Norepinephrine Dose-response Curves Research Articles

Coenzymea glutathione disulfide is a potent modulator of angiotensin II–Induced vasoconstriction

CoenzymeA glutathione disulfide (CoASSG) has recently been isolated from bovine adrenal glands and is assumed to play an important role in blood pressure (BP) control. We used the isolated perfused rat kidney to investigate the modulating effects of CoASSG on angiotensin II (AngII)-induced vasoconstriction. Permanent perfusion with CoASSG (1 μmol/L) for 60 min induced a significant (P < .05) shift to the left in the dose-response curve for AngII (about 3.1-fold), whereas the dose-response curve for norepinephrine (NE) was unaffected. During continuous perfusion with 1 μmol/L CoASSG, the repetitive application of 10 pmol AngII significantly increased its vasoconstriction by 170% ± 14% (P < .05) and 235% ± 50% (P < .05) for 60 and 120 min, respectively. The potentiation of AngII by permanent perfusion with CoASSG is dose- and time-dependent and shows a plateau at 120 min. Glutathione, oxidized coenzymeA, and coenzymeA (each 1 μmol/L) are not able to enhance the vasoconstriction induced by AngII. We conclude that CoASSG is able to potentiate the vasoactive properties of AngII, and that CoASSG might play an important role in BP regulation via modulating effects of AngII.

INVESTIGATION OF ENDOTHELIAL CONTROL OF BONE BLOOD FLOW: DEVELOPMENT OF A RABBIT TIBIA EX VIVO PERFUSION MODEL

An ex vivo rabbit tibia perfusion model was developed to investigate the vascular reactivity and vascular endothelial function of bone tissue. The tibiae of 36 adult New Zealand rabbits were isolated and perfused through the cannulated nutrient artery at a constant flow rate in an organ chamber. The increase in perfusion pressure caused by graded doses of norepinephrine produced a dose response curve, which was first recorded under control condition, and then during perfusion with acetylcholine (ACh), N G -monomethyl-L-arginine acetate (L-NMMA), and/or L-arginine (nitric oxide precursor) infusion. The optimal flow rate for rabbit tibia was 0.3 to 0.4 ml/min, depending on the weight of the tibia. The perfusion baseline and the norepinephrine dose-response curve (NEDRC) remained stable for at least eight hours. Acetylcholine (1 × 10-5 M ) infusion attenuated the NEDRC (33 ± 5%) for 1.5 hours. Thereafter, the vasorelaxant effect of ACh diminished due to depletion of nitric oxide, and ultimately caused an increase in the NEDRC due to a vasoconstrictive action. The rebound vasoconstriction did not occur in the presence of constant L-arginine infusion, which maintained nitric oxide production, and ACh continued to attenuate the NEDRC (36 ± 4.5%) for at least eight hours. L-NMMA, which inhibits the synthesis of nitric oxide, increased the vasoconstrictive effect of norepinephrine significantly (155 ± 16%). The rabbit tibia ex vivo model seems ideal for the study of bone vascular bed activity, due to its stable baseline, reliable NEDRC and cost efficiency. We have further demonstrated that the intraosseous vascular endothelium of rabbit tibia produces nitric oxide as one method of regulating bone perfusion.

Venous responsiveness to norepinephrine in healthy subjects: Effects of single doses of 325 mg aspirin

Antithrombotic doses of aspirin, which are widely used in patients with cardiovascular disease, may inhibit prostaglandin synthesis but the physiologic significance with regard to vascular tone is not well defined. We hypothesized that inhibition of vasodilator prostaglandin synthesis by aspirin would significantly increase sympathetic-mediated venoconstriction. Twelve healthy volunteers (mean age, 24.5 +/- 0.8 years; age range, 19 to 30 years) were studied on two mornings approximately 7 days apart and not less than 90 minutes after a randomized single dose of 325 mg aspirin or matching placebo. Distension of dorsal hand veins was measured with use of the linear variable differential transformer technique during local infusions of exogenous norepinephrine (0.125 to 1,024 ng/min) and during release of endogenous norepinephrine from sympathetic activation by a forehead cold pressor test. Hemodynamic parameters and venous plasma catecholamine levels were measured. Antiplatelet activity of the dose of aspirin was confirmed in three subjects. Aspirin increased venoconstriction to norepinephrine, causing a significant shift to the left (P < .03) of the norepinephrine dose-response curve and a significant decrease in logED50 (P < .03), representing a decrease in the dose of norepinephrine required to reduce vein distension by 50% from 50 to 25 ng/min. Venoconstriction to the cold pressor test was significantly increased by aspirin (10% +/- 3% versus 3% +/- 1% for placebo; P < .02). Cold pressor-induced increases in mean arterial pressure were significantly larger with aspirin compared with placebo (18 +/- 1 versus 14 +/- 1 mm Hg, respectively; P < .03). Baseline levels and stress-induced increases in plasma norepinephrine were not different between days. The results suggest that aspirin inhibits the role of vasodilator prostaglandins in modulating peripheral venoconstriction and increases vascular resistance during physiologic stress in young healthy subjects.

Effect of high Ba(2+) on norepinephrine-induced inhibition of N-type calcium current in bullfrog sympathetic neurons.

The voltage-dependent inhibition of N-type calcium current by neurotransmitters is the best-understood example of neuronal calcium channel inhibition. One of the mechanisms by which this pathway is thought to inhibit the calcium current is by reducing the permeation of divalent cations through the channel. In this study one prediction of this hypothesis was examined, that high concentrations of divalent cations reduce the maximum neurotransmitter-induced inhibition. Norepinephrine (NE)-induced inhibition was compared in external solutions containing either 2 or 100 mM Ba(2+). Initially, NE dose-response curves were generated by averaging data from many neurons, and it was found that the relationship was right shifted in the high-Ba(2+) external solution without an effect on maximum inhibition. The IC(50) was 0.6 and 3 microM in 2 and 100 mM Ba(2+), respectively. This shift was verified by comparing the effect of NE on single neurons exposed to both 2 and 100 mM Ba(2+). The inhibition induced by 1 microM NE was reduced in 100 mM Ba(2+) compared with that in 2 mM Ba(2+). However, the response to 100 microM NE was identical between high and low Ba(2+). Thus, divalent cations appear to act as a competitive inhibitor of NE binding, which likely results from these ions' interacting with negatively charged amino acids that are important for catecholamine binding to adrenergic receptors. Because the maximum inhibition induced by NE was similar in low and high Ba(2+), the effect of inhibition on single N-type calcium channels was not altered by the divalent cation concentration.

COMPARISON OF NOREPINEPHRINE -INDUCED VASO-CONSTRICTION IN SECOND ORDER ARTERIOLES FROM DIAPHRAGM AND RED AND WHITE SKELETAL MUSCLE.

1778 We tested the hypothesis that arterioles from the diaphragm (DIA) and red portion of the gastrocnemius (RG) have reduced vasoconstrictor responses to norepinephrine (NE) as compared to arterioles from the white portion of the gastrocnemius (WG). Vasomotor responses were examined in 2A arterioles which were isolated, cannulated, and pressurized to 60 cm H2O. Cumulative NE dose-response curves (10−9 to 10−4 M) were constructed while intraluminal diameter was monitored continuously. To examine the role of endothelium-mediated mechanisms in responses to NE arterioles were denuded by passing 3 mL of air through the lumen of the arteriole. Results are summarized below: baseline and maximal constriction data are diameters relative to that measured in Ca++-free buffer.(Table)TableNE produced less constriction in DIA compared to WG and RG. Denudation increased maximal constriction in DIA but not WG and RG and NE-sensitivity (EC50) in WG but not DIA and RG. Importantly, NE-constriction was still less in DIA than in RG and WG following denudation. Baseline diameter was reduced in WG but not DIA and RG. These data suggest that there are differences in the VSM response to NE in DIA compared to WG and RG. In addition, the endothelium appears to be important in determining basal tone in WG but not in DIA and RG. Supported by ASCM Foundation Research Grant and HL-36088.

Haloperidol-mediated phosphoinositide hydrolysis via direct activation of α1-adrenoceptors in frontal cerebral rat cortex

In addition to its effect on D2 dopamine receptor blockades, haloperidol is able to interact with multiple neurotransmitters (NTs). Its action on phosphoinositide (PI) turnover was studied on cerebral cortex preparations. It induces an increase in inositol phosphate (IP) accumulation, which was only blunted by the α1-adrenoceptor blocker prazosin. Haloperidol maximal effect (Emax) was less than the effect of the full agonist norepinephrine (NE), and dose-response curves for both NE in the presence of submaximal doses of haloperidol and haloperidol in the presence of Emax doses of NE showed that haloperidol behaves as a partial agonist of cerebral α1-adrenoceptors. Its effect on PI hydrolysis is mediated through phospholipase C activation, as 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC) and 1-[6-([(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione) (U-73122) were able to abrogate both haloperidol and NE actions. Further, the typical neuroleptic exerts a direct activation of α1-adrenoceptors as its actions were not modified by cocaine and persisted in spite of chemical rat cerebral denervation with 6-hydroxydopamine (6-OHDA). The possibility that this agonistic action on α1-adrenoceptors would be involved in haloperidol side effects is also discussed.Key words: haloperidol, neuroleptics, α1-adrenoceptor, phosphoinositide hydrolysis, cerebral frontal cortex.

Haloperidol-mediated phosphoinositide hydrolysis via direct activation of alpha1-adrenoceptors in frontal cerebral rat cortex.

In addition to its effect on D2 dopamine receptor blockades, haloperidol is able to interact with multiple neurotransmitters (NTs). Its action on phosphoinositide (PI) turnover was studied on cerebral cortex preparations. It induces an increase in inositol phosphate (IP) accumulation, which was only blunted by the alpha1-adrenoceptor blocker prazosin. Haloperidol maximal effect (Emax) was less than the effect of the full agonist norepinephrine (NE), and dose-response curves for both NE in the presence of submaximal doses of haloperidol and haloperidol in the presence of Emax doses of NE showed that haloperidol behaves as a partial agonist of cerebral alpha1-adrenoceptors. Its effect on PI hydrolysis is mediated through phospholipase C activation, as 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC) and 1-[6-([(17beta)-3-methoxyestra- 1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione) (U-73122) were able to abrogate both haloperidol and NE actions. Further, the typical neuroleptic exerts a direct activation of alpha1-adrenoceptors as its actions were not modified by cocaine and persisted in spite of chemical rat cerebral denervation with 6-hydroxydopamine (6-OHDA). The possibility that this agonistic action on alpha1-adrenoceptors would be involved in haloperidol side effects is also discussed.

Effects of norepinephrine on the mechanical properties of the human radial artery in vitro

Background The human radial artery has been proposed as an alternative to coronary grafts in subjects with coronary ischemic disease. Because this muscular artery is known to be prone to spasm, changes in its mechanical properties in response to catecholamines are important to investigate. Methods We describe a new echo-tracking technique of high resolution that allows investigation, in vitro, of the diameter and the wall thickness of arterial cylindrical segments. In addition, a classic tissue bath experiment is used to study the vasoreactivity of arterial rings. Mechanical properties of the radial artery are determined over a 0 to 200 mm Hg range of transmural pressure in the presence and absence of norepinephrine in the perfusion medium. Results With tissue bath experiments, the norepinephrine dose-response curve was characterized by an EC 50 value of 1.48 ± 1.09 10 -6 mol/L and a maximal developed tension at 10 -5 mol/L. The results obtained with pressurized segments gave similar results with an EC 50 value of 8.1 ± 2.3 10 -7 mol/L and a maximal change in diameter at 10 -5 mol/L norepinephrine. Under the influence of 10 -5 mol/L norepinephrine, the radial artery constriction reached 22%, significantly affecting the unstressed diameter. Compliance did not show any significant change in the overall transmural pressure range, whereas distensibility significantly increased and elastic modulus significantly decreased. Conclusion The study shows that the capacitive properties of the human muscular radial artery are maintained with norepinephrine not only through decreased stiffness of wall material but also through reduced unstressed diameter. Thus drugs inducing smooth muscle relaxation may be helpful in preventing radial artery spasm after coronary grafts. (Am Heart J 1998;136:624-31.)

Norepinephrine-induced contraction of isolated rabbit bronchial artery: role of alpha 1- and alpha 2-adrenoceptor activation.

The contractile effect of norepinephrine (NE) on isolated rabbit bronchial artery rings (150-300 microns in diameter) and the role of alpha 1- and alpha 2-adrenoceptors (AR) on smooth muscle and endothelium were studied. In intact arteries, NE increased tension in a dose-dependent manner, and the sensitivity for NE was further increased in the absence of endothelium. In intact but not in endothelium-denuded arteries, the response to NE was increased in the presence of both indomethacin (Indo; cyclooxygenase inhibitor) and NG-nitro-L-arginine methyl ester [L-NAME; nitric oxide (NO) synthase inhibitor], indicating that two endothelium-derived factors, NO and a prostanoid, modulate the NE-induced contraction. The alpha 1-AR antagonist prazosin shifted the NE dose-response curve to the right, and phenylephrine (alpha 1-AR agonist) induced a dose-dependent contraction that was potentiated by L-NAME or removal of the endothelium. The sensitivity to NE was increased slightly by the alpha 2-AR antagonists yohimbine and idazoxan, and this effect was abolished by Indo or removal of the endothelium. Similarly, contractions induced by UK-14304 (alpha 2-AR agonist) were potentiated by Indo or removal of the endothelium. These results suggest that NE-induced contraction is mediated through activation of alpha 1- and alpha 2-ARs on both smooth muscle and endothelium. Activation of the alpha 1- and alpha 2-ARs on the smooth muscle causes contraction, whereas activation of the endothelial alpha 1- and alpha 2-ARs induces relaxation through release of NO (alpha 1-ARs) and a prostanoid (alpha 2-ARs).

A neuromodulatory role for neuronal nitric oxide in the rabbit renal artery.

1. The effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on vasoconstrictor responses to transmural electrical nerve stimulation and noradrenaline were examined in the rabbit isolated renal artery with and without an intact endothelium. In addition, the effect of removing the endothelium from the renal artery on vasoconstrictor responses to transmural electrical nerve stimulation and noradrenaline was also investigated. Immunohistofluorescence techniques were carried out to determine if there were any nitrergic nerves supplying the renal artery. 2. The vasoconstriction produced in response to transmural electrical nerve stimulation (2-64 Hz) was significantly enhanced in the presence of L-NAME (3 x 10(-6), 10(-5), 3 x 10(-5) and 10(-4) M). 3. L-NAME (3 x 10(-6), 10(-5), 3 x 10(-5) and 10(-4) M) did not significantly affect the maximum vasoconstriction produced in response to noradrenaline. However, the noradrenaline dose-response curve was significantly shifted to the left by the addition of L-NAME (3 x 10(-6), 10(-5), 3 x 10(-5) and 10(-4) M). 4. The increase in the amplitude of the vasoconstriction, produced in response to transmural electrical nerve stimulation (16 Hz) and noradrenaline (10(-5) M) in the presence of L-NAME (10(-5) M) was not observed when L-arginine (10(-3) M) was added in addition to L-NAME (10(-5) M). 5. Removing the endothelium did not significantly affect the response to transmural electrical nerve stimulation (1-64 Hz). The maximum vasoconstriction in response to noradrenaline was also unaffected by the removal of the endothelium. The pD2 value for noradrenaline obtained from vessels with no endothelium was significantly greater than the pD2 value obtained from vessels with an intact endothelium (5.90 +/- 0.11 and 5.16 +/- 0.03, respectively). 6. On renal artery segments with no endothelium L-NAME (3 x 10(-5) M) significantly enhanced the response to transmural electrical nerve stimulation (2-64 Hz). L-NAME did not affect the maximum response to noradrenaline. However, there was a significant shift to the right of the noradrenaline doseresponse curve in the presence of L-NAME (3 x 10(-5) M). 7. Both nitric oxide synthase-containing and NADPH-diaphorase stained nerves were located on the adventitial-medial border of the rabbit renal artery. 8. The present study has suggested a presynaptic inhibitory action for nitric oxide (probably derived from identified perivascular nitrergic nerves), on perivascular sympathetic vasoconstrictor nerve mediated responses of the rabbit renal artery. In contrast, the enhancement of the response to noradrenaline by L-NAME can be attributed to inhibition of the synthesis of endothelium-derived nitric oxide.

Insulin-induced attenuation of noradrenaline-mediated vasoconstriction in resistance arteries from Wistar rats is nitric oxide dependent.

1. We studied the mechanism of insulin-mediated attenuation of noradrenaline-induced vasoconstriction in mesenteric resistance arteries (approximately 210 microns diameter) from 10-week-old male Wistar rats (n = 10; weight 321 +/- 11 g). Exposure to physiological concentrations of insulin (50 m-units/l) significantly blunted the contractile response to noradrenaline over the concentration range 3 x 10(-6) to 3 x 10(-5) mol/l (16 vessels; 13.1 +/- 4.3% reduction in maximum tension at 3 x 10(-5) mol/l noradrenaline; P < 0.01 versus no insulin). 2. This effect of insulin was prevented by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10(-4) mol/l; 16 vessels; 3.3 +/- 9.1% reduction in maximum tension; P = 0.8 versus no insulin). There was no evidence of fatigue in four noradrenaline dose-response curves for 16 control vessels in the absence of insulin and NG-nitro-L-arginine methyl ester (P = 0.8; first versus second dose-response curve). With L-arginine present in the incubation medium, insulin again attenuated the noradrenaline-induced vasoconstriction (10.7 +/- 3.2% reduction in tension; P = 0.02 versus L-arginine and no insulin; P = not significant versus insulin and no L-arginine). 3. Endothelium-dependent relaxation was initially confirmed in all vessels by demonstrating normal acetylcholine- (5.4 x 10(-7) to 1.1 x 10(-4) mol/l) induced vasodilatation in vessels preconstricted with noradrenaline (6 x 10(-6) mol/l) in the absence of NG-nitro-L-arginine methyl ester, L-arginine and insulin (P = not significant between the different groups of vessels). 4. We conclude that insulin attenuates noradrenaline-induced vasoconstriction in resistance arteries by stimulation of nitric oxide release. Abnormal insulin-stimulated nitric oxide release could be of relevance in the pathogenesis of hypertension and diabetic microvascular disease.

Pharmacological Actions of Naringin on Alpha, Beta-adrenoceptors and Uptake of Noradrenaline in Rat Isolated Vas Deferens

In normal Krebs solution, naringin (1×10−7 Msc–2×10−6 M) enhanced noradrenaline-induced contractions in rat isolated vas deferens increasing this potentiation in a concentration dependent manner. This enhancing effect continued in the presence of yohimbine (10−6 M) or propranolol (10−6 M). Naringin did not modify significantly the dopamine dose-response curves. In a medium containing 10−8 M prazosin, naringin decreased noradrenaline dose-response curves underneath the control curve at all the doses tested. Naringin did not modify significantly the NA dose-response curve in a medium containing cocaine (10−5 M) or oestradiol (10−5 M). The potentiation produced by naringin on the NA-induced contractions in rat vas deferens may be due to alpha-1 receptor activation, together with an interference of naringin in catecholamine uptake process.

Effects of long-term high-altitude hypoxemia on alpha 1-adrenergic receptors in the ovine uterine artery.

To elucidate the effects of chronic hypoxia on alpha 1-adrenergic receptor-mediated contractions of the uterine artery, we examined norepinephrine-induced contractions in tissues obtained from near-term (approximately 140 days gestation) pregnant ewes maintained near sea level (approximately 300 m) and at high altitude (3,820 m) from 30 days gestation. Compared with the sea-level controls, contractions induced by norepinephrine in main and fourth-branch uterine arteries of the high-altitude animals were significantly depressed. The norepinephrine dose-response curves were shifted to the right and the concentrations at which 50% of the maximal response was attained were increased 3.2- and 5.7-fold in the main and fourth-branch uterine arteries, respectively. The maximal responses were decreased 22 and 36% in main and fourth-branch uterine arteries, respectively. The dissociation constants of norepinephrine were increased from 0.77 to 1.53 microM and from 0.72 to 2.05 microM in main and fourth-branch uterine arteries, respectively. Radioligand binding studies with [3H]prazosin revealed a decrease in the density of alpha 1-adrenergic receptors in both vessels from high-altitude animals. We conclude that chronic hypoxia depresses alpha 1-adrenergic receptor-induced contractions of conduit- and resistance-type uterine arteries. The depressed contractility is mediated, at least in part, by decreases in alpha 1-adrenergic receptor density and agonist binding affinity.

Chronic exercise enhances endothelium-mediated dilation in spontaneously hypertensive rats

This study investigated the effect of physical training on endothelial function in spontaneously hypertensive rats (SHR). After 3 months, in conscious trained- and untrained-SHR body weight, systolic blood pressure and heart rate were 220 ± 6 g vs. 271 ± 9 g, 172 ± 7 mmHg vs. 210 ± 8 mmHg and 314 ± 10 vs. 348 ± 12 beats/min, respectively. In vitro, the dose-response curves of norepinephrine in isolated intact aortic and mesenteric rings from the exercise trained-SHR were significantly lower than those from the untrained-SHR. With denuded preparations, norepinephrine concentration-response curves were shifted to the left both in the trained- and untrained-SHR. This shift in the trained-SHR exceeded that in the untrained-SHR. The vasodilator response to acetylcholine in the trained-SHR was significantly greater than that in the untrained-SHR. Either N ω-nitro-L-arginine (100 μmol/l) or methylene blue (10 μmol/l) inhibited acetylcholine-induced vasodilator effect in aorta of trained- and untrained-SHR, but not in mesenteric artery of trained-SHR. Tetraethylammonium (10 mmol/l) inhibited significantly the N ω-nitro-L-arginine and methylene blue-resistant relaxation in mesenteric artery of trained-SHR,but not by indomethacin (10 μmol/l). Collectively, these data demonstrate that chronic exercise increases EDRF/EDHF production (presumably by increasing endothelial shear stress), and may contribute to the enhanced effects of post-exercise hypotension.1

Neonatal hypoxia: long term effects on pulmonary arterial muscle

The purpose of this study was to determine if neonatal hypoxia alters pulmonary arterial smooth muscle (PASM) function in young adult rats. One day old rats were made hypoxic (FI O 2 = 0.1) for 5 days, then maintained under normoxic conditions until young adulthood (45–50 days). Age-matched rats were used as controls. Body weight, hematocrit, dry lung weight, and right to left heart ratios were measured. Reactivity and/or responsiveness of rings of main right and left pulmonary artery of the adult to various agonists, including high K + (80 mM KCl), norepinephrine (NE), serotonin (5HT), adenosine (AD), and acute in in vitro hypoxic vasoconstriction were assessed. Isometric force production was normalized to calculate tissue cross-sectional area (N/cm 2). Maximum force production (P o) in response to 80 mM KCl for isolated rings from the hypoxic group was significantly less than for controls. Isometric force production in response to NE or to 5HT was also lower in the hypoxic group although the difference was significant for 5HT only when the endothelium was rendered non-functional. When the endothelium was intact, arterial rings from experimental animals relaxed at low doses of adenosine (10 −8 M to 10 −5 M), while control arterial muscle showed no response at these concentrations. The mean dose-response curve for NE from preparations with intact endothelium from experimental animals was significantly lower than that for the control animals, at least at doses greater than 10 −7M. To mimic acute hypoxic pulmonary vasoconstriction, isolated rings of the main right and left pulmonary artery were precontracted with either 30 mM KCl or 2.5 × 10 −7 M NE and then made hypoxic by lowering muscle bath P O 2 to 30–40 mmHg. In conclusion there was no difference in the hypoxic response per se between arterial rings from experimental animals and controls. However, maximum reactivity to high potassium stimulation and to norepinephrine stimulation is decreased in pulmonary arterial smooth muscle of adult animals that had been exposed to 5 days of hypoxia as neonates.

Reduction of endothelial function with age in the mesenteric arterial bed of the normotensive rat.

1. Age-related changes in endothelial vasodilator function were studied in an in vitro preparation of the mesenteric arterial bed removed from male, normotensive, Wistar rats. 2. Animals were killed at 2, 12 or 22 months of age, the superior mesenteric artery was cannulated and the gut removed. The mesenteric arterial bed was perfused at a constant flow rate of 4 ml min-1 and perfusion pressure was taken as an index of arteriolar tone. 3. The muscarinic agonist, carbachol, antagonized noradrenaline-induced vasoconstriction in the presence, but not in the absence, of endothelium. This cholinoceptor agonist-induced release of endothelial-derived relaxing factor (EDRF) was impaired in 22 month old rats. 4. Noradrenaline-induced vasoconstriction increased following removal of endothelium suggesting that agonist-induced release of EDRF attenuates vasoconstrictor responses to noradrenaline measured in the presence of endothelium. 5. Removal of endothelium had less effect on noradrenaline-induced vasoconstriction in old rats suggesting once again that agonist-induced release of EDRF is impaired in old rats. 6. The noradrenaline dose-response curve established in the presence of endothelium was shifted to the left in 22 month old rats. 7. In conclusion, aging in the rat appears to lead to a reduction in endothelial vasodilator function in a resistance vessel.

Effect of the vascular endothelium on norepinephrine-induced contractions in uterine radial arteries from the nonpregnant and pregnant human uterus

Our purpose was to investigate the role of the endothelium in the human uterine arterial response to norepinephrine in the nonpregnant and pregnant states. Tissue was obtained from six pregnant and six nonpregnant women undergoing cesarean section or hysterectomy. Uterine radial arteries were isolated and subjected to norepinephrine dose-response curves with and without intact endothelium. Responses were obtained over a dose range of 10(-8) to 10(-4) norepinephrine. Initially there was no difference between vessels from pregnant and nonpregnant patients, but removal of the endothelium significantly increased the response in vessels from pregnant women. Addition of nitro-L-arginine methyl ester when the endothelium was intact did not alter the dose-response curves. In pregnancy human uterine radial arteries are more sensitive to norepinephrine than during the nonpregnant state. This increase is countered by an endothelium-derived relaxing factor. The factor is unlikely to be nitric oxide.

Selective action of two aporphines at α1-adrenoceptors and potential-operated Ca 2+ channels

Contractions evoked by noradrenaline (1 μM) or a depolarizing solution of 60 mM KCI were concentration dependently depressed by the aporphine alkaloids (S)-boldine and (R)-apomorphine in rataorta. Both drugs had a greater inhibitory potency on the contraction elicited by noradrenaline. Dose-response curves for noradrenaline were shifted to the right in presence of (S)-boldine. (R)-Apomorphine acted by a complex mechanism at α 1-adrenoceptors and its inhibitory effects was irreversible. The conformational features of these alkaloids may explain their different behaviour at α 1-adrenoceptors. In Ca 2+-free solution, the alkaloids inhibited the contraction evoked by noradrenaline but did not modify (apomorphine) or increase (boldine) the contractile response induced by caffeine. Both alkaloids interacted with [ 3H]prazosin binding and with the benzothiazepine binding site of the Ca 2+ entry receptor complex but had no effect at the dihydropyridine binding site in the rat cerebral cortex. Both drugs showed some selectivity as inhibitors of [ 3H]prazosin binding as opposed to [ 3H]d-cis ditiazem binding. (R)-Apomorphine slightly inhibited one of the two forms of the Ca 2+-independent, low K m cyclic AMP-phosphodiesterase (type IV), whereas it did not have a significant effect on the other phosphodiesterase forms. (S)-Boldine had negligible inhibitory effects on all phosphodiesterase forms. The present study provides evidence that (S)-boldine and (R)-apomorphine have interesting properties as Ca 2+ entry blockers (through the benzothiazepine receptor site in the Ca 2+ channel) and at α 1-adrenoceptors.

Anticonvulsant effects of intracerebroventricularly administered norepinephrine are potentiated in the presence of monoamine oxidase inhibition in severe seizure genetically epilepsy-prone rats (GEPR-9s)

Pharmacological and neurochemical evidence indicates that brain noradrenergic systems play an important role in the determination of audiogenic seizure severity in genetically epilepsy-prone rats (GEPRs). In earlier studies, intracerebro-ventricular (ICV) injections of norepinephrine suppressed convulsions in a now extinct moderate seizure GEPR colony. Also, ICV noradrenergic agonists are known to produce dose-related anticonvulsant effects in the extant moderate seizure GEPRs (GEPR-3s). The present experiments were undertaken to determine whether ICV norepinephrine also suppresses audiogenic seizure in the extant GEPR-3s and in the severe seizure genetically epilepsy-prone rats (GEPR-9s). Injections of norepinephrine or vehicle were made into the lateral ventricle through implanted guides. GEPR-9s were pretreated systemically either with the monoamine oxidase inhibitor pargyline or with saline. GEPR-3s received no pretreatment. In pargyline pretreated GEPR-9s, seizure severity fell and the fraction of animals exhibiting an anticonvulsant response increased progressively as the dose of norepinephrine was increased. In saline pretreated GEPR-9s, the anticonvulsant dose response curve for norepinephrine was shifted to a higher dose range. Accordingly, the anticonvulsant dose 50 for norepinephrine was significantly greater in saline pretreated GEPR-9s than in pargyline pretreated animals. Moreover, the dose required to produce the anticonvulsant effect in GEPR-9s was approximately 10 fold greater than in the earlier studies in the extinct moderate seizure GEPRs. Also, the current experiment with extant GEPR-3s, showed that ICV norepinephrine was anticonvulsant in the same dose that was effective in the extinct colony of moderate seizure GEPRs. In general terms, these observations provide additional evidence that noradrenergic influences are anticonvulsant in the GEPR. The neurobiological factors responsible for reduced responsiveness of the GEPR-9 are presently unknown.

Effects of serotonin and noradrenaline on superficial hand veins in patients with primary hypertension and in healthy volunteers.

In vitro and animal experiments suggest that a constitutional increase in vascular responsiveness to serotonin (5-HT) may play a role in the development of essential hypertension. We have studied the potential alterations in vascular responsiveness to the direct and catecholamine-potentiating effects of exogenous 5-HT in patients with essential hypertension, by comparing in vivo responsiveness of superficial hand veins to local infusions of 5-HT or to coinfusions of 5-HT and noradrenaline in unmedicated hypertensive patients and in healthy control subjects. The dorsal hand vein compliance technique was employed. There was no significant difference between patients and control subjects in the maximal 5-HT-induced venoconstriction or in the doses required for half-maximal venoconstriction (ED50) for 5-HT. Coinfusions of a constant dose of 5-HT caused a significant leftward shift in the dose response curve for noradrenaline as compared with noradrenaline alone. This was indicated by a 9.7 +/- 13.7 fold and a 10.4 +/- 13.8 fold increase in the ED50 for noradrenaline in the patient and control groups, respectively (p = 0.89 between study groups). Our results argue against a generalized increase in responsiveness to the direct or catecholamine-potentiating effect of 5-HT in vivo in vascular smooth muscle, associated with hypertension.