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Shigetoshi Chiba - One of the best experts on this subject based on the ideXlab platform.

  • effects of low temperature on the Chronotropic and inotropic responses to zatebradine e 4031 and verapamil in isolated perfused dog atria
    Japanese Journal of Pharmacology, 1998
    Co-Authors: Miho Kasama, Yuji Hoyano, Yasuyuki Furukawa, Takeshi Oguchi, Shigetoshi Chiba
    Abstract:

    : We investigated the effects of hypothermia (25 degrees C) on the Chronotropic and inotropic effects of zatebradine (a blocker of hyperpolarization-activated inward current, I(f)), E-4031 (a blocker of the rapid type of the delayed rectifier K+ current, I(Kr)) and verapamil, and on the positive cardiac responses to isoproterenol after treatment with zatebradine and E-4031 in isolated, blood-perfused dog atria. Hypothermia shifted the dose-response curves to the right for the negative Chronotropic and inotropic effects of verapamil and for the negative Chronotropic and positive inotropic effects of zatebradine, but not for the negative Chronotropic and positive inotropic effects of E-4031. Hypothermia attenuated the positive Chronotropic response to isoproterenol or Bay k 8644 (an L type Ca2+ channel agonist) and was attenuated more than the inotropic one. Zatebradine selectively inhibited the positive Chronotropic response to isoproterenol at a normal temperature, but in hypothermia, it inhibited neither the Chronotropic nor inotropic responses. E-4031 did not affect the positive responses to isoproterenol. These results suggest that verapamil and zatebradine but not E-4031 influence the atrial rate and contractile force much less in hypothermia than in normothermia and that the I(f) and inward Ca2+ current are sensitive to hypothermia in the heart.

  • Are negative Chronotropic and inotropic responses to adenosine differentiated at the receptor or postreceptor levels in isolated dog hearts
    Journal of Pharmacology and Experimental Therapeutics, 1995
    Co-Authors: Takeshi Oguchi, Miho Kasama, Yasuyuki Furukawa, Shoji Sawaki, Shigetoshi Chiba
    Abstract:

    Inhibition by zatebradine, a specific bradycardic agent, of the negative inotropic but not Chronotropic responses to adenosine has been briefly reported in the isolated, perfused dog heart. We therefore investigated whether subtypes of adenosine receptors or postreceptor transduction mechanisms differentiated the negative Chronotropic and inotropic responses to adenosine in the isolated, blood-perfused atrial and ventricular preparations of the dog. Adenosine (1-3000 nmol), adenosine A1 receptor agonists, 2-chloroadenosine (CAD, 0.1-300 nmol) and N6-cyclohexyladenosine (CHA, 1-300 nmol) and a nonselective adenosine receptor agonist, 59-N-ethyl-carboxamidoadenosine (NECA, 0.1-100 nmol), induced the negative Chronotropic and inotropic responses. The potency order was NECA > CAD > adenosine > or = CHA. An adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10-300 nmol), dose-dependently inhibited the negative Chronotropic and inotropic responses to adenosine, CAD and NECA in the isolated, perfused right atrium. DPCPX also blocked the negative inotropic responses to adenosine, CAD and NECA in the isolated left ventricle. However, an adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 300 nmol), did not affect the negative cardiac responses to adenosine and NECA. Although the negative inotropic but not Chronotropic responses to CAD and adenosine were dose-dependently inhibited by zatebradine, K+ channel inhibitors 4-aminopyridine and E-4031 did not modify the cardiac responses to adenosine and CAD. These results suggest that the negative cardiac responses to adenosine are mediated by adenosine A1 receptors and the negative Chronotropic and inotropic responses to adenosine are differentiated at the postreceptor transduction level(s) in the dog heart.

  • zatebradine attenuates cyclic amp related positive Chronotropic but not inotropic responses in isolated perfused right atria of the dog
    Clinical and Experimental Pharmacology and Physiology, 1995
    Co-Authors: Shoji Sawaki, Yasuyuki Furukawa, Yasurou Inoue, Takeshi Oguchi, Shigetoshi Chiba
    Abstract:

    SUMMARY 1. Inhibition of If or Ica by zatebradine has been reported in mammalian SA nodal cells. We thus investigated whether zatebradine differentially attenuates the positive Chronotropic and inotropic responses to norepinephrine, isoproterenol, NKH 477 (an adenylyl cyclase activator), 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 (a calcium channel agonist) in the isolated, blood-perfused dog atrium. 2. When zatebradine (0.03–1 μmol) decreased sinus rate from 104 ± 4.5 to 73 ± 4.9 beats/min dose-dependently, it selectively attenuated the positive Chronotropic but not inotropic responses to norepinephrine in a dose-related manner. Zatebradine decreased the norepinephrine-induced tachycardia (by approximately 80% from the control) more effectively than the spontaneous sinus rate (by approximately 30% from the control). 3. Zatebradine similarly attenuated the positive Chronotropic but not inotropic responses to isoproterenol, NKH 477 and IBMX. Fifty per cent inhibition doses of zatebradine (0.10–0.18 μmol) for the Chronotropic responses to each substance were not significantly different. 4. On the other hand, zatebradine attenuated neither positive Chronotropic nor inotropic responses to Bay k 8644. 5. We therefore suggest that zatebradine selectively attenuates the positive Chronotropic but not inotropic responses to cyclic AMP-related substances due to inhibition of If but not Ica in the dog heart.

  • Parasympatholytic effects of vecuronium are mediated by nicotinic and muscarinic receptors in hearts of anesthetized dogs.
    The Journal of pharmacology and experimental therapeutics, 1992
    Co-Authors: Masahiro Narita, Yasuyuki Furukawa, M. Takei, M. Murakami, Lei-ming Ren, Shigetoshi Chiba
    Abstract:

    We investigated the blocking effects of vecuronium and pancuronium on the negative Chronotropic and dromotropic responses to stimulation of the parasympathetic nerves in the anesthetized, open-chest dog. We stimulated the intracardiac parasympathetic nerves to the SA nodal region (SAP stimulation) or to the atrioventricular nodal region (AVP stimulation). SAP stimulation or AVP stimulation selectively decreased heart rate or increased atrioventricular conduction time, respectively. Vecuronium and pancuronium inhibited the Chronotropic response to SAP stimulation and the dromotropic response to AVP stimulation in a dose-dependent manner. The ID50 of each drug for the dromotropic response was less than that for the Chronotropic response. The blocking effect of vecuronium on the negative cardiac responses to parasympathetic stimulation was about 10-fold less potent than that of pancuronium. These results suggest that the blocking effects of vecuronium and pancuronium on the negative Chronotropic and dromotropic responses to parasympathetic stimulation differ from those of atropine in the heart. In the isolated right atrium perfused with blood from the support dog, vecuronium, injected into the external jugular vein of the support dog, dose-dependently inhibited the negative Chronotropic and inotropic responses to carbachol or SAP stimulation and the negative followed by positive Chronotropic and inotropic responses to nicotine. The ID50 values for carbachol, nicotine and SAP stimulation were not significantly different. These results suggest that parasympatholytic effects of vecuronium are mediated by not only muscarinic receptors but also neuronal nicotinic receptors in hearts of anesthetized dogs.

  • Functional participation in M1 receptor subtype on Chronotropic and dromotropic responses to vagus stimulation in anesthetized dogs.
    The Journal of pharmacology and experimental therapeutics, 1991
    Co-Authors: Masahiro Narita, Yasuyuki Furukawa, M. Takei, M. Murakami, Lei-ming Ren, Y. Karasawa, Shigetoshi Chiba
    Abstract:

    We investigated blocking effects of pirenzepine, AF-DX 116 and atropine on the negative Chronotropic and dromotropic responses to stimulation of the intracardiac vagus nerves in the anesthetized, open-chest dogs. Stimulation of the intracardiac vagus nerves to the sinoatrial nodal region (stimulation of the intracardiac parasympathetic nerves to the sinoatrial nodal region) or to the atrioventricular nodal region (stimulation of intracardiac nerves to the atriventricular region) selectively decreased heart rate or increased atrioventricular conduction time, respectively. Pirenzepine at lower doses (0.3-3 microgram/kg i.v.) attenuated the stimulation of the negative Chronotropic response to the intracardiac parasympathetic nerves to the sinoatrial nodal region to 80% of the control response significantly but did not affect the negative dromotropic one. Similarly, higher doses (10-1000 micrograms/kg i.v.) of pirenzepine inhibited the Chronotropic and dromotropic responses to each stimulation in a dose-dependent manner. AF-DX 116 (0.3-300 microgram/kg i.v.) inhibited the Chronotropic and dromotropic responses to each stimulation in a similar dose-dependent manner. Atropine (1-30 microgram/kg i.v.) blocked the cardiac responses to each stimulation. However, the ID50 of atropine for the Chronotropic response was less than that for the dromotropic one, although ID50s of pirenzepine and AF-DX 116 for the Chronotropic and dromotropic responses were not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Yasuyuki Furukawa - One of the best experts on this subject based on the ideXlab platform.

  • effects of low temperature on the Chronotropic and inotropic responses to zatebradine e 4031 and verapamil in isolated perfused dog atria
    Japanese Journal of Pharmacology, 1998
    Co-Authors: Miho Kasama, Yuji Hoyano, Yasuyuki Furukawa, Takeshi Oguchi, Shigetoshi Chiba
    Abstract:

    : We investigated the effects of hypothermia (25 degrees C) on the Chronotropic and inotropic effects of zatebradine (a blocker of hyperpolarization-activated inward current, I(f)), E-4031 (a blocker of the rapid type of the delayed rectifier K+ current, I(Kr)) and verapamil, and on the positive cardiac responses to isoproterenol after treatment with zatebradine and E-4031 in isolated, blood-perfused dog atria. Hypothermia shifted the dose-response curves to the right for the negative Chronotropic and inotropic effects of verapamil and for the negative Chronotropic and positive inotropic effects of zatebradine, but not for the negative Chronotropic and positive inotropic effects of E-4031. Hypothermia attenuated the positive Chronotropic response to isoproterenol or Bay k 8644 (an L type Ca2+ channel agonist) and was attenuated more than the inotropic one. Zatebradine selectively inhibited the positive Chronotropic response to isoproterenol at a normal temperature, but in hypothermia, it inhibited neither the Chronotropic nor inotropic responses. E-4031 did not affect the positive responses to isoproterenol. These results suggest that verapamil and zatebradine but not E-4031 influence the atrial rate and contractile force much less in hypothermia than in normothermia and that the I(f) and inward Ca2+ current are sensitive to hypothermia in the heart.

  • Are negative Chronotropic and inotropic responses to adenosine differentiated at the receptor or postreceptor levels in isolated dog hearts
    Journal of Pharmacology and Experimental Therapeutics, 1995
    Co-Authors: Takeshi Oguchi, Miho Kasama, Yasuyuki Furukawa, Shoji Sawaki, Shigetoshi Chiba
    Abstract:

    Inhibition by zatebradine, a specific bradycardic agent, of the negative inotropic but not Chronotropic responses to adenosine has been briefly reported in the isolated, perfused dog heart. We therefore investigated whether subtypes of adenosine receptors or postreceptor transduction mechanisms differentiated the negative Chronotropic and inotropic responses to adenosine in the isolated, blood-perfused atrial and ventricular preparations of the dog. Adenosine (1-3000 nmol), adenosine A1 receptor agonists, 2-chloroadenosine (CAD, 0.1-300 nmol) and N6-cyclohexyladenosine (CHA, 1-300 nmol) and a nonselective adenosine receptor agonist, 59-N-ethyl-carboxamidoadenosine (NECA, 0.1-100 nmol), induced the negative Chronotropic and inotropic responses. The potency order was NECA > CAD > adenosine > or = CHA. An adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10-300 nmol), dose-dependently inhibited the negative Chronotropic and inotropic responses to adenosine, CAD and NECA in the isolated, perfused right atrium. DPCPX also blocked the negative inotropic responses to adenosine, CAD and NECA in the isolated left ventricle. However, an adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 300 nmol), did not affect the negative cardiac responses to adenosine and NECA. Although the negative inotropic but not Chronotropic responses to CAD and adenosine were dose-dependently inhibited by zatebradine, K+ channel inhibitors 4-aminopyridine and E-4031 did not modify the cardiac responses to adenosine and CAD. These results suggest that the negative cardiac responses to adenosine are mediated by adenosine A1 receptors and the negative Chronotropic and inotropic responses to adenosine are differentiated at the postreceptor transduction level(s) in the dog heart.

  • zatebradine attenuates cyclic amp related positive Chronotropic but not inotropic responses in isolated perfused right atria of the dog
    Clinical and Experimental Pharmacology and Physiology, 1995
    Co-Authors: Shoji Sawaki, Yasuyuki Furukawa, Yasurou Inoue, Takeshi Oguchi, Shigetoshi Chiba
    Abstract:

    SUMMARY 1. Inhibition of If or Ica by zatebradine has been reported in mammalian SA nodal cells. We thus investigated whether zatebradine differentially attenuates the positive Chronotropic and inotropic responses to norepinephrine, isoproterenol, NKH 477 (an adenylyl cyclase activator), 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 (a calcium channel agonist) in the isolated, blood-perfused dog atrium. 2. When zatebradine (0.03–1 μmol) decreased sinus rate from 104 ± 4.5 to 73 ± 4.9 beats/min dose-dependently, it selectively attenuated the positive Chronotropic but not inotropic responses to norepinephrine in a dose-related manner. Zatebradine decreased the norepinephrine-induced tachycardia (by approximately 80% from the control) more effectively than the spontaneous sinus rate (by approximately 30% from the control). 3. Zatebradine similarly attenuated the positive Chronotropic but not inotropic responses to isoproterenol, NKH 477 and IBMX. Fifty per cent inhibition doses of zatebradine (0.10–0.18 μmol) for the Chronotropic responses to each substance were not significantly different. 4. On the other hand, zatebradine attenuated neither positive Chronotropic nor inotropic responses to Bay k 8644. 5. We therefore suggest that zatebradine selectively attenuates the positive Chronotropic but not inotropic responses to cyclic AMP-related substances due to inhibition of If but not Ica in the dog heart.

  • Parasympatholytic effects of vecuronium are mediated by nicotinic and muscarinic receptors in hearts of anesthetized dogs.
    The Journal of pharmacology and experimental therapeutics, 1992
    Co-Authors: Masahiro Narita, Yasuyuki Furukawa, M. Takei, M. Murakami, Lei-ming Ren, Shigetoshi Chiba
    Abstract:

    We investigated the blocking effects of vecuronium and pancuronium on the negative Chronotropic and dromotropic responses to stimulation of the parasympathetic nerves in the anesthetized, open-chest dog. We stimulated the intracardiac parasympathetic nerves to the SA nodal region (SAP stimulation) or to the atrioventricular nodal region (AVP stimulation). SAP stimulation or AVP stimulation selectively decreased heart rate or increased atrioventricular conduction time, respectively. Vecuronium and pancuronium inhibited the Chronotropic response to SAP stimulation and the dromotropic response to AVP stimulation in a dose-dependent manner. The ID50 of each drug for the dromotropic response was less than that for the Chronotropic response. The blocking effect of vecuronium on the negative cardiac responses to parasympathetic stimulation was about 10-fold less potent than that of pancuronium. These results suggest that the blocking effects of vecuronium and pancuronium on the negative Chronotropic and dromotropic responses to parasympathetic stimulation differ from those of atropine in the heart. In the isolated right atrium perfused with blood from the support dog, vecuronium, injected into the external jugular vein of the support dog, dose-dependently inhibited the negative Chronotropic and inotropic responses to carbachol or SAP stimulation and the negative followed by positive Chronotropic and inotropic responses to nicotine. The ID50 values for carbachol, nicotine and SAP stimulation were not significantly different. These results suggest that parasympatholytic effects of vecuronium are mediated by not only muscarinic receptors but also neuronal nicotinic receptors in hearts of anesthetized dogs.

  • Functional participation in M1 receptor subtype on Chronotropic and dromotropic responses to vagus stimulation in anesthetized dogs.
    The Journal of pharmacology and experimental therapeutics, 1991
    Co-Authors: Masahiro Narita, Yasuyuki Furukawa, M. Takei, M. Murakami, Lei-ming Ren, Y. Karasawa, Shigetoshi Chiba
    Abstract:

    We investigated blocking effects of pirenzepine, AF-DX 116 and atropine on the negative Chronotropic and dromotropic responses to stimulation of the intracardiac vagus nerves in the anesthetized, open-chest dogs. Stimulation of the intracardiac vagus nerves to the sinoatrial nodal region (stimulation of the intracardiac parasympathetic nerves to the sinoatrial nodal region) or to the atrioventricular nodal region (stimulation of intracardiac nerves to the atriventricular region) selectively decreased heart rate or increased atrioventricular conduction time, respectively. Pirenzepine at lower doses (0.3-3 microgram/kg i.v.) attenuated the stimulation of the negative Chronotropic response to the intracardiac parasympathetic nerves to the sinoatrial nodal region to 80% of the control response significantly but did not affect the negative dromotropic one. Similarly, higher doses (10-1000 micrograms/kg i.v.) of pirenzepine inhibited the Chronotropic and dromotropic responses to each stimulation in a dose-dependent manner. AF-DX 116 (0.3-300 microgram/kg i.v.) inhibited the Chronotropic and dromotropic responses to each stimulation in a similar dose-dependent manner. Atropine (1-30 microgram/kg i.v.) blocked the cardiac responses to each stimulation. However, the ID50 of atropine for the Chronotropic response was less than that for the dromotropic one, although ID50s of pirenzepine and AF-DX 116 for the Chronotropic and dromotropic responses were not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Jie Zhang - One of the best experts on this subject based on the ideXlab platform.

  • Bradykinin B2-receptor-mediated positive Chronotropic effect of bradykinin in isolated rat atria.
    Journal of Cardiovascular Pharmacology, 1998
    Co-Authors: Qun Li, Juan F. Loro, Martin Pfaffendorf, Jie Zhang, Pieter A. Van Zwieten
    Abstract:

    Summary: The positive Chronotropic effect of bradykinin was investigated in isolated spontaneously beating atria of the rat. Cumulative additions of bradykinin (0.3-100 nM) caused a concentration-dependent increase in the beating rate of the atria by maximally 35 ± 4 beats/min, ∼25% of the 1 μM isoprenaline-induced maximal responses. In contrast, the active metabolite of bradykinin and selective bradykinin B1-receptor agonist, Des-Arg9-bradykinin, did not influence the spontaneous frequency of beating. Propranolol (1 μM) combined with prazosin (1 μM) did not affect the positive Chronotropic effect of bradykinin. A selective bradykinin B2-receptor antagonist, Hoe 140, concentration-dependently shifted the response curves for bradykinin to the right, whereas the bradykinin B1-receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin had no effect. The tachycardic responses to bradykinin were potentiated by ramipril, and angiotensin-converting enzyme/kininase II inhibitor, but not affected by Nω-nitro-L-arginine methyl ester hydrochloride, a nitric oxide synthesis inhibitor. Indomethacin and meclofenamate, two cyclooxygenase inhibitors, abolished the bradykinin-induced Chronotropic effect. These results indicate that exogenous bradykinin induces a positive Chronotropic effect that occurs independent of adrenoceptors. The bradykinin-induced Chronotropic effect is mediated by bradykinin B2 receptors, whereas B1 receptors do not play a role in mediating this effect. Prostaglandins but not nitric oxide appear to be involved in bradykinin-induced positive Chronotropic effect.

  • Bradykinin B2-receptor-mediated positive Chronotropic effect of bradykinin in isolated rat atria
    Journal of cardiovascular pharmacology, 1998
    Co-Authors: Jie Zhang, Juan F. Loro, Martin Pfaffendorf, Pieter A. Van Zwieten
    Abstract:

    The positive Chronotropic effect of bradykinin was investigated in isolated spontaneously beating atria of the rat. Cumulative additions of bradykinin (0.3-100 nM) caused a concentration-dependent increase in the beating rate of the atria by maximally 35+/-4 beats/min, approximately 25% of the 1 microM isoprenaline-induced maximal responses. In contrast, the active metabolite of bradykinin and selective bradykinin B1-receptor agonist, Des-Arg9-bradykinin, did not influence the spontaneous frequency of beating. Propranolol (1 microM) combined with prazosin (1 microM) did not affect the positive Chronotropic effect of bradykinin. A selective bradykinin B2-receptor antagonist, Hoe 140, concentration-dependently shifted the response curves for bradykinin to the right, whereas the bradykinin B1-receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin had no effect. The tachycardic responses to bradykinin were potentiated by ramipril, an angiotensin-converting enzyme/kininase II inhibitor, but not affected by Nomega-nitro-L-arginine methyl ester hydrochloride, a nitric oxide synthesis inhibitor. Indomethacin and meclofenamate, two cyclooxygenase inhibitors, abolished the bradykinin-induced Chronotropic effect. These results indicate that exogenous bradykinin induces a positive Chronotropic effect that occurs independent of adrenoceptors. The bradykinin-induced Chronotropic effect is mediated by bradykinin B2 receptors, whereas B1 receptors do not play a role in mediating this effect. Prostaglandins but not nitric oxide appear to be involved in bradykinin-induced positive Chronotropic effect.

Pieter A. Van Zwieten - One of the best experts on this subject based on the ideXlab platform.

  • Bradykinin B2-receptor-mediated positive Chronotropic effect of bradykinin in isolated rat atria
    Journal of cardiovascular pharmacology, 1998
    Co-Authors: Jie Zhang, Juan F. Loro, Martin Pfaffendorf, Pieter A. Van Zwieten
    Abstract:

    The positive Chronotropic effect of bradykinin was investigated in isolated spontaneously beating atria of the rat. Cumulative additions of bradykinin (0.3-100 nM) caused a concentration-dependent increase in the beating rate of the atria by maximally 35+/-4 beats/min, approximately 25% of the 1 microM isoprenaline-induced maximal responses. In contrast, the active metabolite of bradykinin and selective bradykinin B1-receptor agonist, Des-Arg9-bradykinin, did not influence the spontaneous frequency of beating. Propranolol (1 microM) combined with prazosin (1 microM) did not affect the positive Chronotropic effect of bradykinin. A selective bradykinin B2-receptor antagonist, Hoe 140, concentration-dependently shifted the response curves for bradykinin to the right, whereas the bradykinin B1-receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin had no effect. The tachycardic responses to bradykinin were potentiated by ramipril, an angiotensin-converting enzyme/kininase II inhibitor, but not affected by Nomega-nitro-L-arginine methyl ester hydrochloride, a nitric oxide synthesis inhibitor. Indomethacin and meclofenamate, two cyclooxygenase inhibitors, abolished the bradykinin-induced Chronotropic effect. These results indicate that exogenous bradykinin induces a positive Chronotropic effect that occurs independent of adrenoceptors. The bradykinin-induced Chronotropic effect is mediated by bradykinin B2 receptors, whereas B1 receptors do not play a role in mediating this effect. Prostaglandins but not nitric oxide appear to be involved in bradykinin-induced positive Chronotropic effect.

Pieter A. Van Zwieten - One of the best experts on this subject based on the ideXlab platform.

  • Bradykinin B2-receptor-mediated positive Chronotropic effect of bradykinin in isolated rat atria.
    Journal of Cardiovascular Pharmacology, 1998
    Co-Authors: Qun Li, Juan F. Loro, Martin Pfaffendorf, Jie Zhang, Pieter A. Van Zwieten
    Abstract:

    Summary: The positive Chronotropic effect of bradykinin was investigated in isolated spontaneously beating atria of the rat. Cumulative additions of bradykinin (0.3-100 nM) caused a concentration-dependent increase in the beating rate of the atria by maximally 35 ± 4 beats/min, ∼25% of the 1 μM isoprenaline-induced maximal responses. In contrast, the active metabolite of bradykinin and selective bradykinin B1-receptor agonist, Des-Arg9-bradykinin, did not influence the spontaneous frequency of beating. Propranolol (1 μM) combined with prazosin (1 μM) did not affect the positive Chronotropic effect of bradykinin. A selective bradykinin B2-receptor antagonist, Hoe 140, concentration-dependently shifted the response curves for bradykinin to the right, whereas the bradykinin B1-receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin had no effect. The tachycardic responses to bradykinin were potentiated by ramipril, and angiotensin-converting enzyme/kininase II inhibitor, but not affected by Nω-nitro-L-arginine methyl ester hydrochloride, a nitric oxide synthesis inhibitor. Indomethacin and meclofenamate, two cyclooxygenase inhibitors, abolished the bradykinin-induced Chronotropic effect. These results indicate that exogenous bradykinin induces a positive Chronotropic effect that occurs independent of adrenoceptors. The bradykinin-induced Chronotropic effect is mediated by bradykinin B2 receptors, whereas B1 receptors do not play a role in mediating this effect. Prostaglandins but not nitric oxide appear to be involved in bradykinin-induced positive Chronotropic effect.