Objective: Nitric oxide (NO) may contribute to the actions of angiotensin converting enzyme (ACE) inhibitors. In contrast, angiotensin type 1 (AT1) receptor blockers (AT1B) have been considered to act exclusively by inhibiting angiotensin II actions. However, recent experimental findings suggest that AT1B actions may be also partly mediated by NO. In this study, we explored whether ACE inhibitors and AT1B modulate hemodynamic responses to L-arginine (L-arg), a NO precursor.
Methods: Systemic (Finapres) and renal hemodynamic responses to L-arg (200 mg/kg body weight), associated with markers of systemic and renal NO production, were assessed before (control) and after 3 weeks of randomized pretreatment with the ACE inhibitor ramipril (5 mg/day for 3 weeks) or the AT1B losartan (50 mg/day for 3 weeks) in nine healthy male subjects (33 +/- 2 years; body mass index 25.5 +/- 0.5 kg/m2).
Results: Control L-arg did not influence mean arterial pressure (MAP) (92 +/- 5 versus 90 +/- 5 mmHg; not significant). In contrast, L-arg decreased MAP when administered after pretreatment with ramipril (89 +/- 5 versus 83 +/- 4 mmHg; P< 0.01) or losartan (90 +/- 44 versus 86 +/- 4; P< 0.05). Control L-arg infusion had no effect on renal plasma flow (RPF) (paraminohippuric acid clearance) and renal vascular resistance (RVR), whereas the glomerular filtration rate (GFR) (inulin clearance) decreased (98 +/- 4 versus 89 +/- 5 ml/min; P< 0.05), resulting in a decrease in filtration fraction (P< 0.05). After ramipril, L-arg induced renal vasodilation as indicated by significant changes in RPF (576 +/- 41 versus 669 +/- 21 ml/min; P< 0.01) and RVR (P< 0.05). The GFR did not change statistically after ramipril pretreatment (91 +/- 3 versus 97 +/- 4 ml/min; not significant); however, the trend was different as compared with control (F= 5.7, P < 0.05). L-Arg-induced renal vasodilation was also observed after losartan (RPF, 637 +/- 34 versus 706 +/- 40 ml/min; P< 0.05). Enhanced renal and systemic responses to L-arg after ACE inhibitor and AT1B were associated with a rise in plasma L-citrulline levels, which was greater than after control L-arg (P < 0.05). However, other indicators of NO activity such as plasma and urinary cyclic guanosine 3',5'-monophosphate, and nitrates, remained unchanged throughout all experiments.
Conclusion: The results indicate that ACE inhibitors and AT1B have a potential to enhance L-arg-induced vasodilation both in systemic and renal vascular beds. However, these hemodynamic responses were not associated with convincing changes in indicators of systemic or renal NO activity, suggesting a contribution of NO-independent vasodilator mechanisms.