What is the clinical evidence from this study?

Study design: Other. Population: DOCA-salt hypertension. Intervention: Endothelin receptor stimulation (ET-1, ET-3, BQ-3020) vs. Control rats. Primary outcome: Nitric oxide (NO) release and renal perfusion pressure (p=<.01).

February 15, 1995

Direct Measurements of Endothelium-Derived Nitric Oxide Release by Stimulation of Endothelin Receptors in Rat Kidney and Its Alteration in Salt-Induced Hypertension

Q: What are the key findings of this study?

Stimulation of ETB receptors with BQ-3020 caused significantly less nitric oxide release in kidneys from DOCA-salt hypertensive rats compared to controls (+1.1 vs +9.0 fmol/min/g, P<0.01).

Key Result

Stimulation of ETB receptors with BQ-3020 caused significantly less nitric oxide release in kidneys from DOCA-salt hypertensive rats compared to controls (+1.1 vs +9.0 fmol/min/g, P<0.01).

Structured PICO

Does stimulation of endothelin receptors alter endothelium-derived nitric oxide release and renal perfusion pressure in DOCA-salt hypertensive rats compared to controls?

Population

Isolated kidneys from deoxycorticosterone acetate (DOCA)-salt hypertensive rats and control rats

Intervention

Perfusion with ET-1, ET-3, ETA receptor antagonist (BQ-123), and ETB receptor agonist (BQ-3020)

Comparator

Control rat kidneys

Outcome

Endothelium-derived nitric oxide (EDNO) release and renal perfusion pressure (RPP)surrogate

ETB-mediated nitric oxide release is reduced in DOCA-salt hypertensive rats, which may contribute to altered renal function and blood pressure regulation.

Main Result

p-value: p=<.01

Abstract

BACKGROUND: Stimulation of endothelin subtype B (ETB) receptors has been proposed to induce release of endothelium-derived nitric oxide (EDNO). METHODS AND RESULTS: To obtain direct evidence of its release and its alteration in deoxycorticosterone acetate (DOCA)-salt hypertension, EDNO released from renal vessels by ET stimulation was assayed by a highly sensitive chemiluminescence method. Kidneys were isolated from DOCA-salt and control rats, and renal perfusion pressure (RPP) and EDNO (by hydrogen peroxide-luminol chemiluminescence) in the perfusate were monitored simultaneously during perfusion of ET-1, ET-3, an ETA receptor antagonist (BQ-123), and an ETB receptor agonist (BQ-3020). In control rats, ET-1 and ET-3 dose-dependently increased both RPP and NO release. Although the vasoconstricting effects of ET-1 were greater, their NO-releasing effects were comparable. The increase in NO release by ETs was inhibited by NG-monomethyl-L-arginine. After 10(-6) mol/L BQ-123 treatment, ET-1 decreased RPP and increased NO release in control kidneys. DOCA-salt rats responded to these agents with much less NO release. BQ-3020 at up to 10(-10) mol/L caused vasodilation (RPP, 10(-11) mol/L, -5.4 +/- 1.7%, P < .01) associated with increased NO release in control kidneys (+9.0 +/- 2.7 fmol.min-1.g-1 kidney wt, P < .01). However, in DOCA-salt kidneys, BQ-3020 caused renal vasoconstriction (RPP, +5.4 +/- 2.4%, P < .01 versus control) and a much smaller NO release (+1.1 +/- 0.4 fmol.min-1.g-1 kidney wt, P < .01 versus control). Northern blot analysis revealed that renal ETB mRNA was significantly decreased in DOCA-salt rat kidneys compared with controls (0.36 +/- 0.13 versus 1.00 +/- 0.23, P < .05). CONCLUSIONS: These results suggest that ET-1 and ET-3 release EDNO via ETB receptors in renal vessels. ETB-mediated NO release was reduced in DOCA-salt rats, which may modulate renal function and thus blood pressure regulation in DOCA-salt hypertensive rats.