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Z W Hu

Publications and source records attributed to Z W Hu.

31 records · Page 2Linked to original sources
PubMed1996

Alpha 1 adrenergic receptor activation of proto-oncogene expression in arterial smooth muscle: regulation by nitric oxide and vascular injury.

The role of the endothelium in modulating smooth muscle cell growth is unclear. alpha 1 adrenergic receptors activate proto-oncogene expression in smooth muscle. We have now found in rat aorta that carbachol, a muscarinic cholinergic agonist that promotes release of nitric oxide (NO), inhibits expression of c-fos and c-jun mRNA induced by alpha 1 receptors. NO synthase inhibitors blocked the effects of carbachol on c-fos mRNA and a cGMP analog mimicked carbachol. After balloon injury in rat aorta using in situ hybridization, the catecholamine-induced increase in c-fos mRNA expression in the medial layer was inhibited by the alpha 1 receptor antagonists, prazosin and chloroethylclonidine. In the neointima, this response was fully blocked by prazosin; however, chloroethylclonidine only partially inhibited it. These results suggest that NO, acting through a cGMP-dependent mechanism, inhibits expression of the c-fos and c-jun genes in arteries, which may contribute to the growth-inhibiting effects of the endothelium. After endothelial damage, the activation of c-fos in neointima by adrenergic stimulation may involve a subtype of alpha 1 receptor different from that utilized in medial smooth muscle.

Animals↗
PubMed1995

Angiotensin II induces transcription and expression of alpha 1-adrenergic receptors in vascular smooth muscle cells.

Angiotensin II (ANG II) induces vascular smooth muscle contraction and functions as a growth factor stimulating vascular smooth muscle cell (VSMC) hypertrophy. We wondered whether ANG II might induce expression of alpha 1-adrenergic receptors (ARs) in cultured VSMCs, which would then potentially accentuate the effects of catecholamines in the cells. Rat VSMCs were preincubated with phenoxybenzamine to inactivate alpha 1-ARs; the cells were then treated with ANG II for 24 h. ANG II-treated cells expressed an increased number of alpha 1-ARs compared with controls, suggesting that ANG II increased the rate of alpha 1-AR synthesis. ANG II markedly induced accumulation of alpha 1A/D- and alpha 1B-AR mRNAs in a concentration- and time-dependent manner. This effect of ANG II was blocked by the specific ANG II-receptor agonist [Sar1-Ile8]ANG II. ANG II-induced accumulation of alpha 1A/D-AR mRNAs was completely abolished by transcriptional inhibitor actinomycin D. ANG II markedly increased the transcriptional rate of the alpha 1A/D-AR gene without changing stability of alpha 1A/D-AR mRNAs. Protein kinase C (PKC) activator 4 beta-phorbol 12-myristate 13-acetate also induced accumulation of alpha 1A/D-AR mRNAs, and PKC inhibitor H-7 completely blocked ANG II-induced accumulation of the alpha 1A/D-AR mRNAs. Neither the biologically inactive ANG II analogue des-Phe8-ANG II nor the calcium ionophores A-23187 and BAY K-8466 induced alpha 1A/D-AR mRNAs. Finally, ANG II preincubation increased alpha 1-AR agonist phenylephrine-stimulated expression of the c-fos gene.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1995

Phosphorylation of cyclic AMP response element-binding protein and induction of c-fos gene expression on withdrawal from chronic treatment with carbachol in NG108-15 cells.

Alterations in adenylyl cyclase activity in cultured cells after prolonged exposure to drugs such as morphine have been extensively studied as models for drug tolerance and withdrawal. NG108-15 cells develop increased intracellular cAMP concentrations after abrupt withdrawal from chronic treatment with the muscarinic cholinergic agonist carbachol. To determine whether this withdrawal-induced increase in cAMP modifies gene expression, we studied phosphorylation of the cAMP response element-binding protein (CREB) and expression of the c-fos gene, known to contain a cAMP response element, in NG108-15 cells after abrupt withdrawal from chronic treatment with carbachol. Prostaglandin E1, which activates adenylyl cyclase, caused concentration-dependent increases in the phosphorylation of CREB and in the abundance of c-fos mRNA. These changes occurred with small increments in cAMP accumulation. In cells treated with carbachol for 48 hr, induction of withdrawal with the muscarinic antagonist atropine led to a small increase in intracellular cAMP concentration but an 11.6-fold increase in the phosphorylation of CREB and a 3.4-fold increase in accumulation of c-fos mRNA. The adenylyl cyclase inhibitor 2',5'-dideoxyadenosine, which attenuated the chronic carbachol-induced increase in cAMP concentration, prevented the increased phosphorylation of CREB and the enhanced accumulation of c-fos mRNA during atropine-induced withdrawal. These results indicate that expression of the c-fos gene is induced by the small increments in cAMP concentration that can occur in cells on withdrawal from chronic treatment with drugs such as muscarinic agonists.

Alprostadil↗
PubMed1994

Alpha 1 adrenergic receptor-induced c-fos gene expression in rat aorta and cultured vascular smooth muscle cells.

While growth of blood vessels is important in hypertension, relatively little is known about the contribution of catecholamines. Using isolated rat aorta and cultured smooth muscle cells, we examined adrenergic stimulation of gene expression. Phenylephrine, a selective alpha 1 adrenergic receptor agonist, caused a rapid and transient increase in c-fos mRNA accumulation which was inhibited by prazosin, an alpha 1 receptor antagonist. Similarly, phenylephrine stimulated c-jun and c-myc mRNA accumulation. Chloroethyl-clonidine, a compound which irreversibly blocks alpha 1B receptors, completely blocked the phenylephrine-induced increase in c-fos mRNA. RNase protection experiments demonstrated that rat aorta prominently expressed mRNA for alpha 1B and alpha 1A/D receptors. Phenylephrine-induced c-fos mRNA was partially inhibited by H-7, a protein kinase C inhibitor, and by nifedipine, a Ca2+ channel blocker; these two compounds together had additive effects. In situ hybridization showed that expression of c-fos mRNA induced by phenylephrine was localized to aorta's medial layer. These results suggest that alpha 1 receptor-induced increase in c-fos mRNA in aorta is mediated by a chloroethyl-clonidine-sensitive receptor subtype signaling via increasing intracellular Ca2+ concentrations and activating protein kinase C.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Induction of enhanced release of endothelium-derived relaxing factor after prolonged exposure to alpha-adrenergic agonists: role in desensitization of smooth muscle contraction.

Desensitization of alpha 1-adrenergic receptor-mediated contraction occurs in rat aorta after in vitro exposure to alpha-adrenergic agonists; we previously showed that a component of the desensitization is endothelial cell dependent. Our primary purpose was to examine possible alterations in either the release or action of endothelium-derived relaxing factor (EDRF) in desensitized blood vessels. Rings of rat aorta were desensitized in vitro by exposure to phenylephrine (PE) for 6 h with impaired subsequent ability of PE to induce smooth muscle contraction. PE also induced heterologous desensitization of serotonin-induced contraction, which was blocked by the alpha 1-adrenergic selective antagonist prazosin. Using a "sandwich" bioassay technique, we noted enhanced release of EDRF from the aortic rings that had been previously exposed to PE as compared with controls. The capacity of PE to activate accumulation of inositol monophosphate was impaired in the desensitized blood vessels, both with and without endothelium. Our results suggest that prolonged exposure to alpha-adrenergic agonists leads to several adaptations in vascular smooth muscle (VSM), including enhanced release of EDRF. Although impaired action of EDRF has been suggested to play a role in diseases such as diabetes and atherosclerosis, our results indicate that release and action of EDRF may be enhanced with prolonged exposure to alpha-agonists.

Adrenergic alpha-Agonists↗
PubMed1993

Prolonged activation of protein kinase C induces transcription and expression of the alpha 1B adrenergic receptor gene in DDT1 MF-2 cells.

Protein kinase C (PKC) regulates many cellular functions; we have examined the role of PKC in the regulation of the alpha 1B adrenergic receptor gene. Exposure of DDT1 MF-2 cells to phorbol 12-myristate 13-acetate (PMA) (10 nM) increased values of alpha 1B receptor mRNA with peak changes found at 4 h (3.2-fold increase). Increased values of alpha 1B receptor mRNA occurred at PMA concentrations as low as 10 pM with a maximal response at 100 nM. Also, PMA induced a time-dependent increase in the number of alpha 1B receptors. Stimulation of cells with phenylephrine led to an increase in IP3 production after 3, 6, and 12 h of treatment with PMA. Induction of the alpha 1B receptor mRNA was suppressed by the PKC inhibitors H7 (1-(5-isoquinolinylsulsulfonyl)2-methylpiperazine) and saurosporine; the inactive phorbol ester 4 alpha-phorbol didecanoate and calcium ionophores A23187 and Bay K8644 did not increase alpha 1B receptor mRNA. The half-life of the alpha 1B receptor mRNA was unchanged by PMA. Nuclear runoff assays demonstrated that PMA produced a marked increase in the transcription rate of alpha 1B adrenergic receptor expression is mediated by a PKC-dependent mechanism that occurs at the level of transcription.

Animals↗
PubMed1993

Cycloheximide induces the alpha 1B adrenergic receptor gene by activation of transcription in DDT1 MF-2 smooth muscle cells.

alpha 1-Adrenergic receptors play important roles in mediating a wide range of important cellular responses; regulation of expression of these receptors may have pathophysiological significance in diseases such as hypertension. In order to pursue understanding of mechanisms involved in the regulation of expression of alpha 1 receptors, the effects of protein synthesis inhibitor cycloheximide on alpha 1B receptor gene expression were examined in DDT1 MF-2 smooth muscle cells. Cycloheximide markedly induced accumulation of the alpha 1B receptor mRNAs in a concentration- and time-dependent manner as detected by Northern blotting assays. The increased accumulation of alpha 1B receptor mRNA could be detected at 1 hr (1.7 +/- 0.2-fold) and the maximal accumulation occurred at 6 hr (5.4 +/- 0.3-fold, p < 0.01). Nuclear runoff assays reveal that cycloheximide markedly increased the transcriptional rate of the alpha 1B receptor gene. The stability of alpha 1B receptor mRNAs measured by RNase protection assays was essentially unchanged by cycloheximide. Incubation of DDT1 MF-2 cells with two additional protein synthesis inhibitors, anisomycin and emetine, had similar effects to those of cycloheximide. However, a further inhibitor, puromycin, did not induce alpha 1B receptor mRNAs when protein synthesis was almost completely inhibited. Furthermore, puromycin did not inhibit the capacity of cycloheximide to induce transcription of the alpha 1B receptor gene. These observations suggest that cycloheximide induces alpha 1B receptor gene expression through direct activation of gene transcription rather than inhibition of protein synthesis.

Animals↗
PubMed1992

Prolonged exposure to catecholamines enhances sensitivity of smooth muscle relaxation induced by sodium nitroprusside and atriopeptin.

Desensitization of alpha-1 adrenergic receptor-mediated contraction occurs in aortic smooth muscle from rats after in vitro exposure to norepinephrine (NE). The purpose of this study was to examine effects of pretreatment of blood vessels with catecholamines on relaxant responses of the vessels to sodium nitroprusside (SNP) and atriopeptin III (ANF). Vessels preincubated with NE for 4 hr had a markedly increased sensitivity to relaxation induced by SNP as compared to controls. The concentration of SNP giving half-maximal relaxation (log EC50) was -8.78 +/- 0.09 in the vessels pretreated with NE and -7.40 +/- 0.18 in controls (P less than .001). NE-treated vessels also had an increased sensitivity to ANF (EC50 -8.23 +/- 0.11 vs. -7.03 +/- 0.31, respectively; P less than .01). However, both desensitized and control vessels had similar sensitivity to relaxation induced by 8-bromo-cyclic GMP. The capacity of SNP to stimulate intracellular cyclic GMP accumulation in vessels pretreated with NE was greater than controls at a high concentration of SNP (10(-5) M.). However, there was no correlation between vasodilation induced by lower concentrations of SNP and stimulation of cyclic GMP accumulation in these blood vessels. Activity of soluble and particulate guanylate cyclase in NE-treated vessels was increased compared to controls. Changes in sensitivity of smooth muscle relaxation to SNP and ANF after prolonged exposure to catecholamines may relate to changes in capacity of the cyclic GMP system.

Animals↗
PubMed1991

Desensitization of alpha-adrenergic receptor-mediated smooth muscle contraction: role of the endothelium.

Desensitization of alpha-adrenergic receptor-mediated smooth muscle contraction occur in aortas from New England Deaconess Hospital (NEDH) rats harboring pheochromocytoma (PHEO) and following chronic exposure to the alpha-adrenergic agonist phenylephrine in vitro. Endothelium is known to release an endothelial cell-derived relaxing factor that promotes smooth muscle relaxation. We wondered if the endothelium might contribute to the desensitization of contraction. The role of the endothelium in desensitization was studied using aortic rings with endothelium [E(+)] and with endothelium removed [E(-)]. Maximal phenylephrine (PE)-induced contraction (Emax) for E(+) was 1.7 +/- 0.3 g in controls and 0.4 +/- 0.1 g in PHEO (p less than 0.001), demonstrating desensitization; however, for E(-), Emax was 2.4 +/- 0.2 g in PHEO vs. 2.5 +/- 0.2 g in controls, demonstrating restoration of maximal contraction when the endothelium was removed. However, sensitivity [-log EC50(M)] to PE in E(-) remained significantly lower in PHEO compared to controls (6.94 +/- 0.12 vs. 7.51 +/- 0.14, respectively, p less than 0.001). Similarly, in aortic ring segments desensitized in vitro with phenylephrine, the maximal contraction in phenylephrine-exposed aortas was 60% of that seen in controls. Removal of the endothelium from the vessels pretreated with phenylephrine fully restored the maximal response and sensitivity of these vessels. Treatment of desensitized vessels with hemoglobin (5 x 10(-5) M) restored the maximal contraction and sensitivity to phenylephrine. When the endothelium was removed prior to chronic exposure to phenylephrine, the sensitivity to phenylephrine decreased while the Emax remained similar to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed1990

Captopril improves hypertension and cardiomyopathy in rats with pheochromocytoma.

Hypertension and cardiomyopathy are prominent findings in humans and rats harboring pheochromocytomas, tumors that can secrete enormous quantities of catecholamines. We have previously found that alpha- and beta-adrenergic receptor antagonists may ameliorate the hypertension and cardiomyopathy found in New England Deaconess Hospital rats implanted with pheochromocytoma. The present studies were designed to determine the possible action of the angiotensin converting enzyme inhibitor captopril on these changes in rats harboring pheochromocytomas. Rats were implanted with transplantable pheochromocytomas and treated with captopril dissolved in the drinking water (1 mg/ml) for 4-6 weeks. Systolic blood pressure was monitored by using the tail-cuff technique. In the rats with pheochromocytoma, blood pressure progressively increased to 184 +/- 3 mm Hg after the tumor was implanted. However, in rats with pheochromocytoma treated with captopril in the drinking water before the development of hypertension, blood pressure did not increase (137 +/- 3 mm Hg). In rats with pheochromocytoma with established hypertension, captopril normalized the systolic blood pressure. Plasma norepinephrine was markedly elevated to a similar extent in both groups compared with unimplanted control rats. Plasma renin activities were slightly lower in rats with pheochromocytoma compared with unimplanted control rats. Treatment with captopril of rats with pheochromocytoma did not modify contraction of isolated rings of thoracic aorta exposed in vitro to either phenylephrine or angiotensin II. Treatment with captopril markedly attenuated the cardiomyopathy induced by pheochromocytoma. These results demonstrate that captopril prevents the development of hypertension despite markedly elevated concentrations of catecholamines. In addition, captopril attenuates catecholamine-induced cardiomyopathy in pheochromocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗