Improved cardiovascular function with aminoguanidine in DOCA-salt hypertensive rats

Abstract

The ability of aminoguanidine (AG), an inhibitor of collagen crosslinking, to prevent changes in cardiac and vascular structure and function has been determined in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat as a model of the cardiovascular remodelling observed in chronic human hypertension. Uninephrectomized rats (UNX) administered DOCA (25 mg every fourth day s.c.) and 1% NaCl in drinking water for 28 days developed cardiovascular remodelling shown as systolic hypertension, left ventricular hypertrophy, increased thoracic aortic and left ventricular wall thickness, increased left ventricular inflammatory cell infiltration together with increased interstitial collagen and increased passive diastolic stiffness, impaired contractility, prolongation of the action potential duration and vascular dysfunction. Treatment with AG (0.05-0.1% in drinking water; average 182+/-17 mg kg(-1) day(-1) in DOCA-salt rats) decreased blood pressure (DOCA-salt 176+/-4; +AG 144+/-5 mmHg; (*)P<0.05 vs DOCA-salt), decreased left ventricular wet weights (DOCA-salt 3.17+/-0.07; +AG 2.66+/-0.08 mg g(-1) body wt(*)), reduced diastolic stiffness constant (DOCA-salt 30.1+/-1.2; +AG 24.3+/-1.2(*) (dimensionless)), improved cardiac contractility (DOCA-salt 1610+/-130; +AG 2370+/-100 mmHg s(-1)(*)) and vascular reactivity (3.4-fold increase in maximal contractile response to noradrenaline, 3.2-fold increase in maximal relaxation response to acetylcholine, twofold increase in maximal relaxation response to sodium nitroprusside) and prolonged the action potential duration at 50% repolarization without altering collagen content or inflammatory cell infiltration.Thus, cardiovascular function in DOCA-salt hypertensive rats can be improved by AG independent of changes in collagen content. This suggests that collagen crosslinking is an important cause of cardiovascular dysfunction during cardiovascular remodelling in hypertension.

Figure 1

Daily AG dose (mg kg⁻¹) of UNX rats treated with AG and DOCA-salt rats treated with AG. Values are mean±s.e.m.; n=16–28 for all groups.

Figure 2

Concentration–response curves to noradrenaline (a) for UNX rats (−log EC₅₀ 7.4±0.1, n=9), UNX rats treated with AG (−log EC₅₀ 7.7±0.1, n=7), DOCA-salt rats (−log EC₅₀ 7.8±0.1, n=9) and DOCA-salt rats treated with AG (−log EC₅₀ 8.0±0.1, n=7). Concentration–response curves to acetylcholine (b) for UNX rats (−log EC₅₀ 7.0±0.1, n=9), UNX rats treated with AG (−log EC₅₀ 7.1±0.2, n=7), DOCA-salt rats (−log EC₅₀ 7.0±0.1, n=9) and DOCA-salt rats treated with AG (−log EC₅₀ 7.6±0.2 n=7). Concentration-response curves to sodium nitroprusside (c) for UNX rats (−log EC₅₀ 7.8±0.1, n=9), UNX rats treated with AG (−log EC₅₀ 7.7±0.1, n=7), DOCA-salt rats (−log EC₅₀ 7.4±0.1, n=9) and DOCA-salt rats treated with AG (−log EC₅₀ 8.0±0.2, n=7). Values are mean±s.e.m.; Significance: ^*P<0.05 vs UNX rats; ^**P<0.05 vs DOCA-salt rats.