{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:29:10Z","timestamp":1760243350771,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2014,9,11]],"date-time":"2014-09-11T00:00:00Z","timestamp":1410393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"funder":[{"name":"Canadian Institute of Health Reseaerch"},{"DOI":"10.13039\/501100000194","name":"Nova Scotia Health Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000194","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dalhousie Pharmacy Endowment Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>The benefit of calcium channel blockers for cardiovascular prevention against heart attack and stroke has not been firmly supported. We investigated the possible cardiovascular protective effect of diltiazem (DTZ) against injury induced by isoproterenol using a freely moving rat model in vivo. Sprague Dawley rats were injected subcutaneously (sc) with either 5 or 10 mg\/kg of DTZ, or saline as control, twice daily for five doses. One hour after the last injection, a single dose of isoproterenol (30 mg\/kg) was injected sc to each rat. Blood samples were collected serially for 6 h for measurement of adenine nucleotides (ATP, ADP and AMP) in red blood cell (RBC) by a validated HPLC. The study has shown isoproterenol induced 50% mortality and also increased RBC concentrations of AMP from 0.04 \u00b1 0.02 to 0.29 \u00b1 0.21 mM at the end of the experiment (p &lt; 0.05). Treatment with 10 mg\/kg of DTZ reduced mortality from 50% to &lt;20% and attenuated the increase of RBC concentrations of AMP from +0.25 \u00b1 0.22 in the control rats to +0.072 \u00b1 0.092 mM (p &lt; 0.05). The study concluded that 10 mg\/kg of DTZ reduced mortality and breakdown of ATP induced by isoproterenol in rats.<\/jats:p>","DOI":"10.3390\/metabo4030775","type":"journal-article","created":{"date-parts":[[2014,9,11]],"date-time":"2014-09-11T12:04:41Z","timestamp":1410437081000},"page":"775-789","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Diltiazem Reduces Mortality and Breakdown of ATP in Red Blood Cell Induced by Isoproterenol in a Freely Moving Rat Model in Vivo"],"prefix":"10.3390","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0517-104X","authenticated-orcid":false,"given":"Pollen","family":"Yeung","sequence":"first","affiliation":[{"name":"Pharmacokinetics and Metabolism Laboratory, College of Pharmacy and Department of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaolin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, 5788 University Ave., Halifax, NS B3H 1V8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dena","family":"Seeto","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and Metabolism Laboratory, College of Pharmacy and Department of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3810\/pgm.2011.01.2249","article-title":"Long-term blood pressure control: What can we do?","volume":"123","author":"Neutel","year":"2011","journal-title":"Postgrad. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mallat, S.G. (2012). What is a preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment?. Cardiovasc. Diabetol., 11.","DOI":"10.1186\/1475-2840-11-32"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1185\/03007995.2010.510925","article-title":"Combinations of inhibitors of the renin-angiotensin system with calcium channel blockers for the treatment of hypertension: Focus on perindopril\/amlodipine","volume":"26","author":"Mourad","year":"2010","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_4","first-page":"38","article-title":"[Calcium antagonists: Current and future applications based on new evidence. Effects of calcium channel blockers on oxidative stress]","volume":"20","author":"Nishiyama","year":"2010","journal-title":"Clin. Calcium."},{"key":"ref_5","first-page":"69","article-title":"Calcium antagonists: Current and future applications based on new evidence. Pleiotropic effects of calcium channel blockers on vascular endothelial function","volume":"20","author":"Morimoto","year":"2010","journal-title":"Clin. Calcium."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/j.1524-6175.2004.03683.x","article-title":"The Role of Existing and Newer Calcium Channel Blockers in the Treatment of Hypertension","volume":"6","author":"Basile","year":"2004","journal-title":"J. Clin. Hypertens."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/sj.jhh.1001972","article-title":"The importance of early antihypertensive efficacy: The role of angiotensin II receptor blocker therapy","volume":"20","author":"Basile","year":"2006","journal-title":"J. Hum. Hypertens."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"573","DOI":"10.2165\/11532980-000000000-00000","article-title":"Dipeptidylpeptidase-4 inhibitors (gliptins): Focus on drug-drug interactions","volume":"49","author":"Scheen","year":"2010","journal-title":"Clin. Pharmacokinet."},{"key":"ref_9","first-page":"525","article-title":"Influence of grapefruit juice on the pharmacokinetics of diltiazem in Wistar rats upon single and multiple dosage regimens","volume":"64","author":"Boddu","year":"2009","journal-title":"Pharmazie"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.2042-7158.2010.01160.x","article-title":"Effects of lovastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats: Possible role of cytochrome P450 3A4 and P-glycoprotein inhibition by lovastatin","volume":"63","author":"Hong","year":"2011","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1515\/DMDI.2011.012","article-title":"Comparing Pharmacokinetics and Metabolism of Diltiazem in Normotensive Sprague Dawley and Wistar Kyoto Rats vs. Spontaneously Hypertensive Rats in vivo","volume":"26","author":"Yeung","year":"2011","journal-title":"Drug Metab. Drug Interact."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/j.1751-7176.2011.00513.x","article-title":"Calcium channel blockers","volume":"13","author":"Elliott","year":"2011","journal-title":"J. Clin. Hypertens. (Greenwich)"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1469-7580.2011.01373.x","article-title":"Novel morphological features of developing white matter pericytes and rapid scavenging of reactive oxygen species in the neighbouring endothelia","volume":"219","author":"Quimby","year":"2011","journal-title":"J. Anat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1097\/QCO.0b013e3283463e5b","article-title":"Calcium channel blockers and modulation of innate immunity","volume":"24","author":"Liu","year":"2011","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.2174\/1874073100903010056","article-title":"Pharmacokinetics and hemodynamic effects of diltiazem in rats following single vs. multiple doses in vivo","volume":"3","author":"Yeung","year":"2009","journal-title":"Open Drug Metab. J."},{"key":"ref_16","first-page":"39","article-title":"Hemodynamic effects of diltiazem in spontaneously hypertensive rats vs. normotensive rats following multiple doses in vivo","volume":"12","author":"Yeung","year":"2008","journal-title":"Curr. Top. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1111\/j.2042-7158.1991.tb03458.x","article-title":"Effect of diltiazem and its metabolites on the uptake of adenosine in blood: An in-vitro investigation","volume":"43","author":"Yeung","year":"1991","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s00395-007-0687-7","article-title":"Adenosine: Trigger and mediator of cardioprotection","volume":"103","author":"Cohen","year":"2008","journal-title":"Basic Res. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ejheart.2005.07.012","article-title":"Diltiazem treatment prevents diastolic heart failure in mice with familial hypertrophic cardiomyopathy","volume":"8","author":"Westermann","year":"2006","journal-title":"Eur. J. Heart Fail"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"102","DOI":"10.4172\/2329-6607.1000102","article-title":"A study of the effect of isoproterenol on red blood cell concentrations of adenine nucleotides in a freely moving rat model in vivo","volume":"2","author":"Yeung","year":"2013","journal-title":"Cardiovas. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1177\/1753944710387809","article-title":"Exercise improves hemodynamic profiles and increases red blood cell concentrations of purine nucleotides in a rodent model","volume":"4","author":"Yeung","year":"2010","journal-title":"Ther. Adv. Cardiovasc. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1211\/jpp.61.01.0011","article-title":"Increased sensitivity to diltiazem hypotensive effect in an experimental model of high-renin hypertension","volume":"61","author":"Bertera","year":"2009","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"554","DOI":"10.3109\/13547500903131698","article-title":"Cladribine inhibits a diltiazem-induced increase in red blood cell purine nucleotide concentrations in a zebrafish model","volume":"14","author":"Klein","year":"2009","journal-title":"Biomarkers"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jpba.2008.01.020","article-title":"HPLC assay with UV detection for determination of RBC purine nucleotides concentrations and application for biomarker study in vivo","volume":"47","author":"Yeung","year":"2008","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1874073101105010001","article-title":"Anti-Ischemia Drugs have no Effect on the In Vivo Metabolism of ATP by RBC in Normotensive Restrained Rats","volume":"5","author":"Yeung","year":"2011","journal-title":"Open Drug Metab. J."},{"key":"ref_26","first-page":"H593","article-title":"Erythrocyte adenosine transport: Effects of Ca2+ channel antagonists and ions","volume":"248","author":"Ford","year":"1985","journal-title":"Am. J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/1056-8719(93)90041-C","article-title":"Erythrocyte adenosine transport: A rapid screening test for cardiovascular drugs","volume":"30","author":"Yeung","year":"1993","journal-title":"J. Pharmacol. Meth."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S0022-2828(88)80136-6","article-title":"Diltiazem and verapamil reduce the loss of adenine nucleotide metabolites from hypoxic hearts","volume":"20","author":"Takeo","year":"1988","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1093\/cvr\/27.1.68","article-title":"Nucleoside transport inhibition: A therapeutic approach to cardioprotection via adenosine ?","volume":"27","year":"1993","journal-title":"Cardiovas. Res"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/978-1-4615-5381-6_18","article-title":"Effects of nucleoside transport inhibitors and adenine\/ribose on ATP concentration and adenosine production in cardiac myocytes","volume":"431","author":"Kalsi","year":"1998","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1046\/j.1365-201x.2000.00708.x","article-title":"The red blood cell as an oxygen sensor: What is the evidence?","volume":"168","author":"Ellsworth","year":"2000","journal-title":"Acta Physiol. Scand."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3387","DOI":"10.1242\/jeb.023697","article-title":"The dual roles of red blood cells in tissue oxygen delivery: Oxygen carriers and regulators of local blood flow","volume":"212","author":"Jensen","year":"2009","journal-title":"J. Exp. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/cvr\/26.1.40","article-title":"Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia","volume":"26","author":"Bergfeld","year":"1992","journal-title":"Cardiovasc. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1086\/651584","article-title":"First aid kit for hypoxic survival: Sensors and strategies","volume":"83","author":"Nurse","year":"2010","journal-title":"Physiol. Biochem. Zool."},{"key":"ref_35","unstructured":"eCPS (2014). Compendium of Pharmaceuticals and Speccialties, Canadian Pharmaceutical Association."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/S0090-9556(25)08666-0","article-title":"Species comparison of pharmacokinetics and metabolism of diltiazem in humans, dogs, rabbits, and rats","volume":"18","author":"Yeung","year":"1990","journal-title":"Drug Met. Disp."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3389\/fphys.2013.00321","article-title":"Adrenoreceptors and nitric oxide in the cardiovascular system","volume":"4","author":"Conti","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"314","DOI":"10.3389\/fphys.2013.00314","article-title":"Cardiovascular reactivity, stress, and physical activity","volume":"4","author":"Huang","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.ahj.2007.11.001","article-title":"Associations Between Neurohormonal and Inflammatory Activation and Heart Failure in Children","volume":"155","author":"Ratnasamy","year":"2008","journal-title":"Am. Heart J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1097\/00004872-199816090-00017","article-title":"Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients","volume":"16","author":"Karas","year":"1998","journal-title":"J. Hypertens."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/S0002-9149(97)00722-4","article-title":"Effect of calcium antagonists on plasma norepinephrine levels, heart rate, and blood pressure","volume":"80","author":"Grossman","year":"1997","journal-title":"Am. J. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1097\/00004872-200018120-00023","article-title":"Effects of different dihydropyridine calcium antagonists on plasma norepinephrine in essential hypertension","volume":"18","author":"Fogari","year":"2000","journal-title":"J. Hypertens."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1177\/1753944710387809","article-title":"Exercise improves hemodynamic profiles and increases red blood cell concentrations of purine nucleotides in a rodent model","volume":"4","author":"Yeung","year":"2010","journal-title":"Ther. Adv. Cardiovasc. Dis."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/4\/3\/775\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:15:50Z","timestamp":1760217350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/4\/3\/775"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,11]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,9]]}},"alternative-id":["metabo4030775"],"URL":"https:\/\/doi.org\/10.3390\/metabo4030775","relation":{},"ISSN":["2218-1989"],"issn-type":[{"type":"electronic","value":"2218-1989"}],"subject":[],"published":{"date-parts":[[2014,9,11]]}}}