Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. A hormonal-sympathetic reflex model for long-term control of arterial pressure is presented. It is hypothesized that the hormonal-sympathetic reflex regulates arterial pressure during chronic dietary salt loading by decreasing sympathetic tone. This sympathetic response is mediated by an increase in plasma vasopressin (AVP) and a decrease in plasma angiotensin (AngII). 2. Three new models of neurogenic salt-dependent hypertension are presented. All models are theoretically based on an impaired hormonal-sympathetic reflex. 3. In the first model, sympathetic responsiveness is 'clamped' by long-term alpha-adrenergic blockade with prazosin. Prazosin treated rats exhibit marked salt-dependent hypertension despite normal suppression of the renin-angiotensin system. 4. In the second model, the ability of the central nervous system to respond to salt-induced changes in AVP and AngII concentrations was prevented by long-term administration of antagonists selective for the AVP-V1 and AT1. This 'clamp' of the afferent hormonal signal resulted in salt-dependent hypertension identical in magnitude to that observed in prazosin treated rats. 5. In the third model, the long-term arterial pressure responses to increasing dietary salt were examined in sino-aortic denervated (SAD) rats. SAD rats exhibited salt-dependent hypertension, of lesser magnitude than that observed with 'clamped' afferent and efferent pathways of the hormonal-sympathetic reflex. 6. A primary role for hormonal 'error signals' is presented and the impact this perspective has on past and future investigations of central mechanisms of long-term arterial pressure regulation is discussed.
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PMID:Hormones as long-term error signals for the sympathetic nervous system: importance of a new perspective. 904 15

We have previously shown that sodium restriction upregulates the genes encoding angiotensin II receptor (AT1) subtypes, AT1A and AT1B, in the adrenal gland and that this upregulation is mediated by activation of the AT1 receptor. There are multiple interactions between the renin-angiotensin and the adrenergic nervous systems; thus, we conducted the present experiment to investigate whether low sodium-induced upregulation of adrenal AT1A and AT1B is modulated by the alpha1-adrenoreceptor. Seven-week-old male Wistar rats were divided into four groups and given normal sodium diet (0.5%, NS), NS+prazosin (3.5 microg x kg(-1) x min(-1) by osmotic pump), low sodium diet (0.07%, LS), or LS+prazosin. Body weight and mean arterial pressure were not modified over the 2 weeks of treatment (P>.05). Pressor responses to bolus injection of the alpha1-agonist phenylephrine were inhibited in both prazosin groups, compared with NS and LS rats (P<.05). Adrenal AT1A mRNA, determined by Northern blot analysis, was increased in LS (P<.05) but not in NS+prazosin (P>.05), compared with NS. Prazosin enhanced the LS-induced increase of AT1A mRNA (P<.05). Adrenal AT1B mRNA was increased in both LS and NS+prasozin rats, compared with NS rats (P<.05). Prazosin also enhanced the LS-induced increase in AT1B mRNA (P<.05). Therefore, blockade of alpha1-adrenoreceptor results in an enhancement of LS-induced upregulation of adrenal mRNA for AT1A and AT1B. These data suggest that the sympathetic nervous system exerts an inhibitory action, via activation of the alpha1-adrenoreceptor, on AT1A and AT1B gene expression in the adrenal gland during sodium depletion.
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PMID:Regulation of type 1 angiotensin II receptor in adrenal gland: role of alpha1-adrenoreceptor. 931 15

Angiotensin II (ANG II) and norepinephrine (NE) are important regulators of vascular function and structure. Recent studies showed that there are multiple interactions between these two potent vasoconstrictor agents. The present experiment was designed to investigate the effect of NE on the expression of the type 1 ANG II receptor (AT1) in the aorta and cultured vascular smooth muscle cells (VSMC) of rats. Rats were subcutaneously infused with either NE (0.5 microg x kg(-1) x min(-1), n = 6) or the alpha1-adrenoreceptor antagonist prazosin (3.5 microg x kg(-1) x min(-1), n = 6) for 2 wk. Body weight and tail cuff systolic blood pressure were not modified compared with the vehicle control (P > 0.05). Northern blot analysis showed that AT1 mRNA levels in aorta were decreased by 38% in NE-treated rats and increased 117% in prazosin-treated rats (P < 0.05) compared with control. To determine whether NE directly regulates expression of vascular AT1 mRNA and AT1 receptor density, Northern blot analysis and radioligand binding experiments were performed in cultured VSMC. Incubation of VSMC with NE (10(-7) M) led to 44% decrease in AT1 mRNA levels (P < 0.05) and 39% decrease in AT1 receptor density (P < 0.05). Prazosin, but not the alpha2-adrenoreceptor antagonist yohimbine, prevented NE-induced decrease in AT1 mRNA and AT1 receptor density in these cells. Taken together, our results indicate that vascular AT1 gene expression and receptor protein are regulated by ambient NE levels, and NE-induced downregulation of AT1 mRNA and receptor protein is mediated, at least in part, by activating alpha1-adrenoreceptors.
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PMID:Regulation of type 1 ANG II receptor in vascular tissue: role of alpha1-adrenoreceptor. 936 84

To determine contribution of the autonomic nervous system to cardiovascular reactivity to noise, acoustic startle stimulus (110 dB, 1-20 kHz, 0.150 s) was administered to 35 subjects (19 women, 16 men) with mild essential hypertension. Among these patients, 10 were unmedicated and 25 were receiving long-term monotherapy (10 were taking 100 mg atenolol, 5 were taking 10 mg prazosin, and 10 were taking 50 mg losartan daily). Polygraphic recordings were obtained in supine position. Blood pressure (BP) and heart rate (HR) levels were stable until the noise was administered. In the unmedicated group BP and HR were elevated during the first 10 s. BP returned to resting levels after this period. The calculated hemodynamic indexes showed a biphasic change in total peripheral resistance (TPR), with an overall vasoconstriction associated with the BP rise phase, preceding a delayed vasodilation. The lowest HR changes were observed in the beta-blocker group with increases of 6 beats/min and 3 beats/min after the first and second noise stimulations, compared with 10 beats/min and 5 beats/min in the unmedicated group. Prazosin significantly reduced the BP rises to 7 mm Hg and 6 mm Hg for systolic BP and diastolic BP after the first stimulation compared with 22 mm Hg and 17 mm Hg in the untreated group (p < 0.01). The second stimulation after prazosin determined -5 mm Hg and 1 mm Hg changes for systolic BP and diastolic BP respectively, compared to rises of 13 mmHg for systolic BP and 10 mmHg for diastolic BP in the untreated group (p < 0.01). The hemodynamic percentage changes resulting from the first stimulation indicated prazosin markedly reduced the noise-induced rise in TPR (p < 0.05). No effect of beta-blocker was detectable using percentage changes. The rises in BP were amplified in the losartan-treated subjects compared with the other groups. Because of a low resting TPR in this group, the percentage changes in TPR resulting from noise were amplified in the subjects treated with the AT1 receptor antagonist. In conclusion the acoustic startle stimulus appeared as a simple and reliable procedure for inducing transient increases due to a rise in TPR. Cardiovascular responses differed according to the antihypertensive monotherapy, with a limited effect of noise in the prazosin-treated group.
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PMID:Antihypertensive monotherapy and cardiovascular responses to an acoustic startle stimulus. 1115 67

Quinazoline-based alpha1-adrenoceptor antagonists, in particular doxazosin and terazosin, are suggested to display antineoplastic activity against prostate cancers. However, there are few studies elucidating the effect of prazosin. In this study, prazosin displayed antiproliferative activity superior to that of other alpha1-blockers, including doxazosin, terazosin, tamsulosin, and phentolamine. Prazosin induced G2 checkpoint arrest and subsequent apoptosis in prostate cancer PC-3, DU-145, and LNCaP cells. In p53-null PC-3 cells, prazosin induced an increase in DNA strand breaks and ATM/ATR checkpoint pathways, leading to the activation of downstream signaling cascades, including Cdc25c phosphorylation at Ser216, nuclear export of Cdc25c, and cyclin-dependent kinase (Cdk) 1 phosphorylation at Tyr15. The data, together with sustained elevated cyclin A levels (other than cyclin B1 levels), suggested that Cdk1 activity was inactivated by prazosin. Moreover, prazosin triggered mitochondria-mediated and caspase-executed apoptotic pathways in PC-3 cells. The oral administration of prazosin significantly reduced tumor mass in PC-3-derived cancer xenografts in nude mice. In summary, we suggest that prazosin is a potential antitumor agent that induces cell apoptosis through the induction of DNA damage stress, leading to Cdk1 inactivation and G2 checkpoint arrest. Subsequently, mitochondria-mediated caspase cascades are triggered to induce apoptosis in PC-3 cells.
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PMID:Prazosin displays anticancer activity against human prostate cancers: targeting DNA and cell cycle. 1797 3