Life Sciences Vol. 16, pp " 1923-1930 Priated in the O.S .A .

Pergamon Press

MYOCARDLAL ACTIONS OF PROSTAGLAI®INS IIi ISOLATBD CAT CARDIAC TISSDE* Martin L. Oglntree, Anthony C. Beardeley aad Allan M. Lefer Department of Physiology Jefferson Medical College of Thomas Jefferwn Onlvereity Philadelphie, Pennsylvania 19107 (Received in. final form May 22, 1975) SO!!lARY The isotropic responses to prostaglandine (PG) Al, ßl, ß2 and F2 a were studied is iwlated cat syocardial tissue . PGA1 and F2 a ezhibited no significant isotropic effects, whereas, PG82 and PGßl produced negative isotropic affects at concentrations of 2.8 x 10-7 and 2.8 z 10-6 M in iwlated cat papillary muscles. In isolated perfused cat hearts, PG81 (2 .8 z 10-6M) produced a negative isotropic effect along with a significant increaen in coronary flow . Ae flow declined, the negative isotropic effect became pore severe . PGßl at 2 .8 z 10-9 M produced a sustained increase in coronary flow and oxygea consumption with no isotropic effect . PGß2 and F2a did not eiert significant changes is coronary flow or contractile force . Thus prostaglandins do not appear to azert aignificast positive isotropic effects at physiologic or at generally accepted pharmacologic concentrations in isolated cat heart preparations . At ez ttemely high concentrations, prostaglandias ßl and ß2 eiert a negative isotropic effect ; however, this weld not explain the protective effect of these prostaglandins in circulatory shock. Proataglandias have been tested for isotropic activity under a varietq of eaperiaestal co~itions . For example, PGßl has been reported to eiert reaponses ranging from a parked positive to a substantial negative isotropic effect (1,2,3,4) in isolated cat cardiac tissue . However, the results of these findings have been confusing due to the. lack of carefully controlled ezperinentel conditions employed by different imrestigators (i .e ., the failure to use appropriate vehicle controls or the variability of different cardiac preparations) . Moreover, some of the ezperimental conditions did not preclude the possibility of cardiac effects being mediated by changes in heart rata, coronary blood flow or left ventricular afterload, factors which can strongly influence myocardial contractile performance . Proataglandine are known to be released during hemorrhagic (5) or endotozin shock (6) and are generally considered to be mediators of inflammatory dieordere (7) . However, PGßl and PGF2a have recentlq been reported to eiert a protective action in circulatory shock (8,9,10) . The preaeat study was initiated to daterminn if prostaglasdine eiert a direct influence on cardiac contractile force, and whether these actions can contribute significantly to the protective action of proetaglandine in shock. *Supported by the National Institutes of Health Research Grant iHL-17688 from the National Heart and Lung Institute

1924

Proataglandins on Heart

Vol. 16, No . 12

Materials and Methode Papillary Musçles Cats of either sex raagiag from 2 .0 to 3.6 kg were anesthetized with pentobarbital sodium (30 mg/kg) given intravenously . Papillary ~scles were isolated from the right ventricle and suspended in 10 ml muscle chambers in a modified Kreba-Henseleit (R-H) solution (11) at 37 °C and bubbled with 95X Op and 5X COp . Muscles were stimulated at a frequency of 1/sec for a duration of 16 .7 mast at 2 volts above threshold with field electrodes . Isometric contractions were recorded on an oscillographic recorder using Grass FT-03 force transducers . Each muscle was stretched to a point just below the maximum tenDeveloped tensions were calculated as grams of force develsion development. oped per square millimeter crone-sectional area of muscle and ranged from 1 .7 to 3 .3 g/mmp, the mean for all ~sclea being 2.26 . Responses to PG platesued 10 to 15 minutes after addition of the PG to the bath, and are expressed as X change from pre-drug control values minus the vehicle response . Perfused Hearts Hearts were removed from pentobarbital anesthetized cats (30 mg/kg) and were placed directly in K-H solution at 4°C . Hearts were perfused with K-H solution bubbled with 95X 02 + 5X COp at 37 °C. Perfusion was begun within The three minutes of cardiectomy, and the perfusatas were not recirculated . pulmonary artery was calculated to obtain continuous monitoring of venous POp with an oxygen electrode continuously recorded on a Becl®an oacillographic recorder . Inflow POp was also determined every 10 minutes. Coronary perfusion pressure was maintained at 50 mm Hg throughout the ezperimeat . Cardiac contractile force development was measured by suturing the apex of the heart to a force transducer . A resting force of 10 g was used as a standard pre-load . Thirty minutes of perfusion was sufficient equilibration time to establish constant cardiac contractile force (CCF), coronary flow (CF), and oxygen consumption (qOp) " The hearts were not paced, but heart rate did not change by more than 10 beats/min over the entire perfusion period . In the first series of eaperimeats, each of six hearts was perfused with Perfusion time PG E1, E2 and Fp s (2 .8 a 10 -6 M in K-H buffer) in random order . with each PG was 10 minutes, which was followed by a 10 minute washout with R-H solution . Oae group was Four other groups of hearts were perfused for 60 minutes . A second group was perfused with perfused with oxygenated R-H solution only . The third group was perfused PGEl (2 .8 a 10-6M) in oxygenated K-H solution . The final group was perfused with with oxygenated R-A plus ethanol (0 .02X) . PGEl in physiologic concentration (2 .8 x 10-9 M) in oxygenated R-H solution . Measurements of CF, qOp and CCF were recorded every 10 minutes and all data are expressed se percentage of the 0 time measurement . Prostaglandine Crystalline PGE1, PGEp, PGA1, and PGFp a (Upjohn Co ., Kalamazoo, Mich .) were dissolved in 95X ethanol and diluted with K-H solution to yield PG concentrations of 2 .8 x 10-8 to 2.8 x 10 -4M. Corresponding dilutions of 95X ethanol were made at the same time for use as vehicle controls . PG concentrations in the bath or perfusate varied from 0 .1 ng/ml (2 .8 x 10 -lOM) to 1 yg/ml (2 .8 x 10-6M) and ethanol concentration ranged from 2 x 10-6 to 2 x 10-2X. Statistical significance of all measurements were determined by Student's t test for unpaired data .

1925

Prostaglandine on Heart

Vol. 16, No . 12

Eeeults Papilla~ ètuscles Table 1 summarizes the developed tensions for the papillary muscles in the presence or absence of 2,8 x 10 -6 M prostaglandins, or ethanol and in the presence of 5.1 mM CaC12, a potent positive inotropic agent to test the responsiveness of the preparations . TABLE 1 Besponsiveness of Cat Papillary Muscles to Prostaglandina and Other Isotropic Agents

Agent (Concentration)

N

Developed Tension (g/mm2)

P Value from Control

Control (no drug)

36

2 .26 t 0.16

--

Ethanol (0 .02x)

16

2 .12 t 0.14

NS

PGAl (2 .8 z 10-6M)

8

2 .33 t 0.17

NS

PGEl

(2 .8 a 10-6M)

8

1 .81 ± 0.18

Myocardial actions of prostaglandins in isolated cat cardiac tissue.

Life Sciences Vol. 16, pp " 1923-1930 Priated in the O.S .A . Pergamon Press MYOCARDLAL ACTIONS OF PROSTAGLAI®INS IIi ISOLATBD CAT CARDIAC TISSDE* M...
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