Benzodiazepines: An Old Class of New Antihypertensive Drugs?

Benzodiazepines: An Old Class of New Antihypertensive Drugs? The role of the γ-aminobutyric acid (GABA) signaling in blood pressure regulation is complex and only partially characterized. Old studies on anesthetized animals reported that GABA injection in the central nervous system (CNS) decreased blood pressure, heart rate, and renal sympathetic nerve activity,1 but did not attenuate blood pressure elevation induced by a salt load.2 Other studies demonstrated that the GABAergic activity of different areas of the CNS could affect the neural regulation of blood pressure through sympathoinhibitory signals and that stimulation of GABA-type A receptors in the posterior hypothalamus of spontaneously hypertensive rats decreased blood pressure more than in control animals (Wistar-Kyoto rats).3 The GABAA-receptors are chloride ion channels whose major function is inhibition of neurotransmission in specific areas of the CNS of vertebrates. Benzodiazepines (BDZ) potentiate the inhibitory effect of GABA in the CNS by binding to GABAA-receptor subunits and increasing the GABA ligand-receptor affinity.4 Although BDZ are mainly used in the clinic as anxiolytic and hypnotic drugs, they possess also myorelaxant and vasodilatory effects.5 In an experimental setting, we investigated the vascular effects of midazolam, a short-acting BDZ, on mouse aortic rings. Midazolam induced a reversible vasodilatation of aortic rings that were precontracted with the adrenergic alpha-receptor agonist phenylephrine and a hyperpolarizing solution of potassium chloride. This vasodilatory effect of midazolam was endothelium-dependent at low drug concentrations, whereas at high concentrations endothelial contribution to vasodilatation was irrelevant, being this vascular response a likely result of changes in the activity of voltage-dependent calcium channels.6 In addition to the GABAA-receptor in the CNS, BDZ can bind the 18 kDa translocator protein (TPSO), formerly known as peripheral-type BDZ receptor. The TPSO is located primarily in mitochondria where it is directly involved in the process of steroidogenesis7 and, as such, plays a role in a variety of cellular functions (mitochondrial respiration, response to stress, regulation of voltage-dependent calcium channels, activation of microglia) and events (apoptosis, proliferation, inflammation).8 TPSO is also abundantly distributed in cardiovascular tissues, being involved in the myocardial response to ischemia9 and possibly explaining the endothelium-independent vasodilatory effect of BDZ.10 Consistent with these observations, BDZ were shown to acutely decrease the sympathetic tone and blood pressure values in healthy volunteers11 and in patients undergoing surgery.12 Moreover, 2 randomized controlled trials have demonstrated that BDZ are as effective as angiotensin-converting enzyme inhibitors in the treatment of hypertensive urgencies in the emergency department.13,14 Thus, initial observations obtained in controlled studies suggest potential benefits of BDZ in the setting of acute treatment of hypertension. Conversely, no data on the possible effects of BDZ in the treatment of chronic hypertension are available. The retrospective study of Mendelson et al. published in this issue of the Journal15 provides some insight on this subject reporting significantly lower blood pressure levels in chronic users of BDZ in comparison to subjects who had never taken these drugs. In this study, 4,983 ambulatory blood pressure profiles (ABPM) that had been collected over a 7-year period in subjects representative of the adult population in the Negev region of Israel were analyzed. Five-hundred-twenty-four subjects had regularly used different types of BDZ for at least 3 months before ABPM as ascertained by check of electronic records of drugs purchased in pharmacies. These subjects’ demographics were significantly different from those of 3,581 subjects who did not purchase BDZ prior to ABPM measurement inasmuch as they were older and more frequently females. Also, subjects treated with BDZ were more frequently diabetics and had significantly heavier use of antihypertensive medications than untreated subjects. In a multivariate linear analysis that was adjusted for age, sex, presence of diabetes, and number of antihypertensive drugs, BDZ treatment was independently associated with lower systolic and diastolic blood pressure over 24 hours, daytime, and nighttime. No differences in blood pressure profiles were detected between long- and short-acting BDZ and stratification of the study population according to age revealed that the association of BDZ use with lower blood pressure was present only in subjects older than 60 years. Longitudinal analysis of overall mortality and major cardiovascular events over an average follow-up of 42.4 months did not show any difference in the outcome of subjects treated with BDZ from that of untreated subjects. Strengths of this study are the high statistical power for detection of even a small effect of chronic BDZ use on blood pressure and use of 24-hour ABPM for blood pressure assessment. Conversely, data on subgrouping by age are somehow misleading because of the low number of BDZ users younger than 60 years included in the study, while analysis on continuous variables showed an effect of BDZ use on blood pressure that was independent of age. This discrepancy might be explained by a low statistical power for detection of a difference between BDZ users and nonusers in the younger group. Also, no information on the rate of blood pressure normalization in patients with hypertension included in the study was reported that would have been useful to better define the impact of BDZ use on blood pressure control. Finally, duration of the longitudinal analysis of outcome for a population with a mean age of 58 years and a relatively low cardiovascular risk might have been too short. Taken together, findings of the study of Mendelson et al. and previous studies on use of BDZ in hypertensive urgencies suggest that these old drugs might be formally included among the therapeutic tools in use for hypertension treatment. Indirect evidence of these potential benefits of BDZ on blood pressure came from a study conducted in Taiwan on patients with myocardial infarction who were followed for 4.8 years and in whom use of BDZ reduced significantly the rate of cardiac mortality and heart failure hospitalization.16 On the other hand, potential threats of indiscriminate use of BDZ, in particular in the elderly population, should not be overlooked. A recent meta-analysis including 25 observational studies enrolling more than 2 million subjects on the effect of generic anxiolytic and hypnotic drugs on mortality showed a significantly increased risk (by 43%) that was more evident in the subgroup of patients treated with BDZ (hazard ratio 1.60, 95% confidence interval 1.03–2.49).17 Additional risks of BDZ use that are particularly relevant in the elderly population include drug dependence, respiratory depression when used in concomitance with opioids, alcohol, and barbiturates, memory deficits, depression and suicidal tendency,18 likelihood of falls and fractures17 and have been appropriately discussed in the study of Mendelson et al. Some of these side effects of BDZ, such as falls, might be related to excess reduction of blood pressure and it would have been interesting to know how many BDZ users among those studied by Mendelson et al. had developed hypotension. In conclusion, although BDZ might represent a useful tool to minimize the access of patients with hypertensive urgencies to the emergency department,19 use of these drugs for chronic treatment of arterial hypertension is far to be advisable at all ages. More prospective interventional studies testing different BDZ molecules and doses are needed to evaluate the effects of BDZ use on hypertension and cardiovascular outcomes. Further insight on the mechanisms by which BDZ reduce blood pressure might help to develop new molecules with antihypertensive properties and less side effects. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Antonaccio MJ, Taylor DG. Involvement of central GABA receptors in the regulation of blood pressure and heart rate of anesthetized cats. Eur J Pharmacol  1977; 46: 283– 287. Google Scholar CrossRef Search ADS PubMed  2. Kimura T, Yamamoto T, Ota K, Shoji M, Inoue M, Ohta M, Sato K, Funyu T, Abe K. The roles of GABA in the central regulation of AVP and ANP release and blood pressure in hypertonic saline infusion and hemorrhage. J Auton Nerv Syst  1993; 43: 171– 178. Google Scholar CrossRef Search ADS PubMed  3. Wible JHJr, DiMicco JA, Luft FC. Hypothalamic GABA and sympathetic regulation in spontaneously hypertensive rats. Hypertension  1989; 14: 623– 628. Google Scholar CrossRef Search ADS PubMed  4. Gielen MC, Lumb MJ, Smart TG. Benzodiazepines modulate GABAA receptors by regulating the preactivation step after GABA binding. J Neurosci  2012; 32: 5707– 5715. Google Scholar CrossRef Search ADS PubMed  5. Klockgether-Radke AP, Pawlowski P, Neumann P, Hellige G. Mechanisms involved in the relaxing effect of midazolam on coronary arteries. Eur J Anaesthesiol  2005; 22: 135– 139. Google Scholar CrossRef Search ADS PubMed  6. Colussi GL, Di Fabio A, Catena C, Chiuch A, Sechi LA. Involvement of endothelium-dependent and -independent mechanisms in midazolam-induced vasodilation. Hypertens Res  2011; 34: 929– 934. Google Scholar CrossRef Search ADS PubMed  7. Papadopoulos V, Widmaier EP, Amri H, Zilz A, Li H, Culty M, Castello R, Philip GH, Sridaran R, Drieu K. In vivo studies on the role of the peripheral benzodiazepine receptor (PBR) in steroidogenesis. Endocr Res  1998; 24: 479– 487. Google Scholar CrossRef Search ADS PubMed  8. Veenman L, Gavish M. The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development. Pharmacol Ther  2006; 110: 503– 524. Google Scholar CrossRef Search ADS PubMed  9. Musman J, Paradis S, Panel M, Pons S, Barau C, Caccia C, Leoni V, Ghaleh B, Morin D. A TSPO ligand prevents mitochondrial sterol accumulation and dysfunction during myocardial ischemia-reperfusion in hypercholesterolemic rats. Biochem Pharmacol  2017; 142: 87– 95. Google Scholar CrossRef Search ADS PubMed  10. Erne P, Chiesi M, Longoni S, Fulbright J, Hermsmeyer K. Relaxation of rat vascular muscle by peripheral benzodiazepine modulators. J Clin Invest  1989; 84: 493– 498. Google Scholar CrossRef Search ADS PubMed  11. Kitajima T, Kanbayashi T, Saito Y, Takahashi Y, Ogawa Y, Sugiyama T, Kaneko Y, Aizawa R, Shimizu T. Diazepam reduces both arterial blood pressure and muscle sympathetic nerve activity in human. Neurosci Lett  2004; 355: 77– 80. Google Scholar CrossRef Search ADS PubMed  12. Gupta R, Santha N, Upadya M, Manissery JJ. Effect of different dosages of intravenous midazolam premedication on patients undergoing head and neck surgeries—A Double Blinded Randomized Controlled Study. J Clin Diagn Res  2017; 11: UC01– UC04. 13. Grossman E, Nadler M, Sharabi Y, Thaler M, Shachar A, Shamiss A. Antianxiety treatment in patients with excessive hypertension. Am J Hypertens  2005; 18: 1174– 1177. Google Scholar CrossRef Search ADS PubMed  14. Yilmaz S, Pekdemir M, Tural U, Uygun M. Comparison of alprazolam versus captopril in high blood pressure: a randomized controlled trial. Blood Press  2011; 20: 239– 243. Google Scholar CrossRef Search ADS PubMed  15. Mendelson N, Gontmacher B, Vodonos A, Novack V, Abu-AjAj M, Wolak A, Shalev H, Wolak T. Benzodiazepine consumption is associated with lower blood pressure in ambulatory blood pressure monitoring (ABPM): retrospective analysis of 4938 ABPMs. Am J Hypertens  2018; 31: 431– 437. Google Scholar CrossRef Search ADS   16. Wu CK, Huang YT, Lee JK, Jimmy Juang JM, Tsai CT, Lai LP, Hwang JJ, Chiang FT, Lin JL, Chen PC, Lin LY. Anti-anxiety drugs use and cardiovascular outcomes in patients with myocardial infarction: a national wide assessment. Atherosclerosis  2014; 235: 496– 502. Google Scholar CrossRef Search ADS PubMed  17. Parsaik AK, Mascarenhas SS, Khosh-Chashm D, Hashmi A, John V, Okusaga O, Singh B. Mortality associated with anxiolytic and hypnotic drugs-a systematic review and meta-analysis. Aust N Z J Psychiatry  2016; 50: 520– 533. Google Scholar CrossRef Search ADS PubMed  18. Lader M. Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol  2014; 77: 295– 301. Google Scholar CrossRef Search ADS PubMed  19. Tandeter H. Hypothesis: a single dose of an anxiolitic may prevent unnecessary visits to the emergency room during blood pressure elevations. Med Hypotheses  2016; 88: 35– 37. Google Scholar CrossRef Search ADS PubMed  © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

Benzodiazepines: An Old Class of New Antihypertensive Drugs?

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Abstract

The role of the γ-aminobutyric acid (GABA) signaling in blood pressure regulation is complex and only partially characterized. Old studies on anesthetized animals reported that GABA injection in the central nervous system (CNS) decreased blood pressure, heart rate, and renal sympathetic nerve activity,1 but did not attenuate blood pressure elevation induced by a salt load.2 Other studies demonstrated that the GABAergic activity of different areas of the CNS could affect the neural regulation of blood pressure through sympathoinhibitory signals and that stimulation of GABA-type A receptors in the posterior hypothalamus of spontaneously hypertensive rats decreased blood pressure more than in control animals (Wistar-Kyoto rats).3 The GABAA-receptors are chloride ion channels whose major function is inhibition of neurotransmission in specific areas of the CNS of vertebrates. Benzodiazepines (BDZ) potentiate the inhibitory effect of GABA in the CNS by binding to GABAA-receptor subunits and increasing the GABA ligand-receptor affinity.4 Although BDZ are mainly used in the clinic as anxiolytic and hypnotic drugs, they possess also myorelaxant and vasodilatory effects.5 In an experimental setting, we investigated the vascular effects of midazolam, a short-acting BDZ, on mouse aortic rings. Midazolam induced a reversible vasodilatation of aortic rings that were precontracted with the adrenergic alpha-receptor agonist phenylephrine and a hyperpolarizing solution of potassium chloride. This vasodilatory effect of midazolam was endothelium-dependent at low drug concentrations, whereas at high concentrations endothelial contribution to vasodilatation was irrelevant, being this vascular response a likely result of changes in the activity of voltage-dependent calcium channels.6 In addition to the GABAA-receptor in the CNS, BDZ can bind the 18 kDa translocator protein (TPSO), formerly known as peripheral-type BDZ receptor. The TPSO is located primarily in mitochondria where it is directly involved in the process of steroidogenesis7 and, as such, plays a role in a variety of cellular functions (mitochondrial respiration, response to stress, regulation of voltage-dependent calcium channels, activation of microglia) and events (apoptosis, proliferation, inflammation).8 TPSO is also abundantly distributed in cardiovascular tissues, being involved in the myocardial response to ischemia9 and possibly explaining the endothelium-independent vasodilatory effect of BDZ.10 Consistent with these observations, BDZ were shown to acutely decrease the sympathetic tone and blood pressure values in healthy volunteers11 and in patients undergoing surgery.12 Moreover, 2 randomized controlled trials have demonstrated that BDZ are as effective as angiotensin-converting enzyme inhibitors in the treatment of hypertensive urgencies in the emergency department.13,14 Thus, initial observations obtained in controlled studies suggest potential benefits of BDZ in the setting of acute treatment of hypertension. Conversely, no data on the possible effects of BDZ in the treatment of chronic hypertension are available. The retrospective study of Mendelson et al. published in this issue of the Journal15 provides some insight on this subject reporting significantly lower blood pressure levels in chronic users of BDZ in comparison to subjects who had never taken these drugs. In this study, 4,983 ambulatory blood pressure profiles (ABPM) that had been collected over a 7-year period in subjects representative of the adult population in the Negev region of Israel were analyzed. Five-hundred-twenty-four subjects had regularly used different types of BDZ for at least 3 months before ABPM as ascertained by check of electronic records of drugs purchased in pharmacies. These subjects’ demographics were significantly different from those of 3,581 subjects who did not purchase BDZ prior to ABPM measurement inasmuch as they were older and more frequently females. Also, subjects treated with BDZ were more frequently diabetics and had significantly heavier use of antihypertensive medications than untreated subjects. In a multivariate linear analysis that was adjusted for age, sex, presence of diabetes, and number of antihypertensive drugs, BDZ treatment was independently associated with lower systolic and diastolic blood pressure over 24 hours, daytime, and nighttime. No differences in blood pressure profiles were detected between long- and short-acting BDZ and stratification of the study population according to age revealed that the association of BDZ use with lower blood pressure was present only in subjects older than 60 years. Longitudinal analysis of overall mortality and major cardiovascular events over an average follow-up of 42.4 months did not show any difference in the outcome of subjects treated with BDZ from that of untreated subjects. Strengths of this study are the high statistical power for detection of even a small effect of chronic BDZ use on blood pressure and use of 24-hour ABPM for blood pressure assessment. Conversely, data on subgrouping by age are somehow misleading because of the low number of BDZ users younger than 60 years included in the study, while analysis on continuous variables showed an effect of BDZ use on blood pressure that was independent of age. This discrepancy might be explained by a low statistical power for detection of a difference between BDZ users and nonusers in the younger group. Also, no information on the rate of blood pressure normalization in patients with hypertension included in the study was reported that would have been useful to better define the impact of BDZ use on blood pressure control. Finally, duration of the longitudinal analysis of outcome for a population with a mean age of 58 years and a relatively low cardiovascular risk might have been too short. Taken together, findings of the study of Mendelson et al. and previous studies on use of BDZ in hypertensive urgencies suggest that these old drugs might be formally included among the therapeutic tools in use for hypertension treatment. Indirect evidence of these potential benefits of BDZ on blood pressure came from a study conducted in Taiwan on patients with myocardial infarction who were followed for 4.8 years and in whom use of BDZ reduced significantly the rate of cardiac mortality and heart failure hospitalization.16 On the other hand, potential threats of indiscriminate use of BDZ, in particular in the elderly population, should not be overlooked. A recent meta-analysis including 25 observational studies enrolling more than 2 million subjects on the effect of generic anxiolytic and hypnotic drugs on mortality showed a significantly increased risk (by 43%) that was more evident in the subgroup of patients treated with BDZ (hazard ratio 1.60, 95% confidence interval 1.03–2.49).17 Additional risks of BDZ use that are particularly relevant in the elderly population include drug dependence, respiratory depression when used in concomitance with opioids, alcohol, and barbiturates, memory deficits, depression and suicidal tendency,18 likelihood of falls and fractures17 and have been appropriately discussed in the study of Mendelson et al. Some of these side effects of BDZ, such as falls, might be related to excess reduction of blood pressure and it would have been interesting to know how many BDZ users among those studied by Mendelson et al. had developed hypotension. In conclusion, although BDZ might represent a useful tool to minimize the access of patients with hypertensive urgencies to the emergency department,19 use of these drugs for chronic treatment of arterial hypertension is far to be advisable at all ages. More prospective interventional studies testing different BDZ molecules and doses are needed to evaluate the effects of BDZ use on hypertension and cardiovascular outcomes. Further insight on the mechanisms by which BDZ reduce blood pressure might help to develop new molecules with antihypertensive properties and less side effects. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Antonaccio MJ, Taylor DG. Involvement of central GABA receptors in the regulation of blood pressure and heart rate of anesthetized cats. Eur J Pharmacol  1977; 46: 283– 287. Google Scholar CrossRef Search ADS PubMed  2. Kimura T, Yamamoto T, Ota K, Shoji M, Inoue M, Ohta M, Sato K, Funyu T, Abe K. The roles of GABA in the central regulation of AVP and ANP release and blood pressure in hypertonic saline infusion and hemorrhage. J Auton Nerv Syst  1993; 43: 171– 178. Google Scholar CrossRef Search ADS PubMed  3. Wible JHJr, DiMicco JA, Luft FC. Hypothalamic GABA and sympathetic regulation in spontaneously hypertensive rats. Hypertension  1989; 14: 623– 628. Google Scholar CrossRef Search ADS PubMed  4. Gielen MC, Lumb MJ, Smart TG. Benzodiazepines modulate GABAA receptors by regulating the preactivation step after GABA binding. J Neurosci  2012; 32: 5707– 5715. Google Scholar CrossRef Search ADS PubMed  5. Klockgether-Radke AP, Pawlowski P, Neumann P, Hellige G. Mechanisms involved in the relaxing effect of midazolam on coronary arteries. Eur J Anaesthesiol  2005; 22: 135– 139. Google Scholar CrossRef Search ADS PubMed  6. Colussi GL, Di Fabio A, Catena C, Chiuch A, Sechi LA. Involvement of endothelium-dependent and -independent mechanisms in midazolam-induced vasodilation. Hypertens Res  2011; 34: 929– 934. Google Scholar CrossRef Search ADS PubMed  7. Papadopoulos V, Widmaier EP, Amri H, Zilz A, Li H, Culty M, Castello R, Philip GH, Sridaran R, Drieu K. In vivo studies on the role of the peripheral benzodiazepine receptor (PBR) in steroidogenesis. Endocr Res  1998; 24: 479– 487. Google Scholar CrossRef Search ADS PubMed  8. Veenman L, Gavish M. The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development. Pharmacol Ther  2006; 110: 503– 524. Google Scholar CrossRef Search ADS PubMed  9. Musman J, Paradis S, Panel M, Pons S, Barau C, Caccia C, Leoni V, Ghaleh B, Morin D. A TSPO ligand prevents mitochondrial sterol accumulation and dysfunction during myocardial ischemia-reperfusion in hypercholesterolemic rats. Biochem Pharmacol  2017; 142: 87– 95. Google Scholar CrossRef Search ADS PubMed  10. Erne P, Chiesi M, Longoni S, Fulbright J, Hermsmeyer K. Relaxation of rat vascular muscle by peripheral benzodiazepine modulators. J Clin Invest  1989; 84: 493– 498. Google Scholar CrossRef Search ADS PubMed  11. Kitajima T, Kanbayashi T, Saito Y, Takahashi Y, Ogawa Y, Sugiyama T, Kaneko Y, Aizawa R, Shimizu T. Diazepam reduces both arterial blood pressure and muscle sympathetic nerve activity in human. Neurosci Lett  2004; 355: 77– 80. Google Scholar CrossRef Search ADS PubMed  12. Gupta R, Santha N, Upadya M, Manissery JJ. Effect of different dosages of intravenous midazolam premedication on patients undergoing head and neck surgeries—A Double Blinded Randomized Controlled Study. J Clin Diagn Res  2017; 11: UC01– UC04. 13. Grossman E, Nadler M, Sharabi Y, Thaler M, Shachar A, Shamiss A. Antianxiety treatment in patients with excessive hypertension. Am J Hypertens  2005; 18: 1174– 1177. Google Scholar CrossRef Search ADS PubMed  14. Yilmaz S, Pekdemir M, Tural U, Uygun M. Comparison of alprazolam versus captopril in high blood pressure: a randomized controlled trial. Blood Press  2011; 20: 239– 243. Google Scholar CrossRef Search ADS PubMed  15. Mendelson N, Gontmacher B, Vodonos A, Novack V, Abu-AjAj M, Wolak A, Shalev H, Wolak T. Benzodiazepine consumption is associated with lower blood pressure in ambulatory blood pressure monitoring (ABPM): retrospective analysis of 4938 ABPMs. Am J Hypertens  2018; 31: 431– 437. Google Scholar CrossRef Search ADS   16. Wu CK, Huang YT, Lee JK, Jimmy Juang JM, Tsai CT, Lai LP, Hwang JJ, Chiang FT, Lin JL, Chen PC, Lin LY. Anti-anxiety drugs use and cardiovascular outcomes in patients with myocardial infarction: a national wide assessment. Atherosclerosis  2014; 235: 496– 502. Google Scholar CrossRef Search ADS PubMed  17. Parsaik AK, Mascarenhas SS, Khosh-Chashm D, Hashmi A, John V, Okusaga O, Singh B. Mortality associated with anxiolytic and hypnotic drugs-a systematic review and meta-analysis. Aust N Z J Psychiatry  2016; 50: 520– 533. Google Scholar CrossRef Search ADS PubMed  18. Lader M. Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol  2014; 77: 295– 301. Google Scholar CrossRef Search ADS PubMed  19. Tandeter H. Hypothesis: a single dose of an anxiolitic may prevent unnecessary visits to the emergency room during blood pressure elevations. Med Hypotheses  2016; 88: 35– 37. Google Scholar CrossRef Search ADS PubMed  © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

American Journal of HypertensionOxford University Press

Published: Apr 1, 2018

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