thiourea and Hyperemia

Nitric oxide (NO) release from endothelial NO synthase (eNOS) and/or neuronal NO synthase (nNOS) could be modulated by sympathetic nerve activity and contribute to increased blood flow after exercise. We examined the effects of brachial-arterial infusion of the nNOS selective inhibitor S-methyl-l-thiocitrulline (SMTC) and the nonselective NOS inhibitor N(G)-monomethyl-l-arginine (l-NMMA) on forearm arm blood flow at rest, during sympathetic activation by lower body negative pressure, and during lower body negative pressure immediately after handgrip exercise. Reduction in forearm blood flow by lower body negative pressure during infusion of SMTC was not significantly different from that during vehicle (-28.5 ± 4.02 vs. -34.1 ± 2.96%, respectively; P = 0.32; n = 8). However, l-NMMA augmented the reduction in forearm blood flow by lower body negative pressure (-44.2 ± 3.53 vs. -23.4 ± 5.71%; n = 8; P < 0.01). When lower body negative pressure was continued after handgrip exercise, there was no significant effect of either l-NMMA or SMTC on forearm blood flow immediately after low-intensity exercise (P = 0.91 and P = 0.44 for l-NMMA vs. saline and SMTC vs. saline, respectively; each n = 10) or high-intensity exercise (P = 0.46 and P = 0.68 for l-NMMA vs. saline and SMTC vs. saline, respectively; each n = 10). These results suggest that sympathetic activation increases NO release from eNOS, attenuating vasoconstriction. Dysfunction of eNOS could augment vasoconstrictor and blood pressure responses to sympathetic activation. However, neither eNOS nor nNOS plays an essential role in postexercise hyperaemia, even in the presence of increased sympathetic activation.

Topics: Adult; Blood Pressure; Citrulline; Forearm; Hand Strength; Humans; Hyperemia; Male; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; omega-N-Methylarginine; Physical Exertion; Regional Blood Flow; Sympathetic Nervous System; Thiourea; Vasoconstriction

Isoform-specific nitric oxide (NO) synthase (NOS) contributions to NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle are incompletely understood. The purpose of the present study was to investigate the role of neuronal NOS (nNOS) in the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle of healthy rats. We hypothesized that acute pharmacological inhibition of nNOS would augment sympathetic vasoconstriction in resting and contracting skeletal muscle, demonstrating that nNOS is primarily responsible for NO-mediated inhibition of sympathetic vasoconstriction. Sprague-Dawley rats (n = 13) were anesthetized and instrumented with an indwelling brachial artery catheter, femoral artery flow probe, and lumbar sympathetic chain stimulating electrodes. Triceps surae muscles were stimulated to contract rhythmically at 60% of maximal contractile force. In series 1 (n = 9), the percent change in femoral vascular conductance (%FVC) in response to sympathetic stimulations delivered at 2 and 5 Hz was determined at rest and during muscle contraction before and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg/kg iv) and subsequent nonselective NOS blockade with N(ω)-nitro-l-arginine methyl ester (l-NAME, 5 mg/kg iv). In series 2 (n = 4), l-NAME was injected first, and then SMTC was injected to determine if the effect of l-NAME on constrictor responses was influenced by selective nNOS inhibition. Sympathetic stimulation decreased FVC at rest (-25 ± 7 and -44 ± 8%FVC at 2 and 5 Hz, respectively) and during contraction (-7 ± 3 and -19 ± 5%FVC at 2 and 5 Hz, respectively). The decrease in FVC in response to sympathetic stimulation was greater in the presence of SMTC at rest (-32 ± 6 and -49 ± 8%FVC at 2 and 5 Hz, respectively) and during contraction (-21 ± 4 and -28 ± 4%FVC at 2 and 5 Hz, respectively). l-NAME further increased (P < 0.05) the sympathetic vasoconstrictor response at rest (-47 ± 4 and -60 ± 6%FVC at 2 and 5 Hz, respectively) and during muscle contraction (-33 ± 3 and -40 ± 6%FVC at 2 and 5 Hz, respectively). The effect of l-NAME was not altered by the order of nNOS inhibition. These data demonstrate that NO derived from nNOS and endothelial NOS contribute to the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle.

Topics: Animals; Citrulline; Electric Stimulation; Enzyme Inhibitors; Hemodynamics; Hyperemia; Male; Muscle Contraction; Muscle, Skeletal; Neurons; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type I; Rats; Rats, Sprague-Dawley; Rest; Sympathetic Nervous System; Thiourea; Vasoconstriction

In the present study, a novel sulfonylthiourea, 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-beta-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, sodium salt (HMR 1402), was investigated using in vitro and in vivo systems. HMR 1402 inhibited rilmakalim-induced currents in rat and guinea pig myocytes (IC(50) = 60 and 509 nM, respectively). Hypoxia-induced shortening of action potential duration at 90% repolarization was also significantly attenuated by HMR 1402 (68.1 +/- 3.9% of control at 0.3 microM). In contrast, HMR 1402 had a smaller effect on pancreatic beta-cells (rat insuloma cells, RINm5F) hyperpolarized with 100 microM diazoxide (IC(50) = 3.9 microM, compared with glibenclamide IC(50) = 9 nM). In a similar manner, hypoxia induced increases in coronary flow in isolated guinea pig hearts were only slightly reduced by HMR 1402. These data strongly suggest that HMR 1402 has pharmacological selectivity for cardiac myocytes and, therefore, may protect against ischemically induced ventricular fibrillation (VF) without the untoward effects of nonselective compounds. To test this hypothesis, VF was induced in 8 dogs with healed myocardial infarctions by a 2-min coronary occlusion during the last minute of exercise. On a subsequent day, the exercise plus ischemia test was repeated after HMR 1402 (3.0 mg/kg i.v., n = 4, infusion 4 microg/kg/min for 1 h before exercise, n = 4). This drug significantly reduced the incidence of VF protecting seven of eight animals (p = 0.0007) without altering plasma insulin, blood glucose, or the increases in mean coronary blood flow induced by either exercise or 15-s coronary occlusions. Thus, the ATP-sensitive potassium channel antagonist HMR 1402 can prevent ischemically induced VF without altering coronary blood flow or blood glucose.

Topics: Animals; ATP-Binding Cassette Transporters; Dogs; Female; Guinea Pigs; Heart; Hyperemia; Islets of Langerhans; KATP Channels; Male; Myocardial Ischemia; Papillary Muscles; Patch-Clamp Techniques; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Thiourea; Ventricular Fibrillation

Reactive hyperemia (RH) is an abrupt blood flow increase following release from mechanical occlusion of an artery, with restoration of intra-arterial pressure. The mechanism of this postocclusion increase in blood flow in the gut is multifactorial. Relaxation of intestinal resistance vessels, observed during RH, may involve myogenic, metabolic, hormonal and neurogenic factors. Evidence exists that histamine is an important endogenous mediator of various functions of the gut, including blood flow. The vascular effects of histamine in the intestinal circulation are due its agonistic action on histamine H1, H2 and H3 receptors. In the present study the hypothesis was tested that peripheral histamine H3 receptors are involved in the mediation of RH in the intestinal circulation. In anesthetized rats, anterior mesenteric artery blood flow (MBF) was determined with ultrasonic Doppler flowmeter, and arterial pressure (AP) was determined with a transducer. The increase in the volume of blood accumulating during RH (RH-volume), the peak increase of arterial blood flow (RH-peak response) and the duration of the hyperemia (RH-duration) were used to quantify RH after occluding the anterior mesenteric artery for 30, 60 and 120 s. Hyperemia parameters were determined before and after administration of the selective histamine H3 receptor antagonist clobenpropit. Pretreatment with clobenpropit was without any effect on control MBF and AP but significantly reduced most of RH responses. These findings support the hypothesis that histamine H3 receptors do not play any role in the control of intestinal vasculature at basal conditions but these receptors participate in the intestinal hyperemic reaction in response to complete temporal intestinal ischemia.

Topics: Animals; Blood Pressure; Female; Histamine Agonists; Histamine Antagonists; Hyperemia; Imidazoles; Infusions, Intra-Arterial; Intestinal Mucosa; Intestines; Male; Mesenteric Arteries; Mesenteric Vascular Occlusion; Rats; Rats, Wistar; Receptors, Histamine H3; Regional Blood Flow; Thiourea

Ten normal human volunteers participated in a two-part study of H2-receptor activity in the ocular surface. Dimethylaminopropylisothiourea (trivial name, dimaprit dihydrochloride), a highly selective H2-receptor agonist, produced vasodilation without itch. Pretreatment with the H2-receptor antagonist, cimetidine, significantly blocked the vasodilatory effect of dimethylaminopropylisothiourea, whereas pretreatment with the H1-receptor antagonist, antazoline phosphate, did not. We conclude that H2-receptors are present in the human ocular surface.

Topics: Antazoline; Cimetidine; Conjunctiva; Dimaprit; Humans; Hyperemia; Receptors, Histamine; Receptors, Histamine H2; Thiourea; Vasodilation

Using the hydrogen clearance method, focal spinal cord blood flow was measured in the lateral funiculus of Rhesus monkeys traumatized with a 600 gm cm injury to T10, pretreated with either chlorpheniramine or metiamide. The blood flow in the chlropheniramine treated animals either rose slightly or remained in the normal range. That in the metiamide treated animals remained in the normal range at all times in all animals. On the basis of these results we can further define the previously observed post traumatic lateral white matter hyperemia as mainly an H2 histamine related phenomenon.

Topics: Animals; Chlorpheniramine; Haplorhini; Histamine; Hyperemia; Macaca mulatta; Regional Blood Flow; Spinal Cord; Spinal Cord Injuries; Thiourea

Topics: Animals; Benzyl Compounds; Ethylenediamines; Gastric Juice; Gastric Mucosa; Histamine; Histamine H1 Antagonists; Hyperemia; Imidazoles; Prostaglandins; Pyridines; Rats; Thiourea

Topics: Animals; Connective Tissue; Cysts; Epithelial Cells; Epithelium; Fishes; Gonads; Hyperemia; Hyperplasia; Hypertrophy; Injections, Intraperitoneal; Iodine Isotopes; Pituitary Gland; Temperature; Thiourea; Thyroid Diseases; Thyroid Gland

Topics: Animals; Guinea Pigs; Hyperemia; Hypersensitivity; Microbial Sensitivity Tests; Skin Tests; Thiocyanates; Thiourea