Diminished arteriolar responses in nitrate  tolerance involve ROS and angiotensin II

Frame, Mary D.; Fox, Randall J.; Kim, Dong Soo; Mohan, Amy; Berk, Bradford C.; Yan, Chen

doi:10.1152/ajpheart.00429.2001

Cited by 22 publications

(20 citation statements)

References 35 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…101 In line with the role of ACE inhibitors, nitrate tolerance and nitrate-induced oxidative stress in animal models are markedly attenuated at the level of both conductance and resistance vessels during concomitant administration of angiotensin-1 receptor blockers. 102 Although it is unclear whether this also applies to humans, 103 given the systematic use of ACE inhibitors (eg, in the setting of congestive heart failure), these studies reinforce the concept that nitrate therapy in the modern clinical setting might have totally different implications than what is observed in experimental models (and in former clinical practice).…”

Section: Angiotensin-converting Enzyme Inhibitors and Angiotensin-1 Rmentioning

confidence: 88%

Nitrate Therapy

2011

View full text Add to dashboard Cite

A lthough the short-term vasodilatory properties of organic nitrates are potent and well known, a number of vascular and extravascular changes have been shown to compromise their hemodynamic effects on long-term administration. Among these changes, systemic phenomena such as neurohormonal activation and intravascular volume expansion 1 as well as specific vascular changes such as increased vascular superoxide (O 2 ·Ϫ ) production, 2 increased sensitivity to vasoconstrictors, 3 and decreased responsiveness to nitric oxide (NO) donors 4,5 have long been identified as playing a role. Several hypotheses have been proposed to explain these abnormalities, and over the last 15 years, our groups have focused on the concept that an inappropriate production of reactive oxygen species (ROS), an impairment in the scavenging of these mediators (Figure 1), or both might have a crucial mechanistic importance in all these modifications. 6,7 Independently of the role of ROS in tolerance, the possibility that nitrate-induced oxidative stress might affect patients' prognosis has important implications, and the observation that long-term therapy with most of the drugs in this class causes endothelial dysfunction, the prognostic significance of which is well accepted in patients with coronary artery disease, hypertension, and heart failure, 8 should not be taken as an academic curiosity.Beyond these as-yet insufficiently investigated prognostic implications, recognition of the role of ROS suggests that a number of interventions thought to interfere with the vascular redox balance might also retard or prevent the development of nitrate tolerance and nitrate-induced side effects. Evidence that therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin-1 receptor blockers, certain ␤-blockers, statins, and vitamins such as folic acid or vitamin C beneficially influence nitrate tolerance and glyceryl trinitrate (GTN)-induced endothelial dysfunction suggests that nitrate therapy might have profoundly different implications since these therapies have become diffusely available. In addition, the recognition of important differences in the mechanisms triggered by different nitrates should also be attributed clinical relevance, and evidence suggests that, rather than the generic nitrate tolerance, more specific expressions (GTN tolerance, isosorbide mononitrate [ISMN] tolerance, etc) should be used. 9 This review summarizes the current concepts underlying tolerance and endothelial dysfunction in response to longterm therapy with different nitrates and addresses the question of whether the use of these drugs remains indicated despite these side effects. The Hemodynamic Effects of NitratesVenous capacitance vessels, large and medium-sized coronary arteries, and collateral vessels are most sensitive to GTN, whereas coronary and peripheral arterioles with a diameter Ͻ100 m are relatively more resistant. In the setting of stable angina, the preferential venodilatation induced by antiischemic doses of GTN results in venous pooling an...

show abstract

Section: Angiotensin-converting Enzyme Inhibitors and Angiotensin-1 Rmentioning

confidence: 88%

Nitrate Therapy

2011

View full text Add to dashboard Cite

show abstract

“…These phenomena were prevented by concomitant treatment of angiotensin II antagonist Losartan [21]. More recently, Frame et al provided evidence that angiotensin II is involved in reduction of arteriolar responses in nitrate tolerance [24]. This is the pathophysiologic background to clinical research on the efficacy of AT 1 antagonist Losartan as a drug able to prevent the development of nitrate tolerance.…”

Section: Losartan and Prevention Of Nitrate Tolerance: Experimental Smentioning

confidence: 99%

Angiotensin II-Receptor Antagonist Losartan Does not Prevent Nitroglycerin Tolerance in Patients with Coronary Artery Disease

Longobardi

Ferrara

Leosco

et al. 2004

Cardiovasc Drugs Ther

View full text Add to dashboard Cite

The study evaluated the effect of Losartan in preventing nitrate tolerance during continuous transdermal nitroglycerin (TD-GTN) therapy in patients with coronary disease. Fifteen subjects with chronic stable ischemia evaluated by exercise test, were randomized to 28 days of TD-GTN 20 mg once a day without free interval plus Losartan 100 mg or Losartan-placebo with a double blind crossover design. Myocardial ischemic parameters during stress test were evaluated after each test period and results of Losartan therapy were compared to those with placebo. Time to onset 1 mm ST-depression was significantly higher after acute TD-GTN 20 mg with respect to placebo run-in, sustained TD-GTN 20 mg plus Losartan 100 mg or Losartan-placebo (p < 0.001). ST-depression at peak exercise and time to recovery of ST segment were markedly lower after acute TD-GTN 20 mg compared to placebo run-in (p < 0.05), sustained TD-GTN 20 mg plus Losartan 100 mg (p < 0.001) or Losartan-placebo (p < 0.05). At 1 mm-ST depression and at peak exercise, systolic blood pressure and rate-pressure product significantly decreased after sustained TD-GTN 20 mg plus Losartan 100 mg (p < 0.001, p < 0.05 respectively) with respect to placebo run-in, acute and sustained TD-GTN 20 mg plus Losartan-placebo. Moreover at peak exercise, these data were also observed after acute TD-GTN 20 mg compared to placebo run-in and sustained TD-GTN 20 mg plus Losartan-placebo (p < 0.001). The AT(1) antagonist Losartan administration does not prevent the development of nitrate tolerance during continuous TD-GTN therapy.

show abstract

“…The mechanism of O 2 -ؒ -induced hypertension remains unclear. O 2 -ؒ may increase BP by quenching nitric oxide (NO) [10,11] , endothelium-dependent relaxing factor (EDRF) and/or by increasing the levels of (vasoconstrictor) F 2 -isoprostanes, via nonenzymatic oxidation of arachidonic acid [12] . Endothelial dysfunction caused by long-term AngII treatment is also related to O 2 -ؒ production within the endothelium [13] .…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II Infusion Alters Vascular Function in Mouse Resistance Vessels: Roles of O<sup>–·2</sup> and Endothelium

et al. 2005

View full text Add to dashboard Cite

We hypothesized that prolonged angiotensin II (AngII) infusion would alter vascular reactivity by enhancing superoxide anion (O^–·2) generation. Male C57BL/6 mice were infused with AngII at 400 ng/kg/min (n = 16, AngII mice) or vehicle (n = 16, sham mice) for 2 weeks via subcutaneous osmotic minipumps. Contraction and relaxation of mesenteric resistance vessels (MRVs) were assessed using a Mulvany-Halpern myograph. AngII infusion increased systolic blood pressure, MRV NADPH oxidase activity and expression of p22^phox mRNA. Contraction to norepinephrine was unchanged, but AngII infusion increased contractile responses to AngII (41 ± 5 vs. 10 ± 4%, p < 0.001) and endothelin-1 (ET-1; 95 ± 10 vs. 70 ± 9%, p < 0.05), which was normalized by tempol (10^–4 M, a stable membrane-permeable superoxide dismutase mimetic) and ebselen [10^–5 M, a peroxynitrite (ONOO^–) scavenger]. Endothelium removal enhanced MRV contraction to AngII and ET-1 in sham mice but blunted these contractile responses in AngII mice. Relaxation to ACh was impaired in AngII mice (60.1 ± 8.8 vs. 83.2 ± 3.5%, p < 0.01), which normalized by tempol, whereas relaxation to sodium nitroprusside was similar in both groups. N-nitro-L-arginine (NNLA, a nitric oxide synthase inhibitor), partially inhibited acetylcholine relaxation of vessels from sham mice but not from AngII mice. The residual endothelium-dependent hyperpolarizing-factor-like relaxation was not different between groups. In conclusion,the AngII slow pressor response in mouse MRVs consisted of specific contractile hyperresponsiveness and impairment in the NO-mediated component of endothelium-dependent relaxation, which was mediated by O^–·2 and ONOO^– in the vascular smooth muscle cell.

show abstract

Diminished arteriolar responses in nitrate tolerance involve ROS and angiotensin II

Cited by 22 publications

References 35 publications

Nitrate Therapy

Nitrate Therapy

Angiotensin II-Receptor Antagonist Losartan Does not Prevent Nitroglycerin Tolerance in Patients with Coronary Artery Disease

Angiotensin II Infusion Alters Vascular Function in Mouse Resistance Vessels: Roles of O<sup>–·2</sup> and Endothelium

Contact Info

Product

Resources

About