Vasorelaxant effects of a nitric oxide-releasing aspirin derivative in normotensive and hypertensive rats

Abstract

1. Nonsteroidal anti-inflammatory drugs have been reported to exacerbate hypertension and to interfere with the effectiveness of some anti-hypertensive therapies. In this study, we tested the effects of a gastric-sparing, nitric oxide-releasing derivative of aspirin (NCX-4016) on hypertension in rats. 2. Hypertension was induced by administering L-NAME in the drinking water (400 mg l(-1)). Groups of rats were treated daily with aspirin, NCX-4016 or vehicle. 3. NCX-4016 significantly reduced blood pressure relative to the aspirin-treated group over the 2-week period of treatment. Aspirin and, to a lesser extent, NCX-4016 suppressed whole blood thromboxane synthesis. 4. In anaesthetized rats, acute intravenous administration of NCX-4016 caused a significant fall in mean arterial pressure in hypertensive rats, but was devoid of such effects in normotensive controls. 5. In vitro, NCX-4016 relaxed phenylephrine-pre-contracted aortic rings obtained from both normotensive and hypertensive rats, and significantly reduced their responsiveness to the contractile effects of phenylephrine. 6. These results suggest that NCX-4016 reduces blood pressure in hypertensive rats, not simply through the direct vasodilatory actions of the nitric oxide released by this compound, but also through possible interference with the effects of endogenous pressor agents. These properties, added to its anti-thrombotic effects, suggest that NCX-4016 may be a safer alternative to aspirin for use by hypertensive patients.

Figure 1

Effects of aspirin and NCX-4016 (NCX) on systolic blood pressure in L-NAME treated rats. The arrow indicates the point at which once-daily treatment with the test compounds was initiated. ^δP<0.05 versus the L-NAME+ASA-treated group; ^***P<0.001 versus the L-NAME+vehicle or L-NAME+ASA-treated groups.

Figure 2

(A) Hypotensive effects of increasing intravenous doses of sodium nitroprusside (SNP) obtained from either control or L-NAME-treated rats expressed as percentage of the initial mean arterial pressure (MAP) values. (B) Effects of a single intravenous dose of NCX-4016 (18.6 mg kg⁻¹) on blood pressure in control and L-NAME-treated rats, expressed as percentage of the initial MAP values.

Figure 3

(A) Serum levels of nitrite (squares) and nitrate (circles) as a function of time, following the oral administration of single equimolar doses of either isosorbide dinitrate (37 mg kg⁻¹) or NCX-4016 (93 mg kg⁻¹). (B) Salicylate concentrations measured in serum samples collected after NCX-4016 administration as a function of time.

Figure 4

In vitro dose-dependent relaxation to glyceryl trinitrate (GTN) or NCX-4016 of phenylephrine pre-contracted aortic rings obtained from either hypertensive or the corresponding normotensive controls. Hypertension was induced either by the administration of L-NAME in the drinking water (A) or by partial unilateral occlusion of the renal artery (2K1C model; B).

Figure 5

In vitro dose-dependent contraction to phenylephrine of aortic rings obtained from rats drinking either water (A) or water supplemented with L-NAME (B), and sham-operated rats (C) or 2K1C-renovascular hypertensive rats (D) before (control) and after a 15-min incubation period with 10 μM of either glyceryl trinitrate or NCX-4016.