Comparative regional haemodynamic effects of the nitric oxide synthase inhibitors, S‐methyl‐L‐thiocitrulline and L‐NAME, in conscious rats

Abstract

1 The regional haemodynamic effects of the putative nNOS inhibitor, S-methyl-l-thiocitrulline (SMTC), were compared with those of the nonselective NOS inhibitor, N G -nitro-l-arginine methyl ester (l-NAME), in conscious, male Sprague -Dawley rats. 2 SMTC (0.3 mg kg À1 bolus) produced a significant, short-lived, pressor effect associated with renal, mesenteric and hindquarters vasoconstriction; the same dose of l-NAME did not affect mean blood pressure (BP), although it caused bradycardia and mesenteric vasoconstriction.3 At the highest dose tested (10 mg kg À1 ), l-NAME produced a significantly greater bradycardia and fall in mesenteric vascular conductance than SMTC, although the initial pressor response to SMTC was greater, but less sustained, than that to l-NAME. 4 Infusion of SMTC or l-NAME (3 mg kg À1 h À1) induced rises in BP and falls in renal, mesenteric and hindquarters vascular conductances, but the effects of l-NAME were greater than those of SMTC, and l-NAME also caused bradycardia. 5 The renal vasodilator response to acetylcholine was markedly attenuated by infusion of l-NAME, but unaffected by SMTC. The hindquarters vasodilatation induced by salbutamol was attenuated by l-NAME, but not by SMTC. The mesenteric vasodilator response to bradykinin was modestly enhanced by SMTC, but not by l-NAME. The depressor and renal, mesenteric and hindquarters vasodilator responses to sodium nitroprusside were enhanced by l-NAME, whereas SMTC modestly enhanced the hypotensive and renal vasodilator effects of sodium nitroprusside, but attenuated the accompanying tachycardia. 6 The results are consistent with the cardiovascular effects of low doses of SMTC being attributable to nNOS inhibition.

Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-l-tyrosine Peroxisome Proliferator-Activated Receptor-γ Ligand, GI 262570 [(S)-2-(2-Benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic Acid], in Conscious Rats

“…Experiments began the day after catheter implantation. From previous studies using the approaches described here, we have seen no evidence of hangover effects of the anesthetic regimen (Wakefield et al, 2003;Woolard et al, 2004). Furthermore, in the present study, hemodynamic responses to vasoconstrictor and vasodilator challenges were consistent across the four experimental days in vehicle-infused rats (see Results).…”

Neuronal Nitric Oxide Synthase Regulates Basal Microvascular Tone in Humans In Vivo

“…10 Likewise, a comparison of the effects of systemic infusion of SMTC versus the nonselective NOS inhibitor L-nitroarginine methyl ester in rats in vivo showed that SMTC increased blood pressure and reduced renal blood flow at doses that did not induce such effects with L-nitroarginine methyl ester. 17 Although the above results suggested that local SMTC infusion reduced basal blood flow through the inhibition of nNOS, this assumption is based on the selectivity of SMTC for nNOS over eNOS reported by Furfine et al 10 and its greater potency at reducing basal forearm flow than L-NMMA. The original studies by Furfine et al 10,18 were performed on in vitro preparations, including rodent isoenzymes, whereas the present study aimed to investigate the role of nNOS in the human microvasculature in vivo.…”

Effects of neuronal nitric oxide synthase inhibition on microvascular and contractile function in skeletal muscle of aged rats

“…The use of isoform-selective NOS inhibitors is therefore crucial in such investigations. As discussed in detail elsewhere (12,13) and demonstrated by previous pharmacological studies (18,64) and the current hypotensive responses to ACh (Fig. 1), SMTC represents a viable tool for this purpose based on its selectivity for nNOS over both eNOS and iNOS inhibition.…”

“…Two separate contraction bouts were performed under control (1.2 ml heparinized saline) and selective nNOS inhibition (2.1 mol/kg SMTC dissolved in 1.2 ml heparinized saline) conditions. This dose of SMTC was selected based on previous studies designed to inhibit selectively nNOS in both humans and rodents (18,30,53,64) and our analysis of the highest possible SMTC dose that could be administered without affecting the hypotensive response to ACh, indicative of nonspecific eNOS inhibition (12,13). Each solution was infused at a rate of 0.2 ml/min into the tail artery catheter for a total time of 6 min, after which a ϳ2-min period was allowed for resting muscle PO2mv to stabilize.…”