What is the clinical evidence from this study?

Study design: Other. Population: Hypertension (experimental model) (n=61). Intervention: 7-nitro indazole (7-NI) vs. Vehicle (tap water). Primary outcome: Arterial blood pressure (PA) at 4 weeks (p=<0.05).

May 1, 1997Journal of Clinical Investigation132 citationsOpen Access

Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase.

Q: What are the key findings of this study?

Chronic selective inhibition of neuronal nitric oxide synthase with 7-nitro indazole for 4 weeks significantly increased arterial blood pressure in rats to 152 mmHg compared to 125 mmHg in controls.

AOAnna Ollerstam JPJános Pittner APA. Erik G. Persson

Key Result

Chronic selective inhibition of neuronal nitric oxide synthase with 7-nitro indazole for 4 weeks significantly increased arterial blood pressure in rats to 152 mmHg compared to 125 mmHg in controls.

Structured PICO

Does chronic selective inhibition of neuronal nitric oxide synthase with 7-nitro indazole increase blood pressure and alter renal hemodynamics in rats?

Population

61 male Sprague-Dawley rats utilized to investigate the chronic effects of selective inhibition of neuronal nitric oxide synthase on blood pressure and renal hemodynamics.

Intervention

7-nitro indazole (7-NI) administered acutely (25 mg/kg intraperitoneally) or chronically in drinking water (2.5 mg/d) for 1 to 4 weeks

Comparator

Vehicle (tap water) for 3 to 4 weeks; L-NAME (6 mg/kg/day) used as an additional comparator in Series II

Outcome

Arterial blood pressure (PA), glomerular filtration rate (GFR), and tubuloglomerular feedback (TGF) sensitivitysurrogate

Chronic selective inhibition of neuronal nitric oxide synthase with 7-nitro indazole leads to sustained hypertension in rats, initially driven by increased tubuloglomerular feedback sensitivity.

Main Result

Absolute Event Rate: 152% vs 125%

p-value: p=<0.05

Limitations

Cannot exclude that the elevated blood pressure and renal hemodynamic findings are consequences of direct effects of 7-NI on the central nervous system and/or presynaptic sympathetic ganglia.
Animal model findings may not directly translate to human physiology.

Abstract

In the kidney, nitric oxide synthase (NOS) of the neuronal isoform (nNOS) is predominantly located in the macula densa cells. Unspecific chronic NOS inhibition in rats leads to elevated blood pressure (P(A)), associated with increased renal vascular resistance. This study was designed to examine the effect of chronic selective inhibition of nNOS with 7-nitro indazole (7-NI) on P(A), GFR, and the tubuloglomerular feedback (TGF) system. P(A) was repeatedly measured by a noninvasive tail-cuff technique for 4 wk in rats treated orally with 7-NI, and in control rats. After treatment, the animals were anesthetized and renal excretion rates, GFR, and TGF activity were determined. After 1 wk of 7-NI treatment P(A) was increased from 129+/-4 to 143 2 mmHg. GFR (1.85+/-0.1 vs. 1.97+/-0.2 ml/min in controls) was unchanged, but micropuncture studies revealed a more sensitive TGF than in controls. After 4 wk of 7-NI treatment P(A) was 152+/-4 mmHg, but no change in GFR (1.90+/-0.5 ml/min) or TGF sensitivity was detected. Acute administration of 7-NI to nontreated rats did not affect P(A), but decreased GFR (1.49+/-0.1 ml/min) and increased TGF sensitivity. In conclusion, chronic nNOS inhibition leads to increased P(A). Our results suggest that the elevated P(A) could be caused by an initially increased TGF sensitivity, leading to decreased GFR and an increased body fluid volume.

问 AI

Bookmark

View Full Paper