Relaxation of rat vascular muscle by peripheral benzodiazepine modulators.

Erné, Paul; Chiesi, Michele; Longoni, S; Fulbright, Joy M.; Hermsmeyer, Kent

doi:10.1172/jci114191

Cited by 11 publications

(6 citation statements)

References 26 publications

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“…Existence of the peripheral Bz receptor in vascular smooth muscle has been shown (Cox et al, 1991). Although the precise function of this receptor is not fully understood (Casellas et al, 2002), previous in vivo and in vitro studies showed that Bz agonists can directly cause peripheral vasodilatation in animals (Barker and Clanachan, 1982;Clark and Lipton, 1981;Erne et al, 1989;Seubert et al, 2000). HR after DZP administration can inform us indirectly about this issue.…”

Section: Commentmentioning

confidence: 99%

Heat Loss, Sleepiness, and Impaired Performance after Diazepam Administration in Humans

Echizenya

Mishima

Satoh

et al. 2003

Neuropsychopharmacol

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In spite of the accumulation of knowledge regarding the neuropharmacological action of benzodiazepines (Bz), the physiological process by which their sedative/hypnotic effects are induced remains poorly understood. We conducted a single-blind, crossover trial to evaluate the role of the thermoregulatory process in sleepiness and impaired psychomotor performance induced by a standard Bz, diazepam (DZP). Each of the eight healthy young male volunteers (mean age, 19.75 years; range, 18-23 years) was given a single oral dose of either 5 or 10 mg of DZP or placebo 12 h after his average sleep onset time. Changes in plasma DZP concentration, proximal body temperature (p-BT), distal body temperature (d-BT), subjective sleepiness measured by the Visual Analog Scale and Stanford Sleepiness Scale, and psychomotor performance measured by Choice Reaction Time were monitored under a modified constant routine condition in which various factors affecting thermoregulation, alertness, and psychomotor performances were strictly controlled. Orally administered DZP induced a significant transient decrease in p-BT and psychomotor performance as well as an increase in d-BT and subjective sleepiness. DistalÀp-BT gradient (DPG; difference between d-BT and p-BT), which is an indicator of blood flow in distal skin regions, showed a strong positive correlation with the plasma DZP concentration, indicating that DZP in clinical doses promotes heat loss in a dose-dependent manner. The DPG also correlated positively with the magnitude of subjective sleepiness and impaired psychomotor performance. These findings indicate that the sedative/hypnotic effects of Bz could be due, at least in part, to changes in thermoregulation, especially in the process of heat loss, in humans.

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Section: Commentmentioning

confidence: 99%

Heat Loss, Sleepiness, and Impaired Performance after Diazepam Administration in Humans

Echizenya

Mishima

Satoh

et al. 2003

Neuropsychopharmacol

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“…15 Several studies have shown that stimulation of TSPO with its specific ligands Ro5-4864 and PK 11195 can induce vasodilation through the inhibition of voltage-operated calcium channels. 16,17 However, we found that TSPO does not mediate midazolam-induced vasodilation and that TSPO is not involved in mouse aorta vasodilation. Specifically, the incubation of precontracted rings with the TSPO ligand PK 11195 did not mitigate midazolam-induced vasodilation ( Figure 5), and the stimulation of precontracted rings with increasing doses of Ro5-4864 did not induce vasodilation (data not shown).…”

Section: Discussionmentioning

confidence: 59%

“…14 The cardiovascular system, including the aorta, presents high levels of TSPO. 15 Although specific stimulation of TSPO can induce vasodilation in some models, possibly by inhibiting voltageoperated calcium channels, 16,17 its involvement in BDZ-induced vasodilation appears to be controversial. 18,19 The aim of this study was to assess the vascular effects of BDZs and the possible mechanisms involved in their direct vascular action.…”

Section: Introductionmentioning

confidence: 99%

Involvement of endothelium-dependent and -independent mechanisms in midazolam-induced vasodilation

et al. 2011

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Benzodiazepine (BDZ) infusion has been shown to reduce blood pressure in both humans and animals. Although the inhibitory effects of BDZ on the central nervous system have been well documented, less is known about the direct effects of BDZ on the vascular bed. The aims of this study were to assess the effects of the BDZ midazolam on the vascular system in C57/BL6 mouse aortic rings and to investigate the mechanisms of its direct vascular action. We found that midazolam induced reversible, dose-dependent vasodilation in potassium-and phenylephrine-precontracted rings. In rings that were precontracted with potassium or phenylephrine, treatment with 10 lmol l À1 midazolam increased vasodilation by 15 and 60%, respectively, compared with baseline. Vasodilation increased by 80 and 87%, respectively, after treatment with 50 lmol l À1 midazolam. Only the low concentration of midazolam (10 lmol l À1 ) induced endothelium-dependent vasodilation in phenylephrine-precontracted rings. Vasodilation increased by 60% in rings with endothelium and by 20% in rings without endothelium. Conversely, only the high concentration of midazolam (50 lmol l À1 ) reduced the CaCl 2 -induced vasoconstriction of aortic rings with EC 50 (the concentration giving 50% of the maximal effect) values of 1 and 6 mmol l À1 for vehicle-and midazolam-treated rings, respectively. Furthermore, the incubation of phenylephrine-precontracted rings with an inhibitor of the nitric oxide synthase (NOS) NG-nitro-L-arginine methyl ester or the inhibitors of central or peripheral type BDZ receptors (flumazenil or PK 11195, respectively) produced no change in midazolam-induced vasodilation. Thus, low concentrations of midazolam induce vasodilation via an endothelium-dependent mechanism that does not involve NO production. In contrast, high concentrations of midazolam induce vasodilation via an endothelium-independent mechanism that implies reduced sensitivity of aortic rings to calcium ions. Additionally, neither the central c-amino-butyric acid receptor type A nor the peripheral type BDZ receptors seem to be involved in the mechanism of midazolam-induced vasodilation.

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“…Notably, BZD potentiate the inhibitory effect of γaminobutyric acid (GABA) in the central nervous system and bind the 18 kDa translocator protein (TPSO), also known as peripheral-type BDZ receptor [70]. TPSO is abundantly distributed in cardiovascular tissues and is involved in the myocardial response to ischemia [71], possibly explaining the endothelium-independent vasodilatory effect of BDZ [72]. BDZ have been shown to acutely decrease the sympathetic tone and blood pressure values in healthy volunteers [73] and in patients undergoing surgery [74].…”

Section: Psychogenic Hypertensionmentioning

confidence: 99%