Systemic but not central nervous system nitric oxide synthase inhibition exacerbates the hypertensive effects of chronic melanocortin-3/4 receptor activation
Open accessAbstract
We examined whether systemic or central nervous system (CNS) inhibition of nitric oxide synthase exacerbates the cardiovascular responses of chronic CNS melanocortin 3/4 receptor activation. Sprague-Dawley rats implanted with telemetry probes, venous catheters, and intracerebroventricular (ICV) cannulae were divided in 3 groups. After control measurements, the NO synthase inhibitor L-NAME was infused (10 μg/kg/min intravenous) for 17 days and, starting on day 7 of L-NAME infusion, the melanocortin 3/4 receptor agonist melanotan II (MTII; 10 ng/hr; group 1) or saline vehicle (group 2) was infused ICV for 10 days. A third group not treated with L-NAME also received MTII ICV. Melanocortin 3/4 receptor activation caused a greater increase in mean arterial pressure (MAP) and heart rate in rats treated with intravenous L-NAME (35 ± 6 mm Hg and 56 ± 8 bpm) than L-NAME plus vehicle or MTII alone (22 ± 5 and 9 ± 2 mm Hg, and 26 ± 14 and 27 ± 5 bpm), despite a 58% and 50% reduction in food intake during the first 6 days of MTII infusion. To test if the amplified pressor response to MTII after L-NAME was attributable to a reduction in nitric oxide availability in the brain, we also infused L-NAME directly into the CNS alone or in combination with MTII. ICV infusion of L-NAME plus MTII caused only ≈ 10 mm Hg increase in MAP with no change in heart rate, similar to the effects of ICV infusion of MTII alone, whereas ICV infusion of L-NAME alone had no effect on MAP. These results suggest that reduction in peripheral, but not CNS, nitric oxide production augments MAP sensitivity to CNS melanocortin 3/4 receptor activation.
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MC4R antagonism significantly attenuated hypertension induced by the nitric oxide synthase inhibitor L-NAME.
“We also found that MC4R antagonism significantly attenuated hypertension induced by the nitric oxide synthase inhibitor L-NAME [58] (Figure 2).”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [58]
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 [58]
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“We also found marked accentuated sympathetically mediated hypertension induced by chronic MC3/4R activation in rats treated with L-NAME.17 However, Hilzendeger et al30 showed that blockade of brain AT1 receptors failed to alter the increase in renal SNA elicited by the MC3/4R agonist, MTII.”
BackgroundInfluentialSelf-citation
- Authors
- do Carmo, J. M., Bassi, M., da Silva, A. A., & Hall, J. E.
- Affiliations
- From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS.
- University of Mississippi Medical Center (US)
- Venue
- Hypertension
- Published
- 2011-03
- Volume
- 57
- Issue
- 3
- Pages
- 428-434
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- PMC
- PMC3073740
- OpenAlex
- W2145735174
- Cited by
- 17
- References
- 33
- Citations by year
- 2021: 2 · 2019: 1 · 2018: 1 · 2017: 3 · 2015: 1 · 2014: 2 · 2013: 4 · 2012: 3
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL051971)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- nitric oxide synthase inhibition, L-NAME, melanocortin 3/4 receptor, melanotan II, central nervous system, mean arterial pressure, heart rate, dietary intake, intracerebroventricular infusion, pressor response
- MeSH terms
- alpha-MSH, Analysis of Variance, Animals, Blood Glucose, Body Weight, Catheters, Indwelling, Eating, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Hypertension, Insulin, Male, Peptides, Cyclic, Telemetry, Rats, Sprague-Dawley, Nitric Oxide Synthase, NG-Nitroarginine Methyl Ester, Leptin, Receptor, Melanocortin, Type 3, Receptor, Melanocortin, Type 4, Rats
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