Biomedical subjects

Katsuo Kamata

Publications and source records attributed to Katsuo Kamata.

At least 37 records · Page 2Linked to original sources

PubMed2005

IGF-I-induced enhancement of contractile response in organ-cultured aortae from diabetic rats is mediated by sustained thromboxane A2 release from endothelial cells.

We have investigated the mechanisms underlying the changes in vascular contractile responsiveness induced by insulin and IGF-I in established streptozotocin-induced diabetic rats. The contractile response to noradrenaline (NA) in organ-cultured diabetic rat aortae cultured with insulin or IGF-I was significantly greater than the corresponding responses in (a) diabetic rat aortae cultured in serum-free medium and (b) control rat aortae cultured with insulin or IGF-I. In aortae from which the endothelium was removed after organ culture the contractile response to NA was greater in those cultured with insulin or IGF-I than in those cultured in serum-free medium. This was not true of aortae endothelium denuded before organ culture. The IGF-I-induced enhancement was prevented by treatment with indomethacin (cyclo-oxygenase inhibitor), SQ29548 (thromboxane (TX) A2 receptor antagonist) or fregrelate (TXA2 synthase inhibitor). IGF-I-induced production of TXB2, a metabolite of TXA2, was greater in diabetic than in control aortae and was attenuated by endothelium denudation, indomethacin or AG1024 (IGF-I receptor inhibitor). The expression of the protein and mRNA for the IGF-I receptor (as assessed by RT-PCR and immunohistochemistry) was markedly increased within endothelial cells in diabetic aortae but only slightly increased within smooth muscle cells (versus control rat aortae). Thus, the NA-induced contractile response in aortae from diabetic rats was enhanced by both insulin and IGF-I and this enhancement may be mediated by sustained cyclo-oxygenase-dependent TXA2 production from endothelial cells. The observed enhancement of IGF-I receptor expression within endothelial cells may be causally related to the potentiation of vascular contractility and the increase in TXA2 production.

Animals↗

PubMed2004

Effect of chronic insulin on cromakalim-induced relaxation in established streptozotocin-diabetic rat basilar artery.

Our goals were to determine whether the response of the rat isolated basilar artery to activation of ATP-sensitive potassium (KATP) channels is altered in diabetes mellitus, and to determine the effect of chronic insulin treatment on this response in established diabetic rats. The relaxation induced by cromakalim, an activator of KATP channels, was significantly weaker in insulin-untreated streptozotocin-induced diabetic rats than in the controls. This impairment was significantly improved following chronic administration of insulin. The relaxations induced by two Ca2+-activated K+-channel activators [1-ethyl-2-benzimidazolinone (1-EBIO) or 1, 3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619)] were not significantly different between control and insulin-untreated diabetic rats. The sodium nitroprusside-induced relaxation was similar among the three groups (control, diabetic, and insulin-treated diabetic). These results suggest that: (a) the impaired cromakalim-induced relaxation seen in diabetic rats is not due to a nonspecific effect of diabetes mellitus on vasorelaxation, but at least partly to an effect on KATP channels, and (b) that this impaired relaxation can be restored by chronic insulin treatment.

Animals↗

PubMed2004

Effects of chronic insulin on endothelial dysfunction of basilar arteries from established streptozotocin-diabetic rats.

Our goals were to determine both the effects of chronic insulin treatment on the impaired endothelium-dependent relaxation present in basilar arteries from established diabetic rats and the molecular basis of these effects. Acetylcholine-induced relaxation in basilar artery rings was impaired in the streptozotocin-induced diabetic group, and this impaired response was recovered by insulin treatment. The contraction induced by a nitric oxide synthase inhibitor was decreased in the insulin-untreated diabetic group, but was increased by insulin or NAD(P)H oxidase inhibitor treatment. The manganese-superoxide dismutase (Mn-SOD) mRNA level was significantly lower in basilar arteries from insulin-untreated diabetic rats than in those from the controls, whereas the mRNA for gp91phox, an NAD(P)H oxidase subunit, was increased. In the insulin-treated group, the basilar artery p22phox mRNA level was reduced (vs. insulin-untreated diabetic). These results suggest that the presence of endothelial dysfunction in the diabetic basilar artery is related to increased oxidative stress, and that insulin preserves endothelial function by alleviating oxidative stress. Furthermore, we directly demonstrated that the expression profile for SOD and NAD(P)H oxidase was altered in the streptozotocin-induced diabetic basilar artery.

Animals↗

PubMed2004

Impairment of PI3-K/Akt pathway underlies attenuated endothelial function in aorta of type 2 diabetic mouse model.

The phosphatidylinositol 3-kinase (PI3-K) pathway, which activates serine/threonine protein kinase Akt, enhances endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. We investigated the involvement of the PI3-K/Akt pathway in the relaxation responses to acetylcholine (ACh) and clonidine in a new type 2 diabetic model (streptozotocin plus nicotinamide-induced diabetic mice). Plasma glucose and insulin levels were significantly elevated in our model, and intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness. Although in our model the ACh-induced relaxation and NOx- (NO2-+NO3-)/cGMP production were unchanged, the clonidine-induced and insulin-induced relaxations and NOx-/cGMP production were all greatly attenuated. In control mice, the clonidine-induced and insulin-induced relaxations were each abolished by LY294002 and by Wortmannin (inhibitors of PI3-K), and also by Akt-inhibitor treatment. The ACh-induced relaxation was unaffected by such treatments in either group of mice. The expression level of total Akt protein was significantly decreased in the diabetic mice aorta, but those for the p85 and p110gamma subunits of PI3-K were not. The clonidine-induced Ser-473 phosphorylation of Akt through PI3-K was significantly decreased in our model; however, that induced by ACh was not. These results suggest that relaxation responses and NO production mediated via the PI3-K/Akt pathway are decreased in this type 2 diabetic model. This may be a major cause of endothelial dysfunction (and the resulting hypertension) in type 2 diabetes.

Acetylcholine↗

PubMed2004

Diabetes-related changes in cAMP-dependent protein kinase activity and decrease in relaxation response in rat mesenteric artery.

Using superior mesenteric artery rings isolated from age-matched controls and streptozotocin (STZ)-induced diabetic rats, we recently demonstrated that EDHF-type relaxation is impaired in STZ-induced diabetic rats, possibly due to a reduced action of cAMP via increased phosphodiesterase (PDE) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283-H291, 2003). Here, we investigated the activity and expression of cAMP-dependent protein kinase (PKA), an enzyme that is produced by a pleiotropic and plays key roles in the transduction of many external signals through the cAMP second messenger pathway and in cAMP-mediated vasorelaxation. The relaxation induced by cilostamide, a selective PDE3 inhibitor, was significantly weaker in superior mesenteric artery rings from STZ-induced diabetic rats than in those from age-matched controls. The relaxation responses to 8-bromo-cAMP (8Br-cAMP) and N6,O2-dibutyryl-adenosine-cAMP (db-cAMP), a cell-permeant cAMP analog, were also impaired in the STZ diabetic group. PKA activity in the db-cAMP-treated mesenteric artery was significantly lower in the STZ diabetic group. The expression levels of the mRNA and protein for PKA catalytic subunit Cat-alpha were significantly decreased in the STZ diabetic group, but those for PKA regulatory subunit isoform RII-beta were increased. We conclude that the abnormal vascular relaxation responsiveness seen in STZ-induced diabetic rats may be attributable not only to increased PDE activity but also to decreased PKA activity. Possibly, the decreased PKA activity may result from an imbalance between PKA catalytic and regulatory subunit expressions.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2004

Differential expression of alpha2D-adrenoceptor and eNOS in aortas from early and later stages of diabetes in Goto-Kakizaki rats.

The aim of the present study was to compare vascular dysfunction between the early (12 wk old) and later (36 wk old) stages of spontaneous diabetes in Goto-Kakizaki (GK) rats. We also evaluated the aortic expression of the alpha(2D)-adrenoceptor and endothelial nitric oxide synthase (eNOS). Vascular reactivity was assessed in thoracic aortas from age-matched control rats and 12- and 36-wk GK rats. Using RT-PCR and immunoblots, we also examined the changes in expression of the alpha(2D-)adrenoceptor and eNOS. In aortas from GK rats (vs. those from age-matched control rats): 1) the relaxation response to ACh was enhanced at 12 wk but decreased at 36 wk; 2) the relaxation response to sodium nitroprusside was decreased at both 12 and 36 wk, 3) norepinephrine (NE)-induced contractility was decreased at 12 wk but not at 36 wk, 4) the expressions of alpha(1B)- and alpha(1D)-adrenoceptors were unaffected, whereas those of alpha(2D)-adrenoceptor and eNOS mRNAs were increased at both 12 and 36 wk; and 5) NE- and ACh-stimulated NO(x) (nitrite and nitrate) levels were increased at 12 wk, although at 36 wk ACh-stimulated NO(x) was lower, whereas NE-stimulated NO(x) showed no change. These results clearly demonstrate that enhanced ACh-induced relaxation and impaired NE-induced contraction, due to NO overproduction via eNOS and increased alpha(2D)-adrenoceptor expression, occur in early-stage GK rats and that the impaired ACh-induced relaxation in later-stage GK rats is due to reductions in both NO production and NO responsiveness (but not in eNOS expression).

Acetylcholine↗

PubMed2004

Modulations of shear stress-induced contractile responses and agonist-induced vasodilation in hypercholesterolemic rats.

We used mesenteric arterial beds from normal rats and beef tallow-fed rats (hypercholesterolemic model) to study the interaction between the effects of viscosity-induced shear stress and agonists mesenteric vasoreactivity. Mesenteric arterial beds were perfused under constant-flow conditions (5 ml/min) via a peristaltic pump using warm oxygenated modified Krebs-Henseleit solution containing either 4% BSA to increase viscosity or 300 microM L-arginine, a NO synthase substrate. Whether beds were perfused with BSA alone or L-arginine alone as pretreatment, the methoxamine-induced contractile responses were similar to those in normal beds. However, methoxamine-induced contractile responses were significantly reduced following pretreatment with L-arginine plus BSA. These reduced responses underwent significant recovery when either tyrphostin A23 (30 microM, a tyrosine kinase inhibitor) or wortmannin (300 nM, a PI3K inhibitor) was present. The dose-response curve for methoxamine was shifted to the right and the maximum contractile response was reduced in mesenteric arterial beds from beef tallow-fed rats, but the modulation of this response induced by L-arginine plus BSA was preserved. In beef tallow-fed rats, the ACh-induced endothelium-dependent vasodilation was attenuated in both thoracic aortic strips and mesenteric arterial beds. These results suggest that in hypercholesterolemic rats, agonist-induced endothelial function is impaired, while shear stress-induced responses (tyrosine kinase- and PI3K-mediated NO production) are preserved. These abnormal vascular responses may contribute to hypertension in beef tallow-fed hypercholesterolemic model rats.

Acetylcholine↗

PubMed2004

Mechanisms underlying enhanced contractile response to endothelin-1 in diabetic rat basilar artery.

We investigated the influence of streptozotocin-induced diabetes on the responsiveness of the rat basilar artery to endothelin-1 (ET-1) and nitric oxide (NO), which is known to counteract ET-1. In basilar arteries isolated from diabetic rats: (a) the ET-1-induced contraction was enhanced, (b) the contraction induced by N(G)-nitro-l-arginine [a nitric oxide synthase (NOS) inhibitor] was weaker, and (c) the levels of the mRNAs for ET(A)/ET(B) receptors and prepro-ET-1, but not for NOS, were significantly elevated (all versus age-matched controls). These data indicate that ET-1-induced vasoconstriction may be increased in the diabetic rat basilar artery, and that this hyper-reactivity to ET-1 may be due to an overproduction of ET-1, an up-regulation of ET(A)/ET(B) receptors, and a defect in the bioavailability of NO.

Animals↗

PubMed2004

Endothelin-1-induced impairment of endothelium-dependent relaxation in aortas isolated from controls and diabetic rats.

An accumulating body of evidence indicates that an increased endothelin-1 level is related to endothelial dysfunction in cardiovascular diseases. In this study, we tested whether prolonged treatment of aortas with endothelin-1 induces endothelial dysfunction. When isolated aortas from control rats were cultured with endothelin-1, at levels above the plasma concentration, the acetylcholine-induced endothelium-dependent relaxation was significantly decreased (as compared with endothelin-1-nontreatment). This endothelin-1-induced endothelial dysfunction was more marked in aortas obtained from rats with streptozotocin-induced diabetes than in those from the controls. The endothelin-1- induced attenuation was very strongly suppressed by co-incubation with J-104132, endothelin receptor A/B antagonist, or polyethylene-glycolated superoxide dismutase, a cell-permeant superoxide anion scavenger or LY294002, phosphoinositide 3-kinase inhibitor. These results indicate that endothelin-1 can induce endothelial dysfunction, and that this may be related to superoxide generation and to PI3-kinase activity.

Acetylcholine↗

PubMed2004

Alterations in vascular endothelial function in the aorta and mesenteric artery in type II diabetic rats.

We used the partial protection exerted by suitable dosages of nicotinamide against the beta-cytotoxic effect of streptozotocin (STZ) to create an experimental diabetic syndrome in adult rats that appears closer to type II diabetes mellitus than other available animal models. The dosage of 230 mg/kg of nicotinamide given intraperitoneally 15 min before STZ administration (65 mg/kg i.v.) yielded animals with hyperglycemia (187.8 +/- 17.8 vs. 103.8 +/- 2.8 mg/dL in controls; P < 0.001) and preservation of plasma insulin levels. This study assessed the relationship between endothelial dysfunction and agonist-induced contractile responses in such rats. In the thoracic aorta, the acetylcholine (ACh) induced relaxation was significantly reduced and the noradrenaline (NA) induced contractile response was significantly increased in diabetic rats compared with age-matched control rats. In the superior mesenteric artery, the ACh-induced relaxation was similar in magnitude between diabetic and age-matched control rats; however, the ACh-induced endothelium-derived hyperpolarizing factor (EDHF) type relaxation was significantly weaker in diabetic rats than in the controls. The phenylephrine (PE) induced contractile response was not different between the two groups. The plasma concentration of NOx (NO2- + NO3-) was significantly lower in diabetic rats than in control rats. We conclude that vasomotor activities in conduit arteries are impaired in this type II diabetes model.

Acetylcholine↗

PubMed2004

Flow-induced endothelium-dependent vasoreactivity in rat mesenteric arterial bed.

We studied rat mesenteric arterial beds to determine the relationship between the effects of flow-induced shear stress and agonists on mesenteric vasoreactivity. When beds were perfused at gradually increasing flow rates, perfusion pressure was flow rate-dependently increased. The flow rate-mediated increase in perfusion pressure was significantly enhanced by N(G)-nitro-L-arginine (L-NOARG) plus methylene blue (MB) and slightly enhanced by treatment with tetraethylammonium (TEA). In the presence of L-NOARG, MB, TEA, and indomethacin, the flow rate-induced increase in perfusion pressure was significantly enhanced, but this enhancement was significantly inhibited by combined treatment with BQ-123 plus BQ-788 (ET(A)- and ET(B)- receptor antagonists, respectively). The ET-1 content of the perfusate was significantly increased following combined pretreatment with L-NOARG, MB, TEA, and indomethacin at a high flow rate. The methoxamine-induced contraction was significantly enhanced by NOS inhibition in both high- and low- flow-treated groups. The released nitrite level was significantly greater in high-flow-loaded than in the low-flow-loaded beds. We conclude that in this model, the response of vascular tone to flow stimulation is subtly regulated by endothelium-derived factors (especially, NO, endothelium-derived hyperpolarizing factor, and ET-1), and that these factors interact with each other.

Animals↗

PubMed2003

Possible involvement of IGF-1 receptor and IGF-binding protein in insulin-induced enhancement of noradrenaline response in diabetic rat aorta.

1. We investigated the mechanisms underlying the changes in vascular contractile responsiveness induced by chronic treatment with insulin in controls and established streptozotocin (STZ)-induced diabetic rats. 2. The aortic contractile response to noradrenaline (NA) showed no significant difference between controls and diabetics, but it was significantly greater in insulin-treated diabetic rats than in the other groups. To investigate the mechanism, we examined the changes in NA-induced contractility following treatment with insulin and insulin-like growth factor-1 (IGF-1) in organ-cultured control and diabetic aortas. 3. The contractile response to NA in organ-cultured diabetic rat aortas treated with insulin (500 ng ml-1, 16 h) or IGF-1 (20 ng ml-1, 16 h) was significantly greater than the corresponding values for (a) diabetic rat aortas cultured in serum-free medium, and (b) control aortas incubated with insulin or IGF-1. Incubating control aortas with insulin or IGF-1 had no significant effect on the contraction induced by NA. 4. The expressions of the IGF-1 receptor mRNA and protein were increased in STZ-induced diabetic aortas and further increased in insulin-treated diabetics. The mRNA expressions of IGF-binding protein (IGFBP)-2 and IGFBP-3 were normal in diabetic aortas. In contrast, those of IGFBP-4 and IGFBP-5 were significantly decreased in diabetic aortas, and not restored by insulin treatment. 5. These results suggest that the insulin deficiency and chronic hyperinsulinemia in diabetes upregulate the IGF-1 receptor and downregulate IGFBP-4 and IGFBP-5 in the aorta. This may be a major cause of the increased vascular contractility induced by insulin administration and by hyperinsulinemia in established diabetes, resulting in hypertension.

Angiotensin II↗

PubMed2003

Relationship between peroxisome proliferator-activated receptors (PPAR alpha and PPAR gamma) and endothelium-dependent relaxation in streptozotocin-induced diabetic rats.

(1) The aim of the present study was to investigate the causal relationship between peroxisome proliferator-activated receptor (PPAR) and endothelium-dependent relaxation in streptozotocin (STZ)-induced diabetic rats. (2) Acetylcholine (ACh)-induced endothelium-dependent relaxation was significantly weaker in diabetic rats than in age-matched controls. The decreased relaxation in diabetes was improved by the chronic administration of bezafibrate (30 mg kg-1, p.o., 4 weeks). (3) The expressions of the mRNAs for PPARalpha and PPARgamma were significantly decreased in STZ-induced diabetic rats (compared with the controls) and this decrease was restored partially, but not completely, by the chronic administration of bezafibrate. (4) Superoxide dismutase activity in the aorta was not significantly different between diabetic rats and bezafibrate-treated diabetic rats. (5) The expression of the mRNA for the p22phox subunit of NAD(P)H oxidase was significantly higher in diabetics than in controls, but it was lower in bezafibrate-treated diabetic rats than in nontreated diabetic rats. Although the expression of the mRNA for prepro ET-1 (ppET-1) was markedly increased in diabetic rats (compared with controls), this increase was prevented to a significant extent by the chronic administration of bezafibrate. (6) These results suggest that downregulations of PPARalpha and PPARgamma may lead to an increased expression of ppET-1 mRNA in diabetic states and this increment may trigger endothelial dysfunction.

Animals↗

PubMed2003

Lack of insulin receptor substrate-2 causes progressive neointima formation in response to vessel injury.

BACKGROUND: Insulin resistance is associated with atherosclerosis, but its mechanism is unknown. It has been reported that insulin receptor substrate (IRS)-1 deficient (IRS-1-/-) mice showed insulin resistance without type 2 diabetes, whereas the IRS-2 deficient (IRS-2-/-) mice showed insulin resistance with type 2 diabetes. METHODS AND RESULTS: We investigated neointima formation in the IRS-1-/- and IRS-2-/- mice at 8 and 20 weeks. The IRS-2-/- mice showed much greater neointima formation than the IRS-1-/- and wild-type mice at 8 weeks. At 20 weeks, the IRS-2-/- mice had greater neointima formation than the IRS-1-/- mice, which showed more enhanced neointima formation than the wild-type mice. The IRS-1-/- and IRS-2-/- mice had dyslipidemia, hypertension, and insulin resistance. The IRS-2-/- mice had more metabolic abnormalities than the IRS-1-/- mice at 8 and 20 weeks. IRS-2 expression was detected, but IRS-1 expression was not detected in the vessels. CONCLUSIONS: The neointima formation in the IRS-1-/- and IRS-2-/- mice appears to be related to abnormalities induced by the altered metabolic milieu in insulin-resistant states. Moreover, because neointima formation was much greater in the IRS-2-/- mice than in the IRS-1-/- mice at 8 and 20 weeks, it is suggested that a lack of IRS-2 renders the vasculature more susceptible to injury in the abnormal metabolic milieu, and IRS-2 may have a protective effect on neointima formation. We conclude that IRS-2 is protective and retards the development of neointima formation in insulin-resistant states.

Animals↗

PubMed2003

Effect of thiazolidinediones and metformin on LDL oxidation and aortic endothelium relaxation in diabetic GK rats.

In this study, using GK diabetic rats, we compared the effects of three insulin sensitizers on lipid oxidation and the aortic relaxation response. Eight-week-old rats were treated for 4 wk with either troglitazone or pioglitazone, both of which are thiazolidinediones, or with metformin. Despite the fact that only troglitazone has a similarity in structure to alpha-tocopherol, a potent antioxidant, the level of thiobarbituric acid-reactive substance was lower, and the lag time of the conjugated dienes was longer, in the blood samples from the rats in both troglitazone- and pioglitazone-treated groups. In contrast, another insulin sensitizer, metformin, failed to inhibit the oxidation of blood samples. The aortic vasorelaxation response was increased in both troglitazone- and metformin-treated groups compared with the untreated group. These findings suggest that thiazolidinediones have a beneficial effect on lipid oxidation irrespective of the drug's structural similarity to alpha-tocopherol. It is also suggested that the thiazolidinediones and metformin improve vascular function in diabetes. These effects may play a role in the prevention of atherosclerosis in diabetic patients.

Acetylcholine↗

PubMed2003

Alterations in EDHF-type relaxation and phosphodiesterase activity in mesenteric arteries from diabetic rats.

In isolated superior mesenteric artery rings from age-matched control rats and streptozotocin (STZ)-induced diabetic rats, we investigated the role of cAMP in endothelium-derived hyperpolarizing factor (EDHF)-type relaxation. The ACh-induced EDHF-type relaxation was significantly weaker in STZ-induced diabetic rats than in control rats, and in both groups of rats it was attenuated by 18alpha-glycyrrhetinic acid (18alpha-GA), an inhibitor of gap junctions, and enhanced by IBMX, a cAMP-phosphodiesterase (PDE) inhibitor. These enhanced EDHF-type responses were very similar in magnitude between diabetic and age-matched control rats. The EDHF-type relaxation was enhanced by cilostamide, a PDE3-selective inhibitor, but not by Ro 20-1724, a PDE4-selective inhibitor. The expression levels of the mRNAs and proteins for two cAMP PDEs (PDE3A, PDE3B) were significantly increased in STZ-induced diabetic rats, but those for PDE4D were not. We conclude that the impairment of EDHF-type relaxations in STZ-induced diabetic rats may be attributed to a reduction in the action of cAMP via increased PDE activity.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2003

Lysophosphatidylcholine activates extracellular-signal-regulated protein kinase and potentiates vascular contractile responses in rat aorta.

We previously reported that in the endothelium-denuded rat aorta, lysophosphatidylcholine (LPC) potentiates the contractile responses induced by high-K(+), UK14,304 (a selective alpha(2)-adrenoceptor agonist), and phorbol ester with an associated tyrosine-phosphorylation of proteins. To further investigate this phenomenon, we examined the effects of extracellular-signal-regulated protein kinase (ERK)-kinase (MEK) inhibitors on the LPC-induced potentiation of the contractile responses to high-K(+) and UK14,304 in this tissue. Although PD98059 (3 x 10(-)(5) M) did not affect the high-K(+)-induced contractile response itself, it selectively inhibited the potentiating effect of LPC on the contraction and strongly inhibited the LPC-induced augmentation of the associated increase in [Ca(2+)](i). PD98059 also attenuated the LPC-induced augmentations of the increases in [Ca(2+)](i) and contractile tension induced by UK14,304. U0126 (5 x 10(-)(5) M), another MEK inhibitor, also attenuated the potentiating effect of LPC on high-K(+)-induced contractions. Western blot analysis revealed that LPC produced an increase in ERK-phosphorylation, and that this was inhibited by PD98059. Nicardipine inhibited the contractile response to 15 mM K(+) in the LPC-treated aorta, but not the increase in ERK-phosphorylation induced by LPC. These results suggest that the LPC-induced augmentation of contractile responses in the rat aorta is due to activation of ERK, which in turn regulates Ca(2+) influx.

Animals↗

PubMed2003

Phosphodiesterases in the vascular system.

Cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) are second messengers involved in the intracellular signal transduction of a variety of extracellular stimuli in several tissues. In the vascular system, these nucleotides play important roles in the regulation of vascular tone and in the maintenance of the mature contractile phenotype in smooth muscle cells. Given that cyclic nucleotide signaling regulates a wide variety of cellular functions, it is not surprising that cyclic nucleotide phosphodiesterases (PDEs). In paticular, the accumulating data showing that there are a large number of different PDE isozymes have triggered an equally large increase in interest about these enzymes. At least 11 different gene families of PDEs are currently known to exist in mammalian tissues. Most families contain several distinct genes, and many of these genes are expressed in different tissues as functionally unique alternative splice variants. This article reviews many of the important aspects about the structure, cellular localization, and regulation of each family of PDEs. Particular emphasis is placed on new information obtained in the last few years about vascular disease. The development of novel methods to deliver more potent and selective PDE inhibitors to individual cell types and subcellular locations will lead to new therapeutic uses for this class of drugs in diseases of the vascular system.

Animals↗