Prevention of vascular nitroglycerin tolerance by inhibition of protein kinase C

• Published in: British journal of pharmacology 1996-09, Vol.119 (1), p.3-5
• Main Authors: Zierhut, Wolfgang, Ball, Howard A.
• Format: Article
• Language: English
• Subjects: Animals; Antianginal agents. Coronary vasodilator agents; Aorta - drug effects; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; Drug Tolerance - physiology; Heart Rate - drug effects; In Vitro Techniques; Male; Medical sciences; Muscle, Smooth, Vascular - drug effects; Nitroglycerin - pharmacology; Nitroglycerin tolerance; Pharmacology. Drug treatments; Phenylephrine - pharmacology; Protein Kinase C - antagonists & inhibitors; protein kinase C inhibition; Rats; Rats, Wistar; Vasodilator Agents - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15669.x

We investigated whether in vivo inhibition of protein kinase C (PKC) can prevent the development of vascular tolerance and restore the sensitivity of isolated vessels to nitroglycerin (NTG). Tolerance was induced in male Wistar rats by a constant i.v. infusion of NTG 1 mg kg−1 h−1, a dose which did not alter blood pressure. After 72 h, the aorta was removed and the sensitivity of aortic rings to NTG tested. Chronic NTG infusion resulted in a 5.5 fold decrease in NTG‐sensitivity as compared with controls (vehicle), indicating the development of vascular tolerance. The simultaneous in vivo administration of the specific PKC inhibitor N‐benzoyl‐staurosporine (30 mg kg−1 day−1) prevented this decrease in NTG sensitivity. These results suggest a role for PKC activation in the development of vascular NTG tolerance.