Endothelium-independent potentiating effects of neuropeptide Y in the rat tail artery.

The role of the endothelium in the potentiating action of neuropeptide Y (NPY) to contraction induced by KCl, alpha, beta-methylene ATP (mATP), and noradrenaline (NA) was tested on rat tail arteries. Endothelium-intact and denuded ring segments and freshly isolated single smooth muscle cells were used in the study. Contraction responses to KCl and mATP were potentiated by NPY (50 nM) in both intact and denuded arteries. Contraction to NA was potentiated by NPY at 500 nM but not at 50 nM. The potentiation effect of NPY was antagonized by nifedipine. Similarly, the shortening of single smooth muscle cells in response to KCl and mATP was potentiated by NPY (50 nM). The noradrenaline response was potentiated by NPY at 500 nM but not at 50 nM. Our results suggest that the potentiating effect of NPY is more specific to contraction mediated by nifedipine-sensitive calcium channels and is not dependent on the presence of an intact endothelium.     

Inhibition of neuropeptide Y-induced potentiation of noradrenaline-induced vasoconstriction by PP56 (D-myo-inositol 1,2,6-tris-phosphate).

1. Although neuropeptide Y (NPY) is a potent vasoconstrictor in many vascular beds, nanomolar concentrations of this peptide potentiate the noradrenaline-induced contractions in rabbit gastroepiploic and femoral arteries, and guinea-pig mesenteric and uterine arteries. 2. The potentiating effect of NPY on noradrenaline-induced contraction was present in endothelium-denuded femoral arteries. 3. The potentiating effect of NPY on noradrenaline-induced contraction was antagonized by PP56 (D-myo-inositol 1,2,6-trisphosphate) in low concentrations (down to 0.1 nM). This antagonistic effect was observed in all four types of vessels studied. Contractions induced by noradrenaline, histamine, endothelin-1 and potassium were not altered by PP56 in concentrations upto 1 microM in femoral artery of rabbit. 4. We provide evidence that a non-peptide (PP56) can selectively antagonize NPY-induced effects in rabbit and guinea-pig peripheral arteries without affecting the vasoconstrictor response to noradrenaline.     

INCREASED SENSITIVITY OF RABBIT EAR ARTERY TO NORADRENALINE FOLLOWING PERIVASCULAR NERVE STIMULATION MAY BE A RESPONSE TO NEUROPEPTIDE Y RELEASED AS COTRANSMITTER

Neuropeptide Y (NPY 10(-10)-10(-7) mol/l) had little or no effect on the perfusion pressure of rabbit isolated ear arteries but potentiated the brief contractile responses to injections of noradrenaline, histamine or brief periods of electrical stimulation (2-20 Hz for 5 s). This effect was slowly reversible. Similar potentiation was seen following long periods of electrical stimulation (2-40 Hz for 1-5 min) which produced well sustained increases in perfusion pressure. Following even longer periods of electrical stimulation (10-30 min) during which the perfusion pressure was not maintained, responses to noradrenaline and histamine were potentiated but the responses to electrical stimulation for 5 s were greatly reduced. The increase in sensitivity following prolonged electrical stimulation may be due to NPY released as a cotransmitter.     

Selective potentiation of extracellular Ca2+-dependent contraction by neuropeptide Y in rabbit mesenteric arteries

1. Neuropeptide Y (NPY) potentiated the contractile responses induced by electrical transmural stimulation, noradrenaline and KCl in the rabbit mesenteric artery. 2. In preparations treated with noradrenaline or KCl in Ca2+ free medium, NPY also potentiated the contractile response induced by resupplementation of Ca2+. 3. 3H-efflux from the arteries preincubated with [3H]-noradrenaline was not affected by NPY. 4. These results suggest that NPY selectively acts on the postsynaptic membrane and potentiates the contractions mediated through receptor-operated and voltage-dependent Ca channels.     

Neuropeptide Y potentiates contraction and inhibits relaxation of rabbit coronary arteries

The effects of neuropeptide Y (NPY) on contraction and relaxation of isolated rabbit coronary arteries were studied. NPY alone caused a weak contraction of coronary arteries with a mean EC50 value of 29 +/- 2.0 nM. Following exposure of coronary arteries to 30 nM NPY, the potencies of norepinephrine (in the presence of 3 microM timolol) and histamine in causing contraction were increased twofold, with no change in maximal contraction. After half-maximal contraction of coronary arteries with histamine and addition of 30 nM NPY, relaxation produced by norepinephrine (in the presence of 3 microM phentolamine), adenosine, and acetylcholine was inhibited. Concentration-response curves for all vasodilators were shifted to the right 10-22-fold by 30 nM NPY. Maximal relaxation caused by adenosine and norepinephrine was not changed by NPY, whereas the maximal response to acetylcholine was 37% less in the presence of NPY. Correlation of the tension produced by NPY with the shift in agonist contraction or relaxation concentration-response curves indicated that NPY-induced increases in baseline tone had no effect on the degree of shift in agonist concentration-response curves. These results show that NPY causes a modest potentiation of agonist-induced contraction and a dramatic blockade of vasodilator-induced relaxation of rabbit coronary arteries.     

NEUROPEPTIDE Y INDUCES AND MODULATES VASOCONSTRICTION IN INTRACRANIAL AND PERIPHERAL VESSELS OF ANIMALS AND MAN

• 1 Neuropeptide Y (NPY) has recently been reported to coexist with noradrenaline (NA) in central as well as peripheral noradrenergic nerves. NPY-containing nerve fibres are particularly numerous around blood vessels.
• 2 Studies were performed on isolated pial arteries as well as on arteries and veins from several peripheral vascular beds from rabbit, cat and man. NPY induced a varying degree of direct contraction of the vessels with an E_Am up to 15 mN. Pial arteries were more sensitive than peripheral arteries to NPY (mean EC₅₀ = 7.6 × 10^?9 M). The presence of NPY did not cause any consistent or significant potentiation of the contractile response to NA in any of the vessels tested.
• 3 Transmural electrical stimulation of the perivascular nerves (including blockade with tetrodotoxin) was performed mainly with auricular artery from the rabbit. Blocking experiments confirmed that the neurogenic contraction was mediated by noradrenergic-type fibres. NPY caused a concentration-related potentiation of the neurally evoked contractile response. The peptide also potentiated the tetrodotoxin-resistant probably non-neurogenic contractions obtained during enhanced electrical field stimulation.
• 4 It is concluded that NPY interacts with NA during sympathetic nerve activation primarily through a presynaptic effect.

     

Actions of calcium antagonists on pre- and postjunctional effects of neuropeptide Y on human peripheral blood vessels in vitro

The mechanisms underlying the contractile effects of neuropeptide Y (NPY) in relation to those of noradrenaline (NA) on small human blood vessels were studied in vitro. NPY caused contractions of mesenteric veins, renal and skeletal muscle arteries but not of mesenteric arteries. NPY was about 5- to 10-fold more potent than NA. The maximal contractile responses to NPY (5 X 10(-7) M) were 38 +/- 4, 37 +/- 8 and 95 +/- 16% of the response evoked by NA 10(-5) M in the mesenteric vein, renal and skeletal muscle arteries respectively. The NPY effects were resistant to adrenoceptor antagonists. The calcium antagonist nifedipine reduced the effect of NA but not the contractile response to NPY on mesenteric veins. Nifedipine and felodipine reduced the contractile response to both NA and NPY on renal and skeletal muscle arteries. In contrast to the contractile effects of K+, the responses to NPY and NA were largely uninfluenced by changes in extracellular Ca2+ concentrations. Nifedipine still inhibited the NPY contractions in a Ca2+-free medium while high extracellular Ca2+ (7.5 mM) partly reduced the nifedipine effect. NPY reduced the nerve stimulation-evoked [3H]NA overflow from the mesenteric veins via a nifedipine resistant mechanism. The stable analogue alpha, beta-methylene adenosine triphosphate (mATP) was more potent than ATP and had nifedipine-sensitive contractile effects similar to those of NA on the human blood vessels without influencing the nerve-evoked [3H]NA efflux. In conclusion, NPY exerts a potent nifedipine-sensitive vasoconstrictor activity, especially on human skeletal muscle arteries in vitro, although the influx of extracellular calcium may not be a crucial mechanism. The NPY-induced contractions of mesenteric veins and the inhibition of nerve-evoked [3H]NA efflux seem to be mediated via nifedipine resistant messenger systems.     

Modification of cardiovascular responses to histamine by dithiothreitol.

1 Histamine produced dose-dependent contractile responses on both isolated perfused ear arteries and aortic strips of the rabbit. These responses were blocked by mepyramine and potentiated by both metiamide and dithiothreitol. 2 In the presence of maximum potentiation by metiamide, dithiothreitol still potentiated the contractile response to histamine of both preparations. 3 In the presence of mepyramine, histamine produced dose-dependent reductions in the contractile response to noradrenaline. This vasodilator action of histamine was abolished by metiamide but was unaffected by dithiothreitol. 4 The vasodilator action of histamine on the human isolated perfused temporal artery and the positive inotropic effect of histamine on the isolated spontaneously beating atria of the rabbit were blocked by metiamide but unaffected by dithiothreitol. 5 It is concluded that the rabbit aorta, like the ear artery, contains both H1 and H2 histamine receptors and that dithiothreitol potentiates cardiovascular responses mediated by H1-receptors but not by H2-receptors.     

Dual effect of dihydroergotamine and dihydroergotoxin in isolated human femoral veins and arteries

In human femoral vein strips, dihydroergotamine and dihydroergotoxin caused a slowly proceeding, long-lasting increase in tone. Dihydroergotamine had markedly higher affinity than noradrenaline, it possessed nearly the same intrinsic activity as noradrenaline. Dihydroergotoxin was less effective than dihydroergotamine. In isolated femoral artery strips, dihydroergotamine showed lower affinity and lower intrinsic activity in terms of noradrenaline. Dihydroergotoxin had negligible vasoconstrictor effects in arteries. In veins, dihydroergotoxin had a stronger alpha-adrenolytic effect than in arteries. In isolated arteries, dihydroergotoxin was equieffective to dihydroergotamine whose alpha-adrenoceptor blocking effect did not significantly differ in veins and arteries. Our results show that dihydroergotamine at very low concentrations exerted predominantly venoconstrictor effects and, therefore, it is more suited to increase the venous tone than dihydroergotoxin which at low concentrations showed alpha-adrenoceptor blocking activity.     

Reactivity of endothelin-1 on human and canine large veins compared with large arteries in vitro

In comparison with snake venom sarafotoxins S6, the novel, 21-amino acid peptide, endothelin may have selective coronary artery vasoconstrictor actions. We examined endothelin-1 (ET-1) in vitro in five pairs of large arteries and veins from the greyhound dog; (coronary, internal mammary, mesenteric, renal and femoral) as well as the human forearm vein and internal mammary artery and vein. ET-1 caused concentration-dependent, tonic contractions in each pair of vessels, with EC50s significantly lower (5-10 times more sensitive) in each vein compared with the corresponding artery. The coronary artery did not show selective sensitivity to ET-1. For all veins the maximal contraction to ET-1 was approximately 100% that of the maximal contraction (Fmax) achieved with K+ depolarization. In the arteries, however, the Fmax for ET-1 ranged from only 25 to 80% of K+. The contraction responses to ET-1 in all arteries and veins were well maintained after repeated washing with ET-1-free medium. In the dog coronary artery the contraction curve to ET-1 (0.1-30 nM) was endothelium-independent. At the higher concentrations (10-100 nM), however, the peptide often induced transient, endothelium-dependent relaxations prior to the development of the tonic contractions. These results demonstrate that ET-1 is a more potent and efficacious constrictor of large veins than arteries and at high concentrations can release endothelium-derived relaxing factor-like activity from large arteries.     

PHARMACOLOGICAL COMPARISON OF HUMAN ISOLATED DIGITAL ARTERIES AND METACARPAL VEINS

1 The responses of human digital arteries and metacarpal veins obtained postmortem to various pharmacological agents have been tested. 2 pD₂ values for potassium chloride and barium chloride were found to be greater in arteries than in veins. 3 There was no difference between the arteries and veins in the pA₂ values for phentolamine as an antagonist of either noradrenaline or phenylephrine. pD₂ values for noradrenaline however, were significantly higher in the veins than in the arteries, whereas pD₂ values for phenylephrine in the two tissues were not significantly different. This raises the possibility of there being differences in the populations of a-adrenoceptors in the two tissues. 4 Differences were found between arteries and veins in the contractile and relaxant responses to histamine and in the antagonism of the responses to histamine by cimetidine and mepyramine, thereby suggesting differences in the populations of Hi-and H₂-receptors in these tissues. 5 No differences were found in the responses of arteries and veins to serotonin or in the antagonism of the response to this agonist by phentolamine. 6 Isoprenaline produced relaxant responses in veins (in which tone was induced with 30 mmol/1 potassium chloride) but not in arteries. 7 Dopamine produced very weak relaxant responses in preparations in which tone was induced using 30 mmol/1 potassium chloride. The mean £max value for this response was significantly greater in veins than in arteries. 8 Slight relaxant responses to acetylcholine were seen in veins and arteries precontracted with 30 mmol/1 potassium chloride. The mean £max value was significantly greater in veins than in arteries. 9. It is concluded that human digital arteries and metacarpal veins have differing pharmacological receptor populations and probably also differ in their non-receptor mediated contractile mechanisms.     

Investigation of a combined arteriolar dilator and beta-adrenoceptor antagonist (SK & F 92657) in the peripheral vessels of man.

1 SK & F 92657 is a new compound which in animals has both precapillary vasodilator and beta-adrenoceptor blocking activity. The effects of the drug on forearm blood flow and dorsal hand vein distensibility have been studied in healthy volunteers. 2 Forearm blood flow was measured by venous occlusion plethysmography. The drug was infused directly into a brachial artery. The effects of SK & F 92657 on resting flow and on the dose-response relationship for intra-arterial isoprenaline were studied. 3 Venous distensibility was measured in the large veins on the back of the hand. The drug was infused directly into a selected vein and its effects on resting tone and on the responses to noradrenaline and to isoprenaline were investigated. 4 Intra-arterial infusion of SK & F 92657 over 2 min caused a dose-dependent increase in forearm blood flow which developed gradually to reach a maximum after approximately 40 min. Infusion into dorsal hand veins at 100 ng/min and 500 ng/min had no dilator effect in veins preconstricted with noradrenaline. At higher doses SK & F 92657 potentiated the constrictor effect of noradrenaline. 5 In both veins and arteries SK & F 92657 attenuated the dilator effects of isoprenaline. The drug had no effect on the venodilator effects of bradykinin, histamine or sodium nitroprusside. 6 The pattern of response of these vessels to locally infused SK & F 92657 is exactly that expected of a drug combining the properties of hydralazine-like vasodilatation and beta-adrenoceptor blockade. Furthermore, in the arterioles, both properties were manifest at the same dose.     

Adenosine 5'-triphosphate and neuropeptide Y are co-transmitters in conjunction with noradrenaline in the human saphenous vein

1. Human saphenous veins were used to assess the cooperative participation of adenosine 5-triphosphate (ATP), neuropeptide Y (NPY), and noradrenaline (NA) in the vasomotor responses elicited following electrical depolarization of the perivascular nerve terminals. Rings from recently dissected human biopsies were mounted to record isometric muscular contractions; the motor activity elicited in the circular muscle layer following electrical depolarization (2.5-20 Hz, 50 V, 0.5 msec) were recorded. 2. Incubation of the biopsies with either 100 nM tetrodotoxin (TTX) or 1 microM guanethidine abolished the vasomotor response elicited by electrical nerve depolarization. The independent application of either ATP or NA to vein rings induced concentration-dependent contractions. 3. Tissue incubation with 30 microM suramin or 10 nM prazosin produced 10 fold rightward displacements of the alpha,beta-methylene ATP and NA concentration-response curves respectively. NPY contracted a limited number of biopsies, the vasoconstriction elicited was completely blocked by 1 microM BIBP 3226. A 5 min incubation of the biopsies with 10-100 nM NPY synergized, in a concentration-dependent fashion, both the ATP and the ATP analogue-induced contractions. Likewise, tissue preincubation with 10 nM NPY potentiated the vasomotor responses evoked with 20-60 nM NA. 4. Neither suramin, BIBP 3226, nor prazosin was individually able to significantly modify the derived frequency-tension curves. In contrast, the co-application of 30 microM suramin and 10 nM prazosin or 30 microM suramin and 1 microM BIBP 3226, elicited a significant (P<0.01) downward displacement of the respective frequency-tension curves. 5. The simultaneous application of the three antagonists-30 microM suramin, 1 microM BIBP 3226 and 10 nM prazosin-caused a significantly greater displacement of the frequency-tension curve than that achieved in experiments using two of these antagonists. 6. Electrically-evoked vasomotor activity is blocked to a larger extent by tissue incubation with 2.5 microM chloroethylclonidine and 30 microM suramin rather than with 10 nM 5 methyl urapidil and 30 microM suramin. As a result, the alpha1-adrenoceptor involved in the vasomotor activity has tentatively been associated with the alpha1B adrenoceptor family subtype. 7. Results support the physiological role of ATP in sympathetic neurotransmission. The present results are consistent with the working hypothesis that human sympathetic vasomotor reflexes involve the coordinated motor action of ATP, NPY, and NA acting on vascular smooth muscle cells. The present results support the concept of sympathetic co-transmission in the human saphenous vein.     

Regional involvement of an endothelium-derived contractile factor in the vasoactive actions of neuropeptide Y in bovine isolated retinal arteries.

1. In vitro experiments in a microvascular myograph were designed in order to investigate the effects of human neuropeptide Y (NPY), its receptor subtype and the mechanisms underlying NPY actions in bovine isolated retinal proximal (PRA) and distal (DRA) arteries. 2. A single concentration of NPY (10 nM) induced a prompt and reproducible contraction which reached a plateau within 1-4 min, after which the response returned to baseline over the next 2-10 min. Cumulative addition of NPY induced concentration-dependent contractions of bovine retinal arteries, with an EC50[M] of 1.7 nM and a maximal response equal to 54 +/- 8% of Emax (absolute maximal contractile levels of vessels) and not different from that obtained by a single addition of the peptide. There were no significant differences in either sensitivity or maximal response to NPY between PRA and DRA. 3. Porcine NPY and the selective Y1-receptor agonist, [Pro34]NPY, also induced concentration-dependent contractions of the retinal arteries with a potency and maximal response not significantly different from those of human NPY; in contrast, the selective Y2-receptor agonist, NPY(13-36), caused only a 5% contraction at the highest concentration used. 4. Removal of extracellular Ca2+ or pretreatment with the 1,4-dihydropyridine Ca(2+)-channel blocker, nifedipine (1 microM), reduced the contractile response of 10 nM NPY to 18.4 +/- 3.3% (n = 6) and 18.6 +/- 3.9% (n = 6); respectively, of the controls. 5. Mechanical removal of the endothelium depressed the maximal contraction elicited by NPY in PRA but did not affect either sensitivity or maximal response to the peptide in DRA. In endothelium-intact arteries, blockade of the cyclo-oxygenase pathway with 3 microM indomethacin increased resting tension in both PRA and DRA and significantly inhibited sensitivity and maximal contraction to NPY of PRA and DRA, respectively. The thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor antagonist, SQ30741, reduced both sensitivity and maximal contraction to NPY in PRA but not in DRA. 6. In endothelium-denuded PRA, indomethacin but not SQ30741 significantly reduced NPY maximal response and induced a marked increase in resting tension suggesting a basal release of a vasodilator prostanoid from smooth muscle cells. 7. Superoxide dismutase (SOD) (150 u ml-1) reduced the maximal contraction to NPY in PRA. Inhibition of the nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NOARG) (30 microM), enhanced sensitivity and maximal contraction to NPY in both PRA and DRA. In the presence of L-NOARG, SOD did not further inhibit NPY responses in PRA. 8. NPY (10 nM) induced a 2.9 fold leftwards shift of the noradrenaline concentration-response curves in PRA and increased maximal response by 50 +/- 16%. Neither 1 nor 10 nM NPY affected noradrenaline responses in DRA. [Pro34]NPY (10 nM), but not NPY(13-36), mimicked the potentiating effect of NPY on noradrenaline responses in PRA. 9. TXA2 analogue, U46619, at 10 nM elicited 3.6 fold leftwards shift of the noradrenaline concentration-responses curves in PRA and increased the maximal contraction by 32 +/- 3%, whereas in the presence of 1 microM SQ30741, 10 nM NPY did not potentiate noradrenaline responses. 10. The present results indicate that NPY may play a role in the regulation of retinal blood flow through both a direct contractile action, independent of the vessel size and a potentiation of the responses induced by noradrenaline in the proximal part of the retinal circulation, both effects being mediated by Y1 receptors. NPY promotes Ca2+ influx through voltage-dependent Ca2+ channels and stimulates the synthesis of contractile prostanoids in PRA and DRA, although only in PRA does the peptide trigger the release of an endothelium-derived contractile factor which facilitates the contraction and also seems to account for the potentiating effect of NPY.     

Inhibitory action of neuropeptide Y on agonist-induced responses in isolated guinea pig trachea.

The effect of neuropeptide Y (NPY) was tested on isolated guinea pig trachea. At 30 nM, NPY induced a weak but significant contractile response which was on average less than 6% of responses elicited by standard spasmogens. This myotropic action of NPY was blocked by indomethacin. In addition to its contractile activity, NPY greatly reduced the maximal response to vasoactive intestinal peptide (VIP), noradrenaline (NA), substance P (SP) and 5-hydroxytryptamine (5-HT), without affecting their pD2 values. However, NPY did not influence the response induced by histamine and carbamylcholine. Pretreatment of tracheal spirals with indomethacin (10(-6) M) abolished the NPY-evoked inhibition of VIP, SP and 5-HT responses but failed to reduce the action of NPY on NA-elicited relaxation. This latter effect was however blocked in the presence of tetrodotoxin. In conclusion, NPY inhibits responses elicited by various agonists in the guinea pig trachea. This effect seems to be mediated at both pre- and postjunctional levels. The postjunctionally mediated inhibitory action of NPY appears to be expressed especially with agents that generate prostaglandins concomitantly with inducing their response. In contrast, the NPY-evoked inhibition of NA-evoked relaxation seems to be mediated via a prejunctional mechanism.     

A cytochemical bioassay method for the determination of luteinizing hormone in biological fluids and tissues

1 In helically-cut strips of dog coronary, superior mesenteric, right gastro-epiploic and renal arteries contracted with prostaglandin F2 alpha (PGF 2 alpha), histamine produced a dose-related relaxation, while, in contrast, the amine caused only a contraction of cerebral arterial strips. 2 The contractile response of cerebral arteries to histamine was attenuated by chlorpheniramine (10(-6)M) but was unaffected by cimetidine (10(-5)M). Relaxant responses to histamine of coronary and renal arteries were significantly attenuated by treatment with cimetidine and to a similar extent by combined treatment with cimetidine and chlorpheniramine. Chlorpheniramine alone was ineffective. 3 In mesenteric and gastro-epiploic arteries, relaxant responses to histamine were attenuated only slightly by cimetidine. Chlorpheniramine slowed the development of histamine-induced relaxations but did not alter the magnitude of the relaxations. Combined treatment with these H1- and H2- antagonists attenuated the histamine-induced relaxations to an appreciably greater extent than treatment with cimetidine alone. 4 It may be concluded that the cerebroarterial contraction induced by histamine is mediated through H1-receptors and the relaxations of coronary and renal arteries induced by histamine are mediated through H2-receptors. It appears that H1- and H2-receptors interact with each other to produce potentiation of histamine-induced relaxations of mesenteric and gastro-epiploic arteries.     

Different modulation by cyclooxygenase inhibitors of the response to angiotensin II in monkey arteries and veins

In coronary, renal and femoral arteries and mesenteric veins isolated from Japanese monkeys, tachyphylaxis to angiotensin (ANG) II (10(-7) M)-induced contraction rapidly developed. Contractions caused by ANG II in coronary arteries were attenuated by treatment with indomethacin and aspirin and also by endothelium denudation. Indomethacin inhibited the response of the arteries with and without endothelium to a similar extent. OKY 046, a thromboxane A2 synthesis inhibitor, failed to inhibit the response. In contrast, contractions of renal arteries were potentiated and prolonged by the cyclooxygenase inhibitors. ANG II-induced contractions of mesenteric veins were prolonged but those of femoral arteries were not altered by indomethacin. It is concluded that ANG II contracts monkey coronary arteries, possibly due to the release of vasoconstrictor prostanoids but not thromboxane A2 from endothelial and subendothelial tissues and also due to its direct action on smooth muscle, whereas contractions of renal arteries and mesenteric veins are blunted by vasodilator prostanoids, possibly PGI2. Cyclooxygenase products even if released do not appear to regulate femoral artery contractions produced by ANG II.     

The effects of indomethacin and eicosa-5,8,11,14-tetraynoic acid on the response of the rabbit portal vein to electrical stimulation

1 The effects of indomethacin and eicosa-5,8,11,14-tetraynoic acid (ETYA) on the contractile response of the transmurally stimulated rabbit portal vein were studied in vitro.2 When the veins were stimulated for 240 pulses at 1 and 2 Hz, the responses were potentiated by indomethacin and ETYA. However, responses to 4 and 8 Hz were not potentiated. The responses to continuous electrical stimulation at 2 Hz were also potentiated by indomethacin and ETYA. This potentiating effect was attenuated when the veins were pretreated with alpha-methyl-p-tyrosine. The responses of the veins to noradrenaline were not altered by either indomethacin or ETYA.3 Prostaglandin E(2) inhibited the responses of the portal vein to electrical stimulation. The magnitude of this inhibition was inversely related to the frequency of stimulation. The responses of the vein to noradrenaline were not altered by prostaglandin E(2).4 It is concluded that potentiation by indomethacin and ETYA of the response of the isolated portal vein is due to an increased release of newly synthesized noradrenaline as a result of inhibition of prostaglandin synthesis.     

Neuropeptide Y inhibits double peaked vasoconstrictor responses to periarterial nerve stimulation primarily through prejunctional Y2 receptor subtype in canine splenic arteries

1 The effects of BIIE 0246, a novel and non-peptide neuropeptide Y (NPY) Y2 receptor antagonist on sympathetic vasoconstriction of the canine splenic artery were investigated. 2 The vasoconstrictor response to periarterial electrical nerve stimulation was described to be a double peaked vasoconstriction consisting of an initial transient, dominantly P2X purinoceptor-mediated constriction followed by a prolonged, mainly alpha1 adrenoceptor-induced response. 3 BIIE 0246 at a concentration of 0.1-1 microM dose-dependently potentiated double peaked constrictions at low frequencies (1 and 4 Hz), whereas at high frequency (10 Hz), it failed to affect these responses. BIIE 0246 (1 microM) also enhanced double peaked responses even in the presence of rauwolscine (0.1 microM). NPY (13-36) (1-100 nM), a selective Y2 receptor agonist reduced these two peaked responses in a dose-related manner. The vasoconstriction to noradrenaline (0.1-10 nmol) or adenosine triphosphate (0.01-1 micromol) was not significantly influenced by either 1 microM BIIE 0246 or 100 nM NPY (13-36). Exposure of tissues to 1 microM BIIE 0246 almost completely prevented the suppression of double peaked constrictions by NPY (13-36) (10 nM) or by NPY (10 nM). 4 We conclude that NPY inhibits sympathetic purinergic and adrenergic vasoconstrictions through an activation of prejunctional Y2 receptor subtype in the neurovascular junction of the canine splenic artery.     

Interaction of histaminergic drugs with adrenergic neurotransmission in rabbit ear central artery

The interaction of histamine and other histaminergic agents with adrenergic neurotransmission in blood vessels was studied in vitro. The experiments were carried out on ear central arteries isolated from male Chinchilla rabbits. The proximal segment of the artery was perfused with Krebs-Henseleit solution at a rate of 3.0 ml/min and was allowed a 120-min adaptation before the experiments. Contractions of the arterial smooth muscle were evoked either by noradrenaline (NA) or by low-frequency electrical stimulation (LFES). The effects of histamine and the other histaminergic agents on the arterial tone and on the NA- or LFES-induced contractions were studied. When applied extralumenally in concentrations higher than 1 x 10(-12) M histamine and 2-(2-aminoethyl) thiazole (2-AET) enhanced the LFES-induced smooth-muscle contractions. Dimaprit (DMP) did not markedly change the LFES-contractile effects. Diphenhydramine (DPH) and mepyramine (MEP) in higher concentrations potentiated the contractions in response to LFES. Ranitidine (RAN) moderately potentiated and cimetidine (CIM) did not affect the LFES-evoked contractions of the artery. None of the drugs tested significantly changed the NA-induced contractions. The results only partly confirm the assumption that histamine exerts its modulatory effects on adrenergic neurotransmission via postsynaptic excitatory H1-receptors and presynaptic inhibitory H2-receptors.