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Published in Anthony N. Nicholson, The Neurosciences and the Practice of Aviation Medicine, 2017
Verapamil in dosages starting at 80 mg three times a day is probably the most commonly used prophylactic drug, although unlicensed. The dose may need to be increased to 960 mg per day, depending on response and side effects. It is thought to work predominantly via its calcium channel blocking properties, inhibiting calcium ion influx into the vascular smooth muscle cells and consequently blocking the sequence of events leading to muscle contraction. Cardiac side effects are potentially the most important; serial electrocardiograms are recommended during dose titration and may be needed in the longer term. Monitoring is concerned with changes suggestive of heart block, such as prolongation of PR interval, change in cardiac axis and/or broadening of QRS complex. A number of drugs interact with Verapamil and should be avoided, the most important being beta blockers and digoxin.
Cytochromes P450, Cardiovascular Homeostasis and Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chin Eng Ong, Amelia Dong, Boon Hooi Tan, Yan Pan
There is substantial evidence for the role of enzymes in the EET and HETE pathways, including CYPs and sEHs, in fluid and electrolyte homeostasis and blood pressure control. The best evidence was the report that male animals lacking sEH demonstrated high level of EETs, reduced renal production of DHETs (EET metabolites) and a significantly lower blood pressure (Sinal et al., 2000). In humans, blood EET level is reduced in women with pregnancy-induced hypertension (Catella et al., 1990) and in subjects with renovascular hypertension (Minuz et al., 2008). Moreover, significant drop in blood pressure was noted in different hypertensive models in rodents after the administration of a sEH inhibitor (Manhiani et al., 2009; Sinal et al., 2000). Substantial evidence in animals has also demonstrated that transgenic or overexpression of CYP epoxygenase lowered blood pressure in a number of hypertensive models. For example, recombinant adenovirus vector-mediated overexpression of CYP2J2 blocked blood pressure increase in spontaneously hypertensive rats (Xiao et al., 2010). In addition, the in vivo delivery of the homologous gene of CYP2J2 expressed mainly in rats, CYP2J3, enhanced EET level and reduced blood pressure in fructose-treated rats (Xu et al., 2010). EETs can potentially affect blood pressure through various mechanisms. These include modulation of the expression and activity of ion channels directly involved in the vasculature function and regulation of renal sodium excretion such as inwardly rectifying K channels, BK channels, or epithelial sodium channels (ENaCs) (Wang et al., 2008). BK channels, when activated, have been reported to cause hyperpolarization and relaxation of vascular smooth muscle cells (Ye et al., 2002). In addition to modulating the basal blood pressure, EETs can act via the modulation of the renin-angiotensin system. For example, sEH inhibitors showed their efficacy in hypertension associated with activation of the renin-angiotensin system (Imig, 2012). This is related to angiotensin II being a potent vasoconstrictor and a powerful inducer of sEH expression in the rat vasculature (Ai et al., 2007) as well as the rat heart (Ai et al., 2009). Recently, direct administration of EET analogs has been shown to demonstrate cardiovascular therapeutic potential when administered in vivo. One such compound is an 11,12-EET analog that was shown to lower blood pressure in spontaneously hypertensive rats (Sudhahar et al., 2010). Another compound is disodium (S)-2-(13-(3-pentyl)ureido)-tridec-8(Z)-enamido) succinate (EET-A), which demonstrated a direct vasodilatory effect and attenuated the development of hypertension in angiotensin II-infused rats (Červenka et al., 2018; Sporkova et al., 2017). Furthermore, EET-A has proven its effectiveness in experimental angiotensin II-dependent malignant hypertension, and attenuation of end-organ damage as a result of elevated pressure (Jichova et al., 2016).
Arsenic, cadmium, and mercury-induced hypertension: mechanisms and epidemiological findings
Published in Journal of Toxicology and Environmental Health, Part B, 2018
Airton da Cunha Martins, Maria Fernanda Hornos Carneiro, Denise Grotto, Joseph A Adeyemi, Fernando Barbosa
In the same vein, As also affects contractile function in vascular smooth muscle (De Lanerolle and Paul 1991). Following phenylephrine-induced contraction, serotonin (5-HT) and/or high concentrations of potassium ions (K+) were measured as well as the mechanisms involved such as mediation by myosin light chain (MLC) phosphorylation and intracellular Ca ions influx. Vascular smooth muscle contraction occurs due to a sudden rise in intracellular free Ca2+ ions, which bind to calmodulin, resulting in a complex of Ca-calmodulin. The complex then activates myosin light chain kinase which further phosphorylates MLC resulting in vasoconstriction (De Lanerolle and Paul 1991). Lee et al. (2005) showed that As3+ enhanced vascular contraction induced by phenylephrine, 5_HT, and high K+ in a concentration-dependent manner. However, a difference regarding the mode of action was considered. Phenylephrine and 5-HT act on the α1-adrenoceptor and the 5-HT2 serotonin receptor, respectively, resulting in increases in intracellular Ca2+ levels, formation of the Ca–calmodulin complex, activation of MLC kinase and phosphorylation of MLC. High concentrations of K+, in turn, are associated with a direct elevation in intracellular Ca2+ concentrations by opening Ca2+ channels due to membrane depolarization. Although Lee et al. (2005) reported the As-induced hypercontraction effect stimulated by phenylephrine as evidenced by MLC phosphorylation, direct Ca2+ measurement also showed that As potentiated vasoconstriction induced by high K+ levels. Therefore, data suggested that, rather than direct increases in Ca2+ levels, Ca2+ sensitization may be a major contributor to the enhanced vasoconstriction induced by As. Further As-enhanced contraction is primarily due to hypercontraction of smooth muscle, since the contraction noted in aortic rings occurred without endothelium (Lee et al. 2005).