Adenosine receptor dependent regulation of vascular tone in L‐NAME mouse model of hypertension.

Abstract

L‐NAME, a nitric oxide synthase inhibitor, down regulates eNOS protein expression and leads to depletion of plasma nitric oxide levels in blood. L‐NAME pre‐treatment causes systemic vasoconstriction, increased vascular resistance and high blood pressure (BP). Thus, L‐NAME model of hypertension is used to study endothelial dysfunction and related vascular effects. Adenosine is an important metabolite, which controls local blood flow through activation of four subtypes of adenosine receptors (ARs). Stimulation of A1 and A3 ARs produce contraction while A2A and A2B ARs cause relaxation in mouse aorta and mesenteric arteries (MAs). In present study, we sought to determine whether ARs play a role in altered vascular tone regulation in this model of hypertension. We used L‐NAME (1 mg/ml) in the drinking water for 4 weeks. The BP was monitored using CODA non‐invasive tail cuff system. For vascular tone studies, aortae and MAs were isolated from control and hypertensive mice. Muscle tension studies were performed using DMT for MAs and organ bath for aorta. Systolic BP recorded at the end of 28 days was (mean ± SE; mmHg) 133.9 ± 3.0 in hypertensive while 107.8 ± 2.6 in control group (n=11). Our DMT data analysis in MAs showed that acetylcholine (Ach) induced relaxation responses were (% PE) 98.5 ± 0.2 and 93.4 ± 1.4 (p<0.05, n=10) in control and L‐NAME hypertensive mice, respectively. Vascular studies in MAs revealed higher CCPA (selective A1AR agonist) induced contractions in hypertensive mice. Particularly, 100 nM CCPA (% PE) produced 24.9 ± 14.1 contraction in control whereas 89.2 ± 27.4 (p<0.05, n=7) in L‐NAME mice. Contrary, NECA (non‐selective AR agonist) induced vascular responses were comparable. Pinacidil (KATP channel opener) induced relaxation was significantly increased in hypertensive mice. Pinacidil (1 μM), produced relaxation of 51.72 ± 9.8 and 76.29 ± 5.9 (p<0.05, n=7) in control and L‐NAME mice, respectively. Phenylephrine induced contraction was reduced to (mg) 278.8 ± 32.8 in L‐NAME mice compared to 492.1 ± 33.8 in control (p<0.05, n=11). Angiotensin (ANG) II induced vascular contractions were reduced to (% KCl) 54.3 ± 9.0 in L‐NAME compared to 122.4 ± 14.0 in control mice (p<0.05, n=7). Our organ bath data in aorta showed that CCPA, NECA, pinacidil PE, KCl and Ach induced responses were comparable in both groups. In conclusion, A1AR induced contraction and KATP channel induced relaxation were both higher in MAs of L‐NAME mice. In addition, ANG II induced contraction were lower in MAs. Thus, suggesting altered responses to ARs and ANG II in L‐NAME induced mouse model of hypertension.Support or Funding InformationSupported by HL 027339