Rabbit Saphenous Vein Research Articles

O-188 - Pharmacological evidence that ETB receptor mediates vasoconstriction of isolated rabbit saphenous vein.

O-188 - Pharmacological evidence that ETB receptor mediates vasoconstriction of isolated rabbit saphenous vein.

The vasoconstrictor action of big endothelin-1 is phosphoramidon-sensitive in rabbit saphenous artery, but not in saphenous vein

The effects of big endothelin-1 and endothelin-1 on vascular reactivity were compared in isolated rabbit saphenous artery and vein. The contractile potency of endothelin-1 was three times higher in the vein than in the artery. In contrast, big endothelin-1 was two times more effective in the artery. Phosphoramidon (100 μM), a metalloproteinase inhibitor, antagonised the contractile action of big endothelin-1 in the artery but not in the vein. These data suggest that the biosynthetic pathway leading to the formation of endothelin differs in arterial and venous vessels.

Venous smooth muscle contains vasoconstrictor ETB-like receptors

Two endothelin (ET) receptor subtypes have been identified to date: the ETA receptor which preferentially binds ET-1 over ET-3, and the ETB receptor which is non-selective. This study characterized the ET receptor subtypes present in several vascular smooth muscle preparations using standard in vitro techniques. In all but one of the arteries tested, ET-3 was significantly less potent than ET-1. In contrast, the potency of ET-3 was very similar to that of ET-1 in all of the veins. The selective ETA receptor antagonist BQ-123 blunted the ET-1 contractions in rabbit carotid artery, but not in saphenous vein. The selective ETB receptor ligand sarafotoxin S6c contracted the rabbit saphenous vein, but not the carotid artery. These data suggest that vascular smooth muscle cells express ETA and ETB receptors. Stimulation of either receptor subtype can result in force development.

5-HT 1-like receptors mediate contractions of the rabbit saphenous vein

5-Hydroxytryptamine (5-HT) elicited concentration-dependent contractions of the rabbit isolated saphenous vein. The effects of 5-HT were mimicked by 5-carboxamidotryptamine (5-CT), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-3-(l,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969) and sumatriptan; the rank order of potency (pD 2 values) was 5-CT (7.6) > 5-HT (6.9) > 8-OH-DPAT (6.2) > RU 24969 (6.1) > sumatriptan (5.7). The maximal response to RU 24969 was less than that to the other compounds, implying that RU 24969 may behave as a partial agonist. Methiothepin (10 −8, 3 · 10 −8 and 3 · 10 −7 M). ketanserin (10 −7, 3 · 10 −7 and 10 −6 M) and spiperone (10 −7, 10 −6 and 10 −5 M), but not laH,3α,5αH-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222; 10 −7, 10 −6 or 10 −6 M), cyanopindolol (10 −7 and 10 −6 M) or propranolol (10 −7 and 10 −6 M), shifted the concentration-effect curve of 5-HT to the right in a concentration-dependent manner with pA 2 values of 8.25, 7.51 and 6.12, respectively. The high activity of 5-CT and methiothepin compared to, respectively. 5-HT and ketanserin (and spiperone) suggests that the contraction of the rabbit saphenous vein is not mediated by 5-HT 2 receptors. The receptor involved seems to be mainly 5-HT 1-like, similar to the one mediating contraction of the dog saphenous vein, human basilar artery and porcine cranial arteriovenous anastomoses.

Analysis of the 5-HT receptor in rabbit saphenous vein examplifies the problems of using exclusion criteria for receptor classification

5-Hydroxytryptamine (5-HT) contracts ring preparations of rabbit saphenous vein via direct and indirect components, the latter being compatible with a "tyramine-like" action at sympathetic nerve terminals. Here an attempt was made to establish the identity of the receptor mediating contraction directly, in terms of the currently accepted proposals (Bradley et al. 1986). Results with agonists suggested 5-HT1-like receptor activation: methylsergide behaved as a partial agonist with microcolar affinity and 5-HT effects were mimicked by 5-carboxamidotryptamine (5-CT) and GR43175. The agonist potency order was 5-CT greater than 5-HT greater than methysergide greater than or equal to GR43175, the same as that reported at the 5-HT1-like receptor in dog saphenous vein (Feniuk et al. 1985; Humphrey et al. 1988). Consistent with this, 5-HT effects were resistant to blockade by the selective 5-HT3 receptor antagonist MDL72222 (1.0 mumol/l). In contrast, methiothepin (0.01-0.3 mumol/l), ketanserin (0.3-30.0 mumol/l) and spiperone (0.3-30.0 mumol/l) each produced surmountable antagonism which, although competitive in nature only for methiothepin (pKB = 9.45 +/- 0.09, 17 d.f.), implied 5-HT2 receptor involvement. The possibility that these discrepancies resulted from mixed populations of 5-HT1-like and 5-HT2 receptors can be excluded because; 1). Ketanserin and spiperone blocked the actions of 5-HT and the selective 5-HT1-like receptor agonist GR43175 with equal facility and 2). Responses to all of the agonists studied were similarly antagonised by flesinoxan (pKB approximately 6.4), a simple competitive antagonist at the receptor in rabbit saphenous vein.(ABSTRACT TRUNCATED AT 250 WORDS)

Actions of non-peptide ergot alkaloids at 5-HT1-like and 5-HT2 receptors mediating vascular smooth muscle contraction

This report describes the actions of the non-peptide ergot alkaloids methysergide, methylergometrine and ergometrine at two types of 5-HT receptor mediating vascular contraction; the well established 5-HT2 receptor in rabbit aorta and a non-5-HT2 receptor in rabbit saphenous vein which resembles the 5-HT1-like receptor in dog saphenous vein. In the rabbit aorta ergometrine (1 mumol/l) and methylergometrine (0.3 mumol/l), but not methysergide, produced small contractions (14% and 7% respectively of the maximal response to 5-HT). This contraction was not related to activation of 5-HT2 receptors since it was resistant to blockade by ketanserin (0.3 mumol/l). When examined as antagonists of 5-HT-induced contractions of rabbit aorta, each ergot displayed nanomolar affinity at the 5-HT2 receptor but only methysergide behaved as a simple competitive antagonist (pKB = 8.25). Methylergometrine and ergometrine produced surmountable blockade which was accompanied by a non-parallel displacement of the 5-HT concentration-effect curves. The selective 5-HT1-like receptor agonist GR43175 (less than or equal to 30 mumol/l) was devoid of affinity at the 5-HT2 receptor in rabbit aorta. In the rabbit saphenous vein each of the ergots produced concentration-dependent contractions which resulted in overtly biphasic concentration-effect curves. Only the first phase of contraction mimicked the effects of 5-HT and GR43175 since contractions were not blocked by MDL 72222 (1 mumol/l), but were surmountably antagonised by methiothepin (10 nmol/l), ketanserin (0.3 mumol/l) and spiperone (0.3 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

5-HT 1-iike receptors mediate contractions of the rabbit saphenous vein

5-HT 1-iike receptors mediate contractions of the rabbit saphenous vein

Activities of octopamine and synephrine stereoisomers on alpha-adrenoceptors.

1. The activities of the (-)- and (+)-forms of m- and p-octopamine and m- and p-synephrine on alpha 1-adrenoceptors from rat aorta and anococcygeus and alpha 2-adrenoceptors from rabbit saphenous vein were compared with those of noradrenaline (NA). 2. The rank order of potency of the (-)-forms on alpha 1-adrenoceptors from rat aorta and alpha 2-adrenoceptors was NA greater than m-octopamine = m-synephrine greater than p-octopamine = p-synephrine. The two m-compounds were 6 fold less active than NA on alpha 1-adrenoceptors from rat aorta and 150 fold less active on alpha 2-adrenoceptors. The two p- compounds were 1,000 fold less active than NA on both alpha 1-adrenoceptors from rat aorta and alpha 2-adrenoceptors. The rank order of potency of the (-)- forms on alpha 1-adrenoceptors from rat anococcygeus was NA = m-synephrine greater than m-octopamine greater than p-octopamine = p-synephrine. m-Octopamine was 4 fold less active than NA and (-)-m-synephrine. The two p- compounds were 30 fold less active than NA. 3. The rank order of potency of the (+)- forms was NA greater than m-octopamine greater than m-synephrine greater than p-octopamine greater than p-synephrine on both alpha 1- and alpha 2-adrenoceptors. The potency of each (+)- form was 1-2 orders of magnitude less than that of the (-) counterpart, the differences being greater for the stereoisomers of synephrine than for those of octopamine on both alpha 1- and alpha 2-adrenoceptors. 4. The yohimbine diastereoisomer antagonists, rauwolscine and corynanthine, were tested against (-)-NA and (-)-m-octopamine-induced contractions in both preparations. Based upon the known selectivities of these isomers for alpha-adrenoceptor subtypes, it is concluded that the rat aorta contains only alpha 1-adrenoceptors while the rabbit saphenous vein possesses predominantly alpha 2-adrenoceptors. 5. Ligand binding data for the octopamine and synephrine stereoisomers at alpha 1- and alpha 2-binding sites from rat cerebral cortex was also obtained. (-)-Forms were more active than (+)-forms. The rank order of affinity of the (-)-forms for both alpha 1- and alpha 2-binding sites was NA greater than m-octopamine = m-synephrine greater than p-synephrine greater than p-octopamine. The relative affinities of the members of the series against alpha 1-binding sites were very similar to their relative functional activities on rat aorta. However, the affinities of both m- and p-compounds relative to that of ( -)-NA were much greater at the x2-binding sites than were the relative activities in rabbit saphenous vein, possibly suggesting low intrinsic efficacy. Functional antagonist responses to NA by the (-)-octopamine and synephrines could not, however, be demonstrated on rat aorta or rabbit saphenous vein. 6. The activities of m-octopamine and m-synephrine were not significantly different from each other on either a,-adrenoceptors from rat aorta or x2-adrenoceptors; however, m-synephrine is more active than m-octopamine on a,-adrenoceptors from rat anococcygeus. Both m-octopamine and msynephrine can be considered to be naturally occurring x,-selective amines. However, if m- and poctopamine are co-released with NA in amounts proportional to their concentration, it is concluded that their activities on m,- and x2-adrenoceptors are too low to be physiologically significant.

Pharmacologic differentiation between pre- and postjunctional alpha 2-adrenoceptors by SK&F 104078.

Most alpha 2-adrenoceptor antagonists do not discriminate between pre- and postjunctional alpha 2-adrenoceptors, and this has led to the commonly held belief that pre- and postjunctional alpha 2-adrenoceptors may represent one homogeneous population of receptors. SK&F 104078 has been shown to be a potent antagonist at postjunctional alpha 2-adrenoceptors at concentrations that do not block prejunctional alpha 2-adrenoceptors. Thus, SK&F 104078 is a competitive postjunctional alpha 2-adrenoceptor antagonist in canine and rabbit saphenous veins, canine saphenous artery and human platelet with a dissociation constant of approximately 100 nmol/l. Conversely, SK&F 104078 is inactive as a prejunctional alpha 2-adrenoceptor antagonist in atria from dog, guinea pig, rabbit and rat, and in guinea-pig ileum at concentrations up to 10,000 nmol/l. Likewise, SK&F 104078 has the ability to block postjunctional arterial alpha 2-adrenoceptors in vivo in the pithed rat at doses that do not inhibit prejunctional alpha 2-adrenoceptors in the same model. The results suggest that pre- and postjunctional alpha 2-adrenoceptors may not represent one homogeneous class, but rather are discrete subtypes of the alpha 2-adrenoceptor that may be differentiated by SK&F 104078.

Comparison of potency of α2‐adrenoceptor antagonists in vitro: evidence for heterogeneity of α2‐adrenoceptors

A comparison has been made of affinity of alpha-adrenoceptor antagonists for alpha 2 binding sites in radioligand binding assays, and functional antagonist activity at pre- and postjunctional alpha 2-adrenoceptors in various in vitro preparations. The antagonists displaced [3H]-rauwolscine from rat brain and rabbit spleen membranes but there were substantial differences in rank order and absolute potency in the two tissues. pA2 values for yohimbine, phentolamine and Wy26703 against the selective alpha 2 agonist UK-14,304 were determined in the rat left atrium, rat and rabbit vas deferens and rabbit saphenous vein preparations. The pA2 values varied substantially between the tissues, differing by two orders of magnitude in the case of Wy26703. Yohimbine was more potent in rabbit preparations while Wy26703 was markedly more potent in all the rat preparations. Yohimbine and Wy26703 were compared in the dog saphenous vein preparation where pre- and postjunctional alpha 2 antagonist activity can be compared in the same tissue. As in the rabbit preparations, yohimbine was more potent than Wy26703 at both sites but the absolute potencies were different. It is concluded that alpha 2-adrenoceptors are a heterogeneous population, different subgroups being more apparent between species rather than between tissue types or location.

Comparison of activity of alpha-adrenoceptor agonists and antagonists in dog and rabbit saphenous vein

The alpha adrenoceptors present on the saphenous vein of the dog and rabbit were characterised in vitro using the selective alpha 1 antagonist prazosin and the alpha 2 antagonists rauwolscine and yohimbine. In the dog saphenous vein, prazosin and rauwolscine competitively antagonised contractile responses to phenylephrine and UK-14,304 respectively. Noradrenaline was competitively blocked by prazosin only. In contrast, phenylephrine and methoxamine-induced responses in the rabbit saphenous vein were insensitive to prazosin and corynanthine. Rauwolscine competitively blocked responses to UK-14,304, noradrenaline and phenylephrine and pA2 values were similar against each agonist. Noradrenaline and UK-14,304 were equipotent agonists on the rabbit saphenous vein while in the dog vein noradrenaline has a lower potency than UK-14,304. These results suggest that the dog saphenous vein has a mixed population of alpha adrenoceptors, while the alpha adrenoceptors on the rabbit vein are homogeneous, with characteristics of the alpha 2 subtype.

Effect of contraction on the subsequent responsiveness and maximum contractility of the rabbit ear artery and saphenous vein in vitro.

The purpose of this study was to investigate the effect of prior agonist-induced contraction of vascular smooth muscle on its subsequent responsiveness and maximum contractility. Repeated exposure of the rabbit ear artery to equieffective histamine (Hist) or KCl concentrations increased subsequent norepinephrine (NE) responsiveness and maximum contractility in comparison to rested controls. Tissues exposed in a similar manner to an equieffective serotonin concentration responded to NE more than did controls, but less than Hist- and KCl-pretreated tissues. Prior exposure to NE or KCl increased Hist responsiveness and maximum contractility. However, NE pretreatment did not increase serotonin or KCl responsiveness. The increased responsiveness and maximum contractility lasted for at least 90 and 390 min., respectively. When ear arteries were exposed to agonists in the presence of NaNO2 or papaverine the increase in responsiveness was either reduced or absent. Everted arteries repeatedly exposed to Hist demonstrated an increased tonic phase contraction to NE; there was no change in the initial transient phase of contraction. Exposure of the saphenous vein to Hist oe KCl had no effect on subsequent NE responsiveness; however, maximum contractility was increased. The present results suggest that (1) contraction brought about by agonist drugs can result in two separate phenomena -- increased responsiveness and increased maximum contractility; (2) the increased responsiveness may mask underlying alpha-adrenoceptor desensitization which may be agonist specific; (3) an event following agonist-receptor binding is responsible for increased responsiveness and increased maximum contractility; (4) the mechanism for increased responsiveness may be due to an increased coupling between receptor activation and membrane permeability to calcium; (5) agonist contraction in the saphenous vein and ear artery may be regulated by different mechanisms.

Studies on the vascular action of bradykinin.

Bradykinin (BK) is widely regarded as a potent vasodilator capable of increasing blood flow, increasing vascular permeability, and lowering systemic blood pressure through microcirculatory dilatation. On the other hand, reports have appeared in the literature which indicate that BK may constrict some vessels. Lecomte and Trouquet (1), Gersmyer and Spitzbarth (2) and Klupp and Konzett (3) demonstrated the constriction of the lung vessel. Guth et al. (4) and Rowley (5) reported that BK caused venoconstriction of the rabbit ear and rat skin, respectively. Shimamoto et al. (6) also reported the constriction of the rabbit saphenous vein by BK. The present experiments were undertaken to clarify the BK action on the various portions of blood vessel using several methods. Furthermore some tests were tried to study on the mechanism of venoconstrictive action of BK.

The venoconstrictive property of adrenaline and bradykinin and their tachyphylaxis in isolated rabbit saphenous veins.

The venoconstrictive property of adrenaline and bradykinin and their tachyphylaxis in isolated rabbit saphenous veins.

Venous Bradykinin-Antagonistic Property of Estrogen

Using a single segment of rabbit saphenous vein preparation in vitro a perfusion experiment with Locke-Ringer's solution (pH 7.2, 37°C) has been performed. The venoconstrictive effect of bradykinin, which was injected into the perfusate, was recorded as the decrease of the outflow from the preparation and recorded by dorp counter. A consistent and dose dependent venoconstriction was induced by bradykinin and there was no tachyphylaxis.The conjugated estrogens from the urine of pregnant hourses (Premarin) exhibited a potent antibradykinin activity on the venoconstrictive effect of bradykinin and the potency of bradykinin, the control being 1.0, was reduced by combination of Premarin at concentration of 50μg per ml and 100μg per ml to 0.651 and 0.431 respectively. The washability of Premarin is good. The dose response curves of bradykinin obtained under the perfusion with Locke-Ringer's solution and those obtained under the perfusion of Premarin solution were practically parallel, being the slope 75.8° and the index of precision 0.228.