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PubMed2004

Contractile responses of aortae from WKY and SHR to vasoconstrictors.

Aortae taken from spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats aged 4, 8 and 16 weeks were prepared as rings and used to measure the effects of five vasoconstrictors. The endothelium was removed in order to measure selectively the contractile responses induced by potassium chloride (KCl), phenylephrine (PHE), angiotensin-II (Ang II), endothelin-1 (ET-1) and human urotensin-II (U-II). These responses were assumed to derive from the activation of specific receptors (namely alpha1, AT1, ETA and UT-II) or from depolarization of the smooth muscle fibers by KCl. Specific antagonists prazosin, losartan, BQ-123 and [Orn8]-UII were used at various concentrations for a pharmacological characterization of these latter receptor systems. The primary purpose of the study was to explore mechanisms or factors that may intervene in the development and maintenance of high blood pressure in SHR. Results indicate that isolated aortae of SHR and WKY contain contractile sites (receptors) whose pharmacological profiles (pEC50 for agonists, pA2 for antagonists) are very similar to those of other biological systems and should be considered as typical for the alpha1, AT1, ETA and UT-II receptor types. Aortae taken from SHR 4 (non hypertensive), 8 and 16 weeks old (hypertensive) responded to the vasoconstrictors with reduced maximal contractions compared to those of age-matched WKY. These unexpected reduced responses of aortae, observed with the five vasoconstrictors, may be attributed to a non specific lesions. Maximal contraction of aortae from SHR increased from 4 to 16 weeks for KCI, PHE and U-II, decreased for Ang II, and remained stable for ET-1. There was also an age-dependent increase of maximal contraction induced by U-II in WKY. It is suggested that aortae from SHR undergo early remodelling that leads to reduced contractility in vitro and possibly to vessel rigidity in vivo. The factors involved in this process appear to be of genetic origin since they are present before hypertension: they may contribute to modify aortic compliance and perhaps vascular resistance in hypertensive animals and thus being the cause and not the consequence of high blood pressure.

Age Factors↗

PubMed1992

Effects of vasoconstrictors on isolated rabbit coronary arteries exposed to isotonic iohexol. Potassium chloride-, histamine-, endothelin-, and prostaglandin-F2 alpha-induced contractions on arteries exposed to iohexol without and with osmotic additions (sodium chloride or glucose).

RATIONALE AND OBJECTIVES: A major effect of contrast media (CM) on coronary vessels is vasodilatation, but occasionally, both ionic and nonionic media may cause coronary artery spasm. The influence of CM on the actions of vasoactive substances is not well known. To investigate the effects on rabbit coronary arteries of an iso-osmolar nonionic CM, iohexol (140 mg I/mL) the vasoconstrictors potassium chloride (KCl), histamine, endothelin, and prostaglandin-F2 alpha (PGF2 alpha) were used. The effects of iohexol with 30 to 150 mM sodium chloride (NaCl) or with 25-50 g/L glucose also were investigated. METHODS: Coronary artery segments were mounted between two L-shaped prongs in tissue baths with buffer solution. Before each investigation, buffer was exchanged with iohexol solution. Increasing concentrations of a vasoconstrictor were added, and the constriction of the vessels was recorded. RESULTS: Iohexol caused a comparatively small inhibition of the contractile effects of histamine and endothelin. This meant little reduction in maximal contraction (Emax), and the concentration of constrictory substance resulting in half maximal contraction (EC50) compared with buffer solution. Iohexol also caused a small reduction in Emax of KCl, but EC50 was significantly lower. Adding NaCl or glucose to iohexol decreased Emax and increased EC50. Iohexol inhibited most of the contractile effect of PGF2 alpha, but adding NaCl increased Emax slightly. CONCLUSIONS: The effects caused by a nonionic CM on coronary arteries cannot be attributed to osmolality alone. The CM influenced the effects of vasoconstrictors to differing degrees, but the inhibition of the CM per se was usually small.

Animals↗

PubMed1995

Effects of pulmonary hypertension on vasoconstrictor responses to endothelin-1 and sarafotoxin S6C and on inherent tone in rat pulmonary arteries.

Vasoconstrictor responses to endothelin-1 (ET-1) and the ETB receptor agonist sarafotoxin S6c (SXS6c) were investigated in the main pulmonary artery and pulmonary artery branch removed from rats previously exposed to 10% O2 [chronic hypoxic (CH) rats] or room air (control rats) for 2 weeks. The effects of nitric oxide synthase (NOS) inhibition with L-Nomega-nitroarginine methyl ester (L-NAME) (100 microM) on ET receptor-induced responses in these arteries were also investigated. In control rats, in rings of main pulmonary arteries and pulmonary artery branches. ET-1 induced vasoconstrictor responses. These responses were mediated by the ETA receptor as they were antagonized by the ETA receptor antagonist FR 139317 whereas SXS6c did not vasoconstrict. Chronic hypoxia had no effect on the sensitivity of the main pulmonary arteries to ET-1, whereas small vasoconstrictor responses to SCS6c were evident. ET-1 was more potent in the CH rat pulmonary artery branches than in controls. SXS6c also caused vasoconstriction with a maximum response 30% of that to ET-1 in both endothelium-intact and endothelium-denuded vessels. L-NAME increased the sensitivity to ET-1 in the CH rat main pulmonary arteries and increased the responses to low concentrations of ET-1 in the control rat main pulmonary arteries but did not affect any ET-1 responses in any other vessels. It did disclose responses to SXS6c in control rat main pulmonary arteries. L-NAME itself increased vascular tone to a greater extent in CH rat pulmonary arteries than in controls. In preconstricted pulmonary arteries, however, relaxations to acetylcholine (ACh) were diminished in the CH rats as compared with their controls. All pulmonary artery branches, denuded of their vascular endothelium, relaxed to sodium nitroprusside (SNP) and therefore exhibited endogenous vascular tone. This effect was greatest in the pulmonary artery branches from the CH rats. The results suggest that rat large pulmonary artery responses to ET-1 are normally mediated by ETA receptors. Pulmonary hypertension can potentiate ETA receptor-mediated vasoconstriction and facilitate ETB receptor-mediated vasoconstriction. Endogenous NO may normally suppress ETA receptor-mediated responses in rat main pulmonary arteries. Rat pulmonary arteries exhibit endogenous tone, which is increased by exposure to chronic hypoxia.

Animals↗

PubMed2000

Influence of losartan on alpha-adrenoceptor-mediated vasoconstrictor response in humans.

To evaluate the influence of losartan on alpha-adrenoceptor-mediated vasoconstrictor response, we examined dorsal hand vein constrictor response to phenylephrine (16-8,192 ng/min) and fingertip vasoconstrictor response to cold stimulation with and without pretreatment with losartan (50 mg/day) for 3 days in nine healthy men. The effect of coadministration of angiotensin II (Ang II) (0.3 ng/min) on the venoconstrictor response also was evaluated. Oral pretreatment with losartan alone influenced neither of the responses. The log of the infusion rate of phenylephrine producing half-maximal venoconstriction [log(ED50)] was 2.69 +/- 0.10 (mean +/- SEM) for control and 2.68 +/- 0.09 for losartan, and the reduction ratio of fingertip blood flow was 68.1 +/- 4.0% for control and 66.7 +/- 4.3% for losartan. Coadministration of Ang II, however, significantly enhanced the venoconstrictor response to phenylephrine [log(ED50): 2.43 +/- 0.09, p < 0.05 vs. control], and the pretreatment with losartan attenuated this effect [log(ED50): 2.60 +/- 0.11]. These findings indicate that the alpha-adrenoceptor-mediated vasoconstrictor response is not influenced by losartan; however, it is enhanced by exogenous Ang II, and losartan attenuates the enhanced response, in healthy human subjects.

Adult↗

PubMed1989

Does suppression of responsiveness to beta-adrenoceptor activation explain the enhancement of vasoconstrictor responses by alpha 2-adrenoceptor agonists?

1. The alpha 2-adrenoceptor agonist TL99, in concentrations that had no other observable effect, enhanced constrictor responses to phenylephrine in perfused segments of the rat tail artery. 2. Vasoconstrictor responses to phenylephrine were also enhanced by propranolol (0.3 mumol/L). 3. Vasoconstrictor responses to phenylephrine in the presence of propranolol were further enhanced by TL99 (10 nmol/L). 4. The enhancement of vasoconstrictor responses by alpha 2-adrenoceptor agonists is not due to the removal of a counteracting vasodilator component produced by activation of beta-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1976

The inhibition by glucagon of the vasoconstrictor actions of noradrenaline, angiotensin and vasopressin on the hepatic arterial vascular bed of the dog.

1 The hepatic artery of the anaesthetized dog was cannulated and perfused from a femoral artery, the blood flow and perfusion pressure being monitored continuously. The sympathetic periarterial nerves were divided. 2 Dose-dependent increases in hepatic arterial vascular resistance (HAVR) resulted from intra-arterial injections of noradrenaline, angiotensin and vasopressin. 3 Single injections of glucagon (100 mug, i.a.) caused a transient significant fall in HAVR of 19.9 +/- 3.2%, and infusions of 25 mug/min of glucagon intra-arterially caused maintained reductions in HAVR of 16.9 +/- 4.2%. 4 After single injections of 100 mug glucagon intra-arterially the vasoconstrictor responses to noradrenaline, angiotensin, and vasopressin were reduced by about 85-95%. Recovery occurred in 8-10 minutes. 5 Intra-arterial infusions of glucagon, 2.5-50.0 mug/min, reduced the effects of test doses of noradrenaline, angiotensin and vasopressin throughout the period of the infusions. 6 Dose-response curves to the constrictor agents were constructed before, during and after intra-arterial infusions of 25 mug/min of glucagon. Glucagon caused a parallel shift of the curves for noradrenaline and angiotensin to the right, with no suppression of the maximum response. 7 Infusions of glucagon shifted the dose-response curve for vasopressin to the right, but, in contrast to noradrenaline and angiotensin, the shift was nonparallel and there was a suppression of the maximum response by about one-half. 8 A large dose of insulin, 10 iu, transiently reduced HAVR and caused a weak and very transient inhibition of the effect of test doses of noradrenaline. The characteristics of these effects were quite different from those of glucagon. 9 It is possible that the antagonism by glucagon of the vasoconstrictor responses of the hepatic arterial vasculature may be important in protecting this vascular bed from the effects of concomitantly released vasoconstrictor agents.

Angiotensin II↗

PubMed1982

Coronary vasoconstrictor and vasodilator actions of arachidonic acid in the isolated perfused heart of the rat.

The administration of arachidonic acid (AA) to the isolated perfused heart of the rat usually produced biphasic coronary responses characterized by initial vasoconstriction followed by prolonged vasodilatation. However, some responses were predominantly vasoconstrictor or vasodilator. The non-steroidal anti-inflammatory agents (NSAA) indomethacin (1-5 mg/l) and naproxen (12.5-25 mg/1) reversibly inhibited both phases of the response induced by AA. Pretreatment of animals with indomethacin (5 mg/kg) or naproxen (25 mg/kg) daily, resulted in unaltered coronary response to AA. Subsequent addition of NSAA to the perfusate produced inhibition of the AA effect. Short infusions of acetylsalicylic acid at low concentrations (2.9 micrograms/ml), dipyridamole (0.6 micrograms/ml) and sulphinpyrazone (28.7 micrograms/ml) selectively inhibited the vasoconstrictor phase of the response to AA. It was confirmed that metabolic coronary dilatation induced by cardiostimulation was inhibited by prolonged AA administration; this effect was prevented by NSAA pretreatment. Reactive hyperaemic responses to short lasting occlusions of coronary inflow were unaffected by NSAA. Linolenic, linoleic, dihomo-gamma-linolenic and oleic acid usually produced decreases in coronary flow which were unaffected by NSAA, dipyridamole or sulphinpyrazone. Intra-aortic injections of AA, prostacyclin (PGI2) and prostaglandin E2 (PGE2) in the intact rat produced a dose-dependent decrease in blood pressure with the AA response inhibited by indomethacin. PGI2 and PGE2 produced long lasting coronary vasodilatation in the isolated heart. The coronary actions of AA appear to be due to its transformation, within the easily accessible vascular wall, into prostaglandin and thromboxane-like substances. We suggest that a vasoconstrictor thromboxane A2-like substance may be responsible for coronary vasospasm. Coronary insufficiency may also result from an inhibition of compensatory metabolic coronary dilatation by increased synthesis of PGE2 within the myocardial cell.

Animals↗

PubMed1989

The selective carotid arterial vasoconstrictor action of GR43175 in anaesthetized dogs.

1. GR43175 is a highly selective agonist at 5-HT1-like receptors in the dog saphenous vein. This study describes the haemodynamic effects of GR43175 in barbitone-anaesthetized dogs. 2. GR43175 (1-1000 micrograms kg-1, i.v.) produced dose-dependent decreases in carotid arterial blood flow with little or no change in arterial blood pressure. The decrease in blood flow was associated with an increase in carotid arterial vascular resistance. In preliminary studies, the dose of GR43175 producing 50% of the maximum carotid vasoconstrictor response was 39 +/- 8 micrograms kg-1, i.v. 3. In comparative regional haemodynamic studies, GR43175 (1-1000 micrograms kg-1, i.v.) had little effect on total peripheral resistance or resistance in the mesenteric, vertebral and coronary arterial vascular beds. Low doses of GR43175 decreased, whilst high doses (100 micrograms kg-1, i.v. and above) increased femoral arterial vascular resistance. GR43175 (1-1000 micrograms kg-1, i.v.) had no effect on respiratory inflation pressure. In doses of 100 micrograms kg-1 i.v. and above, GR43175 caused small decreases in heart rate. 4. The carotid arterial vasoconstrictor action of GR43175 was resistant to antagonism by the 5-HT2 receptor, 5-HT3 receptor and alpha-adrenoceptor blocking drugs, ketanserin, MDL72222 and phentolamine respectively, but could be antagonized by the non-selective 5-HT1-like receptor blocking drug methiothepin. Methiothepin had no effect on the carotid vasoconstrictor action of the thromboxane A2 mimetic, U46619. 5. The results demonstrate that GR43175 produces a selective vasoconstriction in the carotid arterial circulation of anaesthetized dogs via activation of 5-HT1-like receptors, which appear similar to those mediating contraction of the dog isolated saphenous vein.

Animals↗

PubMed1993

Vasoconstrictor effects of various neuropeptide Y analogues on the rat tail artery in the presence of phenylephrine.

1. The increase in perfusion pressure induced by neuropeptide Y (NPY), peptide YY (PYY) and related peptides were compared in the perfused rat tail artery precontracted by a submaximal concentration (1 microM) of the vasoconstrictor, phenylephrine. 2. NPY, PYY, [Leu31,Pro34]NPY, [Glu16,Ser18,Ala22,Leu28,31]NPY (ESALL-NPY) and the centrally truncated and stabilized analogues [D-Cys5,8-aminooctanoic acid7-20, Cys24]-NPY (D-Cys5-NPY) and [D-Cys7, 8-aminooctanoic acid8-17,Cys20]-NPY (D-Cys7-NPY) produced a concentration-dependent enhancement of the vasoconstrictor response induced by 1 microM phenylephrine. PYY was two times more potent than NPY and [Leu31,Pro34]NPY while ESALL-NPY, D-Cys7-NPY and D-Cys5-NPY were approximately 3, 5 and 16 times less potent than NPY respectively. NPY, D-Cys5-NPY and D-Cys7-NPY gave similar maximal responses whereas those observed for PYY, [Leu31,Pro34]NPY and ESALL-NPY were much greater than that of NPY. 3. NPY 13-36 and [des-Ser3,Lys4,Cys2,8-aminooctanoic acid3-24, D-Cys27]-NPY ([es-Ser3,Lys4]Cys2-NPY) were practically inactive at concentrations up to 3 microM, whereas [des-Ser3,Lys4,D-Cys2,8-aminooctanoic acid3-24,Cys27]-NPY ([des-Ser3,Lys4]D-Cys2-NPY), which differs from [des-Ser3,Lys4]Cys2-NPY in the disulphide bridge (a D-Cys in position 2 for [des-Ser3,Lys4]D-Cys2-NPY instead of an L-CYs for [des-Ser3,Lys4]Cys2-NPY) was a weak agonist the maximal effect of which could not be ascertained. 4. The contractile effects of [des-Ser3,Lys4]D-Cys2-NPY were additive with those of NPY and [Leu31,Pro34]NPY demonstrating that it is not a partial agonist but may simply not interact competitively with the receptor binding site for NPY. NPY and PYY interacted in a manner expected of agonists competing for the same binding site.5. PYY, NPY and [Leu31,Pro34]NPY were equipotent in displacing the I125-labelled PYY from binding sites on membranes from Y1-receptor expressing SK-N-MC cells, while the centrally truncated analogues were much less potent. The rank order of potencies for displacement of the I125-PYY binding by these peptides in SK-N-MC cells correlated with their activity in enhancing the vasoconstrictor response of phenylephrine in the tail artery. For the [des-Ser3,Lys4]D-Cys2-NPY analogue, the displacement pattern was more complex in that the displacement analysis revealed the presence of two binding sites.6. In conclusion, these data provide no evidence for other than postjunctional Y1-receptors mediating the enhancement of the contractile response elicited by phenylephrine in the perfused rat tail artery. The effects of [des-Ser3,Lys4]D-Cys2-NPY indicate that the Y1-receptor may possess an allosteric binding site.

Amino Acid Sequence↗

PubMed1994

Potentiation of responses to sympathetic nerve stimulation and vasoconstrictor agents by SK&F 103829 in the feline mesenteric circulation.

1. The amplification of vasoconstrictor effects of several agonists and sympathetic nerve stimulation, caused by 5-HT2 receptor activation, was studied in the autoperfused mesenteric circulation of anaesthetized cats. To produce long lasting and selective 5-HT2 receptor stimulation we used SK&F 103829 (2,3,4,5 tetrahydro-8[methyl-sulphonyl]-1H3-benzazepin-7-ol methensulphonate). We assessed that SK&F 103829 was a strong contractile partial agonist in isolated preparations of rat tail artery and calf pulmonary artery. 2. The intrinsic activity of SK&F 103829 with respect to 5-hydroxytryptamine (5-HT) was 0.8 in rat tail artery and 0.6 in calf pulmonary artery. SK&F 103829-induced contractile responses were surmountably antagonized by ketanserin with a potency expected from its affinity for 5-HT2 receptors. SK&F 103829 surmountably antagonized the effects of 5-HT in rat tail artery with a pKp of 5.8. 3. Concentrations of SK&F 103829 causing greater than threshold constrictions enhanced vasoconstrictor responses of sympathetic nerve stimulation, noradrenaline, angiotensin II, methoxamine and alpha, beta-methylene ATP in the mesenteric arterial bed. Increases in mesenteric arterial pressure by noradrenaline, observed in the presence of prazosin, were also potentiated by SK&F 103829. 4. Ketanserin prevented both the constrictor effect of SK&F 103829 and the SK&F 103829-evoked potentiation of the responses to noradrenaline and angiotensin II in the mesenteric arterial bed. Ketanserin, however, failed to abolish (once established) the SK&F 103829-evoked potentiation of the constrictor effects caused by both noradrenaline and angiotensin II. 5. Short lasting constrictor effects of 5-HT were reversed to dilator effects by SK&F 103829 in both the mesenteric arterial and venous bed, thereby revealing the existence of vasodilator 5-HT receptors.6. The main finding is consistent with a sensitization of the mesenteric arterial bed to vasoconstrictor responses mediated through alpha 1- and alpha2-adrenoceptors, angiotensin II receptors and purinoceptors by SK&F 103829-evoked activation of 5-HT2 receptors. This property, together with the direct constrictor effect of the mesenteric arterial bed suggest that SK&F 103829 can reduce portal venous flow thereby being a useful therapeutic principle for the treatment of portal hypertension.

Animals↗

PubMed1994

Evidence from receptor antagonists of an important role for ETB receptor-mediated vasoconstrictor effects of endothelin-1 in the rat kidney.

1. To characterize the receptor subtype(s) mediating the renal vasoconstrictor effects of the endothelin (ET) and sarafotoxin (SX) peptides in the isolated perfused kidney of the rat, we have examined the effects of endothelin-1 (ET-1), sarafotoxin 6b (SX6b) and sarafotoxin 6c (SX6c) as agonists, BQ-123 and FR 139317 as selective ETA receptor antagonists, and PD 145065 as a non-selective (ETA and ETB) receptor antagonist. We have also compared in the anaesthetized rat the systemic pressor and renal vasoconstrictor effects of ET-1 and SX6c alone or after pretreatment with PD 145065. 2. In the isolated perfused kidney, ET-1, SX6b and SX6c all gave similar concentration-dependent increases in perfusion pressure. The ETA receptor selective antagonists, BQ-123 and FR 139317, both partially blocked the increase in perfusion pressure induced by ET-1. In contrast, PD 145065 completely blocked the increase in perfusion pressure caused by ET-1. 3. Indomethacin (10 microM) had no effect on the ET-1-induced increases in perfusion pressure but significantly reduced the vasoconstriction induced by low concentrations of SX6c, without affecting responses to high concentrations. In the anaesthetized rat, indomethacin (5 mg kg-1) did not modify the systemic pressor or renal vasoconstrictor effects of ET-1 or SX6c. 4. In anaesthetized rats, bolus intravenous injections of ET-1 or SX6c (0.1, 0.25, 0.5 or 1.0 nmol kg-1) produced initial transient depressor responses followed by sustained and dose-dependent increases in mean arterial pressure (MAP). Both peptides caused an equipotent fall in renal blood flow (RBF).PD 145065 (5 mg kg-1) partially antagonized the systemic pressor effects of ET-1 and SX6c but completely blocked the fall in RBF and rise in renal vascular resistance (RVR) induced by ET-1 and SX6c. PD 145065 also antagonized the transient depressor effect following the bolus administration of either ET-1 or SX6c.5. These results indicate that ET/SX induced renal vasoconstriction is mediated via ETA and ETB-like receptors with ETB receptors having a predominant role in vivo. This may be of therapeutic relevance for an ETA receptor-selective antagonist may offer only limited protection against the deleterious renal effects of endogenous ETs.

Amino Acid Sequence↗

PubMed1994

Pharmacological reactivity of human epicardial coronary arteries: phasic and tonic responses to vasoconstrictor agents differentiated by nifedipine.

1. Human epicardial coronary artery rings, freshly obtained from cardiac transplantation patients, commonly exhibited phasic contractile activity in vitro. This activity occurred either spontaneously or in response to vasoconstrictor stimulation. 2. Nifedipine pretreatment (1 nM-0.1 microM) reduced both types of phasic contractions in a concentration-dependent manner. At 0.1 microM nifedipine, spontaneous contractions were completely abolished, as were phasic contractions induced by U46619, endothelin-1 or 5-hydroxytryptamine (5-HT). 3. For U46619 (0.1-100 nM), the largest phasic contractions (amplitude peak to trough) occurred over the mid-range of concentrations used (1-10 nM). At higher concentrations (30-100 nM), phasic activity was reduced as the response reached a maximum. Estimated pEC50 values for the upper phasic and lower phasic curves were significantly different (8.71 +/- 0.13 versus 7.90 +/- 0.11; P < 0.05; n = 10). In the presence of nifidepine (0.1 microM), the purely tonic contraction curve to U46619 was similar to the lower phasic curve in the absence of nifedipine (pEC50 = 8.14 +/- 0.06, n = 10). Similar results were obtained for endothelin-1 (0.1-100 nM). 4. Responses to 5-HT (1 nM-3 microM) were more variable. The largest phasic contractions were spread unevenly throughout the concentration-response curve. In the presence of nifedipine (0.1 microM), the curve to 5-HT was significantly depressed in range but not sensitivity (pEC50) when compared with the phasic curves. 5. In conclusion, activation of dihydropyridine-sensitive voltage-operated Ca2+ channels mediated the phasic contractions commonly observed in human epicardial coronary arteries. These contractions amplified the contractile responses to low concentrations of vasoconstrictors. Inhibition of phasic activity by the Ca2+ channel antagonist, nifedipine, allowed the tonic vasoconstrictor profile of human isolated coronary artery to be determined which is important information for the accurate quantitative assessment of vasodilator responses in this tissue in vitro.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2006

Increased wall tension in response to vasoconstrictors in isolated mesenteric arterial rings from patients with high blood pressure.

Essential hypertension is associated with several alterations in arterial function. A wealth of information from animal models is available concerning hypertensive changes in the mesenteric circulation, while only few studies have examined human mesenteric arterial function. The tone of isolated mesenteric arterial segments (outer diameter 0.7-0.9 mm) was examined from individuals with high (n=17) or normal (n=22) blood pressure, grouped using the current definition of elevated blood pressure (140/90 mmHg). Since the majority of them were operated because of malignancies, we evaluated whether functional vascular properties provided information about patient prognosis. Wall tension development (mN/mm) in response to vasoconstrictors (noradrenaline, 5-hydroxy tryptamine, potassium chloride) was higher in mesenteric arterial rings from patients with high than normal blood pressure. There was no difference in vasoconstrictor sensitivity, or endothelium-dependent and endothelium-independent vasorelaxation. Arterial segment weight was higher in hypertensive subjects, suggesting vascular wall hypertrophy. The 10-year follow-up showed no differences in the control of arterial tone between the surviving (n=14) or deceased (n=25) patients. In conclusion, isolated mesenteric arterial segments from hypertensive patients showed increased wall tension in response to vasoconstrictors. Since the mesenteric circulation is an important regulator of peripheral arterial resistance, possible functional alterations in this vascular bed should be further investigated in hypertensive patients.

Adult↗

PubMed1994

The role of nitric oxide in the responses of equine digital veins to vasodilator and vasoconstrictor agents.

Isolated equine digital veins were examined in vitro to study the importance of the endothelium in the responses to both vasodilator and vasoconstrictor agents and to characterise the endothelial-derived mediators involved. Carbachol (Cch; 1 microM) and bradykinin (Bk; 1 nM) caused relaxation of U44069-induced tone by 79.5 +/- 0.35% and 73.7 +/- 4.0% respectively. Mechanical removal of the endothelium completely prevented relaxant responses to Cch and to Bk showing they were mediated by the endothelium. Treatment of veins with NG-nitro-L-arginine methyl ester (L-NAME; 30 and 300 microM) inhibited vasorelaxant responses to both Cch and Bk whereas the cyclooxygenase inhibitor, ibuprofen (10 microM) had no inhibitory effect. The inhibitory action of L-NAME on the relaxations produced by Cch was partly reversed by L-arginine (3 and 10 mM). Cch-relaxations were potentiated in the presence of super oxide dismutase (15 units/ml) and inhibited by methylene blue (10 microM). The vasorelaxant effects of ATP (0.01 microM to 0.1 mM) were not dependent on the presence of the endothelium and the selective P2y receptor agonist, 2-methylthio-ATP proved to be ineffective as a vasodilator. Removal of the endothelium did not enhance the vasoconstrictor effects of the alpha 1 adrenoceptor agonist phenylephrine (0.01 microM to 0.1 mM) and treatment with L-NAME (300 microM) did not change the vasoconstrictor responses to 5-HT (1 nM to 10 microM) or the alpha 2 adrenoceptor agonist BHT-920 (1 nM to 1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed2005

Organ-specific ligation-induced changes in harmonic components of the pulse spectrum and regional vasoconstrictor selectivity in Wistar rats.

It has been shown previously that the amplitudes of the harmonic components of the pulse spectrum vary in specific patterns when the arteries leading to different organs are ligated, with the variations in the harmonics being linearly additive. Since ligation can be regarded as a vast increase in organ resistance, the present study examined the potential of using these ligation-induced variations in the pulse spectrum as reference parameters for an increase in vascular resistance and for regional vasoconstrictor selectivity. A vasoconstrictor, either arginine vasopressin (AVP) or angiotensin II (Ang II), was infused into anaesthetized Wistar rats via the femoral vein for 1 h. The distinct harmonic-specific drug effects on the pulse spectrum were simulated by combining renal artery and superior mesenteric artery ligations in different ratios, the ratio with the lowest mean square difference determining the regional drug selectivity. The ratios indicated that the effect of AVP on the pulse spectrum was attributable to the combined effect of ligating the renal and superior mesenteric arteries, while the effect of Ang II was attributable to ligation of the renal artery. The results are comparable with those of investigations of regional vascular resistance performed using traditional methods. Our findings indicate that the ligation-induced variations in the pulse spectrum can be used to determine regional increases in vascular resistance. This implies that blood pressure can be used as the sole parameter to determine which arterial bed has been affected by the vasoconstrictor, and how seriously.

Angiotensin II↗

PubMed1995

Pivotal role of phosphate chain length in vasoconstrictor versus vasodilator actions of adenine dinucleotides in rat mesenteric arteries.

1. The isolated perfused rat mesenteric arterial bed was used to examine the activity of the adenine dinucleotides: beta-nicotinamide adenine dinucleotide (NAD); beta-nicotinamide adenine dinucleotide phosphate (NADP); flavin adenine dinucleotide (FAD); and of the alpha,omega-diadenosine polyphosphates: adenylyl adenosine (AP1A); P1,P2-diadenosine pyrophosphate (AP2A); P1,P3-diadenosine triphosphate (AP3A); P1,P4-diadenosine tetraphosphate (AP4A); P1,P5-diadenosine pentaphosphate (AP5A); P1,P6-diadenosine hexaphosphate (AP6A). Responses were compared with those of ADP, ATP, 2-methylthio-ATP (2-meSATP) and alpha,beta-methylene ATP (alpha,beta-meATP). 2. In basal tone preparations mono- and dinucleotides elicited vasoconstriction with the order of potency: alpha,beta-meATP > or = AP5A > or = AP6A > or = AP4A > or = 2-meSATP >> ATP >> ADP. The dinucleotides NAD, NADP, FAD, AP1A, AP2A and AP3A had no effect. 3. The P2X-purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (30 microM) virtually abolished vasoconstrictor responses to AP4A, AP5A and AP6A. 4. Auto- and cross-desensitization of vasoconstrictor responses to AP4A, AP5A, AP6A, ATP and alpha,beta-meATP were observed. 5. In raised tone preparations nucleotides elicited endothelium-dependent vasodilatation with the order of potency: 2-meSATP = ADP > ATP > AP3A > AP2A > AP1A = NADP = FAD > NAD. The nucleotides AP4A, AP5A, AP6A and alpha,beta-meATP had no vasodilator effects. 6. It is concluded that the alpha,omega-adenine dinucleotides AP4A, AP5A and AP6A elicit vasoconstriction, but not vasodilatation, in the rat mesenteric arterial bed via P2x-purinoceptors. In contrast, the dinucleotides NADP, FAD, AP1A, AP2A and AP3A elicit vasodilatation, but not vasoconstriction, via endothelial P2Y-purinoceptors. 7. It is suggested that there is a crucial relationship between the structure of the alpha,omega-diadenosine polyphosphates and their activity at P2X- and P2Y-purinoceptors with a pivotal role played by the polyphosphate chain. Molecules with four or more phosphates are vasoconstrictors, while those with three or less phosphates are vasodilators.

Adenine Nucleotides↗

PubMed1998

Role of the endothelium in modulating functional responses of isolated bovine anterior ciliary arteries to vasoconstrictor agonists.

BACKGROUND/AIMS: Endothelium dependent vasodilatation is an important regulator of blood flow to the eye but its role has not been investigated in vessels supplying the ciliary body. This study assessed the role of the endothelium in modulating vasoconstrictor responses of the intraocular bovine anterior ciliary artery. METHODS: Bovine anterior ciliary arteries (n = 33) were mounted in a myograph, containing physiological salt solution at 37 degrees C, for isometric force measurement. Cumulative concentration-response curves were obtained to the constrictor agonists 5-hydroxytryptamine (5-HT), noradrenaline, phenylephrine, prostaglandin, F2 alpha, endothelin-1, and KCl in both endothelium intact and denuded arteries. RESULTS: All vasoconstrictors produced sustained contractile responses which were unaffected by the removal of the endothelium. Responses to 5-HT were also unaffected by inhibition of nitric oxide synthase. CONCLUSION: These results indicate that neither agonist stimulated nor basal release of nitric oxide from the endothelium modulates responses to vasoconstrictor agonists in the isolated bovine anterior ciliary artery when measured in a no flow isometric system.

Animals↗

PubMed1998

Stimulation and inhibition of resting muscle thermogenesis by vasoconstrictors in perfused rat hind limb.

Angiotensin (AII) and serotonin (5-HT) are both vasoconstrictors of the constant-flow perfused rat hind limb that have opposite effects on thermogenesis, possibly the result of differing effects on vascular flow distribution between nutritive and non-nutritive pathways. In the present study interaction between the two opposing agents was examined with the expectation that the combined presence would show additive effects on pressure and mutually neutralizing effects on thermogenesis. Thus doses of AII and 5-HT that gave similar, but opposite, quantitative effects on thermogenesis were infused alone, in combination one after the other, or in combination with the order reversed, and the effects on perfusion pressure (PP) and thermogenesis (oxygen uptake, VO2) were compared. AII (3 nM) alone increased PP by 15+/-1 mmHg (1 mmHg = 133.3 Pa) and VO2 by 3.1-/+0.2 micromol.h(-1).g(-1), whereas 5-HT (1 microM) alone increased PP by 75+/-6 mmHg and inhibited VO2 by 3.9+/-0.2 micromol.h(-1).g(-1). When added in combination, the outcome depended on the order of addition. Following AII, infusion of 5-HT further increased PP by 160+/-11 mmHg and decreased VO2 by 6.3+/-0.2 micromol.h(-1)g(-1). Following 5-HT, infusion of AII further increased PP by 28+/-4 mmHg and increased VO2 by only 1.8+/-0.3 micromol.h(-1).g(-1). The prior presence of 5-HT (1 microM) shifted the AII dose-response curves for VO2 and pressure to the right and left, respectively. The prior infusion of AII increased the dose-dependent response to 5-HT in terms of both the inhibition of VO2 and the increase in PP. At low doses of 5-HT (10(-8)-10(-7) M), but not alpha-methyl serotonin (alphaMT), there was a marked vasodilatation-associated inhibition of AII-mediated increase in VO2. Overall the data show that the combined effect of AII and 5-HT differed from the simple addition of each separately. Since the order of addition appears to be critical in terms of thermogenic outcome, it is concluded that each vasoconstrictor exerts a specific hemodynamic action to affect access of the other to vascular receptor sites. These findings are consistent with the previously reported effects of these vasoconstrictors on substrate and insulin access to muscle of the perfused rat hind limb.

Angiotensin II↗