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Vascular smooth muscles are affected by both agonists (which induce contraction) and antagonists (which induce relaxation). The classic example of agonists/antagonists is epinephrine, whose actions depend on the binding site (which is dependent on the concentration, with beta agonism predominating at low doses, and alpha agonism taking over at higher doses). Alpha-1 receptors, when stimulated, activate the inositol-phospholipid-calcium pathway, leading to the production of IP3 (which causes calcium release from the ER) and the activation of DAG (which activates protein kinase C [PKC]), both of which lead to smooth muscle contraction and vasoconstriction. Beta-receptors, by contrast, work on smooth muscle cells via the cAMP pathway – binding of the beta-receptor results in the activation of adenylyl cyclase and subsequent production of cAMP, which produces smooth muscle relaxation. Both alpha and beta adrenergic receptors (which work through the IP3/DAG and cAMP pathways) are G-protein mediated
Analogous to cAMP-mediated vasodilation due to beta-receptor activation, nitric oxide (produced from arginine via nitric oxide synthase) is able to induce smooth muscle relaxation via production of cGMP (cAMP and cGMP seem to have similar effects). In this case, nitric oxide activates guanylyl cyclase to produce cGMP, which activates protein kinase G (PKG), leading to smooth muscle relaxation. Importantly, nitric oxide production can be triggered by inflammatory mediators (bradykinin, interleukins, cytokines) that result from trauma, pharmacologic agents, shear stress, or cardiopulmonary bypass, thus implicating the NO/cGMP pathway in vasoplegia following bypass, sepsis, etc.
Methylene blue has a variety of effects, several of which inhibit NO-induced vasodilation – inhibition of guanylate cyclase [Cruetter CA et al. Can J Physiol Pharmacol 59: 150, 1981], as well as both endogenous and inducible nitric oxide synthase [Mayer B et al Eur Heart J 14: 22, 1993; Keaney JF et al. Circ Res 74: 1121, 1994; Lomniczi A et al. Neuroimmunomodulation 8: 122, 2000] can potentially counteract the effects of inflammatory mediators on vascular smooth muscle in a variety of physiologic states.
Clinical Applications of Methylene Blue
Kirov et al. randomized twenty patients with septic shock to methylene blue (2 mg/kg followed by 0.25-2 mg/kg/hr, titrated to MAP 70-90) versus normal saline in addition to standard ionotropes. Methylene blue reduced the requirement for norepinephrine, epinephrine, and dopamine by as much as 87%, 81%, and 40%, respectively. At the end of infusion, LVSWI had increased by 32% in the methylene blue group, whereas in the control group LVSWI fell by as much as 40% below baseline (p < .05). Methylene blue maintained DO2, which fell by 69% in the saline group (p < 0.05). The mortality rate in the methylene blue arm was 58%, as compared to 75% in the saline group (p = 0.65) [Kirov et al. Crit Care Med 29: 180, 2001]
Koelzow et. al. investigated the use of methylene blue in ischemia reperfusion syndrome (IRS) during orthotopic liver transplantation (OLT). 36 patients undergoing OLT were randomized to either 1.5 mg/kg methylene blue or saline prior to graft reperfusion. The methylene blue group had higher MAPs (increased by 5% versus fell by 12%, p = 0.035), higher cardiac indices (7.4 vs. 6.2 L/min/m2, p = 0.03 at 30 minutes and 7.6 vs. 6.3 L/min/m2, p = 0.04 at 60 minutes), required less epinephrine (p = 0.02), and no effect on SVR or CVP. One hour after infusion, lactate levels were lower in the methylene blue group (p = 0.03) [Koelzow H et al. Anesth Analg 94: 824, 2002; FREE Full-text at Anesthesia & Analgesia]
Levin et al. randomized 56 vasoplegic patients (defined as hypotensive, with low filling pressures, low peripheral vascular resistance, and elevated or normal cardiac index despite significant vasopressor requirements) following cardiopulmonary bypass to 1.5 mg/kg of methylene blue versus placebo. Patients who received methylene blue showed a significant reduction in mortality (0% versus 21.4% [6 of 28 patients], p = 0.01), as well as in the incidence of renal failure (0 vs. 14%, p = 0.05), respiratory failure (0 vs. 14%, p = 0.05), supraventricular tachycardias (7% vs 28%, p = 0.03), sepsis (0% vs 25%, p = 0.005), and multiorgan failure (0% vs 25%, p = 0.005). No episode of vasoplegia lasted longer than 2 hours in the methylene blue groups, whereas in the placebo groups vasoplegia lasted up to 48 hours [Levin RL et al. Ann Thorac Surg 77: 496, 2004]
Ozal et al. randomized patients “at risk” for post-operative vasoplegia (undergoing CABG procedures and having taken ACE-inhibitors, calcium channel blockers, or heparin preoperatively) to 2 mg/kg methylene blue versus nothing (no placebo). The two groups differed in the incidence of vasoplegia (0% vs. 26%, p < 0.001), average ICU stay (1.2 vs. 2.1 days, p < 0.001), and average hospitalization (6.1 vs. 8.4 days, p < 0.001). The methylene blue group required less volume (1.57 L vs. 1.75 L, p = 0.024), displayed higher SVR (p < 0.001), had lower ionotropic requirements to come off of bypass (p < 0.001), and had higher urine output during bypass (738 vs 631 cc, p = 0.019) despite a trend towards lower time on bypass (68.5 vs 70.7 minutes, p = 0.123) [Ozal E et al. Ann Thorac Surg 79: 1615, 2005]
Maslow et al. randomized 31 patients who had received ACE-inhibitors and who were undergoing cardiopulmonary bypass (CPB) to 3 mg/kg of methylene blue versus saline following CPB and cardioplegia. Methylene blue increased MAPs (statistically significant at post-drug and 20-40 mins of CPB timepoints, but not at 60 minutes of CPB or post-CPB) and SVR (significant up to 40 minutes), thus the effects appeared to last only ~ 40 minutes. Methylene blue administration resulted in lower phenylephrine and norephrine requirements, and resulted in lower serum lactate levels. While the methylene blue group had higher cardiac output post-bypass (6.1 L/m vs. 5.6 L/min), this did not reach statistical significance [Maslow AD et al. Anesth Analg 103: 2, 2006; FREE Full-text at Anesthesia & Analgesia]