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The effects off bradykinin on the isolated rat heart
2227 3.21 "< 10 -~ to 2.00 × 10 -7 mol/l. All effects of BDF 9148 in atria and papillary muscles were promptly reversed by 3 × 10 -6 mol/1 tetrodotoxin. A prolongation of the open state of the sodium channel by BDF 9148, which leads to an increase of the sodium influx during the action potential, seems to be the most likely explanation for the observed drug effects. I P.fr.126 [
The effects of bradykinin on the isolated rat heart Tio, R.A., Scholtens, E., van Gilst, W,H., de Langen, C.D.J. a n d Wesseling, H.
Department of Pharmacology~ClinicalPharmacology, University of Groningen, BIoemsingeli, 9713 BZ Groningen, The Netherlands Coronary flow is regulated by a variety of mechanisms. The local renin angiotensin system has been shown to be an important factor. Converting enzyme inhibitors as well as bradykinin increase coronary flow in the isolated rat heart (Van Gilst et al., 1987; Linz et al., 1986). To estabfish the receptor mediated effects of bradykinin (Sigma B-3259) in the isolated rat heart we used a bradykinin-1 receptor antagonist (Arg-Pro-Pro-Cly-Phe-Ser-Pro-Leu; n = 19; Sig,~a B-6769) and a bi'adykinin-2 receptor antagonists (D-Arg[Hyp2-Thi5,8-DPheT]-bradykinin; n = 17; HOE K86-4321). Male Wistar rats fed at libitum, were anesthetized with diethyl ether. Heparin (1500 IU) was administered intravenously via a tail vein. The heart was excised rapidly and put into ice cold saline. Retrograde perfusion of the aorta with a modified Tyrode solution, as described by Langendorff, was achieved immediately. Thereupon, the heart was cleaned of surrounding fat and other tissue. Perfusion pressure was maintained at. 60 mmHg by means of a microprocessor controlled perfusion pump. After calibration of the perfusion pump, this microprocessor also calculated the coronary flow continuously. All hearts beat spontaneously. Drugs were added to the standard solution starting after a 10 rain equifibration period using all infusion system. Bradykinin was used in dosages of 1, 3, 10, 30, 100 and 300 nmol/l. To each heart, two randomly chosen bradykinin doses were administered during five minutes, separated by a washout period of five minutes. Five minutes after the last bradykinin dose, an infusion contained one of the two antagonists in a concentration of 1.10 -6 tool/1 was started and after ten minutes the procedure described above was repeated, in the presence of the antagonist. Within the concentration range at least 6 observations were made for each dose. The increases in coronary flow (ml/min) are shown in the table: Bradykinin nmol/l
Control
Bradykinin-1 axttagot~Jst
Bradykinin-2 antagonist
1 3 10 30 1~ 3~
2,3~0.3 2.9±0.3 6.9±0.5 8~±0.4 8.9±0.5 8.5±0.4
1.1±0.2 2.0±0.2 6.9±1.2 10.0±0.6" 11.6±1.5"
0.5±0.1" 0.8~0.2" 1.3~0.3" 4.6~1.3" 11.4±0.5" 9.3~1.3
mean values + SEM; significant differences when compared to the control values are indicated * p < 0.05. In the isolated rat heart, bradykinin increased coronary flow dose dependently. The dose-response curve was not shifted by the bradykinin-1 receptor antagonist, but the maximum was higher. The bradykinin-2 receptor antagonist shifted the curve to the right. These results suggest that in the isolated rat heart, increases in coronary flow are mainly due to bradykL-tin-2 receptor stimulation, whereas in this dose range bradykinin-1 receptors do not play a major flow increasing role.
References Van Gilst, W.H. et al., 1987, J. Cardiovasc. Pharmacol. 9 ($2), 531-536. Linz, W. et al., 1986, J. Cardiovasc. Pharmacol. 8 (S10), $91-$99.
The effects of bradykinin on the isolated rat heart Tio, R.A., Scholtens, E., van Gilst, W,H., de Langen, C.D.J. a n d Wesseling, H.
Department of Pharmacology~ClinicalPharmacology, University of Groningen, BIoemsingeli, 9713 BZ Groningen, The Netherlands Coronary flow is regulated by a variety of mechanisms. The local renin angiotensin system has been shown to be an important factor. Converting enzyme inhibitors as well as bradykinin increase coronary flow in the isolated rat heart (Van Gilst et al., 1987; Linz et al., 1986). To estabfish the receptor mediated effects of bradykinin (Sigma B-3259) in the isolated rat heart we used a bradykinin-1 receptor antagonist (Arg-Pro-Pro-Cly-Phe-Ser-Pro-Leu; n = 19; Sig,~a B-6769) and a bi'adykinin-2 receptor antagonists (D-Arg[Hyp2-Thi5,8-DPheT]-bradykinin; n = 17; HOE K86-4321). Male Wistar rats fed at libitum, were anesthetized with diethyl ether. Heparin (1500 IU) was administered intravenously via a tail vein. The heart was excised rapidly and put into ice cold saline. Retrograde perfusion of the aorta with a modified Tyrode solution, as described by Langendorff, was achieved immediately. Thereupon, the heart was cleaned of surrounding fat and other tissue. Perfusion pressure was maintained at. 60 mmHg by means of a microprocessor controlled perfusion pump. After calibration of the perfusion pump, this microprocessor also calculated the coronary flow continuously. All hearts beat spontaneously. Drugs were added to the standard solution starting after a 10 rain equifibration period using all infusion system. Bradykinin was used in dosages of 1, 3, 10, 30, 100 and 300 nmol/l. To each heart, two randomly chosen bradykinin doses were administered during five minutes, separated by a washout period of five minutes. Five minutes after the last bradykinin dose, an infusion contained one of the two antagonists in a concentration of 1.10 -6 tool/1 was started and after ten minutes the procedure described above was repeated, in the presence of the antagonist. Within the concentration range at least 6 observations were made for each dose. The increases in coronary flow (ml/min) are shown in the table: Bradykinin nmol/l
Control
Bradykinin-1 axttagot~Jst
Bradykinin-2 antagonist
1 3 10 30 1~ 3~
2,3~0.3 2.9±0.3 6.9±0.5 8~±0.4 8.9±0.5 8.5±0.4
1.1±0.2 2.0±0.2 6.9±1.2 10.0±0.6" 11.6±1.5"
0.5±0.1" 0.8~0.2" 1.3~0.3" 4.6~1.3" 11.4±0.5" 9.3~1.3
mean values + SEM; significant differences when compared to the control values are indicated * p < 0.05. In the isolated rat heart, bradykinin increased coronary flow dose dependently. The dose-response curve was not shifted by the bradykinin-1 receptor antagonist, but the maximum was higher. The bradykinin-2 receptor antagonist shifted the curve to the right. These results suggest that in the isolated rat heart, increases in coronary flow are mainly due to bradykL-tin-2 receptor stimulation, whereas in this dose range bradykinin-1 receptors do not play a major flow increasing role.
References Van Gilst, W.H. et al., 1987, J. Cardiovasc. Pharmacol. 9 ($2), 531-536. Linz, W. et al., 1986, J. Cardiovasc. Pharmacol. 8 (S10), $91-$99.