Endogenous Melanocortin System Activity Contributes to the Elevated Arterial Pressure in Spontaneously Hypertensive Rats
Open accessAbstract
Previous studies suggest that activation of the CNS melanocortin system reduces appetite while increasing sympathetic activity and arterial pressure. The present study tested whether endogenous activity of the CNS melanocortin 3/4 receptors (MC3/4-R) contributes to elevated arterial pressure in the spontaneously hypertensive rat (SHR), a model of hypertension with increased sympathetic activity. A cannula was placed in the lateral ventricle of male SHR and Wistar (WKY) rats for chronic intracerebroventricular (ICV) infusions (0.5 μL/h). Mean arterial pressure (MAP) and heart rate (HR) were recorded 24 hour/d using telemetry. After 5-day control period, rats were infused with MC3/4-R antagonist (SHU-9119, 1 nmol/h-ICV) for 12 days, followed by 5-day posttreatment period. MC3/4-R antagonism increased food intake in SHR by 90% and in WKY by 125%, resulting in marked weight gain, insulin resistance, and hyperleptinemia in SHR and WKY. Despite weight gain, MC3/4-R antagonism reduced HR in SHR and WKY (≈40 bpm), while lowering MAP to a greater extent in SHR (−22±4 mm Hg) than WKY (−4±3 mm Hg). SHU9119 treatment failed to cause further reductions in MAP during chronic adrenergic blockade with propranolol and terazosin. These results suggest that endogenous activity of the CNS melanocortin system contributes to the maintenance of adrenergic tone and elevated arterial pressure in SHR even though mRNA levels for POMC and MC4R in the mediobasal hypothalamus were not increased compared to WKY. These results also support the hypothesis that weight gain does not raise arterial pressure in the absence of a functional MC3/4-R.
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MC4R antagonism in spontaneously hypertensive rats caused hyperphagia, rapid increases in adiposity, insulin resistance and a reduction in blood pressure.
“Conversely, MC4R antagonism in SHRs caused hyperphagia, rapid increases in adiposity, insulin resistance and a reduction in BP197.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [197]
The blood pressure-reducing effects of MC4R blockade are enhanced in spontaneously hypertensive rats and other models of hypertension associated with increased sympathetic nerve activity.
“The BP-reducing effects of MC4R blockade are enhanced in SHRs and other models of hypertension that are associated with increased SNA197.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [197]
MC4R antagonism decreased blood pressure by more than 25 mmHg in spontaneously hypertensive rats, which have increased sympathetic nerve activity but are not obese and do not have high leptin levels.
“MC4R antagonism also decreased BP by >25 mmHg in SHRs, which have increased SNA but are not obese and do not have high levels of leptin197.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [197]
Blockade of CNS MC4R in rodents causes voracious feeding, rapid weight gain, and reduces rather than increases BP.
“Conversely, blockade of CNS MC4R in rodents causes voracious feeding, rapid weight gain, and reduces rather than increases BP123.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [123]
In experimental models of hypertension with high sympathetic nervous system activity, blockade of the melanocortin-4 receptor reduces blood pressure despite causing marked hyperphagia and obesity.
“In experimental models of hypertension with high SNS activity, blockade of the melanocortin-4 receptor (MC4R) reduces BP despite causing marked hyperphagia and obesity.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [42]
Blockade of central nervous system MC4R in rodents reduces blood pressure despite increasing appetite and causing rapid weight gain.
“Blockade of CNS MC4R in rodents reduces BP despite increasing appetite and causing rapid weight gain which would normally increase BP [42].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [42]
Blockade of endogenous MC4R activity reduced blood pressure in several non-obese experimental models of hypertension, especially those associated with increased sympathetic nervous system activity.
“Blockade of endogenous MC4R activity also reduced BP in several non-obese experimental models of hypertension, especially those associated with increased SNS activity [42, 57] (Figure 2).”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [42]
Blockade of central nervous system MC4R for 12 consecutive days caused a much greater reduction in blood pressure in spontaneously hypertensive rats than in normotensive Sprague-Dawley or Wistar-Kyoto rats despite causing marked hyperphagia, weight gain, and insulin resistance.
“Blockade of CNS MC4R for 12 consecutive days caused a much greater reduction in BP in SHR than in normotensive Sprague-Dawley or Wistar-Kyoto rats despite causing marked hyperphagia, weight gain, and insulin resistance [42, 56].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [42]
The blood pressure-lowering effects of MC4R antagonism are especially pronounced in spontaneously hypertensive rats, a genetic model of hypertension that has increased sympathetic nervous system activity.
“For instance, the BP-lowering effects of MC4R antagonism are especially pronounced in spontaneously hypertensive rats (SHR), a genetic model of hypertension that has increased SNS activity [42].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [42]
The fall in blood pressure in spontaneously hypertensive rats after MC4R blockade was similar to that observed after α/β-adrenergic blockade.
“In addition, the fall in BP in SHR after MC4R blockade was similar to that observed after α/β-adrenergic blockade [42].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [42]
The brain melanocortin system plays a key role in maintenance of sympathetic nervous system activity and blood pressure in normotensive subjects as well as in non-obese forms of hypertension that have increased sympathetic activity.
“These findings highlight the key role of the brain melanocortin system in maintenance of SNS activity and BP in normotensive subjects as well as in non-obese forms of hypertension that have increased sympathetic activity [41, 42, 57, 58].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [42]
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References 25 · Cited by 79
- Authors
- da Silva, A. A., do Carmo, J. M., Kanyicska, B., Dubinion, J., Brandon, E., & Hall, J. E.
- Affiliations
- From the Department of Physiology and Biophysics (A.A.d.S., J.M.d.C., J.D., E.B., J.E.H.), the Department of Anatomy (B.K.), and the Center for Excellence in Cardiovascular-Renal Research (A.A.d.S., J.M.d.C., J.D., E.B., J.E.H.), University of Mississippi Medical Center, Jackson.
- University of Mississippi Medical Center (US)
- ORCID
- Hall, John E.
- Venue
- Hypertension
- Published
- 2008-04
- Volume
- 51
- Issue
- 4
- Pages
- 884-890
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- PMC
- PMC2803054
- OpenAlex
- W2020018784
- Cited by
- 79
- References
- 25
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 8 · 2013: 5 · 2012: 3
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Heart, Lung, and Blood Institute (P01-HL-51971, P01HL051971)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- melanocortin 3/4 receptor, spontaneously hypertensive rats, arterial pressure, intracerebroventricular infusion, dietary intake, weight gain, insulin resistance, leptin, heart rate, adrenergic tone, propranolol, terazosin, proopiomelanocortin, melanocortin-4 receptor, mediobasal hypothalamus, sympathetic activity
- MeSH terms
- Adrenergic alpha-Antagonists, Animals, Antihypertensive Agents, Blood Pressure, Eating, Female, Heart Rate, Hypertension, Renal, Hypothalamus, Male, Melanocyte-Stimulating Hormones, Neuropeptide Y, Prazosin, Pro-Opiomelanocortin, Propranolol, Rats, Inbred SHR, Rats, Inbred WKY, RNA, Messenger, Sympathetic Nervous System, Receptor, Melanocortin, Type 3, Receptor, Melanocortin, Type 4, Rats, Melanocortins, Agouti-Related Protein, Receptors, Leptin
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