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Cardiovascular Research 1999 43(1):13-16; doi:10.1016/S0008-6363(99)00112-1
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Opioid peptides and the heart

Barbara A Barron*

Department of Integrative Physiology, Cardiovascular Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd. Fort Worth, TX 76107, USA

* Tel.: +1-817-7352484; fax: +1-817-7355084

Received 25 February 1999; accepted 11 March 1999

See article by Millington et al. ([1], pages 107–116) in this issue.


   1 Introduction
Top
 1 Introduction
2 Enkephalin biochemistry
 3 Cardiac opioid peptides
 4 Opiate receptors and...
 5 Summary
 References
 
In this issue Millington et al. [1] describe the localization of pro-opiomelanocortin (POMC) message and peptide products in adult and neonatal rat heart. These authors are to be commended for delving into the esoteric area of cardiac endocrine function and opioid peptides. The finding of atrial natriuretic peptide and opioid peptides in cardiac myocytes confirms the ability of the heart to participate in homeostasis beyond simple pumping. Consideration can now be given to the endocrine function of the heart. Besides POMC, proenkephalin and prodynorphin have been identified in heart and cardiomyocytes of different species including rodents, cat, dog, pig and humans [2–6]. The questions then arise: Why do muscle cells make opioid peptides? What are their functions? How are opioid peptides regulated in the cardiac myocyte? Before examining these questions a brief review of opioid peptide biochemistry may be helpful. The proenkephalin family of opioid peptides is used as an example.


   2 Enkephalin biochemistry
Top
 1 Introduction
 2 Enkephalin biochemistry
3 Cardiac opioid peptides
 4 Opiate receptors and...
 5 Summary
 References
 
The proenkephalin sequence contains four copies of methionine-enkephalin (met-enk), one of leucine-enkephalin and two extended forms of met-enk (met-enk-arg-gly-leu and met-enk-arg-phe [MERF], Fig. 1). These small peptides are delineated for processing from the precursor by pairs of basic amino acids. Proenkephalin processing is achieved by prohormone convertases, which are endoproteolytic enyzmes recognizing the dibasic amino acids. Proenkephalin has an early cleavage to peptide B and later cleavages to other intermediate sized products that can finally be cleaved to the penta- to octapeptides [7,8].


Figure 1
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  		Fig. 1 Preproenkephalin A and products isolated from adrenal medulla (adapted from Ref. [9]). The molecular weights are for the peptide beneath the number. SP, signal peptide; M, met-enkephalin; L, leu-enkephalin; M+, met-enk-arg-gly-leu; M*, met-enk-arg-phe.

 
Sequences of processing and enzymatic conditions in nerves may differ from parenchymal tissue resulting in different products. Neural tissues contain a 4:1 ratio of met-enk to MERF as expected from the sequence of the precursor and complete processing. However, proenkephalin processing in peripheral tissue, such as the heart and lung, is not complete. Thus the ratio is reversed and MERF is present in greater concentration than met-enk in both the heart [6,10] and lung [11]. Similarly, prodynorphin was sequenced and shown to have three leucine-enkephalin copies and multiple molecular weight products [9]. As with the enkephalins, heart tissue and isolated cardiac myocytes contain larger molecular weight immunoreactive dynorphin [3,5]. Therefore, the heart processes and uses opioid peptides differently when compared with neuronal tissue. How is this processing regulated? Do opioids signal cardiomyocytes in an autocrine fashion to modulate their own synthesis?


   3 Cardiac opioid peptides
Top
 1 Introduction
 2 Enkephalin biochemistry
 3 Cardiac opioid peptides
4 Opiate receptors and...
 5 Summary
 References
 
Enkephalin distribution in the heart depends on which species is studied and the peptide measured. MERF immunoreactivity is greater than met-enk especially in the ventricles [6]. The exception is the porcine right ventricle and feline and porcine atria where MERF is equal to met-enk. In addition, MERF content is greater in ventricles than atria in both dog and cat while the opposite is true in pigs. This shows that the atria process proenkephalin to a different extent than do the ventricle. The Millington et al. [1] data supports this in the rat showing that atrial β-endorphin is greater than ventricular. Perhaps, the atria contain more neurally derived opioid peptides having greater processing to products than found in the ventricle.

Where in cardiomyocytes are enkephalins stored? The results of Millington et al. [1] support the findings of others. Immunohistochemical staining for peptides, reveals enkephalins are packaged in vesicles, presumably for release as endocrine signals in the atrial but not ventricular tissue. However, the fixation process may ‘wash’ the peptides away. We found good immunohistochemical staining for enkephalins only in frozen ventricular tissue sections [6]. Fixed ventricular slices displayed only neuronal staining patterns for enkephalins (unpublished data). Therefore, ventricular myocytes do not package peptides into vesicles.

Many physiological conditions regulate the cardiac opioid message and the peptide products. Myocardial infarction, aging, hypertension and cardiomyopathy are associated with increased cardiac enkephalins or proenkephalin mRNA [12–15]. Interestingly, the peptide and message content is not tightly correlated. The possibility of changes in opioid precursor processing or peptide degradation cannot be addressed without a chromatographic analysis of the peptides produced by the heart. Is the increase due to more immunoreactive products being processed from the precursor plus increased mRNA production? Are there changes in the rate of peptide product degradation? Further studies are needed to identify the signal for increased cardiac enkephalin production and the mechanisms for increasing the content.

The endogenous opioid peptides act via opiate receptors (µ, {delta}, {kappa}). Opiate receptor stimulation causes direct and indirect functional changes in the heart and cardiomyocytes. In fact, all of the subtype selective opiate receptor agonists have effects on the heart. For instance, {delta}-selective agonists and antagonists mimic and block, respectively, ischemic preconditioning in rats [16]. Only µ-agonists inhibited neurally stimulated contractile response in the guinea-pig atrium but {kappa} and {delta} receptor agonists produced inhibition in the guinea-pig ventricle [17,18]. {kappa}-receptors mediated inhibition of stimulated norepinephrine release measured across the heart in vivo [19,20]. A {kappa}-agonist also caused a reduction in heart rate and contractility, which were prevented by chronic agonist treatment [21] showing that acute and chronic effects of opioids are different. Adaptations occur with chronic elevation of opiates, therefore, pathological changes that elevate endogenous opioid peptides should also display some adaptive changes. Chronic disease states need to be characterized as to opioid peptide changes to understand these phenomena better. Opioid peptide effects on the heart need to be correlated with opioid peptide spillover, cardiac peptide content, processing and degradation, and cardiovascular function.

The possibility that the opioids are produced by the myocytes to influence their own neuronal regulation furthers the idea of feedback systems at a cardiac paracrine level. Opioid peptide production can be stimulated by agents increasing cAMP in isolated cardiomyocytes [4]. Opioids inhibit neurotransmitter release. This makes cardiac opioids good candidates for a role in autonomic nerve ‘crosstalk’. Adrenergic stimulation of cAMP production would increase cardiac opioids providing negative feedback to inhibit neurotransmitter release at the vagal and/or adrenergic nerve terminals. In support of this hypothesis, physiological conditions that increase cardiac nerve stimulation such as exercise, hypertension and hemorrhagic hypotension change cardiac opioid content [12,22,23]. Increased enkephalins may explain the hypoalgesia and diminished cardiac vagal and baroreflex responsiveness found in hypertensive animals.

Another hypothesis for elevated opioids in exercise, hypertension and cardiomyopathy is supported by the Millington et al. [1] data. These conditions lead to different types of cardiac hypertrophy. Opioid peptides in the heart may be involved in pathways leading to hypertrophy, a possible autocrine function. Hypertrophy signaling is thought to involve a return to neonatal signaling. β-endorphin and met-enkephalin are higher in neonatal cardiac tissue than in adult. The ability of opioid peptides to induce changes in hypertrophy cascades can now be tested.


   4 Opiate receptors and the heart
Top
 1 Introduction
 2 Enkephalin biochemistry
 3 Cardiac opioid peptides
 4 Opiate receptors and...
5 Summary
 References
 
Most studies infer the activity of endogenous opioids at cardiovascular opiate receptors by the action of opiate receptor antagonists. Development of selective opiate receptor antagonists has furthered this research. Selective {delta}-receptor antagonism but not µ-receptor antagonism increased blood pressure, cardiac output, contractility and blood flows to the heart, kidneys, GI tract and skeletal muscle in conscious dogs with right heart failure [24]. The blockade of opiate receptors increases the heart’s response to β-adrenergic stimulation [25] suggesting an endogenous opioid effect to decrease cardiac adrenergic stimulation. Conversely, adrenergic stimulators increase cardiac opiate receptor number and affinity [26] thus providing a feedback loop between these two systems. These results implicate the action of endogenous opioid peptides but do not prove it, since any receptor antagonist may have non-receptor effects [27,28]. However, endogenous opioid peptides (enkephalins or dynorphins) acting via cardiac opiate receptors may play an important role in the reciprocal interactions between sympathetic and parasympathetic cardiac control. More direct evidence of peptide action (peptide release, peptide mimicry of effect) is needed in this regard.

Controversy, complicated by species differences, exists about the type of opiate receptor present in the heart. Classical opiate receptor binding studies on cardiac tissue have been carried out only in rodents. In this regard, rat heart {kappa} and {delta} opiate receptors are distributed more to the right side than the left and greater in the atrium than the ventricle [26,29]. Physiologic manipulations can regulate the cardiac opiate receptors. Hemorrhagic hypotension caused a reversible decrease in opiate binding [29]. Spontaneously hypertensive rats had high affinity {delta}-receptors as compared to their normotensive controls that had both high and low affinity receptors in the heart. The mechanism of these changes is unknown. In both experiments (hypotension and hypertension) a greater adrenergic input to the heart is hypothesized. Are the changes in receptors due to release of myocardial opioid peptides or neurally derived opioid peptides? Are changes in myocardial opioid peptide production and release caused by adrenergic stimulation of the heart? Opioid peptides and their receptors are present in the heart but the effects of chronic pathology on the opioid peptide system (synthesis, processing, degradation) have not been explained.


   5 Summary
Top
 1 Introduction
 2 Enkephalin biochemistry
 3 Cardiac opioid peptides
 4 Opiate receptors and...
 5 Summary
References
 
The heart is a complex neuroendocrine (opioids, NPY, VIP) or mechanoendocrine (ANP) organ. Opioid peptides and receptors are present in the heart and nerves such that they can easily modulate cardiac function. Cardiac opioids may have autocrine, paracrine and endocrine function. The challenge is to find the signal that turns them on and then what they do in the face of an overwhelmingly redundant system making knock-out technology hard to interpret. Determining the cardiac release of opioids in an intact system still requires a larger animal model.


   References
Top
 1 Introduction
 2 Enkephalin biochemistry
 3 Cardiac opioid peptides
 4 Opiate receptors and...
 5 Summary
 References
 

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