Maximal Contraction In Response Research Articles

Endothelial dysfunction in rat mesenteric artery after regional cardiac ischaemia–reperfusion

In most previous studies, ischaemia-reperfusion (I/R)-induced vascular injury referred to injury in the tissue or blood vessel that was directly subjected to I/R. However, less attention has been focused on remote vascular injury that might be caused by cardiac I/R. In the present study, we aimed to assess whether cardiac I/R could affect vasoconstriction and vasodilatation in mesenteric arteries from Sprague-Dawley rats. Left anterior descending coronary arteries from adult male Sprague-Dawley rats were occluded (60 min) and then reperfused (120 min). Changes in haemodynamic parameters indicated that this procedure caused evident cardiac dysfunction. In mesenteric arteries isolated from the animals, cardiac I/R significantly increased the maximal contractions in response to KCl, 5-hydroxytryptamine, phenylephrine and U46619 and decreased the maximal relaxation in response to acetylcholine, but not to sodium nitroprusside, compared with sham-operated animals. The nitric oxide synthase inhibitor L-NAME abolished differences of contractile responses to phenylephrine between sham-operated and I/R rats. The antioxidant N-acetyl-L-cysteine reversed the impairment of acetylcholine-stimulated vasodilatation induced by regional cardiac I/R. However, L-NAME caused a similar degree of inhibition of acetylcholine-stimulated relaxation in mesenteric arteries from sham-operated and I/R rats. Electron microscopy revealed that mesenteric arterial endothelial structure was degraded in the I/R group and that N-acetyl-L-cysteine treatment prevented this structural damage. In conclusion, regional cardiac I/R caused by transient occlusion and reperfusion of the left anterior descending coronary artery results in peripheral vascular endothelial dysfunction.

Preferential Myosin Heavy Chain Isoform B Expression May Contribute to the Faster Velocity of Contraction in Veins versus Arteries

Smooth muscle myosin heavy chains occur in 2 isoforms, SMA (slow) and SMB (fast). We hypothesized that the SMB isoform is predominant in the faster-contracting rat vena cava compared to thoracic aorta. We compared the time to half maximal contraction in response to a maximal concentration of endothelin-1 (ET-1; 100 nM), potassium chloride (KCl; 100 mM) and norepinephrine (NE; 10 µM). The time to half maximal contraction was shorter in the vena cava compared to aorta (aorta: ET-1 = 235.8 ± 13.8 s, KCl = 140.0 ± 33.3 s, NE = 19.8 ± 2.7 s; vena cava: ET-1 = 121.8 ± 15.6 s, KCl = 49.5 ± 6.7 s, NE = 9.0 ± 3.3 s). Reverse-transcription polymerase chain reaction supported the greater expression of SMB in the vena cava compared to aorta. SMB was expressed to a greater extent than SMA in the vessel wall of the vena cava. Western analysis determined that expression of SMB, relative to total smooth muscle myosin heavy chains, was 12.5 ± 4.9-fold higher in the vena cava compared to aorta, while SMA was 4.9 ± 1.2-fold higher in the aorta than vena cava. Thus, the SMB isoform is the predominant form expressed in rat veins, providing one possible mechanism for the faster response of veins to vasoconstrictors.

Noradrenaline-induced contraction of mice aorta is enhanced in schistosomiasis

Schistosomiasis, an intravascular parasitic disease caused by Schistosoma mansoni, is related to alterations of murine vascular reactivity in the mesenteric bed, characterized by an impairment of the l-arginine/NO pathway and an increased potency of 5-hydroxytryptamine. The current study was performed to test the hypothesis that a similar alteration of reactivity also occurs in the aorta and to identify the mechanism behind such an increase. We found that aorta from mice infected with male S. mansoni exhibited an enhanced contraction in response to noradrenaline and 100 mM KCl. The inhibition of nitric oxide synthase increased aortic maximal contraction in response to noradrenaline in both groups, but the effect was less pronounced in infected mice than in control mice. Endothelium-dependent relaxation induced by acetylcholine was also smaller in infected mice compared to control mice, while endothelial-independent relaxation induced by sodium nitroprusside and forskolin was similar in both groups. The inhibition of voltage-dependent L-type Ca 2+ channels reduced the maximal contraction in response to noradrenaline more effectively in infected than in control mice. Conversely the inhibition of K ATP channels had a smaller effect in the infected group. As a conclusion, our data indicate that schistosomiasis also alters murine vascular reactivity outside the mesenteric bed, due to a partial impairment of NO signaling, a reduced contribution of K ATP channels and an increased Ca 2+ influx through L-type Ca 2+ channels.

In vitro tracheal hyperresponsiveness to muscarinic receptor stimulation by carbachol in a rat model of bleomycin‐induced pulmonary fibrosis

1 Bleomycin-induced lung injury is widely used as an experimental model to investigate the pathophysiology of pulmonary fibrosis but the alterations in the pharmacological responsiveness of airways isolated from bleomycin-exposed animals has been scarcely investigated. The aim of this study was to examine the in vitro tracheal responses to muscarinic receptor stimulation with carbachol in a rat bleomycin model. 2 Concentration-response curves to carbachol (10 nm to 0.1 mm) were obtained in tracheal rings isolated from Sprague-Dawley rats 14 days after endotracheal bleomycin or saline. The intracellular calcium signal in response to carbachol (10 microm) was measured by epifluorescence microscopy using fura-2 in primary cultures of tracheal smooth muscle cells from bleomycin- and saline-exposed rats. Circulating plasma tumour necrosis factor (TNF)-alpha/interleukin (IL)-1beta levels were measured by enzyme-linked immunosorbent assay. 3 Maximal contraction in response to carbachol was significantly greater in tracheal rings from bleomycin-exposed rats compared with controls (15.8 +/- 1.3 mN vs. 11.8 +/- 1.4 mN; n = 19, P < 0.05). 4 Carbachol (10 microm) elicited a transient increase of intracellular calcium with greater increment in tracheal smooth muscle cells from bleomycin-exposed rats compared with controls (372 +/- 42 nmvs. 176 +/- 20 nm; n = 7, P < 0.01). 5 Circulating plasma levels of TNF-alpha/IL-1beta were augmented in bleomycin-exposed rats compared with controls. Tissue incubation with TNF-alpha (100 ng ml(-1))/IL-1beta (10 ng ml(-1)) increased in vitro tracheal responsiveness to carbachol. 6 In conclusion, tracheal contraction in response to muscarinic receptor stimulation with carbachol was increased in bleomycin-exposed rats. This in vitro cholinergic hyperresponsiveness may be related to the augmented levels of inflammatory cytokines in bleomycin-exposed rats.

Serotonin-induced contractility in human saphenous vein is inhibited by naftidrofuryl.

Vascular endothelial denudation contributes to vasospasm by causing platelet aggregation and the subsequent release of vasoconstrictors such as serotonin. It has recently been suggested that naftidrofuryl fumarate (NFT) may oppose serotonin-induced vasoconstriction. Fourteen rings of human saphenous vein from 14 patients undergoing varicose vein surgery were tested in standard organ bath experiments. Cumulative dose-response curves and maximal contraction in response to serotonin were recorded and this was repeated in the presence of NFT at 10(-6) and 10(-3) mol/l. The difference in maximal contractility between the three sets of curves was significant (P < 0.0001). Sensitivity to serotonin in each of the three curves was measured using the concentration for half-maximal response; differences were again significant (P < 0.0001). It is concluded that NFT reduces serotonin-induced contractility in a dose-dependent fashion in rings of human saphenous vein in vitro. These results suggest a possible role for NFT in reducing vasospasm and support further investigation of this drug.

Cyclo-oxygenase-2, endothelium and aortic reactivity during deoxycorticosterone acetate salt-induced hypertension

To test the hypothesis that the enhanced vascular responsiveness to norepinephrine that occurs during deoxycorticosterone acetate (DOCA)-salt induced hypertension is causally related to increased expression of cyclo-oxygenase (COX)-2 and oxidative stress, which diminishes the vasomodulatory influence of endothelium-derived nitric oxide. Four groups of age-matched, male Sprague-Dawley rats were studied: Sham (normotensive); DOCA-salt (hypertensive); DOCA-salt treated with manganese(III) tetra(4-benzoic acid) porphyrin chloride [MnTBAP, an antioxidant; 15 mg/kg intraperitoneally (i.p.) for 21 days]; DOCA-salt treated with {N-[2-(cyclohexyloxy)-4-nitrophenyl]-methane sulfonamide} (NS-398, a COX-2 selective blocker; 5 mg/kg i.p. for 7 days). Contraction and relaxation were measured with FT03 force transducers coupled to a Grass polygraph in aortic rings bathed with physiologic salt solution (37 degrees C) and bubbled with a 5%CO2/95%O2 gas mixture. Aortic sensitivities (pD2 values) to norepinephrine and serum isoprostanes (8-iso-prostaglandin F2alpha, a marker of oxidative stress) were measured for each experimental paradigm. NS-398 significantly reduced maximal contractions in response to norepinephrine in aortic rings from Sham (44 +/- 3%) and DOCA-salt (96 +/- 2%) group rats. Expression of COX-2 protein increased significantly in vessels from DOCA-salt rats compared with those from Sham group rats. Treatment of DOCA-salt rats with either MnTBAP or NS-398 alleviated hypertension, normalized aortic pD2 values for norepinephrine and restored serum 8-isoprostane concentrations towards those observed in Sham group rats. COX-2 expression increases during DOCA-salt hypertension, and mediates production of factors that enhance rat aortic contractility in response to norepinephrine. Our data also suggest a role for increased oxidative stress, which is at least in part dependent on enhanced COX-2 expression, in the mechanism(s) of enhanced aortic contractility in response to norepinephrine during DOCA-salt hypertension.

Do atherosclerosis and chronic bladder ischemia really play a role in detrusor dysfunction of old age?

To determine whether atherosclerosis-induced chronic pelvic ischemia plays a role in the pathogenesis of aging bladder dysfunction. Old (70 weeks of age), apolipoprotein E gene knockout (APOEKO) mice, known to develop atherosclerosis spontaneously were used. A group of 70-week-old C57B mice were used as controls. The mice were killed and bladder smooth muscle strips obtained for in vitro contractile force determinations. The maximal contractions in response to 110 mM KCl, 10(-5) M bethanechol, and resting muscle tone were compared. The abdominal aortas and iliac arteries were harvested from the mice, and computerized image analysis was used to determine the percentage of surface area of atherosclerosis in each mouse. Although the APOEKO mice had massive atherosclerosis of the abdominal aortas and iliac arteries (lesion surface area +/- SEM 15.93% +/- 3.02%, n = 4), the control mice (n = 5) had no atherosclerosis at all. No statistically significant difference was found in detrusor function (KCl 0.48 +/- 0.11 versus 0.49 +/- 0.05, bethanechol 0.11 +/- 0.02 versus 0.13 +/- 0.04, tone 0.063 +/- 0.019 versus 0.07 +/- 0.004, respectively) between the APOEKO mice (n = 6) and the control mice (n = 6). Pelvic atherosclerosis caused no statistically significant changes in bladder smooth muscle contractile responses to bethanechol, KCl, or resting tone. The difference between these and previously reported results may have been a result of the more gradual onset of atherosclerosis in our model, which better mimics pelvic organ ischemia in the elderly.

Curcumin inhibits Homocysteine-induced endothelial dysfunction in porcine coronary arteries

Background. Curcumin, a yellow polyphenolic compound from the plant Curcuma ionga, has anti-tumor, anti-inflammatory, and anti-oxidant activities. The aim of this study was to determine the effect of curcumin on homocysteine (HCY)-induced endothelial dysfunction and superoxide anion production in a porcine coronary artery model. Methods. Five-millimeter porcine coronary artery rings from 8 hearts were incubated for 24 h as either controls, with HCY (50 μM), curcumin (5 μM), or a combination of curcumin (5 μM) and HCY (50 μM). Following this, vasomotor function was analyzed with a myograph device in response to thromboxane A 2 analogue U466419, bradykinin, and sodium nitroprusside (SNP), respectively. Additionally, superoxide anion production was determined by lucigenin-enhanced chemiluminescence assay. Results. All groups of porcine coronary artery rings showed no difference in maximal contraction in response to U46619. However, endothelium-dependent relaxation (bradykin) was 40% in the HCY-treated group as compared to 73% in controls ( P = 0.03, n = 8). The curcumin plus HCY group showed a significant improvement of endothelium-dependent relaxation as compared to the HCY-treated group ( P = 0.04), but no difference over controls. Curcumin alone showed no difference with controls. All groups showed no difference in endothelium-independent relaxation. Superoxide levels was 13.3 ± 2.1 RLU/s/mm 2 in control vessels, 40.5 ± 8.7 RLU/s/mm 2 in HCY-treated vessels, 20.0 ± 2.2 RLU/s/mm 2 in curcumin treated vessels, and 10.0 ± 1.9 RLU/s/mm 2 in HCY plus curcumin-treated vessels. Conclusion. These results show that curcumin effectively reverses the endothelial dysfunction induced by HCY. Additionally, curcumin also significantly decreases HCY-induced superoxide production. This study may suggest a therapeutic role of dietary curcumin for patients with hyperhomocysteinemia, thereby reducing cardiovascular morbidity and mortality.

Estrogen prevents homocysteine-induced endothelial dysfunction in porcine arteries

Introduction: Hyperhomocysteinemia is an independent risk factor of atherosclerosis and thrombosis. Estrogen may have a cardioprotective effect by improvement of endothelial functions. Thus, we hypothesized that estrogen might protect endothelium from homocysteine damage. The objective of this study was to examine the effect of estrogen on homocysteine treated porcine coronary arteries. Methods: Pig coronary artery rings were incubated with homocysteine (50 μM), estrogen (10−5M), or homocysteine and estrogen (50 μM/10−5M) for 24 h. Myograph tension analysis was performed with thromboxane A2 analogue U46619 for contraction and bradykinin for endothelium dependent vasorelaxation or sodium nitroprusside for endothelium independent vasorelaxation. Results: There were no differences of maximal contraction in response to U46619 among all groups of porcine coronary artery rings. However, endothelium-dependent vasorelaxation was different. Homocysteine treated vessels showed 62% relaxation in response to 10−5M bradykinin, which was significantly reduced compared to control vessels (88% relaxation) (P<0.05). There was no significant difference of endothelium dependent vasorelaxation between estrogen treated and control groups (P>0.05). Furthermore, combining homocysteine and estrogen showed 75% improvement of endothelium dependent vasorelaxation as compared to homocysteine treatment alone. There was no difference in endothelium-independent vasorelaxation (sodium nitroprusside) between all groups. Conclusion: These data demonstrated that homocysteine significantly reduces endothelium dependent vasorelaxation, and estrogen significantly prevents homocysteine-mediated endothelial dysfunction in porcine coronary arteries. This study suggests that estrogen may be of benefit in the hyperhomocysteinemic patient.

Neuromuscular function of the human lower oesophageal sphincter in reflux disease and Barrett's oesophagus

BACKGROUNDColumnar lined (Barrett's) oesophagus is often considered a sequel to chronic severe reflux disease. Aberrant lower oesophageal sphincter (LOS) motility associated with Barrett's oesophagus includes reduced basal LOS pressures. The...

Peroxynitrite induces airway hyperresponsiveness in guinea pigs in vitro and in vivo.

Peroxynitrite (ONOO-) is a cytotoxic product of the rapid reaction between nitric oxide and superoxide that may initiate inflammation. Isolated perfused tracheas from guinea pigs were incubated from the mucosal side for 15 min with peroxynitrite (1 to 100 muM). Thereafter, concentration-response curves to histamine and methacholine were constructed on the preparations. Peroxynitrite (10 muM) caused a significant hyperresponsiveness; the maximal contractions in response to histamine and methacholine were enhanced by 30% and 40%, respectively. In the peroxynitrite-treated group, clear epithelial damage as well as eosinophil destruction were detected. Moreover, 3, 5, and 10 days after intratracheal instillation of peroxynitrite (100 nmol), a significant rise in pulmonary resistance to histamine of anesthetized animals was observed. It is suggested that the generation of peroxynitrite from nitric oxide superoxide radicals during inflammatory processes induces epithelial damage, mediator release, and hence airway hyperresponsiveness. These findings may have clinical implications, because airway inflammation, epithelial damage, and hyperresponsiveness are characteristic features in patients suffering from asthma.

Effects of pulsatile perfusion on human saphenous vein vasoreactivity: a preliminary report

This study examined the effects of exposure to arterial blood pressure and flow on human saphenous vein catecholamine sensitivity. Unused portions of saphenous vein from eight patients undergoing peripheral bypass procedures were mounted parallel in a specially designed organ culture apparatus and perfused with tissue culture medium with 95% CO 2 at 37 °C. One segment was fixed between two cannulas while the medium was gently agitated (control) and the other was actively perfused via a pulsatile pump system at a rate of 60 beats/min, peak pressure of 100 mmHg and peak flow of 200 ml/min (pulsed; mean pressure 60 mmHg; mean flow 115 ml/min). After 48h, vein segments were removed and tested for in vitro isometric contraction in response to KCl, norepinephrine and histamine, and relaxation in response to acetylcholine, calcium ionophore A23187, and sodium nitroprusside. There were no differences in mean(s.e.m.) maximal contraction in response to KCl (control 0.61(0.16)g versus pulsed 0.72(0.27)g; P = n.s.), norepinephrine (control 1.00(0.56) g versus pulsed 1.51(0.54) g; P = n.s.), or histamine (control 1.47(0.85)g versus pulsed 1.95(0.64)g; P = n.s.). However, pulsed veins exhibited increased sensitivity to both norepinephrine (control −logED 50 6.20(0.23) versus pulsed mean(s.e.m.) 6.60(0.17); P < 0.05) and histamine (control −logED 50 5.60(0.27) versus pulsed 6.24(0.20); P = 0.05). Pulsed veins exhibited slightly less acetylcholine-induced relaxation although the difference did not reach statistical significance (control mean(s.e.m.) relaxation at 1 × 10 −6M 9.2(14.0)% versus pulsed −13.3(6.4)%; P = n.s.). There were no differences in relaxation in response to either A23187 (control 1 × 10 −4M 178(19)% versus pulsed 191(68)% or sodium nitroprusside (control 225(15)% versus pulsed 254(17)%; P = n.s.). The data presented herein indicate that exposure of human saphenous vein to the hemodynamics of the arterial environment for 48 h results in catecholamine supersensitivity while contractile and relaxant function are not affected.

Effects of Pulsatile Perfusion on Human Saphenous Vein Vasoreactivity: A Preliminary Report

This study examined the effects of exposure to arterial blood pressure and flow on human saphenous vein catecholamine sensitivity. Unused portions of saphenous vein from eight patients undergoing peripheral bypass procedures were mounted parallel in a specially designed organ culture apparatus and perfused with tissue culture medium with 95% CO2 at 37°C. One segment was fixed between two cannulas while the medium was gently agitated (control) and the other was actively perfused via a pulsatile pump system at a rate of 60 beats/min, peak pressure of 100 mmHg and peak flow of 200 ml/min (pulsed; mean pressure 60 mmHg; mean flow 115 ml/min). After 48 h, vein segments were removed and tested for in vitro isometric contraction in response to KCI, norepinephrine and histamine, and relaxation in response to acetylcholine, calcium ionophore A23187, and sodium nitroprusside. There were no differences in mean(s.e.m.) maximal contraction in response to KCl (control 0.61 (0.16) g versus pulsed 0.72(0.27) g; P= n.s.), norepinephrine (control 1.00(0.56) g versus pulsed 1.51 (0.54) g; P=n.s.). or histamine (control 1.47(0.85) g versus pulsed 1.95(0.64) g; P= n.s.). However, pulsed veins exhibited increased sensitivity to both norepinephrine (control -logED506.20(0.23) versus pulsed mean(s.e.m.) 6.60(0.17); P&lt;0.05) and histamine (control -logED505.60(0.27) versus pulsed 6.24(0.20); P= 0.05). Pulsed veins exhibited slightly less acetylcholine-induced relaxation although the difference did not reach statistical significance (control mean(s.e.m.) relaxation at 1 times 10−6M 9.2(14.0)% versus pulsed −13.3(6.4)%; P= n.s.). There were no differences in relaxation in response to either A23187 (control 1 times 10−4M 178(19)% versus pulsed 191(68)% or sodium nitroprusside (control 225(15)% versus pulsed 254(17)%; P= n.s.). The data presented herein indicate that exposure of human saphenous vein to the hemodynamics of the arterial environment for 48 h results in catecholamine supersensitivity while contractile and relaxant function are not affected.

Different vascular reactivity of human internal mammary and inferior epigastric arteries in vitro

Vascular responses io endogenous agonists may determine patency rates of bypass graft conduits. The effect of constrictors (noradrenaline, phenylephrine, serotonin, histamine, angiotensin II) and dilators (acetylcholine, substance P, bradykinin, nitroglycerin) were compared in human internal mammary and inferior epigastric arteries in vitro. The latter vessel type has been recently advocated as an additional conduit for coronary artery bypass grafting. Whereas the α-adrenoceptor- (noradrenaline, phenylephrine) and serotonin receptor-mediated contractions were similar in both vessels, histamine-induced contractions were greatly enhanced in internal mammary arteries (maximal responses in percent of 80 mmol/L KCl, 131% ± 15% versus 59% ± 8%). Maximal contractions in response to angiotensin II were greater in inferior epigastric arteries (50% ± 6% versus 25% ± 5%). The endothelium-independent relaxations in response to nitroglycerin were identical in both vessels. In contrast, the endothelium-dependent relaxations in response to acetylcholine, substance P, and bradykinin were significantly greater in the inferior epigastric than in the internal mammary arteries (maximal relaxations expressed as percent of prostaglandin F 2α-induced precontraction: acelylcholine, 94% ± 5% versus 77% ± 5%; substance P, 85% ± 4% versus 24% ± 5%; bradykinin, 77% ± 5% versus 26% ± 3%). It is concluded that the inferior epigastric artery has a high endothelial capacity to release endothelium-derived relaxing factor. It appears that the inferior epigastric artery possesses credentials to be successfully used for coronary artery bypass grafting.

In vitro evaluation of endothelial and smooth muscle function of primary varicose veins

Experiments were designed to study functional changes in superficial leg veins of patients with primary varicosity. Excess segments were taken from 19 patients undergoing elective vein resection. Excess segments of greater saphenous veins taken from 13 patients undergoing coronary or lower extremity arterial bypass were used as controls. These rings, some with endothelium deliberately removed, were suspended for the measurement of isometric force in organ chambers. Segments of veins were also evaluated with respect to their total protein content, endothelin content, and histologic structure. In varicose veins, maximal contractions in response to potassium chloride (n = 9), norepinephrine (n = 9), and endothelin (n = 4) were reduced 71.1%, 78.2%, and 75.6%, respectively, compared with contractions in control veins (p < 0.01). In addition, no differences were detected in the maximal tension or tissue sensitivity (EC50) between segments of nonvaricose greater saphenous vein and adjacent varicose tributaries from the same patient. Rings with and without endothelium contracted similarly. In varicose veins, endothelium-dependent relaxations produced by the calcium ionophore A23187 were attenuated 89.7% compared with relaxations in controls (n = 6, p < 0.01). In veins from patients with primary varicosity, endothelium-independent relaxations produced by nitric oxide (n = 6) and forskolin (n = 3) were diminished 86.8% (p < 0.01) and 65.6% (p < 0.05), respectively, compared with relaxations in control veins. In primary varicose veins, protein content was decreased (n = 17, p < 0.01) and endothelin content increased (n = 17, p = 0.1) compared with those values in control veins (n = 5). Microscopic study showed a disrupted arrangement and decreased amount of smooth muscle. These results suggest that both endothelial and smooth muscle function is impaired in vein segments removed from patients with primary varicosity. Similar functional, biochemical, and structural changes were seen not only in varicose tributaries but also in nonvaricose saphenous veins from the same patient. These findings support the hypothesis that abnormalities within the venous wall that affect both smooth muscle and endothelial cells exist before and perhaps contribute to the formation of varicosities.

Responses of human gastroepiploic arteries to vasoactive substances: Comparison with responses of internal mammary arteries and saphenous veins

We examined the responses of human gastroepiploic arteries to histamine, serotonin, and norepinephrine, comparing those of internal mammary arteries and saphenous veins. Fresh specimens of the vessels were obtained intraoperatively from 21 patients. The vessels were suspended in organ chambers to record isometric tensions. With gastroepiploic arteries, histamine induced relaxations in the endothelial rings (85% +/- 7%) but failed to induce any contractions or relaxations in the rings without endothelium. The relaxations were prevented by methylene blue or hemoglobin and the H1-histaminergic receptor antagonist chlorpheniramine. With internal mammary artery rings with endothelium, histamine at a low concentration (10(-8) to 10(-5.5) mol/L) induced relaxations (53% +/- 12%) but evoked contractions at a higher concentration (10(-5) to 10(-4.5) mol/L). With saphenous veins, histamine caused only contractions. Serotonin induced markedly greater contractions in saphenous veins than in either artery. The endothelium inhibited the maximal contraction in response to serotonin in both arteries but not in veins. With the gastroepiploic artery, the responses to norepinephrine and serotonin were similar to those of the internal mammary artery. Histamine induces endothelium-dependent relaxations only, and histaminergic receptors that induce contractions may be absent on vascular smooth muscle cells. These vasoactive properties may contribute to the high patency as a coronary graft.

Bicarbonate-Dependent Action of Bay K 8644 in the Smooth Muscle of the Rat Vas Deferens

Effects of Bay K 8644. partial depolarization with high potassium, and nifedipine on the dose-response curves of the rat vas deferens to norepinephrine, methacholine and KCl were investigated in HEPES-buffered physiological salt solution (PSS) with or without 20 mM sodium bicarbonate. In the bicarbonate-containing PSS, Bay K 8644 at 10-6 M enhanced the maximal contractions in response to norepinephrine, methacholine and KCl by 31.4, 103.3 and 40.1%, respectively. In the bicarbonate-free PSS, where the maximal contractions induced by norepinephrine, methacholine and KCl were 77.5, 75.0 and 68.2% of those in the bicarbonate-containing PSS, respectively, Bay K 8644 did not enhance the maximal contractile response to any of the agonists, although the contractions induced by low concentrations of KCl were increased by Bay K 8644. Increasing the potassium concentration in the PSS from 6 to 20 mM enhanced the maximal contractions in response to norepinephrine and methacholine in the bicarbonate-containing PSS, whereas in the bicarbonate-free PSS, the treatment decreased the contractions. In the two PSSs, nifedipine similarly inhibited the contraction in response to either 10-6 M norepinephrine or 68 mM KCl. These results suggest that bicarbonate ion modulates the function of the voltage-dependent calcium channel in the smooth muscle of the rat vas deferens.

Bicarbonate-dependent action of Bay K 8644 in the smooth muscle of the rat vas deferens.

Effects of Bay K 8644, partial depolarization with high potassium, and nifedipine on the dose-response curves of the rat vas deferens to norepinephrine, methacholine and KCI were investigated in HEPES-buffered physiological salt solution (PSS) with or without 20 mM sodium bicarbonate. In the bicarbonate-containing PSS, Bay K 8644 at 10(-6) M enhanced the maximal contractions in response to norepinephrine, methacholine and KCI by 31.4, 103.3 and 40.1%, respectively. In the bicarbonate-free PSS, where the maximal contractions induced by norepinephrine, methacholine and KCI were 77.5, 75.0 and 68.2% of those in the bicarbonate-containing PSS, respectively. Bay K 8644 did not enhance the maximal contractile response to any of the agonists, although the contractions induced by low concentrations of KCI were increased by Bay K 8644. Increasing the potassium concentration in the PSS from 6 to 20 mM enhanced the maximal contractions in response to norepinephrine and methacholine in the bicarbonate-containing PSS, whereas in the bicarbonate-free PSS, the treatment decreased the contractions. In the two PSSs, nifedipine similarly inhibited the contraction in response to either 10(-5) M norepinephrine or 68 mM KCI. These results suggest that bicarbonate ion modulates the function of the voltage-dependent calcium channel in the smooth muscle of the rat vas deferens.

Differences in sensitivity to vasoconstrictor drugs within the wall of the sheep carotid artery.

1. Controlled heat damage was used to separate the responses of the outer innervated smooth muscle from those of the inner nerve-free smooth muscle of the sheep carotid artery.2. Preparations of smooth muscle from the inner part of the media gave 50% maximal contractions in response to approximately 1/15 the concentration of noradrenaline needed to produce similar responses from outer smooth muscle. The difference in sensitivity was greater in the lower than the upper parts of the dose-response curves.3. Much of the difference in sensitivity was still seen in the presence of Desipramine and after chronic denervation, and so could not be attributed to uptake of noradrenaline by the nerve fibres in the outer smooth muscle; disappearance of the fibres after denervation was confirmed by fluorescence microscopy.4. Similar but generally smaller differences in sensitivity between inner and outer smooth muscle were seen with respect to histamine, angiotensin II and 5-hydroxytryptamine.5. Sympathetic denervation 10-14 days previously increased the sensitivity of outer strips to noradrenaline; it usually also increased their sensitivity to histamine, suggesting that the change largely represented non-specific denervation super-sensitivity.6. The high sensitivity of the inner smooth muscle is likely to be of value in enabling it to respond to the relatively low concentration of noradrenaline reaching it in life.