(Hypertension. 1996;28:444-449.)
© 1996 American Heart Association, Inc.
Articles |
Thromboxane A2 Mediates the Stimulation of Inositol 1,4,5-Trisphosphate Production and Intracellular Calcium Mobilization by Bradykinin in Neonatal Rat Ventricular Cardiomyocytes
the Department of Anesthesiology and Pain Management, Cook County Hospital (F.N., S.F.R.) and Departments of Pharmacology (F.N., R.D.M., G.C. Le B., S.F.R.), Anesthesiology (R.D.M.), and Physiology (S.F.R.), University of Illinois College of Medicine at Chicago.
Correspondence to Sara F. Rabito, MD, Department of Anesthesiology and Pain Management, Cook County Hospital, 637 S Wood St, Rm 427, Chicago, IL 60612.
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Abstract |
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Bradykinin is a mediator of the protection of myocardium by angiotensin I–converting enzyme/kininase II inhibitors. We reported that the activation of B2 bradykinin receptors in neonatal rat cardiac myocytes in primary culture was followed by hydrolysis of phosphatidylinositol 4,5-bisphosphate and formation of inositol 1,4,5-trisphosphate (IP3). Here we examine the regulation of IP3 formation stimulated by bradykinin. Activation of myocytes with 1 µmol/L bradykinin increased IP3 production from 117±8.3 to 1011±48.6 pmol/mg protein. Treatment of the cells with 10 µmol/L indomethacin or 1 µmol/L dexamethasone partially blocked this bradykinin-induced response. Moreover, either U73122, a phospholipase C inhibitor, or (p-amylcinnamoyl) anthranilic acid, a phospholipase A2 inhibitor, blunted the IP3 response to bradykinin. Because thromboxane A2 stimulates inositol bisphosphate metabolism in guinea pig atria, we also investigated the effect of the thromboxane A2 receptor antagonist BM 13177 (1 µmol/L), which strongly attenuated the stimulated IP3 production. Since thromboxane A2 appears to partly mediate the IP3 response to bradykinin, we examined the effect of the stable thromboxane A2 mimetic U46619. Control cultures were stimulated more by U46619 than by bradykinin (1629±14.5 versus 1011±48.6 pmol IP3/mg protein). This property of U46619 was selectively antagonized by BM 13177. Inhibition of either phospholipase C or phospholipase A2 blunted the IP3 response to U46619. Short-term (30 minutes) activation of protein kinase C with phorbol 12-myristate 13-acetate (10 pmol/L to 1 µmol/L) attenuated the IP3 accumulation in response to bradykinin; the effect of phorbol 12-myristate 13-acetate was reversed with 1 µmol/L staurosporine, a protein kinase C inhibitor. Treatment with 1 µg/mL cholera toxin or pertussis toxin for 4 hours amplified the IP3 response to 10 nmol/L bradykinin from 570±20.0 to 1150±51.3 and to 1016.7±21.9 pmol/mg protein. Bradykinin mobilized 9.4% of intracellular calcium stores in cardiomyocytes as assessed by chlortetracycline-based fluorometry, and this effect of bradykinin was blocked by BM 13177 or the B2 bradykinin receptor blocker Hoe 140 by more than 70%. In functional studies, bradykinin (1 µmol/L) increased by 12% the twitch contractile force of neonatal rat ventricular strips paced at threshold intensity, but this was unaffected by BM 13177. In conclusion, in cardiomyocytes, bradykinin enhances IP3 production mostly via phospholipase A2 stimulation and thromboxane A2 formation. This prostanoid in turn stimulates its receptor and activates phospholipase C, which then splits phosphatidylinositol 4,5-bisphosphate into IP3 and diacylglycerol. The effect of bradykinin on phospholipase C, via thromboxane A2, is negatively regulated by protein kinase C activation.
Key Words: bradykinin • angiotensin-converting enzyme inhibitors • phospholipases • phorbol esters • signal transduction
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Introduction |
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Angiotensin I–converting enzyme/kininase II inhibitors have several beneficial effects on heart function. They are used for the treatment of congestive heart failure as first-line drugs,1 and their effectiveness in reducing mortality and morbidity has been widely recognized.2 3 4 However, stimulation of the renin-angiotensin system essentially increases cardiac contractility through angiotensin II receptors on cardiac myocytes.5 6 Therefore, it appears paradoxical that the inhibition of angiotensin II formation would lead to an improvement of cardiac function, but several reports indicate that the inhibition of kininase II activity and the potentiation of bradykinin effects can be important in the cardioprotection provided by angiotensin-converting enzyme inhibitors.7 8 9 10 11 12
The cellular events that mediate the action of bradykinin in the heart are still unclear. We have recently reported that cardiomyocytes express high-affinity B2 bradykinin receptors that, when activated, hydrolyze PIP2 to form IP3.13 Stimulation of a variety of cell surface receptors results in activation of PLC and hydrolysis of membrane PIP2 to generate two second messengers, IP3 and diacylglycerol.14 IP3 releases Ca2+ from intracellular sources in the majority of the cell types studied, whereas diacylglycerol promotes the translocation to the plasma membrane and activation of PKC. Reportedly, PKC has a significant role in the feedback regulation of the receptor-operated IP3-Ca2+ signaling pathway.15 16 17 Moreover, bradykinin receptors could be coupled to more than one second messenger. For example, in several cell types, bradykinin receptors appear to be coupled to both PLA2 and PLC.18 19 Activation of PLA2 results in the release of several prostanoids, including TXA2,20 which has a positive inotropic effect on guinea pig atria that is associated with increased IP2 metabolism.21
In the present study, using primary cultures of neonatal rat cardiomyocytes, we investigated the mechanisms that modulate IP3 formation in response to bradykinin. We provide evidence that in cardiomyocytes, the B2 bradykinin receptor is linked mainly to PLA2. Stimulation of PLA2 by bradykinin results in TXA2 formation, which in turn, acting on its receptor, stimulates PLC to catalyze the release of IP3 and diacylglycerol. Activation of PKC results in a negative-feedback regulation of the IP3 formation induced by bradykinin.
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Methods |
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Cardiomyocyte Isolation and Immunocytochemical Identification
Cardiomyocytes from 1- to 2-day-old Sprague-Dawley rats were isolated and cultured according to a modification of the method of Sadoshima et al22 as described previously.13
To verify the purity of the cardiac myocyte cultures, we used a rat monoclonal antibody to chick cardiac muscle myosin heavy chain (a-MHC) as previously reported.13
IP3 Measurement
We measured the effect of bradykinin on IP2 hydrolysis in cells grown on gelatin-coated 25-cm2 culture flasks. Twenty-four hours before the cells were studied, the culture medium was changed to a serum-free medium. After bradykinin had been added for the indicated duration, the reaction was stopped with the addition of 0.2 mL ice-cold 100% trichloroacetic acid for each 1 mL of medium. The acid extract was homogenized at 0°C to 4°C and centrifuged for 10 minutes at 1000g. Trichloroacetic acid was removed from the extracts by addition of 2 mL of a mixture of 3 vol 1,1,2-trichloro-1,2,2-trifluoroethane plus 1 vol trioctylamine for each 1 mL of trichloroacetic acid extract. IP3 content was determined in the aqueous top layer with a radioreceptor assay kit (NEN Research Products–DuPont).
Measurement of Intracellular Calcium Mobilization
After 3 days in culture in T75 flasks, cardiac myocytes were rinsed twice with 20 mL phosphate-buffered saline. Then, 3 mL of a solution of 0.5 mg/mL trypsin and 0.2 mg/mL EDTA was added to the cultures for 30 seconds and removed. The cells were incubated at 37°C until they rounded-up and detached. The cells were collected in phosphate-buffered saline and centrifuged at 1000g for 10 minutes. The supernatant was aspirated and discarded, and the pellet was resuspended in Hanks' balanced salt solution at the density of 106 cells per milliliter.
To evaluate whether bradykinin or TXA2 causes mobilization of intracellular calcium in cardiac myocytes, we used the fluorescent calcium indicator chlortetracycline according to the method of Brace et al.23 Briefly, the cell suspension was incubated with 10 µmol/L chlortetracycline for 2 hours at 25°C. Four 1-mL samples were withdrawn 1 minute after the addition of vehicle or agonists. Antagonists were added 5 minutes before the addition of agonists. The 1-mL samples were placed into 1.5-mL plastic conical centrifuge tubes and centrifuged at 7000g for 1 minute. Immediately after centrifugation, the supernatant was aspirated, leaving the undisturbed pellets in the tube tips. The tube tips were removed with a hot surgical blade and placed in acrylic holders for fluorescence determination with a photon-counting microspectrofluorometer.
Measurement of Contractile Force of Isolated Neonatal Ventricular Heart Muscle
Contractile experiments were done as previously described.24 Briefly, neonatal rats were anesthetized with halothane, and the heart was rapidly excised. The blood was removed by washing the hearts in cold Krebs-Henseleit solution. Ventricular strips (approximately 10 mm long and 4 mm wide) containing both right and left ventricles were attached between a force-displacement transducer (FT 0.3, Grass Instruments) and a fixed point by means of stainless steel hooks. The muscle was immersed in a water-jacketed glass chamber (volume=100 mL) containing heated (33°C), gassed (100% O2) Krebs-Henseleit solution. After a 30-minute equilibration period, the resting tension of each muscle was adjusted to give a twitch of half the maximal amplitude. The muscles were stimulated at a frequency of 3 Hz by means of rectangular current pulses delivered via a pair of platinum plate electrodes positioned on either side of the preparation. The intensity of electrical stimulation was 10% above threshold. The twitch contractions were recorded on a polygraph (Grass model 7) and simultaneously displayed on the video monitor of a computer (model G/AT 286-10, Gems Computers) after being digitized (Labmaster Board, Tecmar, Inc). On-line, automated measurements of the peak amplitude of twitch contractions were made, and when desired, the measured values were stored for later analysis.
Protein Measurement
Protein was determined by the method of Bradford25 with bovine serum albumin as standard.
Solutions and Chemicals
Hoe 140 was a gift from Hoechst-Roussel Pharmaceuticals, Inc. The TXA2 antagonist BM 13177 was from Boehringer Mannheim. ACA, a PLA2 inhibitor, and U73122, a PLC inhibitor, were purchased from BIOMOL Research Laboratories. The stable analogue of TXA2 U46619, indomethacin, dexamethasone, staurosporine, PMA, bradykinin acetate, pertussis toxin, cholera toxin, cell culture media and supplements, and all chemicals were purchased from Sigma Chemical Co.
Statistical Analysis
Data are expressed as mean±SE. Statistical comparisons were made with ANOVA for repeated measures and the Bonferroni procedure. Differences in mean values were considered significant at a value of P<.05.
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Results |
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Cultures of neonatal rat ventricular cardiomyocytes began beating spontaneously 24 to 48 hours after they were plated on culture flasks coated with 0.1% gelatin. More than 90% of the cells in these cultures reacted with the a-myosin heavy chain antibody,13 indicating the relative homogeneity of the cultured cells.
To determine whether prostaglandins would be involved in the IP3 response to bradykinin, we examined the effect of 10 µmol/L indomethacin and 1 µmol/L dexamethasone. Treatment of the cultures with either indomethacin or dexamethasone for 15 minutes before addition of bradykinin inhibited IP3 formation by 55% and 34% (Fig 1
), respectively.
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We assessed the involvement of PLC and PLA2 in the IP3 response to bradykinin by examining the effects of U73122, a PLC inhibitor, and ACA, a PLA2 inhibitor. We found that these inhibitors markedly reduced the IP3 response to bradykinin by 73% (10 µmol/L U73122) and 65% (0.1 mmol/L ACA) (Fig 2). Because TXA2 stimulates phosphatidylinositol metabolism in guinea pig atria,21 we also investigated the effect of BM 13177, a TXA2 receptor blocker,26 27 on bradykinin-stimulated IP3 production. We found that 1 µmol/L BM 13177 decreased IP3 formation after bradykinin by more than 80% (Fig 2).
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Since these findings indicated that TXA2 mediates the IP3 response to bradykinin, we examined the effect of the compound U46619, a TXA2 mimetic. Control cultures avidly accumulated IP3 when treated with U46619 (Fig 3). The maximal IP3 response after 1 µmol/L U46619 was significantly higher than that after 1 µmol/L bradykinin (1629±14.5 versus 1011±48.6 pmol/mg protein). This effect of U46619 was selectively antagonized by the TXA2 receptor antagonist BM 13177 (Fig 4). Inhibition of either PLC or PLA2 significantly blunted the IP3 response to U46619 (Fig 4).
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To determine whether PKC participates in the regulation of the IP3 response, we treated the cultures with PMA, a potent PKC stimulator, before adding bradykinin. Cells were treated with various concentrations of PMA for 30 minutes and then exposed to 1 µmol/L bradykinin for 20 seconds. PMA treatment led to a concentration-dependent inhibition of IP3 formation (Fig 5). In the absence of bradykinin, PMA did not alter the basal accumulation of IP3 significantly. When cells were pretreated for 30 minutes with 1 µmol/L staurosporine, a potent PKC inhibitor, the bradykinin-stimulated IP3 production was enhanced and the inhibitory effect of PMA on bradykinin-mediated IP3 accumulation was suppressed (Fig 6).
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To characterize whether the bradykinin effect can be altered by cholera or pertussis toxin, we treated the cultures with either toxin for 4 hours before administering 0.1 nmol/L bradykinin. Fig 7 illustrates that 0.1 to 1 µg/mL cholera toxin or 0.01 to 1 µg/mL pertussis toxin amplified the effect of bradykinin on IP3 accumulation, the extent of which depended on the concentration of toxin used.
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Bradykinin mobilized 9.4±0.3% of intracellular calcium stores in cardiomyocytes as assessed by chlortetracycline-based fluorometry, and this effect of bradykinin was blocked more than 70% by 1 µmol/L Hoe 140 and 10 µmol/L BM 13177 (Fig 8). Moreover, bradykinin (1 µmol/L) applied to paced neonatal rat ventricular muscle strips caused a transient positive inotropic effect. The maximal increase in contractile force occurred approximately 1 to 2 minutes after the addition of bradykinin, and the force of contraction returned to baseline 3 to 4 minutes later. The maximal increase in contractility was 12.0±2.4% over baseline (n=6). In the presence of BM 13177 (10 µmol/L), the maximal increase in contractility after the addition of bradykinin was 11.0±3.9% (n=4). This effect of bradykinin on ventricular muscle contractility was not blocked by alprenolol (1 µmol/L), a selective ß1-adrenoceptor blocker.
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Discussion |
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Identification and characterization of the signal-transduction pathways involved in bradykinin signaling is of great importance in understanding the actions of bradykinin in the myocardium. When bradykinin binds to its receptor in the plasma membrane of endothelial cells and fibroblasts, it initiates a chain of events that includes activation of PLC, leading to the cleavage of PIP2 to generate diacylglycerol and IP3, as well as activation of PLA2, which triggers arachidonic acid release.28 These second messenger systems may elicit biological effects independent of one another, or they may interact. For example, in some cell types, bradykinin receptors are known to be coupled to more than one second messenger pathway. In fibroblasts, bradykinin stimulates the separate production of both prostaglandin E2 and IP3,18 and in MDCK cells, there is an independent coupling of PLA2 and PLC to the bradykinin receptor.19 In platelets, arachidonic acid release may result from phosphoinositide hydrolysis or from activation of PLA2, which in turn may occur as a direct consequence of receptor occupancy or secondary to activation of PKC, increased intracellular Ca2+, or pH.
The fact that in neonatal rat cardiomyocytes bradykinin-induced IP3 formation was partially blocked by either indomethacin or dexamethasone indicates that in this cell type, an interaction between PLA2 and PLC occurs after activation of the bradykinin receptor. Furthermore, the ability of ACA, an inhibitor of PLA2, to decrease the bradykinin-mediated IP3 formation as well as U73122, an inhibitor of PLC, suggests that in cardiomyocytes, the activation of PLC by bradykinin is a process that depends on the activation of PLA2. Concerning the specificity of phospholipase inhibitors, it has been shown in cultured rat cardiomyocytes that 0.1 mmol/L ACA blocked arachidonic acid release but not PIP2 accumulation, whereas 10 µmol/L U73122 blocked the PIP2 but not the arachidonic acid release in response to angiotensin II.29
Prostaglandins act as autocrine and paracrine hormones by binding to receptors linked, via G proteins, to adenylate cyclases and guanylate cyclases. However, some actions of prostaglandins, such as the contraction of smooth muscles by prostaglandin F2
and prostaglandin E2, are associated with Ca2+ mobilization secondary to stimulation of PLC. Moreover, TXA2 has been found to act on specific TXA2 receptors in guinea pig atria, in which TXA2 elicits a positive inotropic effect that is related to increased phosphoinositide metabolism.21 In the present study, we have demonstrated that in ventricular myocytes, the effect of bradykinin on IP3 was blocked by TXA2 antagonism at the receptor level. We also found that the IP3 accumulation in response to the stable TXA2 analogue U46619 was significantly attenuated by U73122. Revtyak et al30 could not detect any release of TXB2, the stable metabolite of TXA2, into the medium after stimulation of cardiomyocytes with bradykinin. This would indicate that the amount of TXA2 released from myocytes after stimulation with bradykinin is below the sensitivity of the current methods to measure it but sufficient to stimulate its receptor. The finding that ACA blocked the IP3 response to the TXA2 analogue U46619 implies that in cardiomyocytes, a self-generating system exists in which bradykinin stimulates thromboxane release, which in turn activates PLA2. The increase in intracellular Ca2+ after TXA2 release is probably another regulatory element in PLA2 activation.
In airway smooth muscle cells, the transduction mechanism of bradykinin coupled to phosphoinositide hydrolysis is sensitive to feedback regulation by PKC.15 Likewise in our study, the treatment of cardiac myocytes with PMA resulted in inhibition of bradykinin-stimulated IP3 accumulation. This finding suggests the presence, in cardiac myocytes, of a short inhibitory feedback loop in which diacylglycerol formation and PKC activation cause an attenuation of agonist-stimulated PLC activity.
Bradykinin mobilized 10% of intracellular calcium stores in cardiomyocytes as assessed by chlortetracycline-based fluorometry, and this effect of bradykinin was blocked by the B2 bradykinin receptor blocker Hoe 140 or the TXA2 receptor antagonist BM 13177. The fluorescent calcium probe chlortetracycline has been used as a means of monitoring changes in intracellular calcium in many systems, including sarcoplasmic reticulum, red blood cells, mitochondria, neutrophils, and platelets. Chlortetracycline is a valuable intracellular calcium probe for detection of mobilized calcium in that it forms a highly fluorescent, pH-insensitive adduct when chelated with divalent cations bound to biological membranes. The fluorescent intensity of the calcium-chlortetracycline complex markedly decreases (100-fold) when calcium is released from the membrane to the more polar environment in the cytosol. Therefore, relative changes in cellular fluorescence can be used as an index of calcium mobilization from storage sites to the cytosol. The observed 10% change in fluorescence upon stimulation with bradykinin, which was blocked by Hoe 140 and BM 13177, is consistent with our finding that bradykinin generates IP3 via thromboxane. In several preliminary experiments, we were unable to show significant changes in cytosolic calcium using the indicator fura 2 (unpublished data, 1996). Similar results were observed during investigation of the effect of endothelin-3 on platelets; ie, a measurable change in calcium fluorescence was observed with chlortetracycline but not with fura 2.31
The functional importance of IP3 in the excitation-contraction coupling mechanism in cardiomyocytes is still unclear. In preliminary experiments, we observed that bradykinin, like other agonists that stimulate myocardial receptors coupled to IP3, has a modest positive inotropic effect (12%) when added to paced neonatal rat ventricular strips. This effect, in contrast to that previously reported in the adult rat (left atria or right ventricle), was not sensitive to ß-adrenoceptor blockade.24 The lack of an inhibitory effect of the TXA2 receptor blocker BM 13177 on bradykinin-augmented contractility, when it nearly abolished bradykinin-induced increases in IP3 (Fig 2
), suggests that augmented contraction by bradykinin is not related to increases in IP3. Moreover, the fact that the blockade of TXA2 receptors effectively decreased the mobilization of intracellular calcium by bradykinin without affecting its positive inotropic effect suggests that the bradykinin-sensitive calcium store is not functionally related to the positive inotropic effect of bradykinin. However, increased myocardial contractility is only one of the functional changes induced by bradykinin. This peptide is an autocrine/paracrine factor that protects the heart against the deleterious consequences of ischemia and reperfusion,32 participates in the prevention/regression of left ventricular hypertrophy in hypertension,33 and mediates part of the beneficial effect of angiotensin-converting enzyme inhibitors on myocardial remodeling after myocardial infarction.33 The participation of TXA2, IP3, or both in the signal transduction pathways for these actions of bradykinin remains to be elucidated.
We also investigated the effect of bacterial toxins on bradykinin-stimulated IP3 production. We found that both cholera toxin and pertussis toxin potentiated bradykinin-mediated PIP2 hydrolysis. In human foreskin fibroblasts, bradykinin-stimulated synthesis of prostacyclin was enhanced when cells were pretreated with either cholera toxin or pertussis toxin.34 Similarly, the inositol phosphate formation and arachidonic acid release in response to bradykinin was enhanced in fibroblasts pretreated with either of these toxins.35 36 The mechanism of these stimulatory effects of cholera and pertussis toxins have been postulated as being due to increased intracellular cAMP, which results in an increased number of bradykinin receptors.34
In summary, our results demonstrate that in cardiomyocytes, bradykinin increases the production of IP3 primarily through stimulation of PLA2. TXA2, the intermediate arachidonic acid metabolite that is released from cardiomyocytes upon stimulation of PLA2, mediates the increase in IP3 (Fig 9) and the mobilization of intracellular calcium in response to bradykinin. TXA2 does not appear to play a significant role in mediating the increase in ventricular contractility after bradykinin. The effect of bradykinin on PLC is negatively regulated by PKC activation.
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Acknowledgments |
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This work was supported in part by a grant from the Vasotec Medical School Grants Committee, Merck & Co, Inc, to S.F.R., and National Institutes of Health grant HL-36473. The authors thank Dr Ervin G. Erdos for his critical comments and review of this manuscript.
Received March 11, 1996; first decision March 28, 1996; accepted April 29, 1996.
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Y. Shizukuda and P. M. Buttrick Protein kinase C-zeta modulates thromboxane A2-mediated apoptosis in adult ventricular myocytes via Akt Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H320 - H327. [Abstract] [Full Text] [PDF]
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