Pressor and cardioaccelerator effects of gamma MSH and related peptides

doi:10.1016/0024-3205(85)90197-3

Life Sciences

Volume 36, Issue 8, 25 February 1985, Pages 769-775

https://doi.org/10.1016/0024-3205(85)90197-3 Get rights and content

Abstract

We have recently demonstrated that the hypertensiongenic and natriuretic actions of ACTH^1–39 can be found in a non-steroidogenic fragment of ACTH, ACTH^4–10. These effects of ACTH or ACTH^4–10 may be due to their ability to act as weak agonists of γMSH. γMSH is found in the 16K N-terminus of pro-opiocortin, and contains a sequence analogous to ACTH^4–10, γMSH^3–9.

We investigated the cardiovascular effects of γ₂MSH, γMSH^3–9, and sterically restricted analogs of ACTH^4–10. The results indicate that γMSH^3–9, had essentially the same activities as ACTH^4–10. The addition of five other amino acid residues to γMSH^3–9 (γ₂MSH) resulted in significant enhancement of pressor and cardioaccelerator activity. Steric restriction of the ACTH^4–10 sequence by the substitution of a D-Phe in place of an L-Phe residue in position #7, or cyclization of the peptide by a half-Cys⁴, half Cys¹⁰ intramolecular disulfide-bridge derivatization, resulted in increased cardiovascular activities.

Based on these data, the cardiovascular actions of ACTH^4–10, γMSH^3–9, and γ₂MSH are predicted to be due to the assumption of a reverse-turn three-dimensional structure. The additional residues in γ₂MSH appear to specifically enhance the cardiovascular activities of γMSH^3–9. The results suggest the existence of a new class of hypophyseal peptides with cardiovascular activities, which require the assumption of a defined three-dimensional structure.

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Cited by (51)

Brain effects of melanocortins
2009, Pharmacological Research
Citation Excerpt :
Several important and otherwise unforeseeable discoveries stemmed from the experimental verification of such hypothesis: the role of melanocortins in feeding and energy homeostasis; the importance of POMC and MC receptors mutations in genetic forms of obesity; the effect of several melanocortins in shock and in ischemia/ischemia-reperfusion-induced organ-limited damage; the role of melanocortins in opiate addiction and withdrawal. In normotensive, normovolemic rats, either conscious or under light urethane anesthesia (a condition where cardiovascular reflexes and sufficient sympathetic tone are maintained), the intravenous injection of the adrenocorticotropin fragment ACTH4–10 and of γ1- and γ2-MSH (10 times more potent than ACTH4–10) induce a dose-dependent, short-lasting increase in blood pressure, heart rate and pulse amplitude, with a maximal effect 25 s following administration (for reviews see: [363–365]). Melanocortin peptides with a longer C-terminal extension, including γ3-MSH, α-MSH, ACTH1–17, ACTH1–24, and the whole 1–39 sequence of ACTH, are on the other hand devoid of these cardiovascular effects in the normotensive, normovolemic animal [68,199,366], but have dramatic and long-lasting cardiovascular effects in severe hypotensive conditions (for a review see: [76]).
The melanocortins (α, β and γ-melanocyte-stimulating hormones: MSHs; adrenocorticotrophic hormone: ACTH), a family of pro-opiomelanocortin (POMC)-derived peptides having in common the tetrapeptide sequence His-Phe-Arg-Trp, have progressively revealed an incredibly wide range of extra-hormonal effects, so to become one of the most promising source of innovative drugs for many, important and widespread pathological conditions.
The discovery of their effects on some brain functions, independently made by William Ferrari and David De Wied about half a century ago, led to the formulation of the term “neuropeptide” at a time when no demonstration of the actual production of peptide molecules by neurons, in the brain, was still available, and there were no receptors characterized for these molecules.
In the course of the subsequent decades it came out that melanocortins, besides inducing one of the most complex and bizarre behavioural syndromes (excessive grooming, crises of stretchings and yawnings, repeated episodes of spontaneous penile erection and ejaculation, increased sexual receptivity), play a key role in functions of fundamental physiological importance as well as impressive therapeutic effects in different pathological conditions.
If serendipity had been an important determinant in the discovery of the above-mentioned first-noticed extra-hormonal effects of melanocortins, many of the subsequent discoveries in the pharmacology of these peptides (feeding inhibition, shock reversal, role in opiate tolerance/withdrawal, etc.) have been the result of a planned research, aimed at testing the “pro-nociceptive/anti-nociceptive homeostatic system” hypothesis.
The discovery of melanocortin receptors, and the ensuing synthesis of selective ligands with agonist or antagonist activity, is generating completely innovative drugs for the treatment of a potentially very long list of important and widespread pathological conditions: sexual impotence, frigidity, overweight/obesity, anorexia, cachexia, haemorrhagic shock, other forms of shock, myocardial infarction, ischemia/reperfusion-induced brain damage, neuropathic pain, rheumathoid arthritis, inflammatory bowel disease, nerve injury, toxic neuropathies, diabetic neuropathy, etc.
This review recalls the history of these researches and outlines the pharmacology of the extra-hormonal effects of melanocortins which are produced by an action at the brain level (or mainly at the brain level). In our opinion the picture is still incomplete, in spite of being already so incredibly vast and complex. So, for example, several of their effects and preliminary animal data suggest that melanocortins might be of concrete effectiveness in one of the areas of most increasing concern, i.e., that of neurodegenerative diseases.
Blood pressure regulation and cardiac autonomic control in mice overexpressing α- and γ-melanocyte stimulating hormone
2008, Peptides
Melanocyte stimulating hormones (MSH) derived from pro-opiomelanocortin have been demonstrated to participate in the central regulation of cardiovascular functions. The aim of the present study was to elucidate the chronic effects of increased melanocortin activation on blood pressure regulation and autonomic nervous system function. We adapted telemetry to transgenic mice overexpressing α- and γ-MSH and measured blood pressure, heart rate and locomotor activity, and analyzed heart rate variability (HRV) in the frequency-domain as well as baroreflex function by the sequence technique. Transgenic (MSH-OE) mice had increased systolic blood pressure but their heart rate was similar to wild-type (WT) controls. The 24-h mean of systolic blood pressure was 132 ± 7 mmHg in MSH-OE and 113 ± 4 mmHg in WT mice. Locomotor activity was decreased in the MSH-OE mice. Furthermore, MSH-OE mice showed slower adaptation to mild environmental stress in terms of blood pressure changes. The low frequency (LF) power of HRV tended to be higher in MSH-OE mice compared to WT mice, without a difference in overall variability. The assessment of baroreflex function indicated enhanced baroreflex effectiveness and more frequent baroreflex operations in MSH-OE mice. Baseline heart rate, increased LF power of HRV and increased baroreflex activity may all reflect maintenance of baroreflex integrity and an increase in cardiac vagal activity to counteract the increased blood pressure. These results provide new evidence that long-term activation of the melanocortin system elevates blood pressure without increasing heart rate.
Feeding effects of melanocortin ligands - A historical perspective
2005, Peptides
The process of energy homeostasis is a highly regulated process involving interacting signals between a variety of anorexigenic and orexigenic peptides, proteins and signaling molecules. The melanocortin system is an important component of this complex regulatory network. Involvement of the melanocortin pathway in the control of food intake and body weight regulation has been studied extensively in the past two decades. Previous studies that involve central administration of melanocortin molecules and examination of molecules that effect food intake in melanocortin knockout (KO) mice (MC3R, MC4R, POMC, AGRP and NPY) have been examined. In this review, we have summarized feeding studies that have resulted in the recognition of the melanocortin system as a major contributor to the complex neuroendocrine system regulating energy homeostasis.
γ<inf>2</inf>-Melanocyte-stimulating hormone suppression of systemic inflammatory responses to endotoxin is associated with modulation of central autonomic and neuroendocrine activities
2001, Journal of Neuroimmunology
Central autonomic and neuroendocrine activities are important components of the host response to bacterial inflammation. We demonstrate that intravenous infusion of γ₂-melanocyte-stimulating hormone (γ₂-MSH), a potent autonomic regulating peptide, prevents lipopolysaccharide (LPS)-induced hypotension and tachycardia, and modulates the ACTH response to endotoxin. In the hypothalamic paraventricular nucleus, a major neuroendocrine and autonomic center, γ₂-MSH inhibits LPS-induced increases in CRF mRNA levels, but does not suppress LPS-augmented arginine vasopressin heteronuclear RNA expression. In the locus coeruleus, a brainstem noradrenergic center, γ₂-MSH inhibits LPS-induced increases in tyrosine hydroxylase mRNA levels. γ₂-MSH inhibits LPS-induced IL-1β gene expression in the brain, pituitary and thymus, and prevents increases in plasma NO levels. These findings reveal that γ₂-MSH attenuates systemic inflammatory responses to endotoxin and suggest that modulation of central autonomic and neuroendocrine activities by γ₂-MSH contributes to its anti-inflammatory effects.
Evidence that α-MSH induced grooming not primarily mediated by any of the cloned melanocortin receptors
2000, Neuropeptides
It is well established that melanocortic peptides, such as melanocyte-stimulating hormone (MSH) and adrenocorticotropin, induce grooming behavior. The MC3 and MC4 receptors are the MC receptors which are most abundantly expressed in the brain. γ-MSH, a peptide with preference to the MC3 receptor, however, does not induce grooming. Recent studies have shown that MC4 receptor antagonists are very effective in inhibiting α-MSH induced grooming. These data have indicated that grooming behavior in rodents may be mediated by the MC4 receptor. In this study we investigated if the recently developed MC1 receptor selective agonist MS05 was able to induce grooming in comparison with α-MSH. The results show that MS05 is effective in inducing grooming after either intracerebroventricular or ventral tegmental area administration in rats. Central administration of either MS05 or α-MSH besides grooming also induced stretching, yawning, rearing and locomotion. The results indicate that the earlier hypothesis that the MC4 receptor is the main mediator of grooming behavior has to be modified. Moreover, as this behaviour does not pharmacologically correlate to the profile of any of the five cloned MC receptors, we suggest that α-MSH induced grooming may not primarily be mediated by any of these receptors.
Melanocortins and cardiovascular regulation
1998, European Journal of Pharmacology
The melanocortins form a family of pro-opiomelanocortin-derived peptides that have the melanocyte-stimulating hormone (MSH) core sequence, His–Phe–Arg–Trp, in common. Melanocortins have been described as having a variety of cardiovascular effects. We review here what is known about the sites and mechanisms of action of the melanocortins with respect to their effects on cardiovascular function, with special attention to the effects of the γ-melanocyte-stimulating hormones (γ-MSHs). This is done in the context of present knowledge about agonist selectivity and localisation of the five melanocortin receptor subtypes cloned so far. γ₂-MSH, its des-Gly¹² analog (=γ₁-MSH) and Lys-γ₂-MSH are 5–10 times more potent than adrenocorticotropic hormone-(4–10) (ACTH-(4–10)) to induce a pressor and tachycardiac effect following intravenous administration. The Arg–Phe sequence near the C-terminal seems to be important for full in vivo intrinsic activity. Related peptides with a C-terminal extension with (γ₃-MSH) or without the Arg–Phe sequence (α-MSH, as well as the potent α-MSH analog, [Nle⁴,d-Phe⁷]α-MSH), are, however, devoid of these effects. In contrast, ACTH-(1–24) has a depressor effect combined with a tachycardiac effect, effects which are not dependent on the presence of the adrenals. Although the melanocortin MC₃ receptor is the only melanocortin receptor subtype for which γ₂-MSH is selective, in vivo and in vitro structure–activity data indicate that it is not via this receptor that this peptide and related peptides exert either their pressor and tachycardiac effects or their extra- and intracranial blood flow increasing effect. We review evidence that the pressor and tachycardiac effects of the γ-MSHs are due to an increase of sympathetic outflow to the vasculature and the heart, secondary to activation of centrally located receptors. These receptors are most likely localised in the anteroventral third ventricle (AV3V) region, a brain region situated outside the blood-brain barrier, and to which circulating peptides have access. These receptors might be melanocortin receptors of a subtype yet to be identified. Alternatively, they might be related to other receptors for which peptides with a C-terminal Arg–Phe sequence have affinity, such as the neuropeptide FF receptor and the recently discovered FMRFamide receptor. Melanocortin MC₄ receptors and still unidentified receptors are part of the circuitry in the medulla oblongata which is involved in the depressor and bradycardiac effect of the melanocortins, probably via interference with autonomic outflow. Regarding the effects of the γ-MSHs on cortical cerebral blood flow, it is not yet clear whether they involve activation of the sympathetic nervous system or activation of melanocortin receptors located on the cerebral vasculature. The depressor effect observed following intravenous administration of ACTH-(1–24) is thought to be due to activation of melanocortin MC₂ receptors whose location may be within the peripheral vasculature. Melanocortins have been observed to improve cardiovascular function and survival time in experimental hemorrhagic shock in various species. Though ACTH-(1–24) is the most potent melanocortin in this model, α-MSH and [Nle⁴,d-Phe⁷]α-MSH and ACTH-(4–10) are quite effective as well. As ACTH-(4–10) is a rather weak agonist of all melanocortin receptors, it is difficult to determine via which of the melanocortin receptors the melanocortins bring about this effect. Research into the nature of the receptors involved in the various cardiovascular effects of the melanocortins would greatly benefit from the availability of selective melanocortin receptor antagonists.

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Pressor and cardioaccelerator effects of gamma MSH and related peptides

Abstract

Biochim. Biophys. Acta

Biochem. Biophys. Res. Comm.

Life Sci

Circ. Res.

Hypertension

Hypertension

Biochemistry

Life Sci.