IndiaD J Physiol Pharmacol 2001; 45 (I); 54-62
THE EFFECTS OF VASOPRESSIN IN ISOLATED RAT HEARTS
ZIYA KAYGISIZ', T. ERDAL KABADERE", SADETTIN DERNEK'" AND SERDAR H. ERDEN····
Departments of "'Physiology, "''''Ophthalmology, no·Cardiovascular Surgery and nonoCheckup, Osmangazi University, Medical Faculty, 26480, Eskisehir, Turkey
(Received on January 4, 2000) Abstract: The roles of cOMP, prostaglandins, the entry of extracellular ea2• through slow channels, endothelium and VI receptors in the negative inotropic, chronotropic and coronary vasoconstrictor responses to arginine vasopressin (AVP) have been investigated in isolated perfused rat hearts. The bolus injection of 5)(10·' M AVP produced a significant decrease in contractile force, heart rate and coronary now. AVP also significantly decreased conlractile force, heart rate and coronary now in hearts pretreated with an inhibitor of soluble guanylate cyclase methylene blue (IO-ll M), an effective drug for removing endothelium saponin (500 ~g/ml), an inhibitor of cyclooxygenasc indomethacin (10-5 M) or a calcium channel antagonist verapamil (5)( 10-1 M). The potent V. receptor antagonist (Deamino.Pen' , Val4, D-ArrJ·vasopressin (9xlO'" 11) did not alter effects of AVP but the very potent V. receptor antagonist II3·Mercapto-Ii, p cyc1opentamethylene-propionyl', O·Me.TyrZ, Arrl-vasopressin (8)(10'" M) abolished these effects. Our results suggest that AVP produces negative inotropic. chronotropic and coronary vasoconstrictor effects in isolated perfused rnt hearts. cOMPo prostaglandin release and C 0 2. entry does not involve in the effects of AVP. These effects are endothelium independent and mediated by V I receptors. The use of V l receptor antagonist [1} mercapto-I}. ll-cyclopentamethylene.propionyll, O-Me.Tyr2, Argl ] vasopressin may be beneficial for preventing the negative inotropy, chronotropy and coronary vasoconstriction induced by AVP.
Key words: vasopressin isolated perfused rat hea.rt myocardial 'coronary now heart rllte contractility vasopressin receptor antagonists
INTRODUCTION vasoconstriction (2-4), a reduction in myocardial contractility (2, 5) and heart rate AVP is a polypeptide hormone released (6). It is known that at least two types of from the posterior pituitary (1). Apart from receptors which are termed V 1 and V2 its principal antidiuretic action (1), AVP has mediate the actions of this hormone (7). V1 been reported to produce coronary receptors on vascular smooth muscle and
·Corresponding Author Indian J Physiol Pharmaco! 2001; 45(1) Vasopressin and Heart 55 hepatocytes and V2 receptors on collecting METHODS duct cells of kidney are located (5). The activation of VI receptors lead to ]n the aged of 9-10 months Wistar rats vasoconstriction, whereas V2 receptors of either sex weighing between 350-450 g mediate the antidiUretic action of were used in all the experiments. One hour vasopressin (8, 9). after the administration of heparin 0000 IV, Lp.), the chest was opened under light The mechanisms responsible for the ether anesthesia and heart was rapidly coronary vasoconstrictor, negative inotropic removed and placed in ice·cold (0-4°C) and chronotropic effects of vasopressin have modified Krebs·Henseleit solution (mKHs) not been known exactly. It has been until contractions ceased. After the heart suggested that vasopressin directly was cleaned off surrounding fat and other decreases myocardial contraction (5, 10) or tissues, aorta was immediately tied to a coronary vasoconstriction evoked by the stainless steel cannula of the perfusion peptide reduces contractility (11-13). On the apparatus and heart was perfused other hand, it has been concluded that retrogradely under constant pressure (70 mmHg) with mKHs by the vasopressin induces the release of nonrecirculating langendorff technique. The prostaglandins which contributed to the pulmonary artery was incised to facilitate coronary vasoconstrictor action (14). The complete coronary drainage In the experiments on isolated arteries have been ventricles. The perfusion solution was mKHs demonstrated that vasopressin-induced of the following composition (mM): NaCI contraction is not endothelium dependent 118, KCl 4.7, CaCl2 2.5, MgS04 1.2, KH2P04 (15) and the entry of external Ca2+ through 1.2, NaHCO 25 and glucose 11. mKHs was 2 J voltage·dependent Ca + channels involves in continuously gassed with 95% 02 and 5% contraction (16). CO2 using a disposable infant oxygenator and pH of the solution was 7.4. The 2 The role of extracellular Ca + entry, temperature was continuously measured in cGMP and endothelium in the negative aorta cannula and kept at 37°C. Contractile inotropic, chronotropic and coronary force was measured by attaching one end of vasoconstrictor actions of the vasopressin a piece of silk suture to the apex of the and the role of prostaglandins in the heart and other end to a force displacement negative inotropic and chronotropic effect transducer (Nihon Kohden TB 6lIT, Tokyo). have not been examined. Therefore, we have A resting tension of 5 g was applied and investigated the possible involvement of the developed isometric tension of the heart was entry of extracellular Ca2+, cGMP, displayed on a polygraph (Nihon Kohden RM prostaglandin release and endothelium in 6000). Heart rate was determined from the the neg-ative inotropic, chronotropic and tracings of the contractile force at a paper vasoconstrictor responses to vasopressin in speed of 2.5 mm/s. Coronary flow was the isolated perfused rat hearts. In addition measured by collecting the amount of we have investigated whether this effects perfusate leaving the heart every minute are medjate by VI receptors. with the aid of a graduated cylinder. 56 Kaygi iz t Indian J Physiol Pharmacol 2001; 450)
Th heart were allowed to equilibrate wa vrepared a daily and v rapamil for 30 min b for the admini tration olution wa protected from the light to of drugs. AV at the concentration of avoid photodecompo ition. 5xlO-5 was given to a group of the heart. 5xlO 5 AVP i nificantly d creased Result are pr nt d as the me nand contractile fore, coronary flow and hart ndard error of th means. tati tical rat . Th r for ,thi do. wa used in all analy is of the data wa performed by two other xp rimont. concerning with wayan Iy i of variance (A VA) followed m ch ni. m of cardiac eff cts of this peptidc. by the Tuk y-H D multipl comparison In oth r group of the heart imultaneou t . A P value less than 0.05 wa con id red bolus infections of AVP nd V I r ceptor to b ignificant. antagoni. t (B-m rcapto-B, ~ cyclopentamethyl ne-propionyP, 0- e-Tyr2, RE ULTS Arg8 ]-va.oprc·in (8xlO-5 J or AVP and olh r Vir 'c 'ptor ant goni t (Deamino Th injection of AVP (Fig. 1, 2 and 3) Pen1, Val\ D-ArgllJ-v opres in (9x 10-5M) produc d a significant decrea e in wer mad ., aponin (500 Ilg/ml), verapamil contractil force, coronary flow and heart (5xlO 7 ) or indom thacin (10-5M) w r rat (n = 6). VI rec ptor antagoni t infused to diff r nt ets of th h art for 3, [D amino-Pen I, Va1 4 , D-Arg8 J-va opres in 5 and 6 min, r p C iv ly. AVP wa injected did not alt r the cardiac effect of AVP when in the pres ·oc of the infu ion. In a s parate th ntagoni t and AVP were admini ter d group m thyl 'n blu (10 6M) was infu ed for 1 min. Af er m thyI ne blue infusion was
stopp d AVP was ndmini trat d. The drug '10 w r' infus 'd into aortic perfusion lin using 100 an infusion ump (E, Br un-M I ungen AG, Z- oo Bay 'rnI. AVP end V I r c ptor antagoni ts .§. w 'r' giv 'n as a bolus in a volum of 0.1 ml ., ~ eo into th> pC'rfusat', 2 cm proximal to the ~ ~ ortic cannula. The dos of the drugs used <:; 70 f! C was calculat 'U to a final concentration in 0 () 60 lhl' perfusion m odium. 50
IArglil-vasopressin, [ mino- n 1, V 14, 40 0 2 3 4 5 10 D-ArgSI-vasopressin, IP-M rc pto-~, p nme (min) cyclopen t ;11111'1 hylenc-propionyll, -M -Tyr2 , Aq~lll-v 20 of this antagonist AVP caused only a small 18 and insignificant decrease in contractile force, coronary flow and heart rate (n =6, :? 16 § Fig. 4, 5 and 6). E ;14 0 c 120 ~12 c: --. II II • If ! g10 OaX1CH5 M AVP 100 (,) Z .§. 8 j 80 6 CD 0 2 3 4 5 10 ~ 60 TIme (min) *VI AN{IJ .... AvP 8 +Vt An1(1) + ,,"" Fig. 2: Time course of the effects of AVP on coronary 40 0_+AVP flow. 20 0 2 3 4 5 10 310 Tlm., (min) 290 Fig. 4: Time course of the effects of AVP on :s 270 ~ contractile force in the presence of potent V II) receptor antagonist [V AntO)!, very potent :250 .e. V receptor antagoJist IV Ant(2)l or !!230 virapamil. V AntO) [Deamino-1>en 1, Val·, D· II:.. Arg8)-vasoprJssin, V Ant(2) [~-Mercapto·~. ~. 011><10-5 M AVP ~ 210 cyclopentamethylen~-propionyll. 2 CIl O-Me-Tyr • J: 190 Arg8)-vasopressin. 170 150 0 2 3 4 5 10 26 TIme (min) Fig. 3: Time course of the effects of AVP on heart rate. to the hearts. In this group AVP caused a ~16 c: significant decrease in contractile force, E heart rate (n =5) and coronary flow (n =6) 8 * VI Ant(2J + AVP 11 "'VI Ant(1) + AVP (Fig. 4, 5 and 6). In contrast, when ------.-.. OV.opom/I. AVP the heart were treated with other V1 6L...1_...... _.L--..J._-l-_.l....--..J._-l-_.l....--..J._-l-_.l....- receptor antagoni t [~-Mercapto-~, ~ o 234 5 10 cyc1opentamethylene-propionyll, O-Me-Tyr2, TIme (min) Arg8]-vasopressin and AVP, the antagonist Fig. 5: Time course of the effects of AVP on coronary almost completely abolished the myocardial flow in the presence of [V Ant(l», [V Ant(2») and coronary effects of AVP. In the presence or verapamil. 1 1 58 Kaygisiz et al Indian J Physiol Pharmacol 200]; 45(1} 350 of methylene blue a1. 0 produced a significant decrea in contractil force (n =8), while heart rate (n:: 7) 300 "2 and coronary flow (n:: 8) were not :€II> 'lii.. ignificantly affected (Table I). The B 250 administration of AVP after the infusion oS! 8! of the drug also markedly lower d ! contractile force, coronary flow (n:: 8) :1:200 lIEV'~+AW' +VI "'.') + AW' and heart rate (n:: 7) (Fig. 7, 8 and 9). o v.apunl • AVP 120 o 2 345 10 TIme (min) ~100 Fig. 6: Time course of the effects of AVP on heart ..u rate in the presence of IV Ant(1)I. IV Ant(2)1 !! eo or verapamil. 1 I ~ ~ c: <'3 50 "." A""~ The treatment of the heart with + ••,..,...,., .. A.V~ verapamil did not exert any ignificant o 'MHo"'Mt... AV,. effect on coronary flow and heart rate, 40 0 234 5 10 but significantly reduced contractile Tlmo (min) force (n =5, Table I). During thi treatment AVP markedly reduced Fig. 7: The effects of A-';P on contractile force during indomethacin. saponin or after methylene blue contractile force, coronary flow and heart treatments. Methylene blue (met. blue), rate (n =5, Fig. 4, 5 and 6). The infusion indomethacin (indomet.) TABLE I: The baseline values and maximal decreases in contractility, heart rate and coronary now after administration of verapamil (5xl0-7 M) indomethacin (10-5 M). methylene blue (10-6 M) or saponin (500 Ilg/ml). Contractile force Heart rate Coronary flow (mN) (beats I min) (mllmin) Control 98.6:t5.56 285.2:t10.3 24:tl.09 Verapamil 81:t4.3**· 279.4:t10.02 25.2:t0.86 Control 106.66:t7.1 319.5:t13.14 20.66:t0.33 Indomethacin 101:t7.26 307:t12.56 20.33:t0.21 Control 105.25:t2.2 276.42:t12.88 19.75:t0.67 Methylene blue 85.5:t3.71*** 259.42:t9.77 18.75:t0.72 ontrol 102.57:t3.99 236:tl2.88 18.14:t0.45 Saponin 102.28:t4.26 226:t12.26 17.85:t0.5 ***P As illustrated in Table I saponin alone AVP markedly reduced contractile force, had no significant effect on contractile coronary flow and heart rate (n =6, Fig 7, force coronary flow (n = 7) and heart rate 8 and 9). (n = 5). On the other hand, AVP in the presence of this agent significantly DISCUSSION decreased contractile force, coronary flow (n =7) and heart rate (n = 6) (Fig. 7, 8 Our results demonstrate that and 9). Indomethacin alone also did vasopressin markedly decreases myocardial not affect significantly contractile. contractility heart rate and coronary flow force, coronary flow and heart rate (n =6, in the isolated perfused rat hearts. Our Table 1). In the presence of this drug findings are in agreement with the results from previous studies showing that 25 vasopressin produces coronary vasoconstrictor (2, 3, 17, 18), .negative inotropic (2, 3, 5, 17) and chronotropic (6) '220 effect. ~ s We have used saponin in order to disrupt ~ 15 "" the endothelium. In isolated perfused guinea ie pig hearts electron microscopic examination 810 "me,_ blue + AVP confirmed that saponin treatment destroyed ...aponIn .... AVP o lndom.t. + AVP the endothelium while the vascular smooth muscle was left intact (19). Our data show 5 0 234 5 10 that the negative inotropic, chronotropic and l1me (min) coronary vasoconstrictor effects of Fig. 8: Time course of the effects of AVP on coronary vasopressin may not depend on the presence flow during indomethacin, saponin or after of an intact endothelium because methylene blue treatments. vasopressin after removal of endothelium by saponin treatment produced same effects. We suggest that substances released from 300 endothelial cells may not responsible for mediating these cardiac effects of ~--~ vasopression. We also suggest that vasopressin receptors which mediates ~."._dW contraction may be located predominantly on smooth muscle cells but not endothelial .....aponln + AVP 100 o Ind'om.t. + AVP cells. 5OL.....J._...L-----l._...J-----''----'-_L-.-'-_..L-~--'-----'- 02345 10 It ha been demonstrated that 11m. (min) vasopressin increases guano ine 3', 5' Fig. 9: The effects of AVP on heart rate during monophosphate (cGMP) by interacting with indomethacin, saponin or after methylene blue treatments. oxytocin receptor coupled to soluble 60 Kaygiai:t et al Indian J Physiol Pharmacal 2001; 45(1) guanylate cyclase in LLC-PKI kidney verapamil did not change the effects of this epithelial cells (20). Accordingly the peptide. Similarly, the experiments with possibility that cGMP may mediate the human mesenteric arteries have shown that effect of vasopressin on contractility, heart the other calcium antagonist nifedipine did rate and coronary tone has been not significantly change the constrictor investigated in the present study. We have responses induced by vasopressin (l6). Our found that an inhibitor of soluble guanylate results suggest that an influx of cyclase did not change the negative extracellular Ca2• through slow channels inotropic, chronotropic and vasoconstrictor does not playa role in the cardiac effects of effects of vasopressin. These findings vasopressin. suggest that cGMP does not involve in these effects. In the present study changes induced by AVP were prevented by a very potent V1 We have observed that in the presence receptor antagonist fp-Mercapto-p, p. of indomethacin vasopressin still caused a cyclopentamethylene-propionyll, O-Me-Tyr2 , marked decline in contractility, heart rate Arg8 ].vasopressin. We conclude that and coronary flow. That fact that the effects vasoconstrictor effect of vasopressin is of vasopressin were not modified by mediated by VI receptors. Similarly, it has indomethacin suggests that the release of been reported that this peptide produces a prostaglandins does not playa role in the constrictor effect on human vascular smooth effects of the peptide on heart. It has been muscle due to VI receptor stimulation (15, reported that vasopressin increases coronary 22-25). We have observed that potent V I 1 vascular resistance and PGI2 production in receptor antagonist (Deamino-Pen , Val", D perfused nonbeating (A-V node suppressed) Arg81-vasopressin did not change the effects rat hearts and the inhibition of of vasopressin. We suggest that the cyc100xygenase by indomethacin causes a difference between the effects of these fall in coronary vascular resistance (2l). antagonists may be due to their different However, it has been demonstrated that potencies. It has been suggested that indomethacin increases renal vasopressin produces a direct negative vasoconstrictor respouse to vasopressin in inotropic effect mediated by V1 receptors in conscious rats (6). On the other hand, we the dog heart (5). In some studies it has have observed that indomethacin treatment been reported that the negative inotropic had no effect on vasopressin-induced effect depends on the coronary coronary vasoconstriction. The differences vasoconstriction induced by vasopressin (ll in preparations used in these studies may 13). Further studies are necessary to define be responsible for the different results. the precise mechanism for the negative inotropic effect. An increase in systemic We have also considered the possibility vascular resistance and plasma vasopressin that the effects of vasopressin may depend level with a decrease in stroke volume and on an increase in extracellular Ca2• entry cardiac output have been observed in through slow channels. We have observed patients with burn injury (26). The blockade that the calcium channel antagonist of VI receptors by using [13-Mercapto-l3, 13· Indian J PhYliiol Pharmacol 2001: 45(1) Vasopressin and Heart 61 cyclopentamethylene·propionyll, O-Me-Tyr2, We have observed that AVP produces a Arg8 J.vasopressin may be useful in negative chronotropic effect. In isolated pathophysiological conditions where guinea pig hearts it has been reported that vascular resistance are increased the decrease in coronary flow induced by and contractility are decreased by AVP causes a negative chronotropic effect high plasma vasopressin levels. It has (32). Therefore, the bradycardia observed in been suggested that the V I receptor our experiments may depend on the AVP blockade decreases vascular resistance induced decrease in coronary flow. in clinical conditions such as hypertension and congestive heart failure with In conclusion, our result demonstrate increased plasma vasopressin concentration that vasopressin produces negative (27, 28). inotropic, chronotropic and coronary vasoconstrictor effects in the isolated rat In the present study vasopressin-induced hearts. These effects are mediated by VI vasoconstriction may depend on the increase receptors and independent of endothelium. in cytosolic Ca2 + concentration. It has cGMP, prostaglandin release or an influx been found that vasopressin rises cytosolic of extracellular calcium through slow free Ca2 + concentration in neonatal channels does not playa role in the cardiac rat cardiomyocyte (29, 30) and A7r5 effects of this peptide. {f!·Mercapto-f!, Jl aortic smooth muscle cells (31). 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