Effects of Methoxamine and Phenylephrine on Left Ventricular Contractility in Rabbits

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1350 JACC Vol. 14, No. 5 November 1, 1989:1350-8

MARVIN W. KRONENBERG, MD, FACC, ROBERT W. McCAIN, MD, ROBERT J. BOUCEK, JR., MD, DAVID W. GRAMBOW, MD, KIICHI SAGAWA, MD, GOTTLIEB C. FRIESINGER, MD, FACC

Nashville, Tennessee

The end-systolic pressure-volume relation is employed to oxamine. Pretreatment with propranolol blunted the effect evaluate left ventricular contractility. In clinical studies, of phenylephrine on isovolumic pressure (n = 6, p < 0.02). pharmacologic vasoconstriction is used to increase left In protocol 3, cross-circulation experiments allowed ventricular systolic pressure to assess pressure-volume re- study of the effect of these drugs on isovolumic left ventric- lations. However, the effect of vasoconstrictors on the ular pressure in the isolated heart and simultaneously on ventricular contractile state is not well characterized. The the systemic arterial pressure in the intact anesthetized effects of methoxamine and phenylephrine on systemic rabbit (support rabbit). Methoxamine decreased isovolu- arterial pressure and left ventricular contractility in rabbits mic left ventricular pressure at infusion rates that increased were studied with three protocols. mean arterial pressure in the support rabbit. With phenyl- In protocol 1, anesthetized rabbits (n = 10) were ephrine, both the left ventricular isovolumic pressure and injected with incremental doses of methoxamine and phen- the mean arterial pressure increased. ylephrine intravenously. Methoxamine (4 mg) increased the Thus, in the isolated supported heart, phenylephrine mean arterial pressure by 50 -C 12% (mean t SE) (n = 5, increased left ventricular contractility at doses that pro- p = 0.001). Phenylephrine (0.2 mg) increased mean arterial duced peripheral vasoconstriction in the intact rabbit. pressure by 82 -t 14% (n = 5, p = 0.004). In protocol 2, Conversely, methoxamine reduced ventricular contractility isolated blood-perfused hearts were injected with incremen- in the isolated heart at doses that produced peripheral tal doses of these drugs in the ascending aorta in amounts vasoconstriction in the intact rabbit. The isolated hearts approximately equal to the concentrations injected in the had variable susceptibility to the depressant effect of meth- intact rabbits. Methoxamine (2 mg) reduced isovolumic oxamine. These results demonstrated the allowable range peak systolic left ventricular pressure by 43 f 9% (n = 7, for valid results and the limitations of using pharmacologic p = 0.003), whereas phenylephrine (0.1 mg) increased the vasoconstricting agents to manipulate arterial pressure isovolumic pressure by 24 + 9% (n = 7, p < 0.05). These afterload when assessing left ventricular contractility in thii responses indicated an enhanced contractile state with model and possibly in humans. phenylephrine and a reduced contractile state with meth- (.I Am Co11Cardiol1989;14:1350-8)

The end-systolic pressure-volume relation is an index of left preload volume and is sensitive to changes in inotropy (1). In ventricular contractility that is relatively independent of the intact animal and in humans, pharmacologic vasoconstriction with methoxamine or phenylephrine is commonly From the Departments of Medicine and Pediatrics, Vanderbilt University employed to increase the ventricular pressure afterload to School of Medicine, Nashville, Tennessee. This study was supported in part by Research Career Development Award 1 K04 HLO0852(Dr. Kronenberg) determine pressure-volume relations (2-4). However, the and a National Research Service Award 5 T32 HL07411from the National direct effects of these drugs on the myocardial contractile Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; Biomedical Research SupportGrant 523713(Dr. Boucek) from the state are understood incompletely. A valid estimate of Division of Research Resources, National Institutes of Health, Bethesda, and ventricular contractility is not possible if these agents modify the Dan May Student Scholarship in Cardiology at Vanderbilt University (Dr. contractility. In animals, phenylephrine increases myocar- Grambow). Manuscript received February 13, 1989;revised manuscript received May dial contractility (5-10). However, the data for methoxamine 9, 1989,accepted May 24, 1989. are more controversial (11); some investigators reported Address for ren_dnts: Marvin W. Kronenberg, MD, Cardiology Division, CC-2218,Vanderbilt University Medical Center North, Nashville, Tennessee minimal effects (12), whereas others found dose-related 37232. myocardial stimulation or depression (13-18). Further, the

01989 by the American College of Cardiology 0735-1097/89/$3.50 JACC Vol. 14, No. 5 KRONENBERG ET AL. 1351 November 1, 1989: 1350-S METHOXAMINE, PHENYLEPHRINE AND CONTRACTILITY

effects of methoxamine on pressure-volume relations in an Approximately 100 to 150 ml of blood was withdrawn ejecting heart preparation (19) may be related to the heart or through a femoral artery catheter to prime the isolated heart the arteries, or both (20). perfusion system. Half this volume was replaced with nor- To clarify and quantitate the myocardial and systemic mal saline solution and half with perfluorocarbon (FC-43, efects of methoxamine andphenylephrine, we employed the Alpha Therapeutic Company). The chest was opened by intact rabbit, the isolated isovolumic rabbit heart and a midline sternotomy. The heart was exposed and a cannula cross-circulation experiment in which we assessed contrac- inserted into the aorta. The superior and inferior venae tility in the isolated isovolumic heart and arterial pressure in cavae, the azygos vein and the pulmonary arteries were the intact rabbit simultaneously. ligated. The heart and lungs were excised and suspended by the aortic cannula in a constant temperature chamber that was heated by a water bath to approximately 30°C. Blood Methods drawn from a reservoir with use of a roller pump (Cole- Experimental protocols. New Zealand white rabbits Parmer, model 7562-10) was pumped to the heart at constant weighing 2.5 to 5 kg were anesthetized with intravenous flow through an oxygenation chamber (97% oxygen, 3% pentobarbital (50 mg/kg body weight). Intravascular pres- carbon dioxide), and a 40 p filter (Pall, model SQ4OS), sures were registered by pressure transducers (Gould, series leading to the aortic cannula. The lungs were removed. A P23Db) and recorded on a strip chart recorder (Gould, model polyethylene cannula was placed in the right ventricle from 2400s) running continuously at 1 mm/s. Three types of the pulmonary artery to return the coronary blood flow to protocols were performed: in protocol 1, blood pressure the reservoir. A prestressed balloon attached to a catheter dose-response curves were determined in intact anesthetized was inserted through the mitral valve into the left ventricle rabbits. In protocol 2, left ventricular isovolumic pressure and inflated with a calibrated syringe. A thin polyethylene dose-response curves were evaluated in isolated rabbit cannula was inserted adjacent to the balloon to vent blood hearts. These studies were designed to study the effects of from the Thebesian flow or possible occasional aortic regur- the approximate concentrations found during the protocol 1 gitation. Pressure transducers were connected to the aortic on contractile state. In protocol 3, a cross-circulation study and left ventricular catheters. Small electrodes were clipped was performed with an isolated heart and a support rabbit. to the left atrium for overdrive electrical stimulation at rates This protocol was designed to assess simultaneously the of 90 to 120/min, selected to optimize force development effects of these drugs on arterial pressure in the intact (Grass, model SD9). The preparation was similar to that support rabbit and on left ventricular isovolumic pressure in used previously in this laboratory (21). the isolated heart, with use of the isolated heart as a When the isovolumic systolic pressure was stable, bolus bioassay. injections (0.1 ml each) of serial concentrations of either For the dose-response curves, we used log serial dilutions methoxamine or phenylephrine solution were injected (in in saline solution of methoxamine hydrochloride (20 mg/ml) seven preparations each) into the aortic cannula, starting (Vasoxyl, Burroughs Wellcome) or of phenylephrine hydro- from the most dilute, allowing sufficient time between doses chloride (10 mg/ml) (NeoSynephrine, Winthrop Breon). The to achieve stable isovolumic left ventricular pressure (usu- drugs had similar molecular weights (247.72 versus 203.67 ally 1-5 min). Only one drug was injected into each prepa- g/mole, respectively), but the concentration of methoxamine ration. The arterial pH, PO,, Pco, and bicarbonate concen- per ampule was double that of phenylephrine. tration were measured periodically. The pH was maintained Protocol 1: intact rabbit preparation. After anesthesia, at physiologic levels with injections of sodium bicarbonate catheters were placed in the common carotid artery and the into the venous return of the circuit as necessary. In six internal jugular vein in 10 rabbits. After 210 min of stable phenylephrine studies 0.2 mg of propranolol was injected arterial pressure recording, a series of increasing concentra- after the I mg dose of phenylephrine. Then 1 mg of phenyl- tions of either phenylephrine or methoxamine were injected ephrine was reinjected. In two additional hearts the stability (in five rabbits for each) in the internal jugular vein with use of the isolated heart preparation was assessed for an average of 0.2 ml per bolus and allowing 1 to 2 min between period of 63 minutes. The isovolumic pressure decreased injections. Only one drug was injected into each animal. In 4.7% and the coronary perfusion pressure increased 4.9%. three additional rabbits the stability of the arterial blood This period exceeded the average of 36 min necessary to pressure was assessed for 40 min, the time necessary to perform the dose-response studies. perform the dose-response studies. The average decrease in Protocol 3: isolated supported heart preparation (Fig. 1). the mean arterial pressure was 4%. The isolated heart was prepared as outlined in protocol 2. In Protocol 2: isolated heart preparation. After anesthesia, parallel a “support rabbit” was anesthetized and instru- 14 rabbits were ventilated through a tracheostomy with a mented with a needle in an ear vein for pentobarbital mechanical ventilator (Harvard Apparatus, model 681) and injection, a tracheostomy for ventilation, a carotid artery intravenous heparin was administered for anticoagulation. cannula and an internal jugular vein cannula for pressure 1352 KRONENBERG ET AL. JACC Vol. 14,No. 5 METHO~AMINE,PHEN~LEPHRINEANDCONTRACTILITY November 1, 1989: 13504

Figure 1. Isolated supported heart (protocol 3). The support rabbit (left) is shown with bilateral femoral artery cannulas leading arterial blood to a

OXYGENATOR roller pump and then to the isolated BUBBLETRAP heart (right), which was suspended in a constant temperature water bath. Venous efflux through the coronary sinus was recirculated to the femoral veins with an additional roller pump. The blood level in the reservoir of the VE constant temperature bath was held ;i!?:^,h constant by adjusting the venous (IV) roller pump. In the isolated heart, aortic pressure, as a measure of coronary perfusion pressure (CPP) and left ventricular isovolumic pressure (LVP), were recorded. Left ventricular volume (LVV) was controlled by a balloon in the left ventricle. In the support rabbit, the arterial pressure (ART. BP) and central venous pressure (CVP) were monitored. For the simpler isolated perfused heart protocol, an oxygenator replaced the support rabbit and the venous roller pump was eliminated, as shown by the dashed lines.

monitoring, along with bilateral femoral artery and vein lated heart pressure were recorded continuously at a paper cannulas for cross-circulation. Indomethacin (3 mg/kg) was speed of 1 mm/s. mixed with approximately 6 mg sodium carbonate, dissolved In a control experiment, we studied pressures in the in approximately 5 to 8 ml normal saline solution and isolated supported heart preparation. Over a 2 h period, the injected intravenously into the rabbit. When the isolated mean arterial pressure of the support rabbit decreased 9.5%, heart and the intact rabbit were stable individually, cross- isovolumic left ventricular systolic pressure increased 11.3% circulation was established by substituting the support rabbit and coronary perfusion pressure increased 4.6%. This period for the oxygenator in the circuit. The residual blood in the was approximately twice that necessary to perform the oxygenator was re-infused into the circuit (Fig. 1). One roller experiments. pump maintained a constant blood flow to the isolated heart. Data analysis: dose-response curves. For the intact rabbits The other adjusted venous return to the support rabbit so (protocol l), the mean arterial pressure was measured by that a stable blood volume was present in each part of the electronic low pass filtering or was calculated as the diastolic circuit. This adjustment was achieved by close observation blood pressure plus one third of the pulse pressure. The of the blood level in the reservoir with small modifications of blood volume in intact rabbits was estimated to be approx- the venous flow rate to keep the level constant. (For the imately 200 ml (23). The blood volume in the perfusion isolated heart studies in protocol 2, the oxygenator com- circuit was 100 ml excluding the heart and aorta (approxi- pleted the circuit instead of the support rabbit, and one less mately 10 to 20 ml). To achieve a rough equivalency of drug roller pump was employed.) The preparation was similar to dosage, we injected twice the amount of drug into the intact that used previously in this laboratory (22). The temperature rabbit as that injected into the isolated hearts (protocol 2). on the inner surface of the heart was monitored before the However, we expressed the cumulative dose-response experiment with use of a digital thermometer and was curves in terms of the injected doses, because we could not adjusted and maintained at 35 to 37°C by adjusting the water estimate accurately the volume of distribution on the first bath temperature. The temperature was checked afterward passage of the drug. With use of the calculated distribution and was constant. Drugs were infused into the intact rabbit volume at equilibrium, multiplying by the factor 10m4would through the femoral vein (“intravenous administration”) or convert the milligram dosage to its molar concentration. The into the isolated heart through the femoral artery cannula maximal effect of each drug was assessed after each bolus (“infusion line administration”) with a calibrated infusion injection. We expressed the effect of each dose as a percent pump (Harvard, model 56-8808). The arterial pressure, cen- of the baseline pressure before the first drug injection. For tral venous pressure, coronary perfusion pressure and iso- the isolated supported heart studies (protocol 3), we plotted JACC Vol. 14, No. 5 KRONENBERG ET AL. 1353 November I, 1989: 1350-X METHOXAMINE. PHENYLEPHRINE AND CONTRACTILITY

A. I El. 60

70 Figure 2. Phenylephrine and methoxamine in 60r the intact animal (protocol I). Dose-response P 6O curves for phenylephrine (A) and methoxamine 2 50 (B) demonstrate the percent change in mean w ?? arterial pressure (MAP) as a function of injected p 40 dose (mg). The response to methoxamine was 9 v30 blunted compared with the response to phenyl- N=S -8 ephrine. There was no further increase in mean 20 arterial pressure after the largest methoxamine IO * pso.004 injection. 0 0 l.Jl 0 KiS IO* 16’ IO-’ 162 I8 o 16’ IO- 1154 16’ 10 16’ , PHENYLEPHRINE (mq) METHOXAMINE (mq)

the simultaneous support rabbit and isolated heart pressures. mean arterial pressure after the 4 mg dose (Fig. 2B). Fre- We judged that the preparation was responsive and the quently with 0.4 mg and 4 mg injections, the arterial pressure results valid if the mean arterial pressure of the support decreased transiently before increasing (data not shown). rabbit increased by 2 10% during drug infusion. Phenylephrine increased the arterial pressure more than Statistical analysis. Numerical data were entered into a similar dilutions of methoxamine (p = 0.03) with use of the medical data base system (CLINFO), supplied to the Wilcoxon non-parametric rank sums test. Vanderbilt Clinical Research Center by the Division of Protocol 2. In protocol 2, we administered each drug to Research Resources, National Institutes of Health. The data seven isolated hearts (Fig. 3). Because the left ventricular were analyzed by analysis of variance with adjustment for end-diastolic pressure was always <.5 mm Hg and remained repeated measures. When significant F statistics were de- constant throughout each study, the changes in peak systolic tected, paired t tests were performed, comparing the pres- pressure corresponded to changes in developed pressure sure responses with control values. Results are reported as (data not shown). Coronary blood flow was maintained mean value, +SEM. A statistically significant difference was constant. The left ventricular isovolumic systolic pressure considered to exist when p < 0.05. increased significantly after bolus additions of 0.01 to 1 mg phenylephrine to the coronary circulation (Fig. 3A). In contrast, the effects of methoxamine were qualitatively Results different (Fig. 3B). The isovolumic pressure increased Protocol 1. In protocol 1 (arterial pressure dose-response slightly but significantly at doses of 2 x lo-” mg and 2 x study), we administered each drug to five rabbits (Fig. 2). 10-j mg but then decreased gradually, though insignifi- The mean arterial pressure increased progressively with cantly, at doses of 2 x lo-’ mg, 2 x 10e2 mg, and 2 x 10-l increasing doses of phenylephrine up to 0.2 mg (Fig. 2A), mg. After the latter dose, the systolic pressure decreased by which was associated with an increase in pressure of 82% t 9% ? 14% (p = NS), but with the 2 mg dose it decreased by 14% (p = 0.004). With a 2 mg dose, each of two rabbits died 43% 2 9% (p = 0.003). suddenly. With methoxamine, the mean arterial pressure The similarity of the curves in Figures 2A and 3A sug- increased more slowly up to concentrations of 0.04 mg but gests that there were similar effects of phenylephrine on increased sharply by 52% -+ 6% with the 0.4 mg dose (p = blood pressure and contractile state. In contrast, the effects 0.001). Paradoxically, there was no further increase in the of methoxamine were more complex. This drug progres-

A. 8. 60 20 r Figure 3. Phenylephrine and methoxamine in the iso- %5o lated heart (protocol 2). The format is similar to that of ?I Figure 2. For phenylephrine (A) the left ventricular $yo systolic pressure (LVSP) increased progressively with z doses of klO_’ mg. For methoxamine (B) the left 2 20I ventricular systolic pressure increased initially, then y ,. + declined, decreasing sharply after the 2 mg injection. 6 o#?&&.+& !&a*

0 lb 0 PHENYLEPHRINEtmg) METHOXAMINE(mg) 1354 KRONENBERG ET AL. JACC Vol. 14, No. 5 METHOXAMINE, PHENYLEPHRINE AND CONTRACTILITY November 1, 1989:135&S

50 1mg LVSP PHENYLEPHRINE -r

_ Y 0 5 5 8 -25 I ma I\i-PHENYLEiHRlNE I 0.2 *ma PROPRAiOLOL $tAcanf SEM rpS0.02 N.6 0 5 IO I5 20 TIME WIN) Figure 4. Response to phenylephrinebefore and after propranolol B. (protocol 2). The positive inotropic response to 1 mg phenylephrine ISOr was eliminatedafter administrationof 0.2 mg propranolol.

sively increased mean arterial pressure in the intact rabbit except for a plateau at its highest dose (Fig. 2B); methoxamine decreased isovolumic pressure in the isolated heart at a similar high dose (Fig. 3B). The effects of phenylephrine on left ventricular isovolu- I I I I 1 I OobtI5 20 25 30 35 40 mic pressure in six isolated hearts before and after beta- TIME (MINI adrenergic blockade with propranolol are shown in Figure 4.

Before propranolol, phenylephrine (1 mg) increased the SBP (*29=/J systolic pressure by 27 + 7% (p = 0.01). After 0.2 mg propranolol, the pressure decreased by 23% + 7% from control (p = 0.02) to a new baseline. A second 1 mg bolus of phenylephrine did not increase the systolic pressure significantly (4 + 2%, p = NS) from the new baseline. Protocol 3. In protocol 3 (isolated supported heart), we administered methoxamine into the isolated heart infusion line in nine preparations; in five of these we also used intravenous methoxamine. We administered phenylephrine in two hearts, intravenously in one heart and through the infusion line in another. Typical examples are shown in Fig. I 5, which demonstrates three preparations. During adminis- 17 25 30 tration of intravenous phenylephrine (Fig. 5A), the left TIME (MINI ventricular isovolumic systolic pressure and the support Figure 5. Isolated supported heart preparations (protocol 3). A, rabbit mean arterial pressure increased in parallel as the Response to intravenous (IV) phenylephrine. The systolic blood pressure (SBP)in the support rabbit and the isovolumicleft ventric- infusion rate increased. The rabbit systolic arterial pressure ular systolic pressure (LVSP) in the isolated heart increased in decreased quickly after the infusion was discontinued; how- parallelduring the infusion.The coronary perfusionpressure (CPP) ever, the isovolumic left ventricular systolic pressure con- was constant. B, Responseto intravenous methoxamine.The mean tinued to increase for several more minutes before decreas- arterial pressure (MAP) increased by approximately 30 mm Hg ing. The coronary perfusion pressure and end-diastolic (25%).Simultaneously, left ventricular systolic pressure decreased by approximately20 mm Hg (18%);the coronary perfusionpressure pressure of the isolated heart were constant throughout the was relatively stable. The rabbit and heart pressures returned to study. During administration of intravenous methoxamine baseline after the infusion(INF) was discontinued.C, Responseto (Fig. 5B) the support rabbit mean arterial pressure increased methoxaminethrough the infusion line. The reduction in left ven- by 25%, whereas the left ventricular isovolumic systolic tricular systolic pressure was more pronounced than that by the pressure decreased by 18% from control. During administra- intravenous route. At the end of the infusion, the support rabbit systolic blood pressure had increased 2% above control level, tion of methoxamine into the isolated heart infusion line whereas left ventricular systolic pressure had decreased by 59%. (Fig. SC), the left ventricular isovolumic pressure decreased Pressures returned toward control values after ending the infusion. by 59%, whereas the rabbit systolic arterial pressure in- BEG. = begin; INC = increased. JACC Vol. 14, No. 5 KRONENBERG ET AL. 1355 November 1, 1989: 11X%8 METHOXAMINE. PHENYLEPHRINE AND CONTRACTILITY

Discussion Effect of vasoconstrictor drugs on left ventricular contractility. Pharmacologic afterload stress has been used to assess left ventricular contractility by systolic pressure- volume relations (2,19,20,24), force-velocity relations (4) and stroke work (25). Pharmacologic pressure afterloading by administration of vasoconstrictors is convenient and simple, but these agents may have two types of effects- direct effects on the left ventricular contractile state and indirect effects on the end-systolic pressure-volume relation due to changes in arterial resistance (19,20,24). This study clarifies and extends the available data regarding direct % CHANGE LVSP effects of methoxamine and phenylephrine on contractility. The additional effects on the left ventricular systolic pres- Figure 6. Summary of effects of methoxamine. Paired results are sure-volume relations in the intact circulation were not shown for the five preparations(1 to 5) with both intravenous(IV) assessed. and infusion line (intra-arterial [IA]) administration, shown with equal infusion rates. There was a broad range of responses. The Predictably, both phenylephrine and methoxamine in- support rabbit mean arterial pressure (MAP) increased more after creased the systemic arterial blood pressure in the intact intravenous infusion (66%) than after intra-arterial (33%). The rabbit, but they affected contractility of the isolated heart isolated heart left ventricular systolic pressure (LVSP) decreased and in different manners. Phenylephrine had a positive more after intra-arterial infusion (25%) than after intravenous (5%). The dashed line demonstrates further depression of left ventricular inotropic effect. Methoxamine had a mixed cardiac inotropic systolic pressure in preparation 3 after an increment in the intrave- effect, slightly positive at low concentrations, insignificant at nous infusion rate (3’); this decrease was similar to the decrease medium concentrations but markedly negative at the higher after intra-arterial infusion. concentrations. The threshold for altering blood pressure in the intact rabbit approximated the threshold for affecting left creased by 29%. Pressures returned toward control values ventricular isovolumic pressure in the isolated heart (Fig. 2 after the infusion was discontinued. and 3). The cross-circulation experiments demonstrated For the nine preparations in which methoxamine was these effects simultaneously and confirmed that phenyleph- administered into the isolated heart infusion line, the mean rine and methoxamine had independent peripheral arterial maximal increase in mean arterial pressure of the support and direct cardiac effects. rabbits was 36 + 5% (p < 0.001) and the mean maximal Alpha-receptor agonists cause peripheral arterial vaso- decrease in left ventricular isovolumic systolic pressure was constriction (26). Cardiac alpha-adrenergic receptors are 31 t 5% (p < 0.001). In the five preparations with intrave- present in several species (cat, rat, dog, rabbit) (5,7,8,27). nous methoxamine infusions, the mean maximal increase in Although the number of these receptors in the heart is mean arterial pressure of the support rabbits was 65 ? 14% relatively small compared with that of beta-adrenergic re- (p = 0.009), whereas the mean maximal decrease in the ceptors (27), alpha-adrenergic stimulation can also exert systolic pressure in the isolated hearts was 10 ? 6% (p = positive inotropic effects (5,7-9,15-17,28,29). NS). Phenylephrine. This drug has both alpha- and beta- Figure 6 compares the results of intravenous and infusion adrenergic effects in the heart (5,7,15,29). Schumann et al. line administration of methoxamine at equal infusion rates (7) found that the positive inotropic effects were mediated by in five preparations. The mean arterial pressure increased alpha-adrenergic receptors at low drug concentrations and more during intravenous administration (66 + 14%) than by beta-adrenergic receptors at high concentrations, but during infusion line administration (33 t 9%) (p = 0.04). Bruckner et al. (8) concluded that phenylephrine acted The isolated heart systolic pressure decreased more during exclusively on cardiac alpha-adrenergic receptors. Our infusion line administration (25 * 5%) than during intrave- study confirmed that beta-adrenergic receptor stimulation nous administration (5 t 4%) (p = 0.005); the 5% decrease mediated the cardiac effect of phenylephrine in high concen- was not significant statistically. In a single preparation trations (Fig. 4). We did not address the mechanism at low (preparation 3), the intravenous infusion rate was increased concentrations. to a rate greater than the prior infusion line rate (point 3’). In intact anesthetized dogs, phenylephrine increased the With this increase, the left ventricular systolic pressure arterial diastolic pressure and the right ventricular force of decreased sharply, and to a similar degree as during direct contraction (30). More recently, Tajimi et al. (10) showed in administration into the infusion line, suggesting a concentra- dogs that phenylephrine increased contractility as assessed tion effect. by end-systolic pressure-volume relations. The response 1356 KRONENBERG ET AL. JACC Vol. 14, No. 5 METHOXAMINE, PHENYLEPHRINE AND CONTRACTILITY November 1, 1989: 1350-8

was blocked by propranolol and appeared to be a beta- mm Hg. There were no measurements of right ventricular adrenergic effect. In 12 normal human subjects, we also pressure, volume or rate of rise of isovolumic pressure, and found similar leftward shifts of systolic pressure-volume thus their work could not assess directly the effects of relations at high infusion rates of phenylephrine; these shifts methoxamine on myocardial contractility. Interestingly, af- were blocked by propranolol (p = 0.02) (31). The present ter 2 mg methoxamine, the systemic arterial pressure de- study confirmed these findings and suggests that phenyleph- creased transiently before increasing (their Fig. 3). This tine has cardiac beta-adrenergic effects and induces periph- response suggests transient cardiac depression and is analo- eral alpha-adrenergic stimulation. Sodums et al. (24) found gous to our results in the intact rabbit and to the depression that angiotensin II shifted the left ventricular pressure- of isovolumic systolic pressure in the isolated heart. volume relation leftward, parallel to that in control animals. Possiblemechanism for the methoxamineeffect. There has This shift might be an expression of positive cardiac inotropy been considerable speculation about this mechanism be- in the intact dog, but also might be due to effects on the cause of the unusual combination of positive and negative arterial resistance alone. Large changes in resistance can inotropic effects (11,15,16). The positive inotropic effects produce parallel shifts in ventricular pressure-volume rela- may be due predominantly to alpha-adrenergic stimulation tions in the ejecting isolated supported heart (20). The (9,15-l&28), but there may be several mechanisms to ex- present study expands on this work by demonstrating posi- plain the negative inotropic effect. Imai (32) found that large tive inotropic effects in the isovolumically contracting iso- concentrations of methoxamine reduced phase 0 depolariza- lated heart. tion by a “local anesthetic effect” on sodium conductance, Methoxamine. The blood pressure dose-response curves which would be expected to reduce calcium entry and for methoxamine were shifted to the right compared with reduce contractility (14). However, other studies (14,33) those obtained at equal doses of phenylephrine (Fig. 2) as have shown that methoxamine competitively antagonizes demonstrated by others (26). In the isolated heart, we the chronotropic and inotropic effects of epinephrine, sug- observed a multiphasic response to methoxamine, initially a gesting an underlying beta-adrenergic blocking effect. Coro- small positive inotropic effect, then no net effect, followed nary vasoconstriction may also mediate the negative inotro- by a significant negative inotropic effect as the dose was pit effect. In dogs, methoxamine increases the coronary increased. These results are consistent with prior studies in vascular resistance at systemic pressor doses (34), and a various cardiac preparations. Endoh and Schumann (15) recent study (35) showed that intracoronary methoxamine found that methoxamine produced a dose-dependent posi- increases coronary vascular resistance, decreases left ven- tive inotropic effect in the rabbit papillary muscle that was tricular ejection fraction and produces ST segment changes most apparent at low concentrations, low stimulation fre- suggestive of myocardial ischemia. In the present study, the quencies and low temperatures. There was a marked nega- stability of the coronary perfusion pressure during constant tive inotropic effect at higher concentrations. Phentolamine coronary flow implied that direct myocardial effects were antagonized the positive inotropic effect, implying alpha- more important than coronary vasoconstriction in decreas- adrenergic mediation. Such responses have been confirmed ing left ventricular isovolumic pressure. However, this study in the rabbit papillary muscle (9) and cat papillary muscle did not address the mechanism of the inotropic effects of (16). Others found that methoxamine depressed cardiac methoxamine. force in a dose-dependent manner in anesthetized dogs Clinical studies (4) of left ventricular force-velocity rela- (13,14) and neonatal sheep (18), and decreased the slope of tions employ infusion rates of methoxamine up to 1 mg/min, the end-systolic pressure-volume relation in conscious dogs which increase the systolic arterial pressure by 30 to 60 mm (19), consistent with a negative inotropic effect. Because the Hg. On the basis of the present study, the larger changes in effects of methoxamine on the heart in intact animals (19) arterial pressure would be associated with a greater likeli- might also be influenced by acute changes in the peripheral hood of a negative inotropic effect of methoxamine on the vascular resistance (20), the present study is especially myocardium. However, because we found that individual helpful in implicating a direct cardiac effect. We found hearts had variable susceptibility to the depressant effects of negative inotropic effects of methoxamine on isovolumic methoxamine (Fig. 6), it is difficult to predict that there pressure both in the isolated heart and in the isolated would be a fixed threshold for this depression. The depres- supported heart. sant effects are not limited to the rabbit because we found Clinical studies of left ventricular contractility have em- that intravenous infusion of methoxamine depressed left ployed methoxamine because of earlier work (12) that ventricular systolic pressure in preliminary experiments in showed few effects on right ventricular contractile force in canine isolated supported hearts (Fig. 7). cardiac patients at thoracotomy. Goldberg et al. (12), using Differencesbetween intravenous and infusion line admin- strain gauges in contracting hearts, found only slight changes istration of metboxamine. The isovolumic pressure of the in right ventricular contractile force (-9% to +180/o), isolated supported heart decreased more by administering whereas the systemic systolic pressure increased by 16 to 65 methoxamine directly into the infusion line than by admin- JACC Vol. 14, No. 5 KRONENBERG ET AL. 1357 November 1. 1989: 1350-S METHOXAMINE. PHENYLEPHRINE AND CONTRACTILITY

Figure 7. Intraaortic (“intracoronary” [ICI) and intravenous (IV) methoxamine in a canine isolated supported heart preparation. Three dogs were studied in preliminary experiments. During intravenous (IV) infusion, the left ventricular systolic pressure (LVSP) decreased by 18.7 t 2.9% (p = 0.02), whereas simultaneously the mean arterial pressure (MAP) of the support dog increased by 14.2 ? 1.8% (p < 0.02). This figure illustrates typical changes in one experiment. Serial intracoronary injections of 0.2 mg and 2 mg of methoxamine decreased left 60 ventricular systolic pressure transiently and increased coronary perfusion pressure (CPP) transiently. During intravenous infusion, left ventricular systolic pressure decreased and mean arterial pressure increased, whereas coronary perfusion pressure decreased slightly. These changes resolved after TIME (MN) discontinuation of the infusion. istering methoxamine intravenously to the support rabbit. concentrations that cause moderate changes in the systemic Conversely, the arterial pressure of the support rabbit in- arterial pressure. creased more by administering methoxamine intravenously to the support rabbit rather than directly to the isolated We thank Evelyn Okediji for technical expertise, Joyce Semenya and Kyle heart. These results might occur if the drug were taken up by Balch for data analysis, William D. DuPont, PhD for statistical consultation structures such as the lungs, heart and peripheral arteries, and Sue Warrington for manuscriptpreparation. The advice and assistance of Daniel Burkhoff, MD, PhD and W. Lowell Maughan. MD in preliminary thus enhancing local effects either in the isolated heart or in studies are gratefully acknowledged. the arteries of the support rabbit, depending on the route of administration. 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