Differential Effects of Angiotensin II Versus Endothelin-1 Inhibitions in Hypertrophic Left Ventricular Myocardium During Transition to Heart Failure

Abstract

Background-In view of their mutual crosstalk, the roles of angiotensin II (Ang II) and endothelin-1 (ET-1) in the myocardium are assumed to be synergistic and supplemental. Methods and Results-In the phase of compensated left ventricular (LV) hypertrophy of Dahl salt-sensitive rats, Ang II peptide and the ACE mRNA in the LV were increased by 1.6-and 3.8-fold, respectively. In contrast, ET-1 peptide and the preproET-1 mRNA remained unchanged. In subsequent congestive heart failure (CHF), Ang II and ACE mRNA did not show further increases. But ET-1 and the mRNA were increased de novo by 5.3-and 4.1-fold, respectively. In ascending aorta-banded rats, the local activations of Ang II and ET-1 also showed a differential time course between LV hypertrophy and CHF. Long-term treatments of Dahl salt-sensitive rats with temocapril (an ACE inhibitor) and with bosentan (a mixed ET receptor blocker) equally improved long-term survival. Temocapril reduced the LV/body weight ratio and ameliorated LV fractional shortening. Conversely, although bosentan equally improved fractional shortening, it did not reduce the increase in LV mass. Combined treatment with these 2 drugs further ameliorated the animal's survival without additional decreases in systolic pressure. Conclusions-The pathophysiological roles in the myocardium during the transition to CHF differ qualitatively betweenAng II and ET-1. Thus, long-term therapy with a combination of ACE inhibition and ET antagonism may provide a new approach for heart failure in humans.

Reinduction of T-Type Calcium Channels by Endothelin-1 in Failing Hearts In Vivo and in Adult Rat Ventricular Myocytes In Vitro

“…10 We report that the reappearance of this type of Ca 2ϩ channel is tightly regulated by the local neurohumoral environment, especially by tissue endothelin (ET)-1 but not by angiotensin II (AII), through the use of cultured adult ventricular myocytes and an animal model in which the transition from compensatory LV hypertrophy to failure was distinctively observed. [11][12][13] Our data suggest that suppression of I Ca,T may be achieved by pharmacological regulation over the tissue neurohumoral condition of the failing myocardium in this animal model.…”

“…[11][12][13] In DS rats, a state of compensatory concentric left ventricular hypertrophy (LVH, nϭ16) is obtained at the age of 11 weeks, followed by LV dilation, global hypokinesis, and pulmonary congestion (CHF, nϭ22) at the age of 16 to 18 weeks. 11,12 Normotensive DR rats were used as age-matched control animals (11-week-old animals, nϭ16; 17-week-old, nϭ16).…”

“…11,12 Normotensive DR rats were used as age-matched control animals (11-week-old animals, nϭ16; 17-week-old, nϭ16). Fourteen LVH-DS rats were subjected to chronic treatment with bosentan (100 mg/kg per day PO) 13 …”

“…Sense (S) and antisense (AS) primers for ␣ 1 G (S, 5Ј-CACCCACAAGATGTTTGACC-3Ј [positions 4238 to 4257], and AS, 5Ј-AGCGCAGTCGGATTTGTTAG-3Ј [4768 to 4787]; and for GAPDH (S, 5Ј-TTGCCATCAACGACCCCTTC-3Ј [169 to 188], and AS, 5Ј-TTGTCATGGATGACCTTGGC-3Ј [558 to 577]) were synthesized by using the published cDNA sequences. 13,21 A portion of the PCR reaction product was then resolved by electrophoresis on a 1.5% agarose gel and photographed with Polaroid type 55 films. Quantitative evaluation was carried out with the use of scanning densitometric analysis.…”

“…13 AII content was determined with a radioimmunoassay kit (Nichols Institute Diagnostics). ET-1 levels were measured with an enzyme immunoassay kit (Wako Pure Chemical Industries) originally developed by Suzuki et al…”