Vascular reactivity in mesenteric resistance arteries following chronic nitric oxide synthase inhibition in Wistar rats.
1. Chronic inhibition of nitric oxide synthase (NOS) induces a sustained hypertension in rats. We studied the effects of chronic inhibition on the in vitro vasoreactivity of mesenteric resistance arteries in Wistar rats. We also investigated the effects of acute in vitro NOS inhibition in these vessels. 2. Acute NOS inhibition (N omega-nitro-L-arginine, L-NOARG, 10 microM) had no effect on the contractile response to KCl (125 mM), enhanced the response to the phorbol ester, phorbol dibutyrate (1 microM; 69 +/- 9% of KCl response, n = 6; 38 +/- 7% control, n = 6, P < 0.05), increased sensitivity to phenylephrine (EC50: 1.68 +/- 0.14 microM, n = 5; 2.35 +/- 0.23 microM control, n = 5, P < 0.05) and sodium nitroprusside (SNP; EC50 1.79 +/- 0.61 nM, n = 6; 20.44 +/- 6.87 nM control, n = 6, P < 0.05) and decreased sensitivity to acetylcholine (EC50 123 +/- 12 nM, n = 6; 45 +/- 10 nM control, n = 13, P < 0.05). 3. In contrast, contractile responses to KCl (125 mM; 170 +/- 12 mN mm-3, n = 10; 257 +/- 21 mN mm-3 in control, n = 13, P < 0.005) and phenylephrine (maximum response, 30 microM: 169 +/- 24 mN mm-3, n = 10; 295 +/- 19 mN mm-3 in control, n = 13, P < 0.001) were significantly reduced in magnitude following chronic NOS inhibition. Sensitivity to phenylephrine was not significantly altered. 4. The effects of chronic NOS inhibition (N omega-nitro-L-arginine methyl ester, L-NAME, 10 mg kg-1 daily for 3 weeks) were similar to those of acute NOS blockade with respect to the relaxant responses to SNP and acetylcholine, and also the contraction in response to protein kinase C activation. 5. Chronic inhibition of NOS significantly increased medial cross sectional area of mesenteric resistance arteries (0.013 +/- 0.002 mm2, n = 7; 0.009 +/- 0.0005 mm2 control, n = 15, P < 0.05). 6. Thus, in contrast to the acute effects of NOS inhibition, chronic NOS inhibition results in a down-regulation of the contractile responses to KCl and phenylephrine in mesenteric resistance arteries, despite an increase in medial cross sectional area. However protein kinase C-dependent contraction remains relatively enhanced. Endothelium-dependent relaxation is reduced and endothelium-independent relaxation is enhanced in a manner similar to the effects of acute NOS blockade.
Dowell
F J
FJ
Institut National de la Santé et de la Recherche Médicale INSERM U 141, Paris, France.
Henrion
D
D
Duriez
M
M
Michel
J B
JB
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects*
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D019331:NG-Nitroarginine Methyl Ester