ABSTRACT
The endothelium impairs the vasodilator effect of Ru(terpy)(bdq)NO](3+) (TERPY) in Wistar rat aortas. We hypothesized that endothelial dysfunction could modulate TERPY׳s effect in spontaneously hypertensive rats. The present study investigated the role of the endothelium in the hypotensive and vasodilator effects of TERPY in spontaneously hypertensive rats. We observed a higher hypotensive effect of TERPY in spontaneously hypertensive than in Wistar rats. l-N(G)-Nitroarginine methyl ester, a nitric oxide synthase inhibitor, increased TERPY׳s hypotensive effect in Wistar but not in spontaneously hypertensive rats. TERPY induced a concentration-dependent vasodilator effect in aortas of both rat models. Endothelium removal or l-NAME increased TERPY׳s potency in Wistar rat aortas; this effect was decreased in spontaneously hypertensive rats. TERPY increased nitric oxide level in spontaneously hypertensive rat endothelial cells; this increase was abolished in the presence of l-NAME. In contrast, this effect was increased in Wistar rats. TERPY, with or without l-NAME, decreased levels of reactive oxygen species in spontaneously hypertensive rat endothelial cells. However, it increased these levels in Wistar rats. TERPY reduced aortic endothelial nitric oxide synthase expression in Wistar rats, but did not alter its expression in spontaneously hypertensive rats. In conclusion, different mechanisms underlie the hypotensive and vasodilator effects of TERPY in these two rat models. TERPY reduced endothelial nitric oxide synthase expression and increased reactive oxygen species production in Wistar rat aortas, but did not alter these in spontaneously hypertensive rats. Furthermore, the nitric oxide released by TERPY reacts with reactive oxygen species, decreasing their bioavailability in spontaneously hypertensive rats.
Subject(s)
Hypertension/drug therapy , Hypotension/chemically induced , Nitric Oxide Donors/pharmacology , Vasodilator Agents/pharmacology , Animals , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Aorta/drug effects , Aorta/metabolism , Dose-Response Relationship, Drug , Hypertension/metabolism , Hypotension/metabolism , Male , Nitric Oxide Donors/therapeutic use , Organ Culture Techniques , Rats , Rats, Inbred SHR , Rats, Wistar , Ruthenium/pharmacology , Ruthenium/therapeutic use , Vasodilator Agents/therapeutic useABSTRACT
We have previously demonstrated that the hypotensive effect of the ruthenium complex [Ru(terpy)(bdq)NO](3+) (TERPY) is slow, long lasting, and does not lead to reflex tachycardia. TERPY's hypotensive effect is increased in hypertensive rats (SHR or 2 kidney-1clip) compared with normotensive rats. We hypothesized that sexual differences could interfere in the hypotensive effects of nitric oxide (NO) donors in SHR. Therefore, here we aimed to investigate the role of sexual differences and endogenous NO in the hypotension induced by TERPY. In conscious, unrestrained animals, we evaluated the hypotensive effect of TERPY before and after the administration of N-nitro-L-arginine methyl ester (L-NAME) (nonselective NO synthase inhibitor), APOCYNIN (NADPH/NOX inhibitor), and TEMPOL (superoxide dismutase mimetic). The hypotensive effect of TERPY was higher in male than in female SHR, but this difference was not observed in the normotensive Wistar group. The effect of TERPY increased after administration of L-NAME in Wistar rats; however, this effect was not altered by L-NAME in SHR. In SHR, sexual dimorphism in TERPY effect was still observed in animals treated with L-NAME. TEMPOL increases the effect of TERPY only in female SHR. After TEMPOL, the sexual dimorphism in TERPY effect was abolished in the SHR group. APOCYNIN increased the effect of TERPY in male and female Wistar and SHR, but maintained the previously observed difference between male and female SHR. Thus, this study shows that TERPY's hypotensive effect increased in male compared with female SHR and indicates that sexual dimorphism in TERPY effect is associated with oxidative stress.
Subject(s)
Hypertension/drug therapy , Nitric Oxide Donors/pharmacology , Nitric Oxide/metabolism , Organometallic Compounds/pharmacology , Acetophenones/pharmacology , Animals , Blood Pressure/drug effects , Cyclic N-Oxides/pharmacology , Female , Hypertension/physiopathology , Male , NG-Nitroarginine Methyl Ester/pharmacology , Oxidative Stress/drug effects , Rats , Rats, Inbred SHR , Rats, Wistar , Sex Factors , Spin LabelsABSTRACT
Drugs that release nitric oxide (NO) usually have limitations due to their harmful effects. Sodium nitroprusside (SNP) induces a rapid hypotension that leads to reflex tachycardia, which could be an undesirable effect in patients with heart disease, a common feature of hypertension. The nitrosyl ruthenium complex [Ru(terpy)(bdq)NO(+)](3+) (TERPY) is a NO donor that is less potent than SNP in denuded aortic rings. This study evaluated the hypotension and vasorelaxation induced by this NO donor in Wistar (W) and spontaneously hypertensive rats (SHR) and compared to the results obtained with SNP. Differently from the hypotension induced by SNP, the action of TERPY was slow, long lasting and it did not lead to reflex tachycardia in both groups. The hypotension induced by the NO-donors was more potent in SHR than in W. TERPY induced relaxation with similar efficacy to SNP, although its potency is lower in both strains. The relaxation induced by TERPY is similar in W and SHR, but SNP is more potent and efficient in SHR. The relaxation induced by TERPY is partially dependent on guanylate cyclase in SHR aorta. The NO released from the NO donors measured with DAF-2 DA by confocal microscopy shows that TERPY releases similar amounts of NO in W and SHR, while SNP releases more NO in SHR aortic rings.
