8-bromocyclic-gmp and Hyperemia

Exercise hyperaemia is partly mediated by adenosine A(2A)-receptors. Adenosine can evoke nitric oxide (NO) release via endothelial A(2A)-receptors, but the role for NO in exercise hyperaemia is controversial. We have investigated the contribution of NO to hyperaemia evoked by isometric twitch contractions in its own right and in interaction with adenosine. In three groups of anaesthetized rats the effect of A(2A)-receptor inhibition with ZM241385 on femoral vascular conductance (FVC) and hindlimb O(2) consumption at rest and during isometric twitch contractions (4 Hz) was tested (i) after NO synthase inhibition with l-NAME, and when FVC had been restored by infusion of (ii) an NO donor (SNAP) or (iii) cell-permeant cGMP. Exercise hyperaemia was significantly reduced (32%) by l-NAME and further significantly attenuated by ZM241385 (60% from control). After restoring FVC with SNAP or 8-bromo-cGMP, l-NAME did not affect exercise hyperaemia, but ZM241385 still significantly reduced the hyperaemia by 25%. There was no evidence that NO limited muscle during contraction. These results indicate that NO is not required for adenosine release during contraction and that adenosine released during contraction does not depend on new synthesis of NO to produce vasodilatation. They also substantiate our general hypothesis that the mechanisms by which adenosine contributes to muscle vasodilatation during systemic hypoxia and exercise are different: we propose that, during muscle contraction, adenosine is released from skeletal muscle fibres independently of NO and acts directly on A(2A)-receptors on the vascular smooth muscle to cause vasodilatation.

Topics: Adenosine; Adenosine A2 Receptor Antagonists; Animals; Cyclic GMP; Electric Stimulation; Enzyme Inhibitors; Femoral Artery; Hindlimb; Hyperemia; Isometric Contraction; Male; Muscle, Skeletal; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Oxygen Consumption; Physical Exertion; Rats; Rats, Wistar; Receptor, Adenosine A2A; Regional Blood Flow; S-Nitroso-N-Acetylpenicillamine; Sciatic Nerve; Time Factors; Triazines; Triazoles; Vasodilation

Electrical stimulation of cerebellar parallel fibers (PF) increases cerebellar blood flow (BFcrb), a response that is attenuated by glutamate receptor antagonists and NO synthase (NOS) inhibitors. We investigated whether administration of NO donors could counteract attenuation by NOS inhibitors of vasodilation produced by PF stimulation. In halothane-anesthetized rats the cerebellar cortex was exposed and superfused with Ringer solution. PF were stimulated with microelectrodes (100 microA, 30 Hz), and BFcrb was recorded by a laser-Doppler probe. During Ringer superfusion, PF stimulation increased BFcrb by 56 +/- 7% and hypercapnia by 72 +/- 5% (n = 5). Superfusion with the nonselective NOS inhibitor N-nitro-L-arginine (L-NNA, 1 mM) reduced resting BFcrb and attenuated the response to PF stimulation (-47 +/- 5%) and hypercapnia (-46 +/- 7%; PCO2 = 50-60 mmHg). After L-NNA, superfusion with the NO donors 3-morpholinosydnonimine (100 microM, n = 5) or S-nitroso-N-acetyl-penicillamine (5 microM, n = 5) reestablished resting BFcrb (P > 0.05 vs. before L-NNA) and reversed L-NNA-induced attenuation of the response to hypercapnia (P > 0.05 vs. before L-NNA) but not PF stimulation (P > 0.05 vs. after L-NNA). Similar results were obtained when NOS activity was inhibited with the inhibitor of neuronal NOS 7-nitroindazole (50 mg/kg i.p.). Like NO donors, the guanosine 3',5'-cyclic monophosphate analog 8-bromoguanosine 3',5'-cyclic monophosphate (n = 5), administered after L-NNA, restored resting BFcrb and counteracted inhibition of the response to hypercapnia but not PF stimulation. In contrast to NO donors and 8-bromoguanosine 3',5'-cyclic monophosphate, the NO-independent vasodilator papaverine (100 microM, n = 5) had no effect on attenuation of responses to PF stimulation or hypercapnia. Thus NO donors are unable to reverse the effect of NOS inhibition on vasodilation produced by PF stimulation. The data support the hypothesis that the vascular response to PF stimulation, at variance with hypercapnia, requires NOS activation and NO production. Thus NO plays an obligatory role in vasodilation produced by increased functional activity in cerebellar cortex.

Topics: Animals; Blood Pressure; Carbon Dioxide; Cerebellum; Cyclic GMP; Electric Stimulation; Enzyme Inhibitors; Glutamic Acid; Hyperemia; Indazoles; Male; Molsidomine; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oxygen; Papaverine; Partial Pressure; Penicillamine; Rats; Rats, Sprague-Dawley; Regional Blood Flow; S-Nitroso-N-Acetylpenicillamine; Vasodilation

The increased susceptibility of the stomach to injury observed in portal hypertension may be related to a defect in the hyperemic response to luminal irritants. The aim of this study was to evaluate the components that mediate this hyperemic response in a rat model of cirrhosis and portal hypertensive gastropathy.. Cirrhosis was induced by bile duct ligation, whereas controls underwent sham operation. Gastric blood flow responses to topical application of acid, capsaicin, nitrovasodilators, misoprostol, 8-bromo-cyclic guanosine monophosphate, and 8-bromo-cyclic adenosine monophosphate were measured by laser Doppler flowmetry using an ex vivo gastric chamber preparation. Calcitonin gene-related peptide immunoreactivity was used as an index of the anatomic integrity of the sensory afferent neurons of the stomach.. Blood flow responses to acid, capsaicin, nitrovasodilators, and 8-bromo-cyclic guanosine monophosphate were significantly depressed in cirrhotic rats, whereas they were augmented after topical application of misoprostol and 8-bromo-cyclic adenosine monophosphate. Calcitonin gene-related peptide immunoreactivity was similar in the stomachs of cirrhotic and control rats.. Gastric vasodilation after stimulation of sensory afferent neurons is impaired in cirrhotic rats despite the normal anatomic distribution of these nerves. This effect seemed to be related to a depressed response of the gastric microcirculation to cyclic guanosine monophosphate-dependent vasodilators. This alteration may contribute to the increased susceptibility to gastric ulceration in cirrhotics.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Anesthesia; Animals; Calcitonin Gene-Related Peptide; Capsaicin; Cyclic GMP; Disease Models, Animal; Hyperemia; Hypertension, Portal; Laser-Doppler Flowmetry; Liver Cirrhosis, Biliary; Male; Microcirculation; Misoprostol; Neurons, Afferent; Nitroprusside; Rats; Rats, Sprague-Dawley; Stomach; Vasodilation