ACE inhibitors, enalapril, and mechanisms of oral homeostasis: salivary flow rate and antioxidant capacity

Abstract

Introduction: Saliva is a medium which, due to its components, flow rate and antioxidant capacity, greatly contributes to the oral homeostasis. The most common factors causing reduced salivary flow rate and/or xerostomia (subjective feeling of dry mouth) are adverse oral reactions of drugs, such as antihypertensives, and diseases, such as diabetes mellitus (DM) type 2. ACE inhibitors are the first-line antihypertensive drugs for the control of essential hypertension and hypertension with DM type 2. For the time being, there are no well-controled clinical trials showing xerogenic effect of ACE inhibitors. Beside ACE inhibitors direct effect on angiotensin system components, their protective effects (antioxidant, antiproliferative, antithrombotic) also significantly contribute to the beneficial therapeutic effects of these drugs. However, for the moment there are no data regarding mentioned effects of ACE inhibitors in human salivary glands and saliva. Aims: This study aimed: (1) to determine unstimulated whole saliva (UWS) flow rate in hypertensive patients with and without DM type 2 on enalapril (ACE inhibitor) treatment, as well as in healthy subjects; (2) to determine the presence of xerostomia in hypertensive patients with and without DM type 2 on enalapril treatment, as well as in healthy subjects; (3) to determine ACE and ACE2 presence and concentration in UWS sampled one hour before (minimal concentrations) and 4 hours after (maximal concentrations) enalapril morning dose intake in hypertensive patients with and without DM type 2 on enalapril treatment, as well as in healthy subjects; (4) to determine concentrations of malondialdehyde (MDA) adducts, marker of oxidative stress-lipid peroxidation, in UWS sampled one hour before and 4 hours after enalapril morning dose intake in hypertensive patients with and without DM type 2 on enalapril treatment, as well as in healthy subjects; (5) to determine antioxidant capacity by measuring total antioxidant capacity (TAC) and total glutathione concentration, as well as superoxide dismutase (SOD) activity in UWS sampled one hour before and 4 hours after enalapril morning dose intake in hypertensive patients with and without DM type 2 on enalapril treatment, as well as in healthy subjects; (6) to determine presence of angiotensin system components (ACE, ACE2, AT1 receptors) in human parotid gland tissues; (7) to determine eNOS and iNOS presence and concentrations in UWS sampled one hour before and 4 hours after enalapril morning dose intake in hypertensive patients with and without DM type 2 on enalapril treatment, as well as in healthy subjects...

Uvod: Pljuvaĉka je medijum koji svojim komponentama, protokom i antioksidativnim kapacitetom, u velikoj meri doprinosi oralnoj homeostazi. Najĉešći faktori odgovorni za nastanak smanjenog luĉenja pljuvaĉke i/ili kserostomije (subjektivni osećaj suvoće usta) su neţeljeni efekti lekova, kao što su antihipertenzivi, i bolesti, kao što je dijabetes melitus (DM) tip 2. ACE inhibitori danas predstavljaju lekove prvog izbora za leĉenje, kako esencijalne hipertenzije, tako i hipertenzije udruţene sa DM tip 2. Za sada nema dobro dokumentovanih kliniĉkih studija koje direktno ukazuju na kserogeni efekat ACE inhibitora. Povoljnom terapijskom efektu ACE inhibitora, pored njihovog direktnog dejstva na komponente angiotenzinskog sistema, znaĉajno doprinose i njihovi protektivni efekti (antioksidativni, antiproliferativni, antioagregacioni). O pomenutim efektima ACE inhibitora na nivou pljuvaĉnih ţlezda i pljuvaĉke kod ljudi za sada nema podataka. Ciljevi: 1. Odrediti protok ukupne nestimulisane pljuvaĉke (UNP) kod pacijenata sa hipertenzijom i hipertenzijom sa DM tip 2 na terapiji enalaprilom (ACE inhibitor), kao i kod zdravih osoba; 2. Utvrditi prisustvo subjektivanog osećaja suvoće usta kod pacijenata sa hipertenzijom i hipertenzijom sa DM tip 2 na terapiji enalaprilom, kao i kod zdravih osoba; 3. Odrediti prisustvo i koncentracije ACE i ACE2 u UNP prikupljenoj 1 sat pre (minimalne koncentracije) i 4 sata posle (maksimalne koncentracije) primene jutarnje terapijske doze enalaprila kod pacijenata sa hipertenzijom i hipertenzijom sa DM tip 2 na terapiji ovim lekom, kao i kod zdravih osoba; 4. Odrediti stepen oksidativnog stresa na nivou lipidne peroksidacije merenjem malondialdehida (MDA) vezanog za proteine u UNP prikupljenoj 1 sat pre i 4 sata posle primene jutarnje terapijske doze enalaprila kod pacijenata sa hipertenzijom i hipertenzijom sa DM tip 2 na terapiji ovim lekom, kao i kod zdravih osoba; 5. Odrediti stepen antioksidativnog kapaciteta merenjem totalnog antioksidativnog kapaciteta (TAC), koncentracija ukupnog glutationa i aktivnosti superoksid dizmutaze - SOD u UNP prikupljenoj 1 sat pre i 4 sata posle primene jutarnje terapijske doze enalaprila kod pacijenata sa hipertenzijom i hipertenzijom sa DM tip 2 na terapiji ovim lekom, kao i kod zdravih osoba; 6. Utvrditi prisustvo komponenti angiotenzinskog sistema u tkivu parotidne pljuvaĉne ţlezde ĉoveka: ACE, ACE2 i receptor za angiotenzin II tip 1 (AT1 receptor); 7...