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ABSTRACT: The role of nitric oxide in cerebrovascular response to hypotension was analyzed by evaluating the changes in cerebrovascular resistance after inhibition of nitric oxide synthesis with Nw-nitro-l-arginine methyl ester (l-NAME) during three types of hypotension in conscious goats. Blood flow to one brain hemisphere was electromagnetically measured, hypotension was induced by controlled bleeding, and by i.v. administration of hexametonium (ganglionic blocker) or of diazoxide (vasodilator drug), and l-NAME was injected by i.v. route (35 mg kg−1). Under control conditions (13 goats), l-NAME increased arterial pressure from 98±3 to 123±4 mmHg and decreased cerebral blood flow from 65±3 to 40±3 ml min−1 (all P<0.001); cerebrovascular resistance increased from 1.52±0.04 to 3.09±0.013 mmHg ml−1 min−1 (P<0.01) (Δ=1.59±0.12 mmHg ml−1 min−1). After bleeding (five goats), mean arterial pressure decreased to 60±4 mmHg and cerebral blood flow decreased to 37±4 ml min−1 (all P<0.01); cerebrovascular resistance did not change (1.56±0.14 vs. 1.54±0.12 mmHg ml−1 min−1, P>0.05). During this hypotension, l-NAME increased arterial pressure to reach the normotensive values and did not affect the hypotensive values for cerebral blood flow; cerebrovascular resistance increased from the hypotensive values to 2.91±0.19 mmHg ml−1 min−1 (P<0.01) (Δ=1.37±0.16 mmHg ml−1 min−1), and this increment is comparable to that under control conditions (P>0.05). Ganglionic blockade (six goats) decreased arterial pressure to 67±2 mmHg) and did not affect significantly cerebral blood flow; cerebrovascular resistance decreased from 1.71±0.11 to 1.05±0.09 mmHg ml−1 min−1 (P<0.01). During this hypotension, l-NAME increased arterial pressure to 103±6 mmHg (P<0.001), and did not affect cerebral blood flow; cerebrovascular resistance increased from the hypotensive values to 1.68±0.18 mmHg ml−1 min−1 (P<0.01) (Δ=0.63±0.10 mmHg ml−1 min−1), and this increment was lower than under control conditions (P<0.01). Diazoxide (six goats) decreased arterial pressure to 69±5 mmHg (P<0.01) without changing cerebral blood flow; cerebrovascular resistance decreased from 1.89±0.11 to 1.16±0.14 mmHg ml−1 min−1 (P<0.01). During this hypotension, l-NAME increased arterial pressure to 87±6 mmHg (P<0.05) and did not affect the hypotensive values for cerebral blood flow (P>0.05); cerebrovascular resistance increased from the hypotensive values to 1.53±0.13 mmHg ml−1 min−1 (P<0.05) (Δ=0.36±0.06 mmHg−1 ml−1 min−1), and this increment was lower than under control conditions (P<0.01). Therefore, the role of nitric oxide in cerebrovascular response to hypotension may differ in each type of hypotension, as this role during hemorrhagic hypotension may not change and during hypotension by ganglionic blockade or diazoxide may decrease. These differences may be related to changes in nitric oxide release as stimuli on the endothelium (shear stress and sympathetic activity) may vary in each type of hypotension.
Brain Research. 851:133-140.
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ABSTRACT: This study was performed to examine the role of nitric oxide in the effects of hypoglycemia on the cerebral circulation. Hypoglycemia was induced with insulin and its effects on cerebral blood flow (measured with an electromagnetic flow transducer placed on the internal maxillary artery) were studied in awake goats under control conditions and after administration of the nitric oxide synthesis inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 47 mg/kg). Also, cerebrovascular reactivity to vasodilator stimuli was examined during insulin-induced severe hypoglycemia, before and after l-NAME treatment. In five animals under control conditions (glycemia=90±7 mg/dl, cerebral blood flow=64±4 ml/min, mean systemic arterial pressure=102±4 mmHg, cerebrovascular resistance=1.62±0.11 mmHg/ml per min and heart rate =73±6 beats/min), insulin decreased glycemia: when hypoglycemia was moderate (glycemia=46±2 mg/dl) or severe (glycemia=26±1 mg/dl) cerebral blood flow increased by 25±4% and 47±6%, and cerebrovascular resistance decreased by 18±3% and 34±4%, respectively. Under basal conditions, l-NAME did not affect glycemia but reduced resting cerebral blood flow by 37±2%, increased mean arterial pressure by 33±2% and decreased heart rate by 28±3%; after l-NAME, both moderate and severe hypoglycemia did not alter significantly resting cerebral blood flow and cerebrovascular resistance. In five other goats, l-NAME, administered during severe hypoglycemia, abolished the increase in cerebral blood flow, and increased cerebrovascular resistance and mean arterial pressure over the control (normoglycemic) values. In these animals with severe hypoglycemia, acetylcholine (0.01–1 μg), isoproterenol (0.03–3 μg) and diazoxide (0.3–9 mg), injected into the internal maxillary artery, decreased cerebrovascular resistance in a dose-dependent manner, and this decrease was similar before and after l-NAME. Therefore, insulin-induced hypoglycemia may produce cerebral vasodilatation by releasing nitric oxide and may diminish the capacity of the cerebral vasculature to release nitric oxide in response to acetylcholine.
European Journal of Pharmacology.
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ABSTRACT: This study concerned the effects and mechanisms of action of endothelin-1 on the cerebral circulation. Cerebral blood flow was electromagnetically measured in awake goats. Endothelin-1 (0.01–0.3 nmol) produced dose-dependent decreases in this flow (maximal reduction=34%) and increases in cerebrovascular resistance (maximal increase=74%) (P<0.01). IRL 1620 (Suc-[Glu9, Ala11,15]endothelin-1-(8–21), agonist for endothelin ETB receptors, 0.01–0.3 nmol) slightly decreased cerebral blood flow. The effects of endothelin-1, but not those of IRL 1620, on cerebral blood flow were diminished by 50% during infusion of the antagonist for endothelin ETA receptors, BQ-123 (cyclo-(d-Asp–Pro–d-Val–Leu–Trp), 2 nmol min−1), but not affected during infusion of the antagonist for endothelin ETB receptors, BQ-788 (N-[N-[N-[(2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-l-Leucyl-1-(methoxycarbonyl)-d-tryptophyl]-d-norleucine monosodium), 2 nmol min−1). Intravenous administration of NW-nitro-l-arginine methyl ester (l-NAME, 47 mg kg−1) or NW-nitro-l-arginine (l-NNA, 47 mg kg−1) reduced basal cerebral blood flow by 39 and 33%, increased cerebrovascular resistance by 108 and 98% and mean arterial pressure by 23 and 17%, and decreased heart rate by 27 and 25%, respectively (all at least P<0.05). The increases in cerebrovascular resistance (as absolute values) induced by endothelin-1 were not affected during either l-NAME or l-NNA (as absolute values and percentages). Intravenous administration of meclofenamate (5 mg kg−1) did not change the cerebrovascular effects of endothelin-1 and IRL 1620. In isolated goat cerebral arteries under control, resting conditions, endothelin-1 (10−11–10−7 M) induced concentration-dependent contractions (EC50=4.78×10−9 M; maximal contraction=3177±129 mg), whereas IRL 1620 (10−11–10−7 M) produced no effect. This contraction produced by endothelin-1 was competitively blocked by BQ-123 (10−7–3×10−6 M), and was not affected by BQ-788 (10−6 and 10−5 M). l-NAME (10−4 M), meclofenamate (10−5 M), indomethacin (10−5 M), l-NAME (10−4 M) plus meclofenamate (10−5 M) and phosphoramidon (10−4 M) did not affect the contraction in response to endothelin-1. Endothelium removal increased the response to endothelin-1, as well as the BQ-123 antagonism against endothelin-1 (pA2 values, 7.62 vs. 6.88; P<0.01). In both intact and de-endothelized arteries precontracted with prostaglandin F2α, endothelin-1 induced a further contraction, and IRL 1620 caused no effect. These results suggest that: (1) endothelin-1 produces cerebral vasoconstriction by activating endothelin ETA receptors probably located in smooth muscle; (2) endothelin ETB receptors, nitric oxide and prostanoids might be not involved in the cerebrovascular action of endothelin-1, and (3) endothelium removal may increase cerebrovascular reactivity by increasing sensitivity of endothelin ETA receptors to endothelin-1.
European Journal of Pharmacology.
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ABSTRACT: To examine the role of vasopressin V1 and V2 receptors, nitric oxide and prostanoids in the coronary vascular effects of [Arg8]vasopressin, coronary blood flow was measured with an electromagnetic flow transducer placed around the left circumflex (23 goats) or anterior descending (11 goats) coronary artery and vasopressin (0.03–1 μg) was intracoronarily injected in 34 anesthetized, open-chest goats. Basal mean values for coronary blood flow, mean systemic arterial pressure and heart rate, were 34±2.38 ml/min, 89±3.34 mmHg and 80±3.06 beats/min, respectively. Vasopressin produced dose-dependent decreases in coronary blood flow and the maximal reduction of this flow, attained with 1 μg of vasopressin, was 14±1.49 ml/min (42±2.64% of basal flow) (P<0.01). Desmopressin (0.03–1 μg; 8 goats) did not affect significantly coronary blood flow. The intracoronary infusion of the antagonist for vasopressin V1 receptors d(CH2)5Tyr (Me) arginine vasopressin (2 μg/min per kg, 6 animals) significantly diminished the effects of vasopressin on coronary blood flow (the effects of 1 μg of vasopressin were reduced by 28%, P<0.05). The mixed antagonist for vasopressin V1 and V2 receptors desGly-d(CH2)5-d-Tyr(Et)Val arginine vasopressin (0.2, 0.7 and 2 μg/min per kg, 9 animals) decreased in a dose-dependent manner the effects of vasopressin on coronary blood flow (the effects of 1 μg of vasopressin were decreased by 61% with 2 μg/min per kg, P<0.01). Intracoronary infusion of saline (vehicle, 3 goats) did not change the effects of vasopressin on coronary blood flow. Intravenous administration of the inhibitor of nitric oxide synthesis Nw-nitro-l-arginine methyl ester (l-NAME, 47 mg/kg, 9 animals) decreased resting coronary blood flow by 10% (P<0.01) and augmented mean systemic arterial pressure by 20% (P<0.01), without changing heart rate. During this treatment the reduction in coronary blood flow produced by vasopressin was higher than under control (the effects of 1 μg of vasopressin were increased by 28%, P<0.01). Intravenous administration of the inhibitor of cyclooxygenase, meclofenamate (5 mg/kg, 7 animals), neither modified resting coronary blood flow, arterial pressure and heart rate nor the effects of vasopressin on this flow. These data indicate that vasopressin produces marked coronary vasoconstriction and suggest that: (a) it may be mediated by vasopressin V1 receptors, without involvement of vasopressin V2 receptors, (b) it is probably inhibited by nitric oxide under normal conditions and (c) it may be not modulated by prostanoids.
European Journal of Pharmacology.
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ABSTRACT: Electrical field stimulation (4 Hz, 0.2 ms, 70 V supramaximal voltage, 10 s duration) produced contraction of perfused rabbit central ear arteries, and this contraction was reduced by incubation with insulin (0.6–200 mU/ml). This inhibitory effect of insulin was not significantly modified by removing the endothelium, or by treatment with NW-nitro-l-arginine (l-NA, 10−4 M), meclofenamate (10−5 M), ouabain (10−6 M), or cocaine (10−5 M). Insulin (200 mU/ml) did not modify the vascular contraction due to exogenous norepinephrine (10−8–10−4 M) nor the relaxation due to acetylcholine (10−8–10−4 M). This suggests that insulin may reduce vascular contraction by sympathetic stimulation, and this effect is not dependent on endothelial nitric oxide, prostanoids, or Na+–K+ pump activation.
General Pharmacology: The Vascular System.
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ABSTRACT: Electrical field stimulation (4 Hz, 0.2 ms pulse duration, at a supramaximal voltage of 70 V, for 1 s) of isolated rat tail artery segments produced contraction which was lower in female than in male rats, and was reduced by streptozotocin-induced diabetes in both genders. This contraction was potentiated by vasopressin (10−12–10−10 M) more in normoglycemic male than in normoglycemic female rats, and this effect of vasopressin was increased by the cyclooxigenase inhibitor meclofenamate (10−5 M) in female control rats, but not in diabetic female, or control and diabetic male rats, and it was not modified by the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME, 10−4 M). Endothelin-1 (10−10–3×10−9 M) also potentiated the contraction to electrical stimulation. This potentiation was similar in all experimental groups, and it was not modified by meclofenamate or l-NAME. These results suggest that the potentiating effect of vasopressin, but not that of endothelin-1, on the sympathetic vasoconstriction, is lower in females than in males, probably by an increased release of vasodilating prostanoids, and this release may be reduced by diabetes in females.
European Journal of Pharmacology.
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ABSTRACT: To examine the coronary effects of arginine–vasopressin during reperfusion after a short ischemia, left circumflex coronary artery flow was electromagnetically measured, and 15 min total occlusion of this artery followed by reperfusion was induced in anesthetized goats (five nontreated, five treated with the inhibitor of nitric oxide synthesis Nw-nitro-l-arginine methyl ester (l-NAME) and five treated with the inhibitor of cyclooxygenase meclofenamate). The vasoactive drugs and l-NAME were intracoronarily injected, and meclofenamate by i.v. route. At 60 min of reperfusion, coronary vascular conductance was not changed significantly in nontreated and was decreased by 35% (P<0.01) in l-NAME-treated and by 30% (P<0.01) in meclofenamate-treated animals. During reperfusion, the coronary vasodilatation with acetylcholine (3–100 ng) and sodium nitroprusside (1–10 μg) was not altered in nontreated animals, and the vasodilatation with acetylcholine but not with sodium nitroprusside was partially decreased in l-NAME—but not in meclofenamate-treated animals. The vasoconstriction in response to arginine–vasopressin (0.03–0.3 μg) was increased during reperfusion in nontreated, was not changed in l-NAME-treated and was decreased in meclofenamate-treated animals. Therefore, it is suggested that during reperfusion after a short ischemia: (1) the coronary vasodilator reserve is preserved; (2) the coronary vasodilatation with acetylcholine is also preserved, but in this vasodilatation, the role of nitric oxide may be attenuated and prostanoids may be not involved; and (3) the coronary vasoconstriction with arginine–vasopressin is increased, probably due to both attenuation of the modulatory role of nitric oxide and the release of vasoconstrictor prostanoids.
European Journal of Pharmacology.
