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

Abstract

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.

Avaliação metabólica e hemodinâmica de dois protocolos de sedação prolongada em cães

“…3), com diferença significativa apenas no GMF acima dos valores de referência para a espécie (Haskins et al, 2005). Visto que benzodiazepínicos (Colussi et al, 2011) e opioides (Lopes e Nunes, 2008) não promovem efeito vascular direto em vasos pulmonares, o aumento do IRVP pode estar relacionado à leve diminuição da saturação de oxigênio venosa mista (SvmO 2 ), que ocorreu em ambos os grupos, 62,5±2,6% no GMF e 71,5±4,4% no GCM em M24h (24 horas de infusão), porém mais intensamente no GMF, o que pode ter levado a um leve quadro de hipóxia e consequente vasoconstrição dos vasos pulmonares, como já descrito em humanos (Gille et al, 2012). Outro importante fator que pode ter auxiliado é o aumento na taxa de shunt intrapulmonar (Qs/Qt) (Tab.…”

Catheter entrapment due to severe radial artery spasm during transradial approach

“…Besides the sedative and analgesic action, benzodiazepines also have direct vasoactive effects. Midazolam was shown to induce vasodilation and attenuate the vasoconstrictive response to adrenergic stimuli [29]. Thereby midazolam might have a role in the prevention and reversal of vasospasm in the setting of adrenergic overactivation situations, such as cardiac catheterization-related stress.…”

Benzodiazepines alter nucleotide and nucleoside hydrolysis in zebrafish (Danio rerio) brain

“…The differences in their affinity to receptor subtypes, in combination with a variety of pharmacokinetic profiles, are responsible for various pharmacological effects, such as sedation, hypnosis, decreased anxiety, anterograde amnesia, muscle relaxation, and anticonvulsive activity. Apart from its action on the central nervous system (CNS), they also possess depressant dose-dependent effect, causing a modest reduction in arterial blood pressure and increased heart rate (Colussi et al 2011;Olkkola and Ahonen 2008).…”