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(Circulation Research. 1995;77:206-210.)
© 1995 American Heart Association, Inc.

Articles

Functional Identification of Histamine H₃-Receptors in the Human Heart

Michiaki Imamura, Nahid Seyedi, Harry M. Lander, Roberto Levi

From the Department of Pharmacology, Cornell University Medical College, New York, NY.

Correspondence to Roberto Levi, MD, Department of Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021. E-mail rlevi@med.cornell.edu.

	Abstract

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Abstract Norepinephrine release contributes to ischemic cardiac dysfunction and arrhythmias. Because activation of histamine H₃-receptors inhibits norepinephrine release, we searched for the presence of H₃-receptors directly in sympathetic nerve endings (cardiac synaptosomes) isolated from surgical specimens of human atria. Norepinephrine was released by depolarization with K⁺. The presence of H₃-receptors was ascertained because the selective H₃-receptor agonists (R)-methylhistamine and imetit reduced norepinephrine release, and the specific H₃-receptor antagonist thioperamide blocked this effect. Norepinephrine release was exocytotic, since it was inhibited by the N-type Ca²⁺-channel blocker -conotoxin and the protein kinase C inhibitor Ro31-8220. Functional relevance of these H₃-receptors was obtained by showing that transmural electrical stimulation of sympathetic nerve endings in human atrial tissue increased contractility, an effect blocked by propranolol and attenuated in a concentration-dependent manner by (R)-methylhistamine. Also, thioperamide antagonized the effect of (R)-methylhistamine. Our findings are the first demonstration that H₃-receptors are present in sympathetic nerve endings in the human heart, where they modulate adrenergic responses by inhibiting norepinephrine release. Since myocardial ischemia causes intracardiac histamine release, H₃-receptor–induced attenuation of sympathetic neurotransmission may be clinically relevant.

Key Words: cardiac synaptosomes • histamine H₃-receptors • norepinephrine release • sympathetic nerve endings • myocardial ischemia

	Introduction

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Sympathetic overactivity with excessive norepinephrine release is a recognized cause of cardiac dysfunction and arrhythmias in myocardial ischemia¹ and hypertension.² Accordingly, it is important to identify mechanisms to attenuate norepinephrine release. Among these, inhibitory presynaptic receptors have received much attention.³ We and others have recently reported that histamine H₃-receptors negatively modulate cardiac adrenergic function in the guinea pig both in vitro⁴ and in vivo.⁵ Because selective H₃-receptor agonists attenuated the release but not the effects of norepinephrine, we interpreted these findings as an indication that H₃-receptors are located prejunctionally. We further found that these receptors are quiescent in normal conditions but become activated in the setting of myocardial ischemia, when histamine is copiously released.⁶ If histamine H₃-receptors were present in sympathetic nerve endings in the human heart, their activation could represent a novel mechanism to attenuate the deleterious effects of sympathetic overactivity. Therefore, the aim of the present study was to directly demonstrate the presence of H₃-receptors in sympathetic nerve endings isolated from the human heart and to determine whether these receptors modulate adrenergic responses by decreasing norepinephrine release.

	Materials and Methods

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Specimens of right atrial tissue were obtained from 36 patients undergoing cardiopulmonary bypass for cardiac surgery (coronary artery bypass grafting, 23 patients; valve replacement, 13 patients) by following a protocol approved by our Institutional Review Board. All subjects gave informed consent. No patient was in congestive heart failure at the time of surgery. Nine of the 23 coronary artery bypass patients were chronically treated with ß-adrenoceptor blocking agents. Preoperative treatment with ß-blockers affected neither the response to field stimulation nor the release of norepinephrine from K⁺-depolarized synaptosomes. At the time of surgery, a piece of atrial appendage measuring 1 cm² was removed from the atriotomy site. After excision, the specimen was placed in cold oxygenated Krebs-Henseleit solution of the following composition (mmol/L): NaCl 119.0, CaCl₂ 1.5, KCl 4.6, MgSO₄ 1.1, KH₂PO₄ 1.2, NaHCO₃ 24.9, and glucose 10.0.

Norepinephrine Release From Cardiac Synaptosomes
Specimens of human right atrial tissue were freed from fat and connective tissues and minced in ice-cold 0.32 mol/L sucrose containing 1 mmol/L EGTA, pH 7.4. Synaptosomes were isolated as previously described,^{7 8} with the following modifications. Minced tissue was digested with 150 mg collagenase (type II, Worthington Biochemicals) per 10 mL HEPES-buffered saline solution (HBSS) per gram wet heart weight for 3 hours at 37°C. HBSS contained (mmol/L) HEPES 50 (pH 7.4), NaCl 144, KCl 5, CaCl₂ 1.2, MgCl₂ 1.2, glucose 10, and pargyline 1, to prevent enzymatic destruction of synaptosomal norepinephrine. After low-speed centrifugation (5 minutes at 1000g), the resulting pellet was suspended in 10 vol of 0.32 mol/L sucrose and homogenized with a polytetrafluoroethylene (Teflon)/glass homogenizer. The homogenate was spun at 650g for 10 minutes, and the pellet was rehomogenized and respun. The pellet containing cellular debris was discarded, and the supernatants from the last two spins were recentrifuged for 20 minutes at 20 000g at 4°C. This pellet, which contained cardiac synaptosomes, was resuspended in HBSS (500 µL), incubated with KCl (30 mmol/L) in the presence or absence of pharmacological agents for a total of 20 minutes in a water bath at 37°C, and recentrifuged for 20 minutes (20 000g at 4°C). The supernatant (final synaptosomal fraction) was assayed for norepinephrine content by high-performance liquid chromatography with electrochemical detection, as previously described.⁶ Protein content was measured by a modified Lowry procedure (Markwell et al⁹ ). The pellet was discarded. When high concentrations of KCl were used to depolarize synaptosomes, osmolarity was maintained constant by adjusting the NaCl concentration.

Physiological Experiments
Pectinate muscles¹⁰ were carefully dissected free from the atrial wall and mounted vertically in a 10-mL double-walled Pyrex organ bath filled with Krebs-Henseleit solution (gassed with 95% O₂/5% CO₂ at 30°C, pH 7.4) and prepared for isometric tension measurement. The upper end of the pectinate muscle was connected by a silk thread to a force transducer (model 7D, Grass Instruments). A resting tension of 1 g was applied. The lower end of the preparation was clamped between two small plastic plates containing a pair of platinum electrodes. Pectinate muscles were continuously paced at 1 Hz with rectangular pulses (duration, 5 milliseconds; intensity, 20% above threshold voltage) generated by a stimulator (model S88, Grass Instruments) coupled to an isolation unit (model SIU5, Grass Instruments). The preparations were allowed to stabilize for 30 to 60 minutes. Then, transmural sympathetic nerve stimulation was periodically superimposed on the continuous pacing.⁴ For this, intense field stimuli were delivered at a frequency of 1 Hz by a pair of spiral platinum electrodes and consisted of square-wave pulses 10 milliseconds in duration generated by the same stimulator (model S88, Grass Instruments) and synchronized with the pacing stimuli. The intensity of the current applied was 12 to 15 mA. Concentration-response relations were determined by adding the selective histamine H₃-receptor agonist (R)-methylhistamine¹¹ to the bath in a cumulative fashion, allowing the contractile force to stabilize at each concentration (ie, every 2 minutes). Atropine (1 µmol/L) was added to the incubation medium to prevent the activation of muscarinic receptors by acetylcholine released from parasympathetic nerve terminals.

Statistics
Values are expressed as mean±SEM. Analysis was by ANOVA followed by post hoc testing (Dunnett's test). Student's t test was performed for paired observations. A value of P<.05 was considered statistically significant.

	Results

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Norepinephrine Exocytosis From Isolated Sympathetic Nerve Endings and Its Modulation by Histamine H₃-Receptors
We tested the hypothesis that H₃-receptors are located prejunctionally by determining the action of the selective H₃-receptor agonist (R)-methylhistamine directly on sympathetic nerve endings (cardiac synaptosomes) isolated from surgical specimens of human right atria. As shown in Figs 1 and 2, depolarization of synaptosomes with 30 mmol/L K⁺ elicited a 25% to 60% increase in endogenous norepinephrine release above basal levels. The N-type Ca²⁺ channel blocker -conotoxin (10 nmol/L) prevented this release (Fig 1A). Norepinephrine release was also inhibited by 70% by the protein kinase C (PKC) inhibitor Ro31-8220 at 1 µmol/L (Fig 1B). Neither -conotoxin nor Ro31-8220 by themselves affected basal norepinephrine release from unstimulated synaptosomes (norepinephrine release was 76±22 and 71±8.4 pg/mg of protein in the absence and presence, respectively, of -conotoxin [n=8] and 62±10 and 60±6.5 pg/mg of protein in the absence and presence, respectively, of Ro31-8220 [n=6]). As shown in Fig 2A, (R)-methylhistamine (0.3 µmol/L; pD₂, 8.07±0.04 for inhibition of electrically evoked contraction of guinea pig ileum)¹² reduced the K⁺-evoked norepinephrine exocytosis by 65%. The specific H₃-receptor antagonist thioperamide (0.3 µmol/L; pA₂, 8.5±0.09 in the guinea-pig ileum)^{12 13} blocked this effect. Another selective H₃-receptor agonist, imetit (0.1 µmol/L), known to be three times as potent as (R)-methylhistamine on the basis of inhibition of the binding of [³H](R)-methylhistamine to rat brain membranes,¹⁴ also reduced by 65% the K⁺-evoked norepinephrine exocytosis (Fig 2B). Again, the H₃-receptor antagonist thioperamide (0.3 µmol/L) blocked this effect (Fig 2B); thioperamide alone had no effect on K⁺-induced norepinephrine release (n=4; data not shown). Notably, the EC₅₀ values for the effects of (R)-methylhistamine and imetit for H₃-receptors are in the nanomolar range and for H₂- and H₁-receptors are in the high micromolar range. Similarly, the K_i for thioperamide is in the nanomolar range for H₃-receptors and in the high micromolar range for H₂- and H₁-receptors.¹³

View larger version (27K): [in this window] [in a new window]   Figure 1. Bar graphs showing the release of endogenous norepinephrine (NE) from human heart synaptosomes by depolarization with 30 mmol/L K+ and its inhibition by the N-type Ca2+-channel antagonist -conotoxin (-CTX, 10 nmol/L; A) and by the protein kinase C (PKC) inhibitor compound Ro31-8220 (1 µmol/L; B). Each bar represents the mean of percent changes in NE release. Basal NE release was as follows: panel A, 76±22 pg/mg of protein (n=8); panel B, 62±10 pg/mg of protein (n=6). *P<.01 vs corresponding basal value by ANOVA followed by post hoc Dunnett's test.

View larger version (38K): [in this window] [in a new window]   Figure 2. Bar graphs showing that the H3-receptor agonists (R)-methylhistamine (MeHA, 0.3 µmol/L; A) and imetit (0.1 µmol/L; B) attenuate the 30 mmol/L K+–induced norepinephrine (NE) release from human heart synaptosomes. The H3-receptor antagonist thioperamide (Thio, 0.3 µmol/L) blocks the effects of (R)-methylhistamine (A) and imetit (B). Not shown is that thioperamide alone did not affect the K+-induced NE release (n=4). Each bar represents the mean of percent changes in NE release. Basal NE release was as follows: panel A, 93±7 pg/mg of protein (n=6); panel B, 172±39 pg/mg of protein (n=10). *P<.01 vs corresponding basal value by ANOVA followed by post hoc Dunnett's test.

Positive Inotropic Response of Human Right Atrium to Transmural Sympathetic Nerve Stimulation or to Norepinephrine Administration
To strengthen the functional relevance of these H₃- receptors, we next subjected atrial tissue to transmural electrical stimulation of sympathetic nerve endings so as to elicit an adrenergically evoked inotropic response on which to study the effects of H₃-receptor agonists. Pectinate muscles, isolated from human right atrial surgical specimens, were paced at 1 Hz. In the presence of atropine (1 µmol/L), transmural stimulation of sympathetic nerve endings elicited a greater than 10-fold increase in contractile force (from 0.08±0.02 to 1.37±0.16 g, n=11, P<.05). Exogenous norepinephrine (1 µmol/L) elicited a 15-fold increase in contractile force (from 0.027±0.003 to 0.410±0.123 g, n=11, P<.05). The ß-adrenoceptor antagonist propranolol (1 µmol/L) inhibited these responses by 36.9±4.3% (n=7, P<.05) and 38.2±16.2% (n=5, P<.05), respectively. In contrast, the selective ₂-adrenoceptor agonist UK 14,304 (0.1 µmol/L) inhibited only the increase in contractile force elicited by transmural stimulation by 33.6±8.7% (n=5), but not the response to exogenous norepinephrine (data not shown). This suggested that the contractile response to transmural stimulation was due to norepinephrine released from sympathetic nerve endings.

Effect of (R)-Methylhistamine on the Positive Inotropic Responses of Human Right Atrium to Transmural Sympathetic Nerve Stimulation or to Norepinephrine Administration
As shown in Fig 3, (R)-methylhistamine at 0.03 to 10 µmol/L caused a concentration-dependent inhibition of the positive inotropic response of human right atrial tissue to transmural stimulation of sympathetic nerve endings. In contrast, (R)-methylhistamine at 0.3 µmol/L failed to inhibit the positive inotropic effect of exogenous norepinephrine, suggestive of a prejunctional effect of (R)-methylhistamine [norepinephrine at 1 µmol/L caused a 2.8±2.9% greater increase in contractility in the presence of (R)-methylhistamine than in its absence; n=6]. In the presence of the histamine H₃-receptor antagonist thioperamide (0.3 µmol/L), the concentration-response curve for the inhibitory effect of (R)-methylhistamine was shifted markedly to the right (see Fig 3). Furthermore, 1 µmol/L imetit inhibited the positive inotropic response of human right atrial tissue to transmural stimulation of sympathetic nerve endings by 21±5%; thioperamide (0.3 µmol/L) reduced this effect to 2.8±2.0% (n=5, P<.05 by paired t test).

View larger version (21K): [in this window] [in a new window]   Figure 3. Line graph showing that the histamine H3-receptor agonist (R)-methylhistamine (-MeHA) inhibits the positive inotropic effect caused by stimulation of adrenergic nerve endings in pectinate muscles isolated from human right atrium. In all experiments, (R)-methylhistamine was added after the increase in contractile force elicited by field stimulation had reached steady state. Concentration-response relations were determined by adding (R)-methylhistamine to the bath in a cumulative fashion. Experiments were performed in the presence of atropine (1µmol/L) to prevent the inotropic effects of acetylcholine released from parasympathetic nerve endings. Points are mean±SEM (n=6 to 9) of percent inhibition of adrenergic inotropic response by (R)-methylhistamine in the absence (control, ) and presence of the H3-antagonist thioperamide (0.3 µmol/L, ). Basal contractile force was as follows: control, 0.08±0.02 g (n=6); thioperamide, 0.08±0.02 g (n=6). The increase in contractile force by field stimulation was as follows: control, 1.37±0.16 g; thioperamide, 1.36±0.17 g. *P<.05 and **P<.01 vs corresponding control value by paired Student's t test.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
These findings directly demonstrate that histamine H₃-receptors are present on sympathetic nerve endings in the human heart, where they function to modulate adrenergic responses by decreasing norepinephrine exocytosis. We show in the present study that the selective H₃-receptor agonists (R)-methylhistamine¹¹ and imetit¹⁴ inhibit the depolarization-induced release of norepinephrine from cardiac synaptosomes isolated from human myocardium and that these responses are antagonized by the specific H₃-receptor antagonist thioperamide.¹³ The inference that the K⁺-induced depolarization of the synaptosomal preparation elicits an exocytotic release of norepinephrine is supported by our finding that the specific N-type Ca²⁺-channel antagonist -conotoxin¹⁵ inhibited this release. Also, the PKC inhibitor Ro31-8220¹⁶ antagonized the K⁺-induced synaptosomal norepinephrine release. Since PKC participates in the exocytotic cascade,¹⁷ antagonism of norepinephrine release by PKC inhibition further supports the exocytotic nature of the norepinephrine release.

(R)-Methylhistamine and imetit also attenuated the positive inotropic response of human myocardium to transmural stimulation of sympathetic nerve endings, and thioperamide antagonized the effect of (R)-methylhistamine. The ß-adrenoceptor antagonist propranolol inhibited the positive inotropic response to sympathetic nerve stimulation as well as the response to exogenous norepinephrine, whereas compound UK 14,304, a selective agonist at prejunctional inhibitory ₂-adrenoceptors, attenuated only the response to sympathetic nerve stimulation. Thus, the inotropic effect of transmural stimulation was exclusively due to norepinephrine release from sympathetic nerve endings. Like the ₂-agonist, (R)-methylhistamine inhibited the effect of adrenergic nerve stimulation but not the response to administered norepinephrine. This confirms that histamine H₃-receptors responsible for the action of (R)-methylhistamine operate from a prejunctional site and demonstrates the functional relevance of these receptors.

The inhibitory effect of (R)-methylhistamine on the inotropic response to adrenergic nerve stimulation reached a maximum of 20%. This is comparable to what we had previously observed in the guinea pig atrium.⁴ This seemingly modest inhibition does not detract from the physiological importance of H₃-receptors. In fact, we had found that the H₃-receptor–mediated inhibition of the positive chronotropic effect to cardiac sympathetic stimulation amounts to 30%^{4 6} and that the inhibition of norepinephrine release in ischemia/reperfusion models exceeds 50%.^{6 18}

Although H₃-receptor activation inhibited both the inotropic response to adrenergic nerve stimulation and the K⁺-induced synaptosomal release of norepinephrine, greater inhibitory effects were achieved in synaptosomes than in pectinate muscles (65% versus 20%, respectively). This discrepancy most likely reflects the difference between the two preparations. Whereas in synaptosomes we directly measured norepinephrine release in response to K⁺-induced depolarization, in atrial tissue we measured the increase in contractility elicited by field stimulation. In any event, the fact that (R)-methylhistamine and imetit significantly inhibited both responses, whereas thioperamide antagonized them, strongly indicates that both responses are mediated by H₃-receptors.

We had previously investigated H₃-receptor signaling in the guinea pig heart and demonstrated the involvement of a pertussis toxin–sensitive G_i/G_o protein and a decrease in Ca²⁺ influx through N-type channels.⁴ Given the similarity of H₃-receptor–mediated effects in human and guinea pig hearts, we suspect that coupling of H₃-receptors to inhibitory G proteins in the human heart may ultimately result in an inhibition of Ca²⁺ entry via N-type channels. Because inhibition of PKC with compound Ro31-8220 decreased K⁺-induced norepinephrine release from synaptosomes, it is possible that PKC inhibition plays a role in the modulation of norepinephrine release associated with H₃-receptor activation. Indeed, H₃-receptors have been found to be coupled to a pertussis toxin–sensitive G protein and to decrease phosphoinositide turnover in a human gastric carcinoma cell line.¹⁹ Histamine H₃-receptor–mediated decrease in phosphoinositide turnover and diacylglycerol formation could decrease PKC activity and, therefore, norepinephrine release from sympathetic nerve endings.

Although we had access only to human atrial specimens, in view of our findings in the guinea pig heart^{6 18} and canine ventricular myocardium (unpublished data, 1995), we believe that histamine H₃-receptors are also present on sympathetic nerve endings in human ventricle. Therefore, our discovery that sympathetic nerve endings in the human heart harbor histamine H₃-receptors that can reduce exocytotic norepinephrine release may be clinically relevant. Indeed, myocardial infarction is often accompanied by arrhythmias that can be fatal.¹ Sympathetic overactivity and excessive norepinephrine release may increase metabolic demand, thus aggravating the primary ischemia and initiating a vicious cycle leading to further myocardial damage.²⁰ Therefore, negative modulation of norepinephrine release from cardiac sympathetic nerves is a crucial protective mechanism. In the ischemic guinea pig heart, sufficient amounts of histamine are released to activate H₃-receptors and attenuate norepinephrine exocytosis.⁶ Accordingly, our findings imply that H₃-receptors may mitigate the consequences of the sympathetic overactivity that accompanies myocardial ischemia in humans and suggest new therapeutic strategies to alleviate dysfunctions associated with this condition.

	Acknowledgments

 
This study was supported by National Institutes of Health grants HL-34215 and HL-46403. We gratefully acknowledge the help of Dr O. Wayne Isom, Chairman of the Department of Cardiothoracic Surgery of Cornell University Medical College, in providing us with surgical specimens of human right atria. Compound Ro31-8220 was a gift of Dr T.J. Hallam, Roche Research Centre, Welwyn Garden City, Herts, UK. Imetit was graciously provided by Prof C.R. Ganellin, Department of Chemistry, University College, London, UK.

	Footnotes

 
Preliminary version presented at the meeting of Experimental Biology '95, Atlanta, Ga, April 9-13, 1995, and published in abstract form (FASEB J. 1995;9:A933).

Received March 20, 1995; accepted April 21, 1995.

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				N. Seyedi, R. Maruyama, and R. Levi Bradykinin Activates a Cross-Signaling Pathway between Sensory and Adrenergic Nerve Endings in the Heart: A Novel Mechanism of Ischemic Norepinephrine Release? J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 656 - 663. [Abstract] [Full Text]

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				N. Seyedi, T. Win, H. M. Lander, and R. Levi Bradykinin B2-Receptor Activation Augments Norepinephrine Exocytosis From Cardiac Sympathetic Nerve Endings : Mediation by Autocrine/Paracrine Mechanisms Circ. Res., November 19, 1997; 81(5): 774 - 784. [Abstract] [Full Text]

				E. Hatta, K. Yasuda, and R. Levi Activation of Histamine H3 Receptors Inhibits Carrier-Mediated Norepinephrine Release in a Human Model of Protracted Myocardial Ischemia, J. Pharmacol. Exp. Ther., November 1, 1997; 283(2): 494 - 500. [Abstract] [Full Text]

				S. J. Hill, C. R. Ganellin, H. Timmerman, J. C. Schwartz, N. P. Shankley, J. M. Young, W. Schunack, R. Levi, and H. L. Haas International Union of Pharmacology. XIII. Classification of Histamine Receptors Pharmacol. Rev., September 1, 1997; 49(3): 253 - 278. [Abstract] [Full Text] [PDF]

				M. Imamura, N. C.E. Smith, M. Garbarg, and R. Levi Histamine H3-Receptor–Mediated Inhibition of Calcitonin Gene-Related Peptide Release From Cardiac C Fibers : A Regulatory Negative-Feedback Loop Circ. Res., May 1, 1996; 78(5): 863 - 869. [Abstract] [Full Text]

				M. Imamura, H. M. Lander, and R. Levi Activation of Histamine H3-Receptors Inhibits Carrier-Mediated Norepinephrine Release During Protracted Myocardial Ischemia : Comparison With Adenosine A1-Receptors and {alpha}2-Adrenoceptors Circ. Res., March 1, 1996; 78(3): 475 - 481. [Abstract] [Full Text]

				R. B. Silver, K. S. Poonwasi, N. Seyedi, S. J. Wilson, T. W. Lovenberg, and R. Levi Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings PNAS, January 8, 2002; 99(1): 501 - 506. [Abstract] [Full Text] [PDF]

				R. B. Silver, C. J. Mackins, N. C. E. Smith, I. L. Koritchneva, K. Lefkowitz, T. W. Lovenberg, and R. Levi Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia PNAS, February 27, 2001; 98(5): 2855 - 2859. [Abstract] [Full Text] [PDF]

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