Melatonin differentially affects vascular blood flow in humans

Cook, Jonathan S.; Sauder, Charity L.; Ray, Chester A.

doi:10.1152/ajpheart.00710.2010

Cited by 62 publications

(47 citation statements)

References 25 publications

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“…Before the end of experiment, rats were anesthetized with ketamine (80 mg/kg, ip) and xylazine (6 mg/kg, ip) and then renal artery blood flow velocity was measured by ultrasound imaging (Vevo 770 system, VisualSonics, Toronto, ON, Canada) 30–32 using pulse-wave Doppler mode with a dedicated 16MHz probe. The average velocity of blood flow during 1 minute was determined by multiplying Velocity Time Integral by Heart Rate 33 .…”

Section: Methodsmentioning

confidence: 99%

Silencing of Hypoxia-Inducible Factor-1α Gene Attenuated Angiotensin II–Induced Renal Injury in Sprague-Dawley Rats

et al. 2011

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Although it has been shown that up-regulation of hypoxia-inducible factor (HIF)-1α is protective in acute ischemic renal injury, long-term over-activation of HIF-1α is implicated to be injurious in chronic kidney diseases. Angiotensin II (ANG II) is a well-known pathogenic factor producing chronic renal injury and has also been shown to increase HIF-1α. However, the contribution of HIF-1α to ANG II-induced renal injury has not been evidenced. The present study tested the hypothesis that HIF-1α mediates ANG II-induced renal injury in Sprague-Dawley rats. Chronic renal injury was induced by ANG II infusion (200ng/kg/min) for 2 weeks in uninephrectomized rats. Transfection of vectors expressing HIF-1α shRNA into the kidneys knocked down HIF-1α gene expression by 70%, blocked ANG II-induced HIF-1α activation and significantly attenuated ANG II-induced albuminuria, which was accompanied by inhibition of ANG II-induced vascular endothelial growth factor, a known glomerular permeability factor, in glomeruli. HIF-1α shRNA also significantly improved the glomerular morphological damage induced by ANG II. Furthermore, HIF-1α shRNA blocked ANG II-induced upregulation of collagen and α-smooth muscle actin in tubulointerstitial region. There was no difference in creatinine clearance and ANG II-induced increase in blood pressure. HIF-1α shRNA had no effect on ANG II-induced reduction in renal blood flow and hypoxia in the kidneys. These data suggested that over-activation of HIF-1α-mediated gene regulation in the kidney is a pathogenic pathway mediating ANG II-induced chronic renal injuries and normalization of over-activated HIF-1α may be used as a treatment strategy for chronic kidney damages associated with excessive ANG II.

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Section: Methodsmentioning

confidence: 99%

Silencing of Hypoxia-Inducible Factor-1α Gene Attenuated Angiotensin II–Induced Renal Injury in Sprague-Dawley Rats

et al. 2011

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“…Conversely, melatonin dilates the rat and rabbit aorta, iliac, renal, and basilar arteries (49,57). In humans, melatonin increases blood flow in certain vascular beds (e.g., forearm) while decreasing flow in others (e.g., renal) (10). The vasomotor effects of melatonin are mediated primarily via the activation of two distinct receptor subtypes, termed MT 1 and MT 2 (16), which are present in the vasculature.…”

mentioning

confidence: 99%

Melatonin inhibits nitric oxide signaling by increasing PDE5 phosphorylation in coronary arteries

Shukla

Sun

O’Rourke

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Melatonin inhibits nitric oxide (NO)-induced relaxation of coronary arteries. We tested the hypothesis that melatonin increases the phosphorylation of phosphodiesterase 5 (PDE5), which increases the activity of the enzyme and thereby decreases intracellular cGMP accumulation in response to NO and inhibits NO-induced relaxation. Sodium nitroprusside (SNP) and 8-Br-cGMP caused concentration-dependent relaxation of isolated coronary arteries suspended in organ chambers for isometric tension recording. In the presence of melatonin, the concentration-response curve to SNP, but not 8-Br-cGMP, was shifted to the right. The effect of melatonin on SNP-induced relaxation was abolished in the presence of the PDE5 inhibitors zaprinast and sildenafil. Melatonin markedly inhibited the SNP-induced increase in intracellular cGMP in coronary arteries, an effect that was also abolished by zaprinast. Treatment of coronary arteries with melatonin caused a nearly fourfold increase in the phosphorylation of PDE5, which increased the catalytic activity of the enzyme and thereby increased the degradation of cGMP to inactive 5'-GMP. Melatonin-induced PDE5 phosphorylation was markedly attenuated in the presence of the PKG1 inhibitors DT-2 or Rp-8-Br-PET-cGMPS and in those arteries in which PKG1 expression was first downregulated by 24-h incubation with SNP before exposure to melatonin. The selective MT(2) receptor antagonist 4-phenyl-2-propionamidotetralin completely blocked the stimulatory effect of melatonin on PDE5 phosphorylation as well as the inhibitory effect of melatonin on SNP-induced relaxation and intracellular cGMP. Thus, in coronary arteries, melatonin acts via MT(2) receptors and PKG1 to increase PDE5 phosphorylation, resulting in decreased cGMP accumulation in response to NO and impaired NO-induced vasorelaxation.

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“…Moreover, all but one of the rodent experiments were performed on animals that modeled human disease, and thus they may have questionable applicability to healthy humans. In humans, other vascular studies-those of Cook et al (2011), Kitajima et al (2001), Arangino et al (1999), Cagnacci et al (1998), andNishiyama et al (2001)-expressed no safety concerns. Because melatonin may have greatly different effects in humans compared to rodents in certain circumstances (Peschke et al, 2010), caution needs to be used in applying the results of animal studies when evaluating the safety of melatonin consumption by humans.…”

Section: Safety Of Melatoninmentioning

confidence: 99%