Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes.

Abstract

Studies in streptozotocin (STZ)-induced diabetic rats have demonstrated cardiovascular abnormalities such as depressed mean arterial blood pressure (MABP) and heart rate (HR), endothelial dysfunction, and attenuated pressor responses to vasoactive agents. We investigated whether these abnormalities are due to diabetes-associated activation of inducible nitric oxide synthase (iNOS). In addition, the effect of the duration of diabetes on these abnormalities was also evaluated. Diabetes was induced by administration of 60 mg/kg STZ via the tail vein. One, 3, 9, or 12 wk after STZ injection, MABP, HR, and endothelial function were measured in conscious unrestrained rats. Pressor response curves to bolus doses of methoxamine (MTX) and angiotensin II (ANG II) were constructed in the presence of N-[3(aminomethyl)benzyl]-acetamidine, dihydrochloride (1400W), a specific inhibitor of iNOS. Depressed MABP and HR and impairment of endothelial function were observed as early as 3 wk after induction of diabetes. Acute inhibition of iNOS with 1400W (3 mg/kg i.v.) restored the attenuated pressor responses to both MTX and ANG II without affecting the basal MABP and HR. Immunohistochemical and Western analysis blot studies in cardiovascular tissues revealed decreased expression of endothelial nitric oxide synthase (eNOS) concomitant with increased expression of iNOS and nitrotyrosine with the progression of diabetes. Our findings suggest that induction of iNOS in cardiovascular tissues is dependent on the duration of diabetes and contributes significantly to the depressed pressor responses to vasoactive agents and potentially to endothelial dysfunction.

• Authors: Prabhakara Reddy Nagareddy, Zhengyuan Xia, John H McNeill, Kathleen M MacLeod
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 289 Issue 5 Pg. H2144-52 (Nov 2005) ISSN: 0363-6135 [Print] United States
• PMID: 16006542 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amidines
• Benzylamines
• Enzyme Inhibitors
• N-(3-(aminomethyl)benzyl)acetamidine
• Vasoconstrictor Agents
• Angiotensin II
• Neurotensin
• Methoxamine
• NG-Nitroarginine Methyl Ester

Topics

• Amidines (pharmacology)
• Angiotensin II (pharmacology)
• Animals
• Benzylamines (pharmacology)
• Blood Pressure (drug effects, physiology)
• Blotting, Western
• Diabetes Mellitus, Experimental (enzymology, physiopathology)
• Endothelium, Vascular (physiology)
• Enzyme Inhibitors (pharmacology)
• Heart Rate (drug effects)
• Hemodynamics (drug effects, physiology)
• Immunohistochemistry
• Male
• Methoxamine (pharmacology)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Neurotensin (physiology)
• Rats
• Rats, Wistar
• Vascular Diseases (physiopathology)
• Vasoconstrictor Agents (pharmacology)