Potentiation of endothelium-dependent relaxations to bradykinin by angiotensin I converting enzyme inhibitors in canine coronary artery involves both endothelium-derived relaxing and hyperpolarizing factors.

Abstract

Studies were designed to investigate the mechanisms underlying the augmentation by angiotensin I converting enzyme (ACE) inhibitors of the endothelium-dependent relaxations evoked by bradykinin. Isometric tension, tissue levels of cGMP, and transmembrane potential were measured in isolated canine coronary arteries as indications of the respective contribution of nitric oxide and endothelium-derived hyperpolarizing factor. In rings of coronary artery with endothelium, relaxations to bradykinin were potentiated by the ACE inhibitors cilazaprilat and perindoprilat. NG-Nitro-L-arginine (NLA), a nitric oxide synthase inhibitor, impaired relaxations to bradykinin. But the presence of ACE inhibitors partially restored this activity. Bradykinin stimulated the production of cGMP, and this was enhanced significantly by ACE inhibitors, indicating an augmented release of nitric oxide. NLA abolished the increase induced by bradykinin irrespective of the presence of ACE inhibitors. Electrophysiological studies revealed that bradykinin elicited an endothelium-dependent hyperpolarization of vascular smooth muscle that was insensitive to NLA and potentiated by ACE inhibitors. The bradykinin-induced hyperpolarization and NLA-resistant relaxations were transient and impaired by potassium depolarization. Thus, production of endothelium-derived hyperpolarizing factor may account for the NLA-resistant relaxations of canine coronary arteries. The relaxations induced by bradykinin were unaffected by the B1 kinin receptor antagonist des-Arg9,[Leu8]-bradykinin either in the absence or in the presence of NLA but were antagonized by the B2 kinin receptor antagonist D-Arg[Hyp3,D-Phe7]-bradykinin. Molecular exclusion chromatography of 125I-labeled [Tyr8]-bradykinin and its degradation products demonstrated that the breakdown of the kinin by isolated coronary arteries was prevented in the presence of perindoprilat.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Endothelium-Derived Hyperpolarizing Factor in ACE Inhibitor-Induced Renal Vasodilation in Vivo

“…24 -26 In the present in vivo study, we found that proadifen completely eliminated the remaining vasodilator response of juxtamedullary afferent arterioles observed during the inhibition of angiotensin II and NO. These findings therefore are compatible with previous in vitro observations that a part of the ACE inhibitor-induced vasodilation is associated with EDHF 27,28 and further allow extrapolation to the in vivo actions of this agent. Caveat is in order, because proadifen is reported to inhibit the K channel activity and the cytochrome P450-mediated EDHF production.…”

Stimulation of Bradykinin B 1 Receptors Induces Vasodilation in Conductance and Resistance Coronary Vessels in Conscious Dogs

“…13 In vitro, the bradykinin-induced vasorelaxation is potentiated by ACE inhibitors. 24 In humans, bradykinin is involved in the vascular effect of ACE inhibitors. 25 A recent study from our laboratory has shown that enalaprilat extends the duration of the effect of bradykinin with no significant changes in the peak CBFv response to bradykinin.…”

New perspectives in hypertension research. Potentials of vascular biology.

“…Conversely, restoration of nitric oxide generation by either the administration of the substrate L-arginine 12 or treatment with angiotensin-converting enzyme (ACE) inhibitors results in a lowering of blood pressure. 13 These by guest on May 11, 2018 http://hyper.ahajournals.org/ Downloaded from data indicate that the regulation of nitric oxide generation by the endothelium may be a critical determinant of blood pressure in hypertension. Advances in vascular biology have also reshaped our understanding of previously characterized classic hormonal systems.…”