Optically Driven Collective Spin Excitations and Magnetization Dynamics in the Néel-type Skyrmion Host GaV_{4}S_{8}.

GaV_{4}S_{8} is a multiferroic semiconductor hosting magnetic cycloid (Cyc) and Néel-type skyrmion lattice (SkL) phases with a broad region of thermal and magnetic stability. Here, we use time-resolved magneto-optical Kerr spectroscopy to show the coherent generation of collective spin excitations in the Cyc and SkL phases. Our micromagnetic simulations reveal that these are driven by an optically induced modulation of uniaxial anisotropy. Our results shed light on spin dynamics in anisotropic materials hosting skyrmions and pave a new pathway for the optical manipulation of their magnetic order.

Hydrogen sulfide as a novel mediator for pancreatic pain in rodents.

OBJECTIVE: Hydrogen sulfide (H(2)S) is formed from l-cysteine by multiple enzymes including cystathionine-gamma-lyase (CSE) in mammals, and plays various roles in health and disease. Recently, a pronociceptive role for H(2)S in the processing of somatic pain was identified. Here, the involvement of H(2)S in pancreatic pain is examined. METHODS: Anaesthetised rats or mice received an injection of NaHS, a donor for H(2)S, or capsaicin into the pancreatic duct, and the expression of spinal Fos protein was detected by immunohistochemistry. Pancreatitis was created by 6 hourly doses of caerulein in unanaesthetised mice, and pancreatitis-related allodynia/hyperalgesia was evaluated using von Frey hairs. CSE activity and protein levels in pancreatic tissues were measured using the colorimetric method and western blotting, respectively. RESULTS: Either NaHS or capsaicin induced the expression of Fos protein in the superficial layers of the T8 and T9 spinal dorsal horn of rats or mice. The induction of Fos by NaHS but not capsaicin was abolished by mibefradil, a T-type Ca(2+) channel blocker. In conscious mice, repeated doses of caerulein produced pancreatitis accompanied by abdominal allodynia/hyperalgesia. Pretreatment with an inhibitor of CSE prevented the allodynia/hyperalgesia, but not the pancreatitis. A single dose of mibefradil reversed the established pancreatitis-related allodynia/hyperalgesia. Either the activity or protein expression of pancreatic CSE increased after the development of caerulein-induced pancreatitis in mice. CONCLUSIONS: The data suggest that pancreatic NaHS/H(2)S most probably targets T-type Ca(2+) channels, leading to nociception, and that endogenous H(2)S produced by CSE and possibly T-type Ca(2+) channels are involved in pancreatitis-related pain.

Gastrointestinal roles for proteinase-activated receptors in health and disease.

It has been almost a decade since the molecular cloning of all four members of the proteinase-activated receptor (PAR) family was completed. This unique family of G protein-coupled receptors (GPCRs) mediates specific cellular actions of various endogenous proteinases including thrombin, trypsin, tryptase, etc. and also certain exogenous enzymes. Increasing evidence has been clarifying the emerging roles played by PARs in health and disease. PARs, particularly PAR1 and PAR2, are distributed throughout the gastrointestinal (GI) tract, modulating various GI functions. One of the most important GI functions of PARs is regulation of exocrine secretion in the salivary glands, pancreas and GI mucosal epithelium. PARs also modulate motility of GI smooth muscle, involving multiple mechanisms. PAR2 appears to play dual roles in pancreatitis and related pain, being pro-inflammatory/pro-nociceptive and anti-inflammatory/anti-nociceptive. Similarly, dual roles for PAR1 and PAR2 have been demonstrated in mucosal inflammation/damage throughout the GI tract. There is also fundamental and clinical evidence for involvement of PAR2 in colonic pain. PARs are thus considered key molecules in regulation of GI functions and targets for development of drugs for treatment of various GI diseases.

Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts.

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FUra) selectively in tumors through the intermediate metabolite 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine). 5'-dFUrd is metabolized to 5-FUra by thymidine phosphorylase (dThdPase) located in high levels in various types of solid tumors from patients, whereas 5-FUra generated is catabolized to dihydrofluorouracil by dihydropyrimidine dehydrogenase (DPD). The present study investigated whether the efficacy of capecitabine and its intermediate metabolite 5'-dFUrd correlates with levels of these enzymes in various human cancer xenograft models. Capecitabine and 5'-dFUrd were highly effective and inhibited tumor growth by more than 50% in 18 of 24 xenograft lines (75%) and 15 of 24 xenograft lines (63%), respectively, whereas 5-FUra and a mixture of tegafur and uracil were effective only in 1 of 24 (4.2%) and 5 of 24 (21%), respectively. The efficacy of capecitabine correlated with dThdPase activity. However, capecitabine was effective even in tumors with lower levels of dThdPase if DPD levels were also lower. In contrast, it was not as effective even in tumors with sufficient levels of dThdPase if DPD levels were very high. The efficacy of capecitabine consequently correlated very well with and depended on the ratio of these two enzymes in tumors. These results indicate that capecitabine might exert its efficacy through 5-FUra generated in tumor tissues but not through that generated in normal organs. On the other hand, there was no correlation between the efficacy of a mixture of tegafur and uracil and these enzyme activities in tumors. The efficacy of capecitabine would be optimized by selecting patients who have tumors with a high ratio of dThdPase to DPD activities.

X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts.

Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the cytostatics capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) and its intermediate metabolite 5'-deoxy-5-fluorouridine (5'-dFUrd) to 5-fluorouracil (5-FUra) in tumors. We observed previously that several cytokines and cytostatics up-regulated dThdPase expression and consequently enhanced the efficacy of capecitabine and 5'-dFUrd. In the present study, we found that X-ray irradiation also up-regulated dThdPase expression in several human cancer xenografts. A single-dose local irradiation at 5 Gy increased dThdPase levels by up to 13-fold at 9 days after the irradiation. Whole-body irradiation also up-regulated dThdPase in a tumor, but it did not increase the enzyme level in the liver. We also observed that the irradiation increased the levels of human tumor necrosis factor alpha (TNF-alpha), which is an up-regulator of dThdPase, prior to the dThdPase up-regulation. These results indicate that X-ray irradiation might increase dThdPase levels indirectly through the human TNF-alpha in the tumor tissue. In the WiDr colon and MX-1 mammary human cancer xenograft models, the combination of a single local X-ray irradiation with either capecitabine or 5'-dFUrd was much more effective than either radiation or chemotherapy alone. In contrast, treatment with X-ray irradiation and 5-FUra in combination showed no clear additive effects. Combined modality treatment of cancer patients with cape-citabine and X-ray irradiation would have greater potential usefulness than conventional radiochemotherapy with 5-FUra.

Characterization of four extensin genes in Arabidopsis thaliana by differential gene expression under stress and non-stress conditions.

From Arabidopsis thaliana we isolated four different cDNAs that encode extensins, a family of cell-wall hydroxyproline-rich glycoproteins (HRGPs). Putative proteins (AtExt2-5) contained one open reading frame and characteristic Ser-(Pro)4 sequences organized in a high-order repetitive motif. AtExt2-5 genes were strongly expressed during rehydration after dehydration. They were also expressed after treatment with various amino acids. In particular, AtExt3 and five mRNAs were abundantly accumulated after treatment with L-Ser, Hyp, and L-Pro, which are major components of extensin proteins. The AtExt transcripts were strongly expressed in root tissues of both unbolted and bolted plants. The transcripts of AtExt2, 3, and 5 were also detected in the lower stem and flower buds, and that of AtExt4 was detected in bolted flowers. Therefore, we suggest that these four AtExt genes are novel extensin genes in A. thaliana, because the expression of atExt1, which has already been isolated from A. thaliana, was different from these.

Effects of cyclopiazonic acid and thapsigargin on electromechanical activities and intracellular Ca2+ in smooth muscle of carotid artery of hypertensive rats.

1. The effects of cyclopiazonic acid (CPA) and thapsigargin (TG), both of which are known to inhibit sarcoplasmic reticular Ca(2+)-ATPase, on the mechanical activities, intracellular Ca2+ level and electrical activities of smooth muscle of the carotid artery of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY) were compared. 2. Both CPA and TG induced elevation of tension of the smooth muscle, which was composed of a phasic and a tonic component. The level of tension attained, especially the tonic component, was greater in the preparation from SHRSP. 3. The elevation of tension was associated with an increased intracellular Ca2+ level. Both the elevation of tension and the increase in intracellular Ca2+ were diminished by the removal of extracellular Ca2+ or by the application of verapamil. 4. The resting membrane potential of the preparations from SHRSP were depolarized to a greater extent than those from WKY.CPA depolarized the smooth muscle from both SHRSP and WKY, and the final level was also more depolarized in the preparation from SHRSP. 5. These results indicate that the elevation of tension induced by these drugs is mainly due to increased Ca2+ influx through voltage-dependent Ca2+ channels, and the difference in the action between the preparation from SHRSP and that from WKY can be explained mainly by the changes in the channels. 6. Thus, differences in the action of these drugs on the tension of smooth muscle between preparations from WKY and SHRSP can mainly be explained by the difference in the membrane potential which is related to the difference in voltage-dependent Ca2+ influx.

Endothelium-derived relaxing, contracting and hyperpolarizing factors of mesenteric arteries of hypertensive and normotensive rats.

Differences in the acetylcholine (ACh)-induced endothelium-dependent relaxation and hyperpolarization of the mesenteric arteries of Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) were studied. Relaxation was impaired in preparations from SHRSP and tendency to reverse the relaxation was observed at high concentrations of ACh in these preparations. Relaxation was partly blocked by NG-nitro-L-arginine (L-NOARG, 100 microM) and, in the presence of L-NOARG, tendency to reverse the relaxation was observed in response to higher concentrations of ACh, even in preparations from WKY. The relaxation remaining in the presence of L-NOARG was also smaller in preparations from SHRSP. The tendency to reverse the relaxation observed at higher concentrations of ACh in preparations from SHRSP or WKY in the presence of L-NOARG were abolished by indomethacin (10 microM). Elevating the K+ concentration of the incubation medium decreased relaxation in the presence of both indomethacin and L-NOARG. Relaxation in the presence of L-NOARG and indomethacin was reduced by the application of both apamin (5 microM) and charybdotoxin (0.1 microM). This suggests that the relaxation induced by ACh is brought about by both endothelium-derived relaxing factor (EDRF, nitric oxide (NO)) and hyperpolarizing factor (EDHF), which activates Ca2+-sensitive K+ channels. Electrophysiological measurement revealed that ACh induced endothelium-dependent hyperpolarization of the smooth muscle of both preparations in the presence of L-NOARG and indomethacin; the hyperpolarization being smaller in the preparation from SHRSP than that from WKY. These results suggest that the release of both NO and EDHF is reduced in preparations from SHRSP. In addition, indomethacin-sensitive endothelium-derived contracting factor (EDCF) is released from both preparations; the release being increased in preparations from SHRSP.

Effects of cyclopiazonic acid on contraction and intracellular Ca2+ in oesophageal striated muscle of normotensive and spontaneously hypertensive rats.

1. The effects of cyclopiazonic acid (CPA), a selective inhibitor of sarcoplasmic reticulum (SR) Ca2+-ATPase, on twitch contraction and on the resting state of tension and intracellular Ca2+ level ([Ca2+]i) of the oesophageal striated muscle of stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY) were compared. 2. CPA (10 micronM) augmented the twitch contraction of oesophageal striated muscle preparations from both SHRSP and WKY, reducing the rate of relaxation (-dT/dt), and thus resulting in the prolongation of the time to 80% relaxation. The effect was significantly smaller in the SHRSP preparations. 3. In the resting state, CPA caused a sustained elevation of [Ca2+]i. The elevation was greater in the WKY preparations. Tension development accompanied by the elevation was observed in WKY preparations, but not in SHRSP preparations. 4. The sustained elevation of [Ca2+]i induced by CPA was eliminated by the removal of extracellular Ca2+. Both the elevated [Ca2+]i and tension in the preparations from WKY were reduced by flufenamic acid (100 micronM), mefenamic acid (100 micronM), lanthanum (La3+, 100 micronM), gadolinium (Gd3+, 100 micronM) and SK&F 96365 (100 micronM) but not by verapamil (10 micronM). 5. Thapsigargin (3 micronM), another SR Ca2+-ATPase inhibitor, produced similar effects on basal tension to those of CPA, although it reduced the amplitude of twitch contraction. 6. These results suggest that in the rat oesophageal striated muscle, (1) CPA extends the sequestrating time of Ca2+ into the SR, (2) CPA induces a Ca2+ influx mediated through verapamil-insensitive pathways, possibly nonselective cation channels, and (3) the mechanism of [Ca2+](i) modulation due to CPA-sensitive SR Ca2+-ATPase is deteriorated in the oesophageal striated muscle from SHRSP as compared with WKY preparations.

Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts.

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate that is converted to 5-fluorouracil (5-FUra) by three enzymes located in the liver and tumors; the final step is the conversion of 5'-deoxy-5-fluorouridine (5'-dFUrd) to 5-FUra by thymidine phosphorylase in tumors. The present study compared the efficacy of capecitabine and 5-FUra at their maximum tolerated doses in CXF280, HCT116, COLO205, and WiDr human colon cancer xenograft models, and measured subsequent 5-FUra and 5'-dFUrd levels in tumors and in the plasma and muscle. Capecitabine was effective in the first three models, whereas 5-FUra was effective only in CXF280, which is a cell line highly susceptible to fluoropyrimidines. In the three susceptible models, 5-FUra AUCs in tumors after capecitabine administration were 210 to 303 nmol x hr/g, whereas those after 5-FUra administration were 8.54 to 13.1 nmol x hr/g. In addition, capecitabine gave higher levels of 5-FUra AUC in tumors than in plasma (114- to 209-fold higher) and muscle (21.6-fold higher), whereas 5-FUra was not selectively distributed to tumors. In the refractory model, WiDr, 5-FUra AUC in tumors after capecitabine administration was only 62.8 nmol x hr/g, although the level of the intermediate metabolite 5'-dFUrd was high (AUC: 695 nmol x hr/g). The ratio of 5-FUra/5'-dFUrd levels in the WiDr tumors was 0.09, which was 23.8-fold lower than that in the HCT116 tumors. The mechanism of resistance would be the inefficient conversion of 5'-dFUrd to 5-FUra by thymidine phosphorylase in tumors. Thus, capecitabine might show its high efficacy as a result of delivering high levels of 5-FUra selectively to the tumors.

Age-related changes in learning and memory and cholinergic neuronal function in senescence accelerated mice (SAM).

The senescence-accelerated mouse (SAM) has been established as a murine model of accelerated aging. We investigated learning ability and memory in various tasks in a SAM strain, SAMP1TA, and in a control strain of SAMR1TA at the ages of 20, 30 and 40 weeks. We also measured choline acetyltransferase (ChAT) and cholinesterase (ChE) activity in the brains of these mice at the same ages. In a Y-maze task, in which short-term memory can be examined, there was no difference in learning ability between SAMP1TA and SAMR1TA at any age. Ability in latent learning and passive-avoidance tasks was less in SAMP1TA at 30 weeks of age than in age-matched SAMR1TA. The level of ChAT activity in the striatum of SAMP1TA was lower, than that of SAMR1TA at the ages of 20 and 30 weeks. At the ages of 40 and 50 weeks, ChE activity in the striatum of SAMP1TA was lower than that of SAMR1TA. These results suggest that SAMP1TA has a deficit, with cholinergic neuronal dysfunction, in learning ability and memory, as shown by impairment of performance in latent learning and long-term memory, but not in short-term memory.

Factors involved in the time course of response to acetylcholine in mesenteric arteries from spontaneously hypertensive rats.

The time course of the response to prolonged application of acetylcholine in mesenteric arteries from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY) was compared. Only a relaxing response, which was blocked by N(omega)-nitro-L-arginine (L-NOARG), was observed after the prolonged application of a low concentration of acetylcholine (10(-8) M) in both preparations; the response was impaired in SHRSP preparations. Prolonged application of a high concentration of acetylcholine (10(-5) M) induced a second contractile response after a first relaxing response in SHRSP preparations under basal conditions and in WKY preparations in the presence of L-NOARG. This contractile response was attenuated by indomethacin. In the presence of a combination of apamin and charybdotoxin, the relaxing response to the high concentration of acetylcholine was reduced and a contractile response, which was abolished by indomethacin, appeared. In the presence of all of these blockers, a contractile response, which was blocked by cyclo(D-alpha-aspartyl-L-propyl-D-valyl-L-leucyl-D-tryptophyl) (BQ-123), was observed in preparations from WKY but not in preparations from SHRSP. Results indicate that prolonged application of acetylcholine in rat mesenteric arteries induces the release of endothelium-derived relaxing, contracting, hyperpolarizing factors and endothelin-1, and that the mode of action differs between preparations from WKY and SHRSP.

Unaltered endothelium-dependent modulation of contraction in the pulmonary artery of hypertensive rats.

Involvement of endothelium-derived nitric oxide (EDNO) in alpha-adrenoceptor agonist-induced contractile responses was studied in isolated pulmonary arteries from Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). In the presence of propranolol, noradrenaline-induced contraction was potentiated by endothelium removal or by N(G)-nitro-L-arginine (L-NOARG). The magnitude of the potentiation was independent of the noradrenaline concentration. L-NOARG also shifted the concentration-response curves for phenylephrine and methoxamine to the left and upward. Contractile responses to 2-amino-5,6,7,8, -tetrahydro-6-ethyl-4H-oxazolo-(5,4-d)-azepine-dihydrochloride (BHT-933) and 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK-14304) were augmented by L-NOARG in a concentration-dependent manner. There were no differences in the effects of L-NOARG on the contractile responses to alpha-adrenoceptor agonists between the preparations from WKY and SHRSP. Endothelium-dependent relaxation in response to acetylcholine was not impaired in the preparations from SHRSP when compared with those from WKY. These observations suggest that the contractile responses to the alpha(1)-adrenoceptor agonists were depressed mainly by basally released EDNO, while the responses to the alpha(2)-adrenoceptor agonists were depressed mainly by EDNO released in response to alpha(2)-adrenoceptor stimulation. The comparable influence of the endothelium on the alpha-adrenoceptor agonist-induced contractions in the pulmonary arteries from WKY and SHRSP, which were markedly different from other arteries, could be explained by the unaltered endothelium-dependent relaxation in the preparations from SHRSP.

Effects of amiloride on the neurally mediated contraction of rat mesenteric artery.

The effects of amiloride on contraction evoked by perivascular nerve stimulation were studied in a ring preparation of rat mesenteric artery. The contraction evoked by nerve stimulation was abolished by tetrodotoxin or prazosin. Amiloride depressed the nerve-induced contraction concentration dependently. Noradrenaline induced a tonic contraction in the artery. Amiloride inhibited the noradrenaline-induced contraction concentration dependently. The excitatory junctional potential (e.j.p.) recorded intracellularly was abolished by tetrodotoxin. The amplitude of the e.j.p. was not altered by prazosin or amiloride. These results indicate that amiloride inhibits the perivascular nerve-mediated contraction of mesenteric artery mainly through postsynaptic adrenoceptor inhibition and not through mechanisms related to e.j.p.

Membrane potential of mesenteric artery from carvedilol-treated spontaneously hypertensive rats.

The effects of chronic treatment of stroke-prone spontaneously hypertensive rats (SHRSP) with carvedilol, an antihypertensive agent which has both alpha- and beta-adrenoceptor-blocking actions, on membrane potential and relaxation of mesenteric resistant artery were studied. Five-week old SHRSP were treated with carvedilol for three months. At 16 weeks, the resting membrane potential of arteries from carvedilol-treated SHRSP was more negative than that of arteries from untreated SHRSP. The magnitude of acetylcholine-induced hyperpolarization in arteries from carvedilol-treated SHRSP was not different from that of arteries from untreated SHRSP. In the presence of noradrenaline, the membrane potential of arteries from carvedilol-treated SHRSP was more negative than that of arteries from untreated SHRSP. The membrane potential of arteries from carvedilol-treated SHRSP in the presence of noradrenaline and acetylcholine was more negative than that of arteries from untreated SHRSP. The acetylcholine-induced relaxation in noradrenaline-precontracted preparations from carvedilol-treated SHRSP was greater than that in preparations from untreated SHRSP and was smaller than that in preparations from Wistar Kyoto rats. Scanning electronmicroscopy showed that carvedilol-treatment decreased the structural abnormalities of the endothelium of arteries from SHRSP. These results indicate that chronic carvedilol treatment made the membrane potential of smooth muscle more negative and improved endothelial function in the mesenteric artery of SHRSP, which may contribute to the antihypertensive effect of carvedilol.

Cerebellar nitric oxide synthase activity is reduced in nervous and Purkinje cell degeneration mutants but not in climbing fiber-lesioned mice.

We measured nitric oxide synthase activity in nervous, Purkinje cell degeneration mutant mice and 3-acetylpyridine-treated mice to determine the cellular localization of nitric oxide synthase in the cerebellum. Nitric oxide synthase activity per cerebellum was reduced to less than 50% of that of controls in nervous and Purkinje cell degeneration mutants, while in 3-acetylpyridine-treated mice there was no reduction.

Blood pressure and age-dependent changes of endothelium-dependent tension oscillations in different strains of spontaneously hypertensive rats.

The influence of blood pressure and age of spontaneously hypertensive rats on endothelium-dependent tension oscillation of aortic preparation were studied. Rats with different blood pressures, normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and malignant type of SHRSP (M-SHRSP), were used. The effects of antihypertensive treatment of SHRSP on the tension oscillation were also studied. High doses of noradrenaline induced tension oscillations in endothelium-intact preparations of all strains of young rats. The rate of the occurrence of the tension oscillation decreased age-dependently. The decrease was faster when the blood pressure of the rats was higher. Application of acetylcholine in the presence of noradrenaline induced a relaxation and tension oscillations, both of which were negatively dependent on age and blood pressure. Antihypertensive treatment of hypertensive rats with hydralazine or captopril prevented a decrease in incidence of the tension oscillation. These influences of age and blood pressure as well as antihypertensive treatments on the tension oscillation resembled those on the endothelium-dependent relaxation and are thought to be brought about by functional changes of the endothelium.

Altered beta-adrenoceptor-mediated responses in the gastric smooth muscle of hypertensive rats.

Effects of isoproterenol on contraction and membrane potential of gastric smooth muscle were studied in stroke prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY). Circular muscle preparation from the gastric fundus developed tonic contraction by re administration of Ca2+ to a nominally Ca2+-free solution. The contraction was inhibited by nifedipine or nicardipine. Isoproterenol induced relaxation when it was applied to the Ca2+-induced contraction. The amplitude of isoproterenol induced relaxation was concentration-dependent. Propranolol 10(-6) M abolished the relaxation induced by isoproterenol 10(-7) M. In the preparation from SHRSP, the amplitude of isoproterenol induced relaxation was smaller than that from WKY between 3 x 10(-9) and 10(-7) M. Forskolin, an adenylate cyclase activator, induced concentration-dependent relaxation. There was no difference in the relaxation induced by forskolin between preparations from WKY and SHRSP. Dibutilyl cyclic AMP, a membrane permeable analogue of cyclic AMP, also induced similar relaxation in preparations from WKY and SHRSP. Resting membrane potential of smooth muscle cell was not different between preparations from WKY and SHRSP. Isoproterenol hyperpolarized the membrane concentration-dependently. Isoproterenol-induced hyperpolarization in the preparation from SHRSP was smaller than that from WKY between 10(-8) and 10(-6) M. When the membrane was depolarized by Tyrode's solution containing 40 mM K+, isoproterenol-induced hyperpolarization was almost abolished. In this condition, the isoproterenol-induced relaxation was inhibited partly, however, there was no difference in the amplitude of relaxation between preparations from WKY and SHRSP. Therefore, isoproterenol-induced hyperpolarization contributed at least partly to the relaxation. Forskolin hyperpolarized the membrane by the same amplitude in the preparations from WKY and SHRSP. These results indicate that a decrease in hyperpolarization may contribute to the decreased relaxation by isoproterenol in the preparation from SHRSP.

Effects of NG-nitro-L-arginine on alpha-agonists-induced contraction of aortae from Wistar Kyoto rats and stroke-prone spontaneously hypertensive rats.

Differences in the influences of endothelium-derived nitric oxside (NO) on alpha-agonists-induced contraction in the aortae of spontaneously hypertensive and normotensive rats were studied by blocking NO synthesis with NG-nitro-L-arginine (L-NNA). L-NNA potentiated the contraction induced by noradrenaline. The potentiation was smaller in the preparation from stroke-prone spontaneously hypertensive rats (SHRSP) than in the preparation from Wistar Kyoto rats (WKY). Similar potentiation was observed in the contraction induced by phenylephrine; the potentiation was also smaller in the preparation from SHRSP. alpha 2-agonists, clonidine and UK-14304 induced dose-dependent contraction only in the presence of L-NNA. The dose-response curves for alpha 2-agonists in SHRSP aorta were different from those in WKY aorta; the maximum tension was observed at the concentration of 10(-6) M in the preparation from WKY, while the contraction further increased up to 10(-4) M in the preparation from WKY. Noradrenaline, clonidine and UK-14304 but not phenylephrine induced relaxation which was blocked by L-NNA. The relaxation was impaired in the preparation from SHRSP in greater extent than that by acetylcholine. It is suggested that basic or noradrenaline-stimulated NO release from endothelium decreased in the preparation from SHRSP and that alpha 2-adrenoceptor of both the endothelium and smooth muscle may be altered in the preparation from SHRSP.