6M phentolamine or ergotamine. This suggests that the effects of phenyleph- rine were due to both alpha adrenergic and non-adrenergic receptor stimulation. The known positive inotropic ef- fects of isoproterenol were unaffected by the addition of lo-6M phentolamine. The known positive inotropic effects of norepinephrine (r-1=17) were partially blocked at low doses by lo-6M propranolol and at high doses by lo-6M phentolamine. Parallel measurements of the effects of these agents on myocardial adenyl cyclase activity con- firmed that the beta agents stimulated adenyl cyclase activity while the alpha agonists did not increase adenyl cylcase activity. Thus, the present study suggests that alpha agonists have positive inotropic effects on the myocardium in a manner similar to beta adrenergic agents. These effects do not appear to be mediated by stimulation of adenyl cyclase activity. DYNAMIC RESPONSIVENESS OF DISTANT MYOCARDIUM DURING TRANSIENT ANTERIOR WALL ISCHEMIA Frederic Pashkow, MD; Roger Holland, BS, Harold Brooks,MD University of Chicago, Chicago, Illinois The regional responses of distant myocardium (DIST) sup- plied by the left circumflex artery to acute ischemia of anterior myocardium (ISCH) supplied by anterior descend- ing artery (LAD) was studied in 12 open chest anesthe- tized pigs. Three markers of regional response were used for both areas; a newly-designed, low impedance surface ECG electrode, a force gauge sutured in series with outer wall fibers, and coronary inflow to the region. Flow was measured by electromagnetic flowmeter cuff-probes around the proximal coronary artery of supply, with special care taken in dissection and placement to minimize interrup- tion of vascular innervation. With transient LAD occlu- sions (I5 to 120 sec.) the characteristic rapid decline in contractile force and evolution of surface ECG changes in the ISCH area was almost invariably accaepanied by a significant increase in contractile force in the DIST area (91% of 57 occlusions). DIST QRS-T voltage changes occurred less frequently (67% of 30 occlusions). In only 58% of 34 occlusions in which there was an increased DIST contraction, was there a concommitant rise in circumflex coronary inflow. High dose propranolol or phentolamine did not block the DIST responses. When the circumflex artery was cannulated and perfused from the carotid artery the DIST response was obliterated - suggesting interrup- tion of vascular neural fibers by the tight cannulating ligature. The almost uniform finding of overcontraction of DIST normal myocardium during early ischemia is con- sistent with a reflex homeostatic mechanism for conserva- tion of whole ventricular performance perhaps induced by the abnormal stretch of asynchronous contraction. The absence of a consistent rise in circumflex flow suggests the stimulation of anastomotic inflow. DIGCKIN EFFECTS ON SINUS NODE REENTRY IN THE DOG Karlen L. Paulay, MD; Anthony N. Damato, MD, U. S. Public Health Service Hospital, Staten Island, New York Using the recently described experimental model for sinus node reentry (SNR) the effect of digoxin (D) was assessed in 10 dogs with extrinsic cardiac denervation (group I) and in five dogs with an intact cardiac nerve aupply (group II). In all dogs, before D, after the last basic beat, Al, a premature atria1 beat, A2, was followed by a sinus node reentrant beat, A3, vhen A2 fell within the reentry zone. Thirty-five minutes (av) after an i.v, bolus (7.5 ug/kg) and infusion (2.5 ug/kg/min) of D, toxicity developed manifest by either increased ven- tricular and/or ectopic atria1 automaticity (14 dogs) or high degree A-V block (one dog in group II). D had re- latively little effect on SNR in both groups, and SNR could be demonstrated at the onset of toxicity in all dogs. D delayed the appearance of A3 during SNR (i.e. increased the A2A3 interval) by 40 msec (av for groups I and II) with a maximum delay of 200 msec in one dog in group II. This increase in the A2A3 interval which indicated delay along the reentrant pathway did not cor- relate with atria1 refractoriness which increased 14 msec (av; atria1 effective refractory period) in group I and decreased 22 msec (av) in group II. In seven dogs that developed Increased ectopic atria1 automatlcity with D, premature atria1 stimulation was followed by reentry that appeared to originate from the site of the ectopic atria1 focus, and suggested that automaticity per se may prediapoae to reentry. The knowledge of the relative in- sensitivity of SNR to D, at least in this experimental model, contrasts with the previously reported sensitivity of SNR to guinidine, and may be important in the manage- ment of SNR in man. January 1974 The American Journal of CARDIOLOGY Volume 33 161

The role of alpha adrenergic receptors in mediating positive inotropic effects in ventricular myocardium

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Page 1: The role of alpha adrenergic receptors in mediating positive inotropic effects in ventricular myocardium

ABSTRACTS

B?wxNGaPlnE pfJIxmmAHpERyINm- IucyPariei, MI) tiD. C!omWQ DcmaldC. qyler,m)r Childrm'sHa3pitall4sdicalCenter,Bcetcm,Msss.

Bandingofthepllmmry arteryhasprovedeffective indecreasing excesspulnmaqblocdflavandprevsnting ~lopmntofpulnmxy~iarincriticallyill infIantS.lheN6wEzng1andBghIalInfantCardiacPrcgram expWisncewithtMspzxmdWe (7/68-6/72) has been re- vimed.Basoverallmrtality forbaiingin 206Mants is36%krluding64eerlydeathsandlOlateare~.The latterincludes&ceewhoeqiredduringcormcti~sur- gery.Infantswithventricularssptaldefect(88)~ sentthelxgmtgroup~mrtalityanmg48tithsinple defectswas 8% aapamdto 42% amxq 4Owifhass~ated lesicns.mallinf~~~ty~~~o~~ whenthsd~isintemqted (45 vs. 3l%).prcbably reflecting sicker and ycunger patient~Transpktimswithatrialsepte&nyhavea ~mcrrtaLitythanthagrcupwithout (38vs.47%).Sig- nifioanthpmmmntinnnrtality~ultswhenthefi~ uresarecorxectsdforIcwbiMmqhtandseriousass~ ciatedammlies,particularlymmgthoeetithandocar dialaWhicndefect@!ms).m3lImu.ityforbanding mmginfan~withessentially rnrcprrectablelesiarsis 49% (range l2-80%) with vhkually all deaths occmrhg early.Althaqhthemortalityfigurmfortheto~grmp arehighamlleadonetoahatanpleterxmxhcmata earlierage,fornmtofthelesiasitshculdbeborne inmind&atpllhmaq arterybandingis ~~~ti==d=df~ahast

stilt. thsally

. andpcst~ative lImMgm&manyofthepatients suc~fullyplliah3draayb3ccmcandidatesfor caxmc&Rsurgezy.

THE ROLE OF ALPHA ADRENERGIC RECEPTORS IN MEDIATING POSI- TIVE INOTROPIC EFFECTS IN VENTRICULAR MYOCAPDIUM William W. Parmley, MD,FACC; Babeth Rabinowitz, MD, Leonard Chuck, BA, Cedars-Sinai Medical Center, Los Angeles, California.

It has been traditionally assumed that there are no alpha adrenergic receptors of importance in left ventricular myocardium. In order to evaluate this assumption, dose response curves to alpha agonists and antagonists were obtained in isolated cat papillary muscles studied in vitro. Methoxamine (n=6) produced a 30 and 45% increase in contractile force at doses of lo-5 and lo-4M. These effects were unchanged following beta adrenergic blockade with 10-6~ propranolol, but were totally abolished by alpha adrenergic blockade with 10w6M phentolamine or ergotamine. Phenylephrine produced the following in- creases in contractile force: 10% at 10_7M, 30% at lo-6M and 60% at lo-5M (n=B). These effects were not altered by 10e6M propranolol although they were reduced by at least half with alpha blockade by lo-6M phentolamine or ergotamine. This suggests that the effects of phenyleph- rine were due to both alpha adrenergic and non-adrenergic receptor stimulation. The known positive inotropic ef- fects of isoproterenol were unaffected by the addition of lo-6M phentolamine. The known positive inotropic effects of norepinephrine (r-1=17) were partially blocked at low doses by lo-6M propranolol and at high doses by lo-6M phentolamine. Parallel measurements of the effects of these agents on myocardial adenyl cyclase activity con- firmed that the beta agents stimulated adenyl cyclase activity while the alpha agonists did not increase adenyl cylcase activity. Thus, the present study suggests that alpha agonists have positive inotropic effects on the myocardium in a manner similar to beta adrenergic agents. These effects do not appear to be mediated by stimulation of adenyl cyclase activity.

DYNAMIC RESPONSIVENESS OF DISTANT MYOCARDIUM DURING TRANSIENT ANTERIOR WALL ISCHEMIA Frederic Pashkow, MD; Roger Holland, BS, Harold Brooks,MD University of Chicago, Chicago, Illinois The regional responses of distant myocardium (DIST) sup- plied by the left circumflex artery to acute ischemia of anterior myocardium (ISCH) supplied by anterior descend- ing artery (LAD) was studied in 12 open chest anesthe- tized pigs. Three markers of regional response were used for both areas; a newly-designed, low impedance surface ECG electrode, a force gauge sutured in series with outer wall fibers, and coronary inflow to the region. Flow was measured by electromagnetic flowmeter cuff-probes around the proximal coronary artery of supply, with special care taken in dissection and placement to minimize interrup- tion of vascular innervation. With transient LAD occlu- sions (I5 to 120 sec.) the characteristic rapid decline in contractile force and evolution of surface ECG changes in the ISCH area was almost invariably accaepanied by a significant increase in contractile force in the DIST area (91% of 57 occlusions). DIST QRS-T voltage changes occurred less frequently (67% of 30 occlusions). In only 58% of 34 occlusions in which there was an increased DIST contraction, was there a concommitant rise in circumflex coronary inflow. High dose propranolol or phentolamine did not block the DIST responses. When the circumflex artery was cannulated and perfused from the carotid artery the DIST response was obliterated - suggesting interrup- tion of vascular neural fibers by the tight cannulating ligature. The almost uniform finding of overcontraction of DIST normal myocardium during early ischemia is con- sistent with a reflex homeostatic mechanism for conserva- tion of whole ventricular performance perhaps induced by the abnormal stretch of asynchronous contraction. The absence of a consistent rise in circumflex flow suggests the stimulation of anastomotic inflow.

DIGCKIN EFFECTS ON SINUS NODE REENTRY IN THE DOG Karlen L. Paulay, MD; Anthony N. Damato, MD, U. S. Public Health Service Hospital, Staten Island, New York

Using the recently described experimental model for sinus node reentry (SNR) the effect of digoxin (D) was assessed in 10 dogs with extrinsic cardiac denervation (group I) and in five dogs with an intact cardiac nerve aupply (group II). In all dogs, before D, after the last basic beat, Al, a premature atria1 beat, A2, was followed by a sinus node reentrant beat, A3, vhen A2 fell within the reentry zone. Thirty-five minutes (av) after an i.v, bolus (7.5 ug/kg) and infusion (2.5 ug/kg/min) of D, toxicity developed manifest by either increased ven- tricular and/or ectopic atria1 automaticity (14 dogs) or high degree A-V block (one dog in group II). D had re- latively little effect on SNR in both groups, and SNR could be demonstrated at the onset of toxicity in all dogs. D delayed the appearance of A3 during SNR (i.e. increased the A2A3 interval) by 40 msec (av for groups I and II) with a maximum delay of 200 msec in one dog in group II. This increase in the A2A3 interval which indicated delay along the reentrant pathway did not cor- relate with atria1 refractoriness which increased 14 msec (av; atria1 effective refractory period) in group I and decreased 22 msec (av) in group II. In seven dogs that developed Increased ectopic atria1 automatlcity with D, premature atria1 stimulation was followed by reentry that appeared to originate from the site of the ectopic atria1 focus, and suggested that automaticity per se may prediapoae to reentry. The knowledge of the relative in- sensitivity of SNR to D, at least in this experimental model, contrasts with the previously reported sensitivity of SNR to guinidine, and may be important in the manage- ment of SNR in man.

January 1974 The American Journal of CARDIOLOGY Volume 33 161