An examination of the sources of calcium for contractions mediated by postjunctional alpha 1- and alpha 2-adrenoceptors in several blood vessels isolated from the rabbit.

1. The roles of intracellular and extracellular-derived Ca2+ in alpha-adrenoceptor-mediated contractions to noradrenaline (NA) have been investigated in several isolated blood vessels from the rabbit by examining responses in the presence of a modified Krebs-Henseleit saline with 2.5 mM Ca2+ and a Ca2(+)-buffered saline with 0.1 microM free Ca2+. 2. NA was tested in preparations of the abdominal aorta, distal saphenous artery, renal vein, lateral saphenous vein, plantaris vein and ear vein exposed to a Ca2(+)-buffered saline with 0.1 microM [Ca2+]. A concentration of NA which was maximally effective in modified Krebs-Henseleit saline, produced an initial transient contraction (ITC) followed by a relaxation towards baseline. This is evidence that alpha-adrenoceptor-mediated responses in all these blood vessels depend upon calcium from both sources. 3. The ITC was particularly pronounced in the arteries and was associated more closely with the alpha 1-receptor subtype. In the abdominal aorta, distal saphenous artery and renal vein the ITC can almost exclusively be attributed to an alpha 1-adrenoceptor (prazosin-sensitive, rauwolscine-resistant). In the ear vein, and to a lesser extent the plantaris vein, the ITC was mediated in part by an alpha 2-adrenoceptor (prazosin-resistant, rauwolscine-sensitive). 4. alpha 2-Adrenoceptors in the lateral saphenous vein largely account for the response to NA in modified Krebs-Henseleit saline, but alpha 1-adrenoceptors mediate the ITC in Ca2(+)-buffered saline. After selective inactivation of alpha 1-adrenoceptors with a combination of phenoxybenzamine and rauwolscine, responses to NA in modified Krebs-Henseleit saline are slow in onset and there is no ITC in Ca2(+)-buffered saline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influences of the endothelium and hypoxia on alpha 1- and alpha 2-adrenoceptor-mediated responses in the rabbit isolated pulmonary artery.

1. The effects of the inhibitor of nitric oxide synthase, N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M), mechanical disruption of the endothelium and hypoxia on contraction to noradrenaline (alpha 1- and alpha 2-adrenoceptor agonist), phenylephrine (alpha 1-adrenoceptor agonist) and UK 14304 (alpha 2-adrenoceptor agonist) were compared in the rabbit isolated pulmonary artery. The effects of the selective antagonists rauwolscine (10(-6) M, alpha 2-adrenoceptors) and prazosin (10(-7) M, alpha 1-adrenoceptors) on the contractions to noradrenaline before and after exposure to L-NAME were also assessed. 2. Noradrenaline, phenylephrine and UK 14304 all produced concentration-dependent increases in vascular tone. The responses to noradrenaline were sensitive to both rauwolscine and prazosin (effect of prazosin >> rauwolscine). L-NAME increased the potency of both noradrenaline and UK 14304, and also the maximum tension achieved. It had no effect on the responses to phenylephrine. After L-NAME, contractions to noradrenaline, although still sensitive to both rauwolscine and prazosin, were now more sensitive to inhibition by rauwolscine. 3. Endothelium removal augmented the potency and maximum contractions to noradrenaline, phenylephrine and UK 14304. 4. Hypoxia decreased both the potency of phenylephrine and its maximum contractile response, but increased the maximum response to noradrenaline without effecting responses to UK 14304. 5. In conclusion, in the rabbit pulmonary artery, augmentation of contractile responses to noradrenaline by L-NAME involves a potentiation of alpha 2-adrenoceptor-mediated contraction probably through an effect on the synthesis of endothelium-derived nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alpha 2-adrenoceptor-mediated contractions in the rabbit aorta treated with BAY K 8644.

We tested the effect of the selective alpha 2-adrenoceptor agonists B-HT 920 and B-HT 933 on the rabbit aorta. These drugs had weak contractile effects in the tissue, which were inhibited by the selective alpha 1-adrenoceptor antagonist prazosin (10(-5) M). Their contractile effects were potentiated by the Ca2+ channel facilitator BAY K 8644 (10(-6) M). The selective alpha 2-adrenoceptor antagonist yohimbine (10(-5) M) reduced the contractions elicited by B-HT 920 and B-HT 933 in the presence of BAY K 8644 (10(-6) M), but did not alter the control effect of these drugs. In the rabbit aorta, the contractile effect of B-HT 920 and B-HT 933 in the presence of BAY K 8644 (10(-6) M) was partly caused by alpha 1-adrenoceptor stimulation, because prazosin (10(-5) M) relaxed the contractions elicited under these conditions. In the aorta preincubated with BAY K 8644 (10(-6) M) and prazosin (10(-5) M), B-HT 920 (3 x 10(-4) M) elicited non-sustained phasic contractions (1-5 g), which were probably due to alpha 2-adrenoceptor stimulation, as they were inhibited by yohimbine (10(-5) M). In similar experiments B-HT 933 (3 x 10(-4) M) caused inconsistent and slight contractions (< 0.5 g developed tension).     

Contributions of alpha 1-adrenoceptors, alpha 2-adrenoceptors and P2x-purinoceptors to neurotransmission in several rabbit isolated blood vessels: role of neuronal uptake and autofeedback.

1. The roles of autofeedback and neuronal uptake in neurotransmission produced by electrical field stimulation in several rabbit isolated blood vessels were examined. 2. Blocking drugs were used to separate the possible purinergic and noradrenergic contributions to the end organ response: prazosin, antagonist at postjunctional alpha 1-adrenoceptors; rauwolscine and yohimbine, antagonists at pre- and postjunctional alpha 2-adrenoceptors; alpha,beta-methylene ATP, desensitizing agent at postjunctional P2x-purinoceptors. In addition to desensitizing postjunctional P2x-purinoceptors, alpha,beta-methylene ATP potentiated the noradrenergic component of the nerve-induced responses. 3. In the presence of an intact neuronal uptake mechanism, the vessels showed different contributions of purinergic (via P2x-purinoceptors) and noradrenergic (via alpha 1-adrenoceptors and alpha 2-adrenoceptors) components to the end organ response to nerve stimulation: saphenous artery (approximately equal contributions from P2x-purinoceptors and alpha 1-adrenoceptors), ileocolic artery (mainly P2x-purinoceptors with a smaller contribution from alpha 1-adrenoceptors), plantaris vein (mainly alpha 1-adrenoceptors with a small contribution from alpha 2-adrenoceptors and P2x-purinoceptors) and saphenous vein (alpha 1-adrenoceptors). 4. The presence of alpha 2-adrenoceptor-mediated autofeedback could be demonstrated for both purinergic and noradrenergic components of the nerve-induced responses in the artery preparations. In the veins, potentiation of nerve-induced responses by alpha 2-adrenoceptor antagonists could not be studied due to blockade of postjunctional alpha 2-adrenoceptor-mediated vasoconstriction. 5. Blockade of neuronal uptake with cocaine potentiated the noradrenergic component of the nerve-induced responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different sensitivities of rabbit isolated blood vessels exhibiting co-transmission to the slow calcium channel blocker, nifedipine.

1. Antagonist drugs were used to separate the purinergic and adrenergic contributions as well as the adrenoceptor sub-types involved in the sympathetic vasoconstrictor responses produced by electrical field stimulation in rabbit isolated ileocolic and proximal saphenous arteries. Blocking drugs were applied either alone or in various combinations and sequences. 2. Nifedipine attenuated vasoconstrictor responses to sympathetic nerve stimulation both in the presence and in the absence of alpha-adrenoceptor blocking agents. However in the presence of alpha,beta-methylene ATP, nifedipine produces at best only a small attenuation of the vasoconstrictor response. 3. These results suggest that the purinergic component of the response to sympathetic nerve stimulation, at least in these tissues, can be antagonized by nifedipine, whereas the alpha 1-adrenoceptor-mediated response is relatively resistant.     

An examination of the postjunctional alpha-adrenoceptor subtypes for (-)-noradrenaline in several isolated blood vessels from the rabbit.

1. Postjunctional alpha-adrenoceptors in several isolated blood vessels from the rabbit have been characterized on the basis of the relative potency of the agonists noradrenaline (NA, non-selective), phenylephrine (alpha 1-selective) and UK-14304 (alpha 2-selective), and the potency of antagonists rauwolscine (alpha 2-selective) and corynanthine (alpha 1-selective) against contractions elicited by NA. In addition, the potency of prazosin against NA was also assessed in the venous preparations. 2. The thoracic aorta, ear artery and left renal vein appear to possess alpha 1-adrenoceptors since the agonist potency order was NA greater than phenylephrine greater than UK-14304, while corynanthine was 3-10 fold more potent than rauwolscine. 3. The ear vein appears to possess alpha 2-adrenoceptors. The rank order of agonist potency was UK-14304 greater than NA much greater than phenylephrine and all three agonists elicited responses of similar magnitude. Furthermore, rauwolscine was 30 fold more potent than corynanthine while prazosin failed to produce a concentration-dependent inhibition. 4. The saphenous vein and the plantaris vein appear to possess a mixture of both subtypes since the rank order of agonist potency was UK-14304 greater than NA much greater than phenylephrine, while responses elicited by UK-14304 were smaller than those to the other agonists. However, although rauwolscine was 20 to 100 fold more potent than corynanthine in both preparations, suggestive of predominantly alpha 2-adrenoceptors, prazosin was either potent (saphenous vein) or relatively inactive (plantaris vein). 5. The characteristics of postjunctional alpha 1- and alpha 2-adrenoceptors on isolated blood vessels from the rabbit are discussed in relation to the value of both the agonists, particularly NA, and the antagonists used in this study.     

Lack of effect of D600 on alpha 1-adrenoceptor-mediated contractions of rat isolated anococcygeus muscle

The experiments concerned the contractile responses of rat anococcygeus muscle to the selective alpha 1-adrenoceptor agonists cirazoline, phenylephrine, methoxamine, St 587, Sgd 101/75, amidephrine and SK&F 89748-A and the effect of the calcium entry blocker D600 on the responses. The effects of noradrenaline, adrenaline, K+, tyramine and electrical field stimulation were studied as well. The potency series of the various agonists on rat anococcygeus muscle differed from the series for rat and guinea-pig aorta, indicating differences in the structure of the alpha 1-adrenoceptors on these tissues. D600 was ineffective in inhibiting contractions of rat anococcygeus muscle to the various agonists, but effectively attenuated the responses to K+ in anococcygeus muscle from rats pretreated with reserpine or in prazosin-induced preparations. These data indicate that alpha 1-adrenoceptor activation in rat anococcygeus muscle triggers contractions which do not primarily require the influx of extracellular calcium. In this respect, the smooth muscle from the rat anococcygeus muscle differs from vascular smooth muscle from this species.     

Amplifying effects of several vasoconstrictor agents of alpha 1-adrenoceptor-mediated contraction of isolated thoracic aortae of the guinea pig

In guinea-pig aorta phenylephrine and noradrenaline induced concentration-dependent contractions when beta-adrenoceptors were blocked. The contractile response to phenylephrine was amplified by previous application of subthreshold concentrations of 5-hydroxytryptamine, ouabain, B-HT 920, Bay K 8644, phorbol-12-myristate-13-acetate and arachidonic acid. Bay K 8644 also enhanced the contractile response to noradrenaline. The amplification was not substantially altered by removing the endothelium of the aorta. The increase in cytosolic calcium availability induced by the vasoconstrictor agents investigated may be responsible for the enhancement of the alpha 1-adrenoceptor-mediated contractions.     

A comparison of the effects of angiotensin II and Bay K 8644 on responses to noradrenaline mediated via postjunctional alpha 1-and alpha 2-adrenoceptors in rabbit isolated blood vessels.

1. The effects of angiotensin II (AII) and Bay K 8644 on responses to noradrenaline (NA) mediated via postjunctional alpha 1- and/or alpha 2-adrenoceptors have been compared in three isolated venous preparations from the rabbit, the lateral saphenous vein, the left renal vein and the ear vein. 2. A similar action of AII and Bay K 8644 was observed only in the lateral saphenous vein; each potentiated responses to NA after isolation of a homogeneous population of postjunctional alpha 2- adrenoceptors. However, even in this preparation the mechanism of action for these agents was not identical. The sensitivity of KCl-induced contraction to changes in extracellular calcium ions (reflecting activation of voltage-dependent Ca2+ channels) was enhanced by Bay K 8644 but reduced by AII. 3. All produced a selective facilitation of responses mediated via postjunctional alpha 2-adrenoceptors. In the lateral saphenous vein it reduced the effectiveness of prazosin and facilitated responses after isolation of alpha 2-adrenoceptors with phenoxybenzamine and rauwolscine. It directly enhanced responses to NA in the ear vein, where only alpha 2-adrenoceptors are involved. In contrast, AII did not influence responses mediated via postjunctional alpha 1-adrenoceptors in the left renal vein (even after the receptor reserve had been removed with phenoxybenzamine) nor the 'rauwolscine-resistant' component of responses to NA in the saphenous vein. 4. Bay K 8644 enhanced contractile responses to NA mediated both via alpha 2-adrenoceptors, in the lateral saphenous vein, and via alpha 1-adrenoceptors in the left renal vein. Thus, unlike angiotensin II, no preferential effect was apparent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective antagonism by PPADS at P2X-purinoceptors in rabbit isolated blood vessels.

1. Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), a P2-purinoceptor antagonist, was investigated for its ability to antagonize: (1) P2X-purinoceptor-mediated contractions of the rabbit central ear artery and saphenous artery evoked by either alpha,beta-methylene ATP (alpha,beta-MeATP) or electrical field stimulation (EFS); (2) P2Y-purinoceptor-mediated relaxations of the rabbit mesenteric artery; (3) endothelium-dependent and endothelium-independent, P2Y-purinoceptor-mediated relaxations of the rabbit aorta. 2. alpha,beta-MeATP (0.1-100 microM) caused concentration-dependent contractions of the rabbit ear and saphenous arteries. The negative log[alpha,beta-MeATP] that produced a contraction equivalent to the EC25 for noradrenaline (ear artery) or histamine (saphenous artery) in the absence of PPADS was 6.60 +/- 0.18 (9) and 6.18 +/- 0.17 (9) in the ear artery and saphenous artery, respectively. These effects of exogenous alpha,beta-MeATP were concentration-dependently inhibited by PPADS (1-30 microM). In the ear artery, the negative log[alpha,beta-MeATP] producing a contractile response equivalent to the EC25 of noradrenaline, in the presence of PPADS at 1, 3 and 10 microM was 6.16 +/- 0.18 (8), 5.90 +/- 0.18 (8) and 4.72 +/- 0.36 (8), respectively (P < 0.01). In the saphenous artery, the negative log[alpha,beta-MeATP] values equivalent to the EC25 for histamine in the presence of PPADS at concentrations of 1, 3, 10 and 30 microM were 5.90 +/- 0.19 (8), 5.73 +/- 0.16 (8), 4.99 +/- 0.14 (8) and 4.51 +/- 0.13 (8), respectively (P < 0.01). 3. PPADS at a concentration of 1 microM had no effect on contractions of the ear artery evoked by EFS (4-64 Hz; 1 microM phentolamine present).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of acidosis on alpha 1- and alpha 2-adrenoceptor-mediated vasoconstrictor responses in isolated arteries

We have investigated the effect of reducing the pH (from 7.5 to 7.0 by addition of HCl) on vasoconstrictor responses to noradrenaline in cat middle cerebral artery (in which responses are mediated almost entirely by alpha 2-adrenoceptors) and in rabbit pulmonary artery (in which responses are mediated by alpha 1-adrenoceptors). In the cerebral artery, a reduction in pH caused a pronounced inhibition of the responses to noradrenaline, and the antagonistic effect of idazoxan (100 nM) was increased 10-fold. In contrast, in the pulmonary artery, a reduction in pH had no effect on the responses to noradrenaline and the antagonistic effect of prazosin (100 nM) was not altered. We conclude that acidosis selectively reduces the vasoconstriction mediated by alpha 2-adrenoceptors in vitro.     

alpha(2)-adrenoceptor and NPY receptor-mediated contractions of porcine isolated blood vessels: evidence for involvement of the vascular endothelium

1. Enhanced contractions to the alpha(2)-adrenoceptor agonist UK14304 and neuropeptide Y (NPY) in the porcine ear artery can be uncovered by pharmacological manipulation. The aim of this study was to determine whether similar pharmacological manipulation can uncover enhanced contractions in the porcine splenic artery, and to determine whether the endothelium modulates these responses. 2. UK14304 (0.3 microM) and NPY (0.1 microM) produced small contractions of the porcine splenic artery. After pre-contraction of the tissue with U46619, followed by relaxation with forskolin, the responses to both UK14304 and NPY were enhanced. Enhanced contractions to both UK14304 and NPY were also obtained after relaxation with SNP. These results demonstrate that, as in the porcine ear artery, alpha(2)-adrenoceptors and NPY receptors are able to produce enhanced contractile responses through both adenylyl cyclase-dependent and -independent signal transduction pathways. 3. Removal of the endothelium had no significant effect on responses to UK14304 either alone or in the presence of U46619 and forskolin in the porcine splenic artery. On the other hand, responses to UK14304 after relaxation with SNP were reduced after endothelium-denudation in both the porcine splenic artery and ear artery. Similar results were obtained with NPY in the porcine ear artery. 4. In conclusion, enhanced contractile responses to UK14304 and NPY in the porcine splenic artery can be uncovered using methods similar to those employed in the porcine ear artery. Under certain conditions the responses to both agents are modulated by the endothelium. These data highlight further the similarities in the signal transduction pathways used by both alpha(2)-adrenoceptors and NPY receptors to induce vasoconstriction.     

Heterogeneity of alpha 1-adrenoceptor subtypes involved in adrenergic contractions of dog blood vessels.

1. We determined the alpha 1-adrenoceptor subtypes involved in adrenergic contractions of eight different blood vessels isolated from the dog. 2. Noradrenaline produced concentration-dependent contractions in all the blood vessels tested, which were competitively inhibited by prazosin, WB4101, HV723 and 5-methylurapidil. However, there was considerable difference between the vessels with regard to the pKB values for all the antagonists. The alpha 1-adrenoceptors of dog vertebral and carotid arteries had high affinity for prazosin (pKB > 9.0) but low affinity for WB4101 (< 8.5), 5-methylurapidil (< 7.5) and HV723 (< or = 8.5). By contrast, HV723 had higher affinity (> 9.0) than prazosin (< 8.3), WB4101 (< 8.7) and 5-methylurapidil (< 8.2) in the portal vein, mesenteric artery and vein, and renal artery. In the femoral artery and vein, however, the four antagonists showed pKB values in the range 8.0-8.7. 3. Chloroethylclonidine (10 microM) produced a remarkable reduction of the contractile responses to noradrenaline in the vertebral and carotid arteries as compared with those in the other vessels. Nifedipine inhibited the responses to noradrenaline in all the tissues tested, and had marked effects in the portal vein. 4. Sympathetic adrenergic contractions induced by transmural electrical stimulation were also inhibited by prazosin and HV723 at different potencies among tissues. The relative potencies of both the antagonists paralleled the relationship in inhibiting the responses to exogenous noradrenaline in each vessel.(ABSTRACT TRUNCATED AT 250 WORDS)     

N-ethylmaleimide diminishes alpha 2-adrenoceptor-mediated effects on norepinephrine release in rat tail arteries.

Isolated tail arteries from Wistar rats, prelabeled with [3H]norepinephrine (NE) were subjected to electrical field stimulation (24 pulses at 0.4 Hz and 200 mA). Both NE release and vasoconstriction were measured in parallel. The selective alpha 2-adrenoceptor agonist B-HT 933 diminished the evoked NE release in a concentration-dependent manner. This effect of B-HT 933 was counteracted by the selective alpha 2-adrenoceptor antagonist rauwolscine, which given alone enhanced evoked transmitter release, indicating the presence of autoinhibition. N-Ethylmaleimide (NEM) (3 microM), which also in itself increased transmitter release, virtually abolished facilitation of release by 0.1 microM rauwolscine and diminished its inhibition by 10 microM B-HT 933. The diminution of the inhibitory effect of B-HT 933 was even more pronounced when the current strength was decreased from 200 mA to 90 mA to compensate for the NEM-induced increase in transmitter release. Treatment of the arteries with NEM did not affect the perfusion pressure. In contrast, however, the B-HT 933-induced increase in basal perfusion pressure was significantly diminished by NEM. Although 10 microM B-HT 933 given alone did not affect stimulation-evoked vasoconstriction, it caused a significant increase in arteries treated with NEM. In conclusion, the observed NEM-sensitivity of the presynaptic and vascular alpha 2-adrenoceptor mechanisms is compatible with the idea that both pre- and postsynaptic alpha 2-adrenoceptors couple to Pertussis toxin (PTX)-sensitive G proteins.     

Potentiation by treatment with reserpine of alpha 2-adrenoceptor-mediated contractions of rat tail artery

The effects of a treatment with reserpine on alpha-adrenoceptor-mediated contractile responses of rat tail arteries were investigated in vitro. The potency of norepinephrine was slightly increased in arteries obtained from rats treated with reserpine. There was no significant change in the sensitivity of the arteries to serotonin, KCl and selective alpha 1-adrenoceptor agonists (methoxamine and phenylephrine). However, the potency of clonidine and UK-14,304, both selective alpha 2-adrenoceptor agonists, was greatly increased. UK-14,304-induced contractions of the arteries from rats treated with reserpine were inhibited strongly by rauwolscine, a selective alpha 2-adrenoceptor antagonist, but only slightly by corynanthine, a selective alpha 1-adrenoceptor antagonist. The contractions caused by re-introduction of Ca2+ during exposure to UK-14,304 but not to methoxamine in a Ca2(+)-free medium were potentiated by treatment with reserpine. Bay K 8644, an agonist of Ca2+ channels, produced a concentration-dependent contraction only in the arteries from rats treated with reserpine. These results suggest that treatment with reserpine potentiates alpha 2- but not alpha 1-adrenoceptor-mediated responses in rat tail arteries and that the potentiation could be related to changes in mechanisms linked to Ca2+ influx.     

Effect of NG-nitro-L-arginine methylester (L-NAME) on functional and biochemical alpha 1-adrenoceptor-mediated responses in rat blood vessels.

1. The modulation by NG-nitro-L-arginine methylester (L-NAME) of alpha 1-adrenoceptor-mediated contraction was investigated on isolated segments of rat tail artery and aorta. The influence of L-NAME on inositol phosphates accumulation by alpha 1-adrenoceptor agonists was also investigated to elucidate the intracellular mechanism responsible for this modulation. 2. In aorta but not in tail artery L-NAME (30 microM) enhanced the sensitivity (3.3 times) and the maximum contraction (Emax) induced by the full agonist, phenylephrine. 3. St-587, a partial alpha 1-adrenoceptor agonist, behaved as a weak agonist in the aorta (22.2% of phenylephrine Emax). However, when the same agonist was studied in tail artery rings a maximum contraction that was 78.4% of the phenylephrine induced Emax was reached. 4. L-NAME increased (3.3 times) the Emax for St-587 contraction in the aorta but not in the tail artery. Sensitivity to St-587 was slightly but significantly (P < 0.001) enhanced (1.9 times) by L-NAME in tail artery segments. 5. Contractile responses to phenylephrine after partial alkylation with phenoxybenzamine were analyzed by the nested hyperbolic null method. To elicit 50% of Emax for contraction only 1.1% of the receptors in the tail artery and 21% of the receptors in the aorta need to be occupied. These results indicate a higher receptor reserve for the tail artery than the aorta. 6. In the tail artery but not in the aorta, St-587 activates phosphoinositide turnover. The presence of L-NAME was without effect on inositol phosphates accumulation induced by this partial alpha 1-adrenoceptor agonist. 7. The maximum contraction induced by phenylephrine, after partial alpha-adrenoceptor alkylation, was enhanced by L-NAME in tail artery rings. However, the NO synthase inhibitor was unable to modify the phenylephrine-induced accumulation of inositol phosphates in the presence of phenoxybenzamine. 8. These results indicate that the differences in St-587-induced contraction and the modulation by L-NAME of alpha 1-adrenoceptor-mediated contraction observed between the tail artery and aorta are associated with differences in receptor reserve. In addition, our biochemical studies indicate that the potentiating effect of L-NAME is independent of intracellular calcium release via phosphatidylinositol turnover.     

Vascular effects of hyperthermia on isolated blood vessels

1. The contractile response of isolated human umbilical and sheep renal arteries to 5-hydroxytryptamine (5-HT) with increasing temperatures was investigated. 2. In the umbilical artery the threshold value was lowest at 30 degrees C and increased with increasing temperature, the maximal response being lower at temperatures above 30 degrees C. 3. Spontaneous rhythmic contractions of the umbilical artery were not augmented by warming above 37 degrees C. 4. The sheep renal artery exhibited an opposite response pattern: increasing temperature lowered the threshold and increased the maximal response. 5. Addition of indomethacin to the bathing fluid resulted in increased responsiveness of the umbilical arteries to 5-HT. With lower threshold, ED50 and higher maximal response.     

Relative contribution of intracellular and extracellular Ca2+ to alpha2-adrenoceptor-mediated contractions of ovine pulmonary artery.

We have examined the mechanism of contractions elicited by guanfacine, a selective agonist for alpha(2A/D)-adrenoceptors and its modulations by cyclic nucleotides in isolated ovine resistance intra-pulmonary artery. Guanfacine (10 nM-30 microM) produced concentration-dependent contraction of the pulmonary artery rings mounted for isometric recording. Yohimbine (0.1 microM), a nonspecific alpha(2)-adrenoceptor antagonist caused a parallel shift to the right (1.2 log unit) in the concentration-response curve of guanfacine without depressing the maxima. Preincubation of the tissues with Ca(2+)-free solution (EGTA 1mM) for 30 min caused a rightward shift (0.8 log unit) of the concentration-response curve of guanfacine with the inhibition of the maxima by 30+/-4.6%. L-type calcium channel blocker, nifedipine (1 microM) slightly inhibited (20%) the maximal contraction elicited with guanfacine (10 microM). On the other hand, brief exposure to cyclopiazonic acid (10 microM), an inhibitor of IP3-sensitive sarcoplasmic reticulum Ca(2+)-ATPase, resulted in marked inhibition of concentration-dependent contractions elicited with guanfacine (10 nM-30 microM), with the maxima being inhibited by 51+/-3.11%. In addition, agents that increase intracellular cAMP and cGMP suppressed guanfacine-induced contractions. The results of the present study suggest that alpha(2)-adrenoceptor-mediated contractions in ovine resistance pulmonary artery is primarily dependent on intracellular Ca(2+) with a small contribution from Ca(2+)-influx through voltage-dependent L-type calcium channels.     

Effects of nifedipine on isolated human pulmonary vessels

The effects of the Ca-blocker nifedipine on the contractile response to K and NA in isolated human pulmonary vessels were studied. Specimens of macroscopically normal pulmonary vessels, obtained from patients undergoing surgery for lungtumours were carefully dissected and cut into rings. The results suggest that nifedipine, by blocking the entry of extracellular calcium, inhibits K-induced contractions in isolated pulmonary vessels. The effect is more pronounced on K than on NA-induced response in both the pulmonary arteries and veins.     

多沙唑嗪对映体对兔四种血管α受体的作用

多沙唑嗪(doxazosin，DOX)作为高选择性α₁受体阻断药，是临床上治疗良性前列腺增生(benign prostatic hyperplasia, BPH)的一线药物，但同时引起心血管系统的不良反应。本研究采用兔离体动脉环张力实验及电场刺激兔离体隐动脉诱发交感嘌呤能血管收缩实验观察R-多沙唑嗪(R-doxazosin，R-DOX)和S-多沙唑嗪(S-doxazosin，S-DOX)对兔耳动脉、肠系膜动脉和肺动脉血管平滑肌α₁受体的作用，以及较高浓度R-DOX和S-DOX对兔隐动脉交感神经突触前膜α₂受体的作用。结果表明，在兔耳动脉、肠系膜动脉和肺动脉，R-DOX和S-DOX竞争性拮抗去甲肾上腺素(noradrenaline，NA)诱发的血管收缩反应；其pA₂值分别为7.91±0.03和7.53±0.05，7.80±0.05和7.29±0.07以及8.32±0.06和7.97±0.07；且S-DOX的pA₂值均明显小于R-DOX的pA₂值(P<0.01)。R-DOX和S-DOX(0.1～10 μmol·L^-1)对电刺激诱发的血管收缩反应无明显影响；R-DOX或S-DOX(100 μmol·L^-1)显著抑制电刺激诱发的血管收缩反应，完全抑制外源性NA诱发的血管收缩反应，但对1 mmol·L^-1腺苷三磷酸诱发的血管收缩反应无明显影响。上述结果提示，R-DOX和S-DOX对NA诱发兔耳动脉、肠系膜动脉和肺动脉收缩反应具有竞争性拮抗作用，对上述三种血管S-DOX拮抗NA的pA₂值均明显小于R-DOX。此外，R-DOX和S-DOX的浓度升至10 μmol·L^-1时，对血管交感神经末梢突触前膜α₂受体仍无明显影响。