title: Discrepant regulation of QT (QTc) interval duration by calcium channel blockade and angiotensin converting enzyme inhibition in experimental hypertension.
abstract: Antihypertensive treatment may reduce prolonged QT duration in hypertension. Generally, the reductions of blood pressure and/or of cardiac mass are believed to be the responsible factors. However, drugs are not equivalent in QT modulation despite similar antihypertensive and antihypertrophic action. We investigated the effect of a calcium channel blocker, lacidipine and an angiotensin-converting enzyme inhibitor, enalapril on QT duration in rats. Normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated with lacidipine (at the dose of 1.5 mg/kg per day for WKY and 3 mg/kg per day for SHR) or enalapril (5 mg/kg per day for WKY and 10 mg/kg per day for SHR) during 8 weeks. Tail-cuff systolic blood pressure (sBP), left ventricular weight (LVW), vascular function of isolated aorta and mesenteric artery and duration of QT (and QTc) interval on Frank electrocardiograms were evaluated. As expected, untreated SHR showed elevated sBP, impaired vascular reactivity, increased LVW and prolonged QT when compared with WKY (p < 0.05). After treatment, both agents markedly improved vascular reactivity and reduced sBP in SHR (p < 0.05). Additionally, enalapril reduced LVW in both hypertensive (by 17%; p < 0.05) and normotensive rats (by 13%; p < 0.05) and, consequently, corrected QT duration in SHR. Interestingly, lacidipine also reduced LVW in SHR (by 9%; p < 0.05), but without influence on prolonged QT. Moreover, lacidipine had no effect on LVW in WKYs but prolonged their QT interval (by 10%; p < 0.05). In conclusion, lacidipine did not reverse a progressive prolongation of QT in SHR, despite sBP lowering and LVW reduction. Thus, the lowering of blood pressure and/or reduction of LVW are not sufficient per se to normalize ventricular repolarization in hypertensive cardiac disease. More likely, modulation of QT prolongation by antihypertensive drugs is a function of their complex action on blood pressure, vascular function, cardiac mass and on reflex neurohumoral activation.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic. klimas@fpharm.uniba.sk
authors.forename: Jan
authors.initials: J
authors.lastname: Klimas
authors.forename: Vaclav
authors.initials: V
authors.lastname: Vaja
authors.forename: Miriam
authors.initials: M
authors.lastname: Vercinska
authors.forename: Jan
authors.initials: J
authors.lastname: Kyselovic
authors.forename: Peter
authors.initials: P
authors.lastname: Krenek
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; C060285:lacidipine; D004656:Enalapril; D000109:Acetylcholine; D009638:Norepinephrine