Effect of <i>L</i>-Arginíne on Reactivity of Hamster Cheek Pouch Arterioles during Diabetes mellitus

Abstract

The goal of this study was to determine whether exogenous application of L-arginine could restore impaired agonist-induced increases in arteriolar diameter during diabetes mellitus. We used intravital microscopy to examine reactivity of cheek pouch arterioles (50 µm in diameter) in nondiabetic and diabetic (2 weeks after injection of streptozotocin) hamsters in response to histamine and substance P. In nondiabetic hamsters histamine (1.0 and 5.0 µM) dilated cheek pouch arterioles by 15 ± 1 and 22 ± 1%, respectively, and substance P (50 and 100 nM) dilated arterioles by 14 ± 3 and 21 ± 4%, respectively. In addition, dilatation of arterioles in response to histamine and substance P in nondiabetic hamsters was abolished by application of an enzymatic inhibitor of nitric oxide synthase (L-NMMA). In contrast, histamine-and substance P-induced increases in arteriolar diameter were markedly reduced in diabetic hamsters. Histamine (1.0 and 5.0 µM) dilated arterioles by only 5 ± 1 and 4 ± 2%, respectively, and substance P (50 and 100 nM) dilated arterioles by only 6 ± 2 and 5 ± 3%, respectively (p < 0.05 vs. nondiabetic hamsters). Nitroglycerin produced similar vasodilatation in nondiabetic and diabetic hamsters. Next, we examined whether exogenous application of L-arginine (100 µM) could restore impaired histamine- and substance P-induced increases in arteriolar diameter in diabetic hamsters. We found that L-arginine did not restore altered nitric oxide synthase-dependent vasodilatation in diabetic hamsters. These findings suggest that short-term diabetes mellitus alters agonist-induced increases in arteriolar diameter. In addition, the mechanism of altered arteriolar reactivity during diabetes mellitus does not appear to be related to an impaired availability of L-arginine.

Endothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type 1 diabetes under near-normoglycemic conditions.

“…Also in some, but not all, studies in diabetic animals, an improvement of endothelium-dependent vasodilatation was observed after L-arginine supplementation (14)(15)(16)35). In our type 1 diabetic patients without microangiopathy or with microalbuminuria, we did not find any evidence that L-a r g inine improves endothelium-dependent vasodilatation.…”

Review of Alterations in Endothelial Nitric Oxide Production in Diabetes

“…187 There are reports that appear not to support the concept of defects in L-arginine utilization. In one case, topical application of L-arginine apparently did not improve relaxation in basilar artery of streptozotocin-induced diabetic rats, 188 in cheek pouch microcirculation of diabetic hamsters, 189 or in mesenteric artery of BB diabetic rats. 34 Additional information is needed to determine with total certainty whether these studies reflect important regional differences in the beneficial action of L-arginine on reversal of diabetic endothelial dysfunction because of differences in arginine concentration, duration of exposure, location of application, and duration of disease (see "Discussion") and the potential for crossover effects due to multiple agonist challenges in the same preparation in at least two of these studies.…”

“…34 Additional information is needed to determine with total certainty whether these studies reflect important regional differences in the beneficial action of L-arginine on reversal of diabetic endothelial dysfunction because of differences in arginine concentration, duration of exposure, location of application, and duration of disease (see "Discussion") and the potential for crossover effects due to multiple agonist challenges in the same preparation in at least two of these studies. 34,189 In addition, the ineffectiveness of L-arginine in mesenteric arteries of BB rats is inconclusive, since a short incubation period was used as well as a concentration (ie, 10 mol/L) that is 20 times lower than the physiological concentration of arginine in rat plasma and 10 times lower than the K m of arginine transport into endothelial cells. 129 Furthermore, the potential of masking by crossover effects due to multiple agonist administration has not been excluded in these studies.…”

Endothelial dysfunction in diabetes

“…In accordance, an increased NO synthase activity, measured by conversion of 3 H-L-arginine to 3 H-L-citrulline, was demonstrated in diabetic rat heart endothelium (RoÈ sen et al, 1996). Exogenous L-arginine (partially) restored endotheliumdependent vasodilatation in certain (Pieper & Peltier, 1995;Fulton et al, 1996;Matsunaga et al, 1996;Angulo et al, 1998), but not all studies (Heygate et al, 1995;Koltai et al, 1997;Mayhan et al, 1997). These variable results may relate to an aspeci®c e ect of L-arginine: this amino acid is known to release insulin, which by itself may stimulate endothelium-dependent vasodilatation (MacAllister et al, 1995).…”