Tissue levels of glyceryl trinitrate and cGMP after in vivo administration in rat, and the effect of tolerance development.
The present study compares the tissue distribution of glyceryl trinitrate (GTN) in plasma, heart, brain, aortic tissue, and adipose tissue from GTN tolerant and GTN nontolerant rats at various time points. Furthermore, the cGMP levels in brain, heart, and aortic tissue were studied at various time points as well as the concentration-effect relationship for GTN in aorta isolated at different time points after the last exposure to GTN. Concentrations of GTN were found to be higher in all tissues studied as compared with plasma, and the concentrations of GTN were higher in tissues from tolerant rats as compared with nontolerant rats, except for aortic tissue. Concentration-effect curves obtained in vitro showed that aortic smooth muscle was still tolerant 24 h after the last dose of GTN. The cGMP level in brain was significantly increased by 40% 2 h after a single dose of GTN (50 mg/kg) and in aortic tissue by 50% at 15 min and at 2 h after a single dose of GTN (50 mg/kg). There was no effect on cGMP in brain, while an increase was seen in aortic tissue 15 min after the last dose in tolerant animals. No change in cGMP level was seen in heart neither in nontolerant nor in tolerant animals at 15 min and at 2 h. No effect on cGMP levels in brain, heart, and aortic tissue was seen 8, 16, and 24 h after exposure to GTN in either tolerant or nontolerant rats. In conclusion, GTN does not involve the cGMP system in heart, and tolerance development caused a less pronounced GTN-induced cGMP increase in aortic tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Torfgård
K
K
Department of Pharmacology, Faculty of Health Sciences, University Hospital, Linköping, Sweden.
Ahlner
J
J
Axelsson
K L
KL
Norlander
B
B
Bertler
A
A
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D005996:Nitroglycerin / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution / Q000502:physiology
D005996:Nitroglycerin; D006152:Cyclic GMP