Co-administration of metformin and/or glibenclamide with losartan reverse NG-nitro-l-arginine-methyl ester-streptozotocin-induced hypertensive diabetes and haemodynamic sequelae in rats

Microvasc Res. 2023 May:147:104497. doi: 10.1016/j.mvr.2023.104497. Epub 2023 Feb 3.

Abstract

Over the years, there have been opinions on whether to reduced blood pressure (BP) to a different levels in patients with diabetes mellitus. Hence, this study investigated the efficacy of the co-administration of losartan (angiotensin receptor blocking antihypertensive agent) with metformin and/or glibenclamide (antidiabetic agents) on hypertensive-diabetic experimental rats induced by NG-nitro-l-arginine-methyl-ester hydrochloride (l-NAME), and streptozotocin (STZ). STZ (45 mg/kg, i.p.)-induced diabetic rats combined with l-NAME (40 mg/kg, p.o.)-induced hypertension were allotted into different groups. Group 1 received distilled water (10 mL/kg) and served as normal control, group 2 comprised hypertensive diabetic rats with distilled water, groups 3-5 were hypertensive-diabetic rats but received combination treatments of losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide daily for 8 weeks, respectively. Our finding revealed no changes in the body weights, but there was a significant increase in fasting blood sugar levels in l-NAME - STZ-induced hypertensive-diabetes, which were lowered by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide treatments. Moreover, the increased systolic-BP, mean arterial pressure but not diastolic-BP and heart rate by l-NAME + STZ were attenuated more significantly by losartan + metformin + glibenclamide between weeks 2-8 relative to hypertensive-diabetic control. l-NAME + STZ-induced elevated levels of lactate dehydrogenase and creatinine kinase, were differentially reversed by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide. However, l-NAME + STZ-induced decreased nitrite level was significantly restored by all treatments, suggesting increased nitrergic transmission. Additionally, l-NAME + STZ-induced degeneration of pancreatic islet and myocardial cells were dramatically alleviated by losartan + metformin + glibenclamide treatments. Our findings suggest hyperglycemia with raised systolic-BP should be managed with losartan combined with both metformin and glibenclamide than single combination of losartan with antidiabetics.

Keywords: Antidiabetics; Antihypertensives; Cardiac injury; Diabetes; Hypertension; Nitrergic stress.

MeSH terms

  • Animals
  • Antihypertensive Agents
  • Blood Pressure
  • Diabetes Mellitus, Experimental* / complications
  • Esters / adverse effects
  • Glyburide / adverse effects
  • Hypertension*
  • Hypoglycemic Agents / pharmacology
  • Losartan / adverse effects
  • Metformin*
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Rats
  • Streptozocin / adverse effects
  • Water

Substances

  • Losartan
  • Streptozocin
  • NG-Nitroarginine Methyl Ester
  • Glucovance
  • Glyburide
  • Antihypertensive Agents
  • Metformin
  • Hypoglycemic Agents
  • Esters
  • Water