Renin is produced by the kidney and secreted into the systemic circulation. However, its biochemical and physiological role of regulating renal blood flow with changing renal perfusion pressure (RPP) is not fully understood. In this study, the function of the intrarenal renin for production of angiotensin (Ang) I and maintenance of vascular tone was evaluated in dogs under normal conditions and when the kidney was perfused at low RPP. The dog left kidney was perfused first at normal (100 mm Hg) and then at low (30 mm Hg) RPP in the presence or absence of the renin inhibitor ciprokiren (3 mg/kg, i.v.). Both hemodynamic and biochemical parameters were measured. Lowering RPP markedly reduced left renal blood flow and elevated left renal vascular resistance. These effects were prevented by ciprokiren, which blocked the intrarenal production of Ang I. Lowering RPP increased the renal venous/ arterial ratio from 1.4+/-0.1 to 3.6+/-0.3 for plasma renin activity and from 2.4+/-0.2 to 9.8+/-1.1 for Ang I, but did not change the venous/arterial ratio for Ang II. The net renal venous conversion rate of Ang I to Ang II decreased from 0.22 to 0.09 after RPP was lowered, whereas the conversion rate in arterial blood was 1.35 and did not decrease significantly. Our results demonstrated the importance of intrarenal renin-angiotensin system for Ang I production and for the maintenance of the vascular tone, especially at low RPP. Our study also shows the limited capacity for Ang I conversion in the renal vasculature in vivo.

1998-12-22·Circulation1区 · 医学

Preserved Vasodilator Effect of Bradykinin in Dogs With Heart Failure

1区 · 医学

Article

作者: Hittinger, Luc ; Houel, Rémi ; Barbe, Fabrice ; Crozatier, Bertrand ; Guyene, Thanh Tam ; Su, Jin Bo

Background —In heart failure (HF), vasoconstrictor systems are activated and endothelium-derived vasodilation is blunted. Bradykinin, a potent vasodilator, may play an important role in this setting. However, it is not known whether its vasodilator effect is modified in HF. Methods and Results —Fourteen chronically instrumented dogs were studied in the control state and in pacing-induced HF (250 bpm for 3 weeks). The dose-dependent decrease in mean aortic pressure (MAP) induced by acetylcholine was significantly blunted in HF. In contrast, in both control and HF, bradykinin infusion caused similar dose-dependent decreases in MAP and increases in cardiac output (CO). This vasodilator effect of exogenous bradykinin was potentiated similarly in both states by enalaprilat, which blocks both angiotensin conversion and bradykinin degradation. For evaluating the role of endogenous bradykinin, the effects of enalaprilat were compared with those of ciprokiren, a pure renin inhibitor. In control, ciprokiren did not produce any effect. Enalaprilat, however, produced a significant decrease in MAP and a significant increase in CO, which were attributed to the inhibition of bradykinin degradation, because these effects were absent after pretreatment with Hoe 140 (a bradykinin B 2 receptor antagonist). In contrast, in HF, vasodilator effects of ciprokiren were observed, but enalaprilat produced larger changes in MAP and CO, and after Hoe 140, the hemodynamic effects of enalaprilat were significantly decreased, showing the effects of endogenous bradykinin, which were similar to those measured in control. Conclusions —In this model of HF with a blunted endothelium-derived vasodilation, the vasodilator effects of exogenous and endogenous bradykinin are preserved. These results suggest that bradykinin may play an important role in HF, in which vasoconstriction is present and endothelium-dependent vasodilation is blunted.

1998-03-01·The Journal of pharmacology and experimental therapeutics

Angiotensin I-converting enzyme inhibition but not angiotensin II suppression alters angiotensin I-converting enzyme gene expression in vessels and epithelia.

Article

作者: Costerousse, O ; Clozel, J P ; Alhenc-Gelas, F ; Allegrini, J ; Ménard, J

The concentration of angiotensin-converting enzyme (ACE) increases during chronic treatment with ACE inhibitors for unknown reasons. We investigated whether alterations in ACE mRNA and ACE concentration occur in the different tissues during ACE inhibition and the role of angiotensins in these regulations by comparing ACE inhibitors with other blockers of the renin-angiotensin system. Enalapril, an ACE inhibitor, in the range of 0.3 to 10 mg/kg/day in rats induced dose- and time-dependant increases in plasma ACE up to two to three times control values. There were significant increases in the steady state ACE mRNA in the lung (32%), duodenum (64%) and aorta (324%) and 40% to 140% increases in membrane-bound enzyme concentration in these tissues and in the heart and kidney. The ACE content of purified duodenal brush border was increased by 80%, but the enzyme and its mRNA in the testis were not altered. The angiotensin II receptor antagonist losartan at several regimens of up to 30 mg/kg twice a day for 14 days produced no change in plasma ACE level or lung ACE mRNA. The human renin inhibitor ciprokiren was tested in guinea pigs, a species sensitive to this compound. Both enalapril and cilazapril induced 2-fold increases in plasma ACE, but ciprokiren (24 mg/kg/day for 12 days) had no effect. Enalapril treatment of BN/Kat rats (lacking circulating kininogens) caused a similar increase in ACE as in other rats. This study documents a general increase in ACE gene expression and enzyme concentration in tissues during ACE inhibition, with the exception of the testis, most probably reflecting an activation of the 5', so-called somatic promoter of the ACE gene. Angiotensins are not involved in this regulation and do not seem to control ACE gene expression in normal rodents.

100 项与 Ciprokiren 相关的药物交易

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