Vascular effects of deletion of melanocortin-4 receptors in rats

David W. Stepp, Christabell C. Osakwe, Eric J.Belin de Chantemele, James D. Mintz

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Obesity is a major cause of hypertension, but links between the obese and hypertensive states remain incompletely understood. A major component of cardiovascular function in obese individuals is a state of sympathoactivation. A postulated mechanism of this sympathoactivation is the activation of specific classes of neurons commonly associated with metabolic control, which also affect sympathetic outflow to cardiovascular targets. One class of neurons is characterized by expression of melanocortin-4 receptors (MC4R) which are activated by metabolic signals such as leptin and insulin. In this study, we examined the effects of deletion of MC4R in a novel rat model. MC4R knockout (KO) rats are obese and profoundly insulin resistant without frank diabetes. Despite these conditions, MC4R KO rats are normotensive. Moderate bradycardia and significant increases in peripheral resistance were evident in MC4R KO rats. To determine if the dissociation between hypertension and obesity was associated with changes in vascular function, in vitro reactivity to vasoactive agents and in vivo reactivity to sympathetic blockade were examined. Vasodilator function was not affected by obesity in MC4R KO rats. Reactivity to phenylephrine was reduced, suggesting desensitization of adrenergic signaling. In response to ganglionic blockade with mecamylamine, blood pressure and hindlimb resistance fell more in MC4R KO rats, suggesting that sympathoactivation of the vascular was still evident, despite the absence of hypertension. These findings suggest that obesity causes sympathoactivation of the vasculature despite the absence of MC4R. Dissociation of obesity from hypertension in this model may reflect more renal mechanisms of blood pressure control.

Original languageEnglish (US)
Article numbere00146
Pages (from-to)1-7
Number of pages7
JournalPhysiological reports
Issue number6
StatePublished - Nov 2013


  • Blood pressure
  • Obesity
  • Vascular

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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