Possible mechanisms of age-associated reduction of vascular relaxation caused by atrial natriuretic peptide.
We investigated the effect of aging on atrial natriuretic peptide (ANP)-induced relaxation and cyclic GMP (cGMP) formation in the rat thoracic aorta. In the aorta from young rats (4 weeks old), removal of the endothelium, and treatment with the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), the radical scavenger, hemoglobin (Hb), and the soluble guanylate cyclase inhibitor, methylene blue (MB), attenuated ANP-induced relaxation and considerably reduced ANP-stimulated cGMP formation. With increasing age of the rats, the ANP-induced relaxation and cGMP formation in endothelium-intact aorta decreased, and Hb, L-NAME and MB no longer inhibited the ANP-induced effects, irrespective of whether the endothelium was present or absent. In the arteries without endothelium, the age-associated reduction in ANP-induced relaxation was less than in arteries with endothelium. Aging also decreased the relaxation induced by the soluble guanylate cyclase activator, nitroprusside. Potentiation due to the cGMP-phosphodiesterase (cGMP-PDE) inhibitor, M&B 22948, of the ANP-induced relaxation was greater in aortas from old rats than in those from young rats, suggesting that the degradation of cGMP may be accelerated in old rats. These results suggest that the relaxant action of ANP on the thoracic aorta from young rats is in part modulated by endothelium-derived relaxing factor (EDRF/nitric oxide), which in turn activates soluble guanylate cyclase, thus elevating the cGMP level. Aging may decrease the ANP-induced relaxation and ANP-stimulated increase in cGMP level by decreasing the ability of endothelial cells to produce EDRF, by decreasing guanylate cyclase activity, and by enhancing cGMP-PDE activity.
Moritoki
H
H
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
Yoshikawa
T
T
Hisayama
T
T
Takeuchi
S
S
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D006152:Cyclic GMP / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism; D006454:Hemoglobins / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D006454:Hemoglobins; D011688:Purinones; D009320:Atrial Natriuretic Factor; D001120:Arginine; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006162:Guanylate Cyclase; C011145:zaprinast; D006152:Cyclic GMP; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester