THE ACTION OF METARAMINOL (ARAMINE 1)) ON MYOCARDlAL CONTRACTILITY 2)

Transcription

1 Acta Physil. Pharmacl. Neerlandica 11 (1962) ; Nrth-Hlland Publishing 00., Amsterdam University Department f Oardilgy and Clinical Physilgy, Wilhelmina Gasthuis, Amsterdam, The Netherlands histamine aramine -092: THE ACTION OF METARAMINOL (ARAMINE 1)) ON MYOCARDlAL CONTRACTILITY 2) ' t BY F. L. MEIJLER AND 1. S. MEERSCHWAM Received: Nv. 30, 1962 Accepted fr publicatin: Dec. 3, 1962 Metaraminl [lev-l-(m-hydrxy-phenyl)-2-amin-l-prpanl] - a ptent weapn in cmbating mycardial shck - can be administered intra-venusly, intra-muscularly r subcutaneusly and is therefre f great imprtance in daily practice. Reprts (SARNOFF et al., 1954; LINSAY et al., 1954; MORGAN et al., 1957; STECKEL, 1956; WEIL and SPINK, 1955; BESTERMAN, 1959) suggest that besides a peripheral vas-cnstrictive actin metaraminl als has a stimulating effect n ventricular functin. Metaraminl causes a rise in mean bld-pressure and increases the heart rate. Since these factrs may be respnsible fr the imprvement f cardiac functin (KRUTA, 1937; MEIJLER, et al., 1961, 1962), a direct effect n the mycardium has nt been prved. T demnstrate a pssibly direct effect f metaraminl n mycardial cntractility it is necessary t design a set-up which allws this effect t be studied at a cnstant crnary perfusin-pressure and a cnstant heart rate. METHODS Islated hearts frm 250 g white rats were perfused at 37 C (T, Fig. 1) using the Langendrff technique (LANGENDORFF, 1) Aramine was kindly supplied by Dr. H. Kppejan f Merck, Sharp and Dhme, Hlland. 2) This study was supprted in part by grants fr m The Netherlands Organizatin fr Pure Research (Z.W.O.), The Hague, The Netherlands. 418

2 ACTION OF METARAMINOL ON MYOCARDlAL CONTRACTILITY 419 B Fig. 1. Diagrarnrnatic representatin f the recrding system f electrcardigram, istnic cntractins and perfusin f the islated rat heart. Fr further details see text. 1895; MEIJLER et al., 1960). The uniplar electrcardigram (Channel 1, Fig. 1) is recrded simultaneusly with the istnic cntractins f the heart (Channel 2, Fig. 1). The cil (Fig. 1) belngs t an electrnic recrding system described previusly (MEIJLER et al., 1962). Cntractility is expressed as recrded amplitude f the istnic cntractins. Cntrl f heart rate was achieved thrugh stimulating electrdes sewed n the right auricle (Stimulus, Fig. 1). The stimuli were square waves f 0.5 ma and msec. Cnstant perfusin pressure f 55 mm Hg was achieved by an verflw pipe (A, Fig. 1) fitted int the bubble trap (B, Fig. 1). The perfusin fluid leaving the

3 420 F. L. MEIJLER AND 1. S. MEERSCHWAM heart was cllected in a small funnel (D, Fig. 1). Crnary perfusin was measured by cunting the drplets leaving the funnei. Cnstant surface tensin f the perfusin fluid and the unvarying utlet f the funnel warrant a cnstant size f the drps. By adding a dye t the perfusin fluid, it culd be demnstrated that under these experimental circumstances the artic valves are cmpetent. By cllecting and weighing 100 drps, the vlume f ne drp was estimated t be apprx mi. Each drp leaving the fmmel clses a circuit. The resulting signal is added t that frm the electrmanmeter measuring the perfusin pressure and recrded n the direct-writing electrcardigraph (Channel 3, Fig. 1). Metaraminl f 37 C (0.5 g- 1.0 {tg/mi perfusin fluid) was injected (S, Fig. 1) int the perfusin fluid just befre the stpcck (K, Fig. 1) and the artic cannula (C, Fig. 1). During each experiment the aramine slvent was administered in the same dilutin. RESULTS 12 experiments were perfrmed t make a dse-respnse curve f metaramini. Amunts f aramine surpassing 100 {tg always gave rise t serius and f ten irreversible rhythm disturbances by auricular r ventricular escapes frm the driving impulses. Smetimes there was even a decrease f cntractin-amplitude. Dses f 5-25 {tg had a transitry stimulating effect. Belw 5 {tg very small effects were fund. These preliminary experiments were als used t test the stimulatin rate necessary t prevent the ccurrence f escape phenmena af ter administratin f the drug. It was fund that the ptimal stimulatin rate fr these experiments was 5-6/sec. 6 experiments were perfrmed t test the actin f 25 {tg metaraminl n the cntractility f the islated rat heart perfused at a cnstant pressure f 55 mm Hg and cntracting at a ènstant rate f 5.5/sec. Under these experimental cnditins metaraminl increases the amplitude f the istnic cntractins f the heart. This can be seen in Fig. 2 which is derived frm a representative experiment. In A (Fig. 2) the he art is cntracting at its wn frequency. At B (Fig. 2) stimula-

4 Fig. 2. Electrcardigram, istnic cntractins and perfusin f the islated rat heart af ter the administratin f 25 p,g f m etaraminl Fr further details see t ext. " i> i:l z "':I t' Z ê - f"'f"""'_f>,., I,,, ':' O!<;1 f 5 mm.l..-l... t..t... ';-1'1"',1r \" j. " i t,, (ft) 2:5min rlseej _ -\..\.I..!A-<"""""""'_"'\"":u',..JJ...\.\... \..\.t.v ' I. _.,...\.',..M.41).Á-'_u..... "...l..l,..;..:.,..l...>, L1,..\.""'-\->...u..\... "" I1".!'\i" "...,,,'"...,. 't'''1 N 1/'''!1''1:'''j'';''''\'',-; " 11"''''!' '1. ti : l" \...,t..... "t I1 " "r.1" :,' 'I;.,. \,}I " \ \ \'1... \ "\, ; \,u V',\\ \ \\, \ } H \ - ' (I \ \ t \ \ t \ i \.., \ 1 ", \... ';h; I, " ' i.., f ",. i} t, n tnv: I, I t ïl 1 } f f ' j, 11,' (dtil". t f tin" tf rif t t' r ftl'fr ro ';'IHttflH Ji" 'ft, f'rt""'pi/hffr-;ftl "tl1ü't_'h" ' l u 30m,n 2 5 ARAMINE l.j..\.<j..\..-<...;""; \ ",.' \ 305rnl n _... "",... v..""""':"" \ - - \ ')' '\,\ _ k- 31mï n... i...j.:j..i..j':"...,j \.\. l_,,\l 4.\. '"'.\)J.J...> "... L,.:...v..... J.t.w I-..(, ",q,!,", 't '\.... ' "'..,l" "..,,. r ::.. ""."-'..\..... "',:" I f 1..6 'l! Hrt, /:",1 \ ,111. l 11 ',I\'\r' ","I, y," 'I' " "i'l. 1"t:f\ 4 -r, t'lt " f h 'l! 1 j' }fh* ":'1' " " I!!:! 0 (J) <D 32mln 33 m ln 34min Sm j n 37min 38mln 39tnin 41 m ln - -I",...," "... '\, '"/rr....,... '-.- "j>' 0 43mitt 45min

5 422 F. L. MEIJLER AND 1. S. MEERSCHWAM tin has been instituted. In C (Fig. 2) at the arrw 25 p..g aramine is injected int the perfusin fluid. Frm D t 0 (Fig. 2) recrdings at different times are shwn. Aftel' 10 seends the beginning f a stimulating effect ean be seen. Heart rate and perfusin pressure are kept cnstant. The inerease in cntractin height is maximal 25 secnds aftel' the administratin f the drug. lt takes 15 minutes befre the effect f metaraminl has disàppeared. There is a slight decrease f crnary perfusin rate which is demnstrated by an increased interval between the drps. The effect f metaraminl n cntractility and perfusin is summarized in table 1. TABLE I Effect f 25 flg metaraminl n cntractility and perfusin f an islated rat heart (Stimulatin rate 5.5/sec. Perfusin pressure 55 mm Hg) Befre 25 sec. af ter 15 min af ter administratin administratin administratin f aramine f aramine f aramine (B. Fig. 2) (C. Fig. 2) (0. Fig. 2) Cntractin height mm Interval between drps sec In3 experiments aramme was added fr a secnd time. It was fund that tachyphylaxis did nt ccur. Finally we cmpared the actin f metaraminl with that f nr-epinephrine in c mp ara bie dses. It was fund that aramine has the same effect as nr-epinephrine but the actin f aramine lasts abut 5 minutes lngel' than that f nr-epinephrine. DISCUSSION Previus experiments prve that increasing heart rate r crnary perfusin pressure imprve the cntractility f the heart. A pssible effect n mycardial cntractility f drugs which als act n cardiac frequency and bld pressure has t be tested

6 ACTION OF METARAMINOL ON MYOCARDlAL CONTRACTILITY 423 while heartrateand crnary perfusin pressure are kept. cnstant. Metaraminl has a stimulating effect n cntractility f islated rat he arts even if precautins are made t prevent increase in rate r perfusin pressure. 25 flg metaraminl administered t the heart f a rat f 250 g is cmparable t a dse f 7 mg t the heart f a human adult f 70 kg. This is within the therapeutic range. It may be cncluded th at metaraminl has a stimulating effect n the heart muscle itself cmparable t that f nr-epinephrine. SUMMARY The actin f metaraminl n istnic cntractins f islated rat hearts perfused accrding t Langendrff was tested. It was fund that at a cnstant perfusin pressure and at a cnstant he art rate metaraminl increases the cntractility f the heart. REFERENCES, BESTERMAN, E. M. M., Treatment f cardiac shck by metaraminl, Brit. Med. J. 1; 1081 (1959). KRUTA, V., Sur l'activité rythmique du muscle cardiaque, 1. Variatins de la répnse mécanique en functin du rythme, Arch. Int. Physil. 45; 332 (1937). LANGENDORFF, 0., Untersuchungen am überlebenden Säugethierherzen, Pfiügers Arch. 61; 291 (1895). LINSAY, W. R., J. H. MOYER and D. W. CHAPMAN, The cardivascular and renal hemdynamic effe cts f aramine, Am. Heart J. 47; 745 (1954). MEIJLER, F. L., J. WIEBERDINK and D. DURRER, Unpublished data(1961)., Staircase, rest cntractins, and ptentiatin in the islated rat heart, Am. J. Physil. 202; 636 (1962)., A. F. WILLEBRANDS and D. DURRER, The infiuence fplyvinylchlride (P.V.C.) tubing n the islated perfused rat's heart, Circulatin Research 8; 44 (1960)., F. v. D. BOGAARD, L. H. v. D. TWEEL and D. DURRER, "Pstextrasystlic ptentiatin" in the islated rat heart, Am. J. Physil. 202; 631 (1962). MORGAN, W. L., J. T. BINION and S. J. SARNOFF, Circulatry depressin induced cunteracted by metaraminl (aramine), J. Appl. Physil. 10; 26, (1957).

7 , 424 F. L. MEIJLER AND I. S. MEERSCHWAM SARNOFF, S. J., R. P. CASE, E. BERGLUND and CH. L. SARNOFF, Ventricular functin. The circulatry effects f aramine ; Mechanisms f actin f "Vaspressr" drugs in cardigenic shck, Circulatin 10; 84 (1954). STECKEL, G. H., The use f aramine in clinical shck, Circulatin 13; 834 (1956). WEIL, M. H. and W. W. SPINK, Clinical studies n a vaspressr agent, metaraminl (aramine), I. Observatins in nrmtensive subjects, Am. J. Med. Sc. 229; 661 (1955).