nitroarginine and ridogrel

Previous studies from our own laboratory have shown that abdominal aorta rings from two kidney - two clip hypertensive rats (HT) develop hypersensitivity to serotonin (SER) which is related to a decreased nitric oxide (NO) availability and enhanced thromboxane A2 production. In the present study we investigated whether calcium and prostanoid-NO interactions are involved in these findings. To this purpose, the aortic responses to SER were analyzed in calcium-free medium and in calcium-depleted aorta placed in normal medium. Moreover, effects of ridogrel (RID, an antagonist of TxA 2/PGH2 receptors and inhibitor of thromboxane synthetase) were analysed by cumulative dose-response curves to SER in the presence and in the absence of the NO synthase inhibitor N(omega)-nitro-L-arginine (NOLA). Vascular responses to SER in vessels from HT rats were associated with increased intracellular calcium mobilization. In addition, hypersensitivity to SER in HT group respect to sham group (SH) disappeared in the presence of RID, NOLA and RID plus NOLA. RID decreases the maximum tension to SER and this effect was prevented by NOLA. This inhibition was of a greater magnitude in rings from sham rats (SH): 34 +/- 6% than in HT rats: 15 +/- 6% (p < 0.05). Besides, RID decreased the sensibility to SER in the presence of NOLA only in the HT group. In conclusion, the present study suggests that SER hypersensitivity observed in HT rats is related to a facilitated intracellular calcium mobilization and enhanced TxA2-endoperoxide response. Changes in membrane SER-gated calcium channels opening are observed only during the early hypertensive period. Besides, the lower depressor effect of RID on the maximal tension to SER in aorta rings from HT rats are related with a decreased NO availability in this model of renovascular hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blood Pressure; Calcium; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Hypertension; Kidney; Male; Muscle Contraction; Nitroarginine; Pentanoic Acids; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyridines; Rats; Rats, Wistar; Serotonin; Thromboxane B2; Time Factors

To determine the role of endothelium-derived contracting factor (EDCF) in the response to endothelin-1 in arteries with regenerated endothelium.. Rings of porcine coronary arteries, with and without endothelium of previously deendothelialized left anterior descending coronary arteries and native left circumflex coronary arteries, were suspended in conventional organ chambers for the measurement of isometric force.. In quiescent rings of the previously deendothelialized left anterior descending coronary artery treated with the NO-synthase inhibitor nitro-L-arginine, endothelin-1 caused contractions which were larger in rings with than that in those without endothelium. Under the same experimental conditions, in the left circumflex coronary artery, the contractions to endothelin-1 were augmented markedly by the removal of the endothelium. In rings with endothelium of the previously deendothelialized left anterior descending coronary artery, indometacin (inhibitor of cyclooxygenase) and ridogrel (thromboxane A2 receptor antagonist and inhibitor of thromboxane synthase) inhibited contractions to endothelin-1. Dazoxiben (inhibitor of thromboxane synthase) inhibited, to the same extent as indometacin and ridogel, the response to higher concentrations of endothelin-1. The endothelium-dependent component of the response to lower concentrations of endothelin-1 was inhibited by indometacin and ridogrel, but not by dazoxiben. In rings without endothelium of both previously deendothelialized left anterior descending and native left circumflex coronary arteries, indometacin and ridogrel did not affect the contractions to endothelin-1.. These findings suggest that in regenerated endothelium, high concentrations of endothelin-1 stimulate the release of thromboxane A2. Endoperoxides generated by activation of endothelial cyclooxygenase may be the endothelium-derived contracting factor(s) released in regenerated endothelium by lower concentrations of the peptide.

Topics: Animals; Coronary Vessels; Cyclooxygenase Inhibitors; Endothelin-1; Endothelium, Vascular; Imidazoles; Indomethacin; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroarginine; Pentanoic Acids; Pyridines; Swine; Thromboxane A2; Thromboxane-A Synthase

Inhibition of nitric oxide (NO) synthesis induces vasoconstriction and reduction of the blood flow in the brain, indicating that basal release of NO provides a resting vasorelaxant tone in the cerebral circulation. In the present study, the contractile effect of the NO synthase blocker NG-nitro-L-arginine (100 mumol/L) in isolated rat middle cerebral arteries was attenuated markedly in the presence of the cyclooxygenase inhibitor indomethacin (5 mumol/L), the thromboxane A2 synthase inhibitor ridogrel (10 mumol/L), or the thromboxane receptor antagonist ICI 192605 (100 mumol/L). These results indicate that removal of the endogenous NO stimulates the release of thromboxane A2 in cerebral vessels and basal NO production regulates the resting cerebrovascular tone, at least in part, by suppressing thromboxane A2.

Topics: Animals; Cerebral Arteries; Cyclooxygenase Inhibitors; Dioxanes; Enzyme Inhibitors; Indomethacin; Male; Muscle Contraction; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pentanoic Acids; Pyridines; Rats; Rats, Wistar; Thromboxane A2; Thromboxane-A Synthase

The effects of Androctonus crassicauda scorpion venom on acetycholine (ACh)-induced relaxations and contractions of rabbit thoracic aorta were studied. Endothelium-dependent relaxations induced by ACh in phenylephrine-precontracted arteries were enhanced by the scorpion venom. ACh-induced contractions in endothelium-intact open aortic rings were less than those obtained in denuded preparations (n = 6, P < 0.05, ANOVA). Venom (5, 10 and 30 micrograms/ml) potentiated ACh-induced contractions in intact and denuded segments. In the denuded segments, this potentiation was inhibited by indomethacin (10 microM). Thromboxane synthase inhibitor, BW 149H (100 microM) and thromboxane A2 (TXA2) receptor antagonist, R 68070 (10 microM) partly inhibited venom-induced potentiation. NG-nitro-L-arginine (100 microM) increased venom-potentiated ACh responses in intact arterial segments. Venom increased the basal tone by 25-35% at 30 micrograms/ml. These results suggest that A. crassicauda venom may release a relaxing factor from endothelium and contracting factor from the smooth muscle of rabbit isolated thoracic aorta. The contracting factor may be a cyclooxygenase-like product, most likely TXA2. The increase in basal tone by 30 micrograms/ml venom was inhibited by phentolamine (10 microM) and guanethidine (10 microM), indicating a venom-induced release of a neurotransmitter from adrenergic nerve endings.

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aorta, Thoracic; Endothelium, Vascular; Enzyme Inhibitors; Female; In Vitro Techniques; Indomethacin; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitroarginine; Organic Chemicals; Pentanoic Acids; Pyridines; Rabbits; Scorpion Venoms; Thromboxane-A Synthase

To investigate dilator effects of endothelins (ETs) on the pulmonary circulation and possible changes induced by chronic hypoxia, we examined vascular responses to ET-1 and ET-3 as well as ET binding to receptor subtypes ETA and ETB in the lungs from rats exposed to either room air (controls), hypoxia (10% O2) for 3 wk (3 WH), or 3 WH followed by recovery to room air (3 WH+R). In controls, both ETA and ETB receptor binding was present in smooth muscle of airways and vessels. Infusion of ET-1 or ET-3 (3-100 pM) to isolated perfused lungs preconstricted by U-46619 produced dose-dependent vasodilation with a greater potency of ET-3 (P < 0.01). The vasodilator responses to ET-1 and ET-3 were potentiated by the cyclooxygenase blocker meclofenamate (3 x 10(-6) M) or by the thromboxane synthetase inhibitor R-68070. In meclofenamate-treated lungs, the vasodilator responses to ET-1 and ET-3 remained unaffected by the inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (5 x 10(-4) M) or by the guanylate cyclase inhibitor, methylene blue (10(-4) M). Conversely, the K+ channel blockers glibenclamide (10(-4) M) and tetraethylammonium (10(-4) M) attenuated the vasodilator responses to both ET-1 and ET-3. The selective ETA receptor antagonist BQ-123 did not alter ET-induced vasodilation, whereas it attenuated ET-induced vasoconstriction. Vasodilation to both ET-1 and ET-3 was abolished in lungs from 3 WH rats (P < 0.01) but was fully restored in lungs from 3 WH+R rats. Pulmonary vasodilation induced by the K+ channel opener pinacidil, which was suppressed by glibenclamide, did not differ between controls and 3 WH rat lungs. We found no change in ETA and ETB receptor binding from pulmonary vessels in H rat lungs compared with controls. In conclusion, endothelin-induced pulmonary vasodilation which may involve activation of K+ channels is abolished during chronic hypoxia. This abolition does not appear to be related to alterations in ET-receptor subtypes or to unresponsiveness of K+ channels in the pulmonary circulation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arginine; Autoradiography; Dose-Response Relationship, Drug; Endothelins; Glyburide; Guanidines; Hypoxia; In Vitro Techniques; Iodine Radioisotopes; Lung; Male; Meclofenamic Acid; Nitroarginine; Pentanoic Acids; Pinacidil; Potassium Channel Blockers; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Pyridines; Rats; Rats, Wistar; Receptors, Endothelin; Tetraethylammonium; Tetraethylammonium Compounds; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents