Effect of Ivabradine on a Hypertensive Heart and the Renin-Angiotensin-Aldosterone System in L-NAME-Induced Hypertension

Int J Mol Sci. 2018 Oct 3;19(10):3017. doi: 10.3390/ijms19103017.


Ivabradine, the selective inhibitor of the If current in the sinoatrial node, exerts cardiovascular protection by its bradycardic effect and potentially pleiotropic actions. However, there is a shortage of data regarding ivabradine's interaction with the renin-angiotensin-aldosterone system (RAAS). This study investigated whether ivabradine is able to protect a hypertensive heart in the model of L-NAME-induced hypertension and to interfere with the RAAS. Four groups (n = 10/group) of adult male Wistar rats were treated as follows for four weeks: control, ivabradine (10 mg/kg/day), L-NAME (40 mg/kg/day), and L-NAME plus ivabradine. L-NAME administration increased systolic blood pressure (SBP) and left ventricular (LV) weight, enhanced hydroxyproline concentration in the LV, and deteriorated the systolic and diastolic LV function. Ivabradine reduced heart rate (HR) and SBP, and improved the LV function. The serum concentrations of angiotensin Ang 1⁻8 (Ang II), Ang 1⁻5, Ang 1⁻7, Ang 1⁻10, Ang 2⁻8, and Ang 3⁻8 were decreased in the L-NAME group and ivabradine did not modify them. The serum concentration of aldosterone and the aldosterone/Ang II ratio were enhanced by L-NAME and ivabradine reduced these changes. We conclude that ivabradine improved the LV function of the hypertensive heart in L-NAME-induced hypertension. The protective effect of ivabradine might have been associated with the reduction of the aldosterone level.

Keywords: L-NAME; aldosterone; angiotensin II; fibrosis; heart function; hypertension; ivabradine.

MeSH terms

  • Aldosterone / blood
  • Angiotensins / blood
  • Animals
  • Biomarkers
  • Blood Pressure / drug effects
  • Cardiovascular Agents / pharmacology*
  • Collagen / metabolism
  • Disease Models, Animal
  • Echocardiography
  • Hydroxyproline / blood
  • Hydroxyproline / metabolism
  • Hypertension / diagnosis
  • Hypertension / etiology*
  • Hypertension / metabolism
  • Hypertension / physiopathology*
  • Ivabradine / pharmacology*
  • Male
  • NG-Nitroarginine Methyl Ester / adverse effects*
  • Rats
  • Renin / blood
  • Renin-Angiotensin System / drug effects*
  • Ventricular Function, Left / drug effects


  • Angiotensins
  • Biomarkers
  • Cardiovascular Agents
  • Ivabradine
  • Aldosterone
  • Collagen
  • Renin
  • Hydroxyproline
  • NG-Nitroarginine Methyl Ester