Sex and Age Modulate the Blood Pressure and Cardiac Hypertrophy Response to L-NAME

Hypertension is characterized by elevated blood pressure which can cause damage to multiple organs, including pathological cardiac hypertrophy. Deficiency in nitric oxide (NO), a natural vasodilator, can contribute to hypertension. L-NG-Nitroarginine methyl ester (L-NAME) has been shown to be an antagonist of nitric oxide synthase (NOS), an enzyme that catalyzes the reaction that produces NO, and has been used as a non-surgical model of hypertension and cardiac hypertrophy in rodent studies. However, the dosages used across published reports differ substantially, potentially contributing to variability in the findings. Moreover, there are inconsistencies in reported sex differences in response to L-NAME in rats and limited published reports assessing sex differences in mouse models. Therefore, the objective of this study was to establish a L-NAME dosing protocol to induce hypertension and cardiac hypertrophy in both male and female mice. In this study, we investigated three different dosing strategies in male and female C57BL6/N mice of different ages. In Trial 1, we treated 14-week-old male and female mice (n=4 each group) with 80mg/kg of L-NAME for 8 weeks. In Trial 2, we treated 12-week-old male mice (n=5) with 0.75g/L of L-NAME and female mice (n=4) with 0.55 g/L of L-NAME, which equated to ~140mg/kg. In Trial 3, we treated 26-week-old male mice (n=9) with 0.75g/L of L-NAME and female mice (n=8) with 0.55 g/L of L-NAME, which equated to ~110mg/kg. A cohort of age-matched male and female mice (n=3-4 each group) were used as controls (CON). L-NAME was purchased from a commercial vendor and mixed in the drinking water at the indicated doses. At the end of the treatment period, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured via the tail with a non-invasive blood pressure system. Hearts were harvested from mice, weighed, and normalized to tibia length (TL) to assess cardiac hypertrophy. In Trial 1, SBP was mildly increased in male and female mice (main effects of drug, p=0.04) without a significant increase in heart weight to TL (HW/TL). In Trial 2, SBP rose to 135.9 ± 9.3 mmHg in males and 165.2 ± 6.5 mmHg in females while DBP increased to 109.6 ± 7.9 mmHg and 137.7 ± 5.4 mmHg in males and females, respectively (p < 0.05 vs. respective CON). Despite the significant increases in blood pressure, HW/TL was significantly lower in males with no change observed in females. In Trial 3, both SBP and DBP were significantly higher in both males and females relative to CON groups. Interestingly, both males and females experienced an ~10% increase in HW/TL (P < 0.05 vs. respective CON). In all three trials, SBP and DBP responses to L-NAME were greater in female mice. In summary, our data show that L-NAME dosages above 100 mg/kg are more effective in elevating blood pressure in mice, with a greater effect in females. Furthermore, changes in cardiac hypertrophy appear to be dependent on the age of the mouse at the start of the treatment. Overall, our findings suggest that age and sex modulate the blood pressure and cardiac hypertrophy responses to L-NAME This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.