The response of gastric submucosal arterioles to topical (submucosal) application of calcitonin-gene-related peptide (CGRP) or capsaicin with and without the human CGRP antagonist, hCGRP-(8-37), was studied using in vivo microscopy. CGRP (10(-11) to 10(-8) M) induced dose-dependent dilation. Topical treatment with hCGRP(8-37) (10(-6) M, for 10 min) caused a significant decrease in basal arteriolar diameter from 33 +/- 2 to 27 +/- 2 microns. hCGRP(8-37) did not alter acetylcholine- or adenosine-induced vasodilation but did significantly reduce CGRP 10(-8) M vasodilation from 97.3 +/- 10.1 to 15.9 +/- 4.4% of the maximal response. Topical capsaicin (10(-9) M to 5 x 10(-7) M) induced dose-dependent arteriolar dilation. This vasodilation was markedly attenuated by hCGRP(8-37). Selective ablation of capsaicin-sensitive sensory neurons nearly completely inhibited capsaicin-induced vasodilation, suggesting that this vasodilation is primarily neurogenic in origin. We conclude that 1) topical application of capsaicin stimulates capsaicin-sensitive sensory neurons and induces dose-dependent arteriolar dilation; 2) this vasodilation is mediated in part by CGRP; and 3) CGRP may be involved in modulating the basal tone of gastric resistance vessels.
The gastric vasoconstrictor actions of the arachidonate lipoxygenase products leukotrienes B4, C4, and D4 and the prostanoids prostaglandin F2 alpha (PGF2 alpha) and the endoperoxide analogue U-46619 have been investigated in vivo in the submucosal microcirculation of the anesthetized rat using direct microscopy. Topical application of PGF2 alpha (1-100 microM) to the exposed submucosa reduced vessel diameter of the venules, with peak vasoconstriction occurring within 1 min and remaining during the 3-min period of administration. Constriction of the arterioles by PGF2 alpha was less pronounced. U-46619 (1-1,000 nM), a thromboxane mimetic, induced vasoconstriction in both arterioles and venules, reaching plateau responses within 1.5-2.0 min of application. Leukotriene C4 (25-400 nM) induced vasoconstriction in the venules, which was more pronounced than in the arterioles, reaching peak responses within 1-1.5 min, which were unaffected by indomethacin administration. No significant vasoactive action with leukotrienes B4 or D4 in the submucosal microcirculation could be detected. With both leukotriene C4 and U-46619 intense focal vasoconstriction in the venules was observed, leading to sluggish blood flow or stasis within the vessel. In contrast, norepinephrine had no significant action on submucosal venules at concentrations that substantially reduced arteriolar vessel diameter. Such potent vasoconstrictor actions of leukotriene C4 and U-46619 in the gastric submucosa identify this leukotriene and thromboxane A2 as potential endogenous proulcerogenic agents and suggest that these arachidonate products could play a role in microcirculatory events accompanying gastric damage.
The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, on the vagal cholinergic increase in gastric mucosal blood flow (GMBF) and acid secretion induced by intracisternal injection of the thyrotropin-releasing hormone (TRH) analogue, RX 77368, were studied. GMBF and acid secretion were measured simultaneously by the hydrogen gas clearance technique and titration of gastric perfusate in urethan-anesthetized rats. RX 77368 (30 ng) injected intracisternally stimulated gastric acid secretion and GMBF for 90 and 180 min respectively. GMBF was increased from basal 63 +/- 4 to 166 +/- 14 ml.min-1.100 g-1 at 60 min postinjection. L-NAME (3 mg/kg) injected intravenously 15 min before RX 77368 completely prevented the increase in GMBF induced by the TRH analogue, whereas the acid response was not modified. The effect of L-NAME was reversed by L-arginine but not by the stereoisomer D-arginine. These results show that the increase in GMBF, but not the stimulation of acid secretion, induced by central vagal activation is mediated through a product of L-arginine-NO pathway.
The role of L-arginine-derived nitric oxide (NO) in cholinergic vasodilation of resistance vessels was studied in the intact stomach of the rat, utilizing an in vivo microscopy technique. Two L-arginine analogues, NG-monomethyl-L-arginine (L-NMMA) and nitro-L-arginine methyl ester (L-NAME), were used to block NO synthesis. Cholinergic dilation of gastric submucosal arterioles was induced by topical application of various concentrations of acetylcholine (ACh) (10(-7)-10(-4) M). Intravenous but not topical administration of L-NMMA and L-NAME caused an increase in arterial pressure. Intravenous or topical L-NAME reduces resting arteriolar diameter. These findings support the contention that NO formation modulates basal vascular tone and suggest that NO release may play a significant role in the regulation of the gastric circulation. L-Arginine analogues attenuated the arteriolar dilating effect of ACh but not adenosine or nitroglycerin. Substantial arteriolar responses to ACh remained after systemic or topical treatment with either L-NMMA or L-NAME. These results indicate that the L-arginine-NO pathway accounts only in part for ACh-induced vasodilation in gastric resistance vessels in vivo.
The aim of the study was to characterize the gastric and mesenteric vascular changes induced by diabetes and the implication of endothelial [nitric oxide (NO) and prostaglandins] and humoral (glucagon) factors in such changes. Diabetes was induced in rats by a single streptozotocin injection. Four weeks later, gastric mucosa, left gastric artery, and superior mesenteric artery blood flows were measured using hydrogen gas clearance and perivascular ultrasonic flowmeter techniques, respectively, in anesthetized and fasted diabetic and control rats. Blood pressure, hematocrit, blood volume, and blood viscosity were also measured. Left gastric (41 +/- 6 vs. 25 +/- 4 ml.min-1.100 g-1) and superior mesenteric artery blood flows (83 +/- 8 vs. 65 +/- 4 ml.min-1.100 g-1) were significantly higher in diabetic than in control rats. The increased blood flow in the left gastric artery was distributed to a hypertrophic mucosa in diabetic rats; therefore, the blood flow per 100 g tissue in the gastric mucosa was not significantly different in diabetic compared with control rats. Pretreatment with indomethacin reduced both increase gastric and mesenteric flows of the diabetic rats to the same levels as in control rats. NG-nitro-L-arginine methyl ester decreased gastric blood flow in a dose-dependent manner and to a similar extent in diabetic and control rats. In contrast, an increased sensitivity to the higher doses of the NO inhibitor was observed in the mesenteric vascular bed of diabetic rats. Glucagon reduction achieved by somatostatin infusion did not influence either gastric or mesenteric blood flow in diabetic rats. In summary, the present study revealed an increase in gastric and mesenteric arterial blood flows in streptozotocin-induced diabetic rats. The gastrointestinal hyperemia seems to be due, at least in part, to the increased demand of a hypertrophic mucosa and is mediated primarily by endogenous prostaglandins. Increased vascular sensitivity to NO may also contribute to the mesenteric vasodilation.
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