Nicorandil but not ISDN Upregulates Endothelial Nitric Oxide Synthase Expression, Preventing Left Ventricular Remodeling and Degradation of Cardiac Function in Dahl Salt-sensitive Hypertensive Rats With Congestive Heart Failure

Cardiac endothelial nitric oxide synthase (ecNOS) was suppressed and inducible NOS (iNOS) enhanced at the decompensated heart failure stage in 18-week-old Dahl salt-sensitive (DS) hypertensive rats to which a high-salt diet had been administered from the age of 6 weeks. Nicorandil (NIC) enhanced ecNOS by activating Adenosine triphosphate-sensitive potassium channels (K-ATP channels) in the normal rat left ventricle. In this study, left ventricular hypertrophy, remodeling, function, cardiac ecNOS, and iNOS were compared between NIC and isosorbide dinitrate (ISDN) treatments in DS hypertensive rats with congestive heart failure. We examined DS hypertensive rats of 18 weeks of age to which 8% NaCl had been administered from the age of 6 weeks, and to which subdepressor doses of NIC (6 mg/kg/d), ISDN (6 mg/kg/d), and vehicle (CON) were administered from the age of 11 weeks. Contractility (Ees), stiffness (Eed), left ventricular end-diastolic volume, and left ventricular end-systolic volume were measured by conductance catheter and micromanometer on the basis of the pressure-volume relationship, and mRNA and protein levels of ecNOS and iNOS in the left ventricle were measured by reverse transcription-polymerase chain reaction and Western blot analysis at 18 weeks. LV mass index and LV dimensions were smaller in the NIC and ISDN groups than in the CON group (P<0.01), and the first parameter was lower in the NIC than in the ISDN group (P<0.01). Ees was also better maintained in the NIC and ISDN groups than in the CON group (NIC: 3349±649; ISDN: 2950±577, P<0.05 vs. NIC; CON: 1424±375 mL/mmHg, P<0.01 vs. treatments). Eed was exacerbated only in the ISDN group. NIC enhanced whereas ISDN suppressed ecNOS mRNA and protein levels (NIC 2.0-fold and 1.8-fold, ISDN 0.70-fold and 0.8-fold vs. CON; P<0.01, respectively). However, no intragroup differences in iNOS mRNA or protein levels were observed for the 3 groups. More significant improvements in cardiac function and LV hypertrophy regression were observed in an NIC group than in an ISDN group of DS hypertensive rats. Activation of the K-ATP channel seems to induce this beneficial effect, which may be mediated in part by enhanced ecNOS expression in the heart in DS hypertensive congestive heart failure rat model.