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British Journal of Clinical Pharmacology 1986The clinical pharmacology of doxazosin is reviewed from studies in normotensive young (21-39 years) and elderly (62-89 years) subjects following oral (2 mg) and...
The clinical pharmacology of doxazosin is reviewed from studies in normotensive young (21-39 years) and elderly (62-89 years) subjects following oral (2 mg) and intravenous (1 mg) administration. In young subjects the mean bioavailability was 65% and the mean terminal elimination half-lives were 9.5 and 10.5 h following acute intravenous and oral administration respectively. These parameters were similar in the elderly with bioavailability of 69% and half-lives of 8.8 and 11.9 h. The apparent volume of distribution and clearance were significantly higher in elderly (1.7 1 kg-1 and 140 ml min-1) than in young subjects (1.01 kg-1 and 83 ml min-1). In both groups blood pressure reductions were most marked in the standing position and the maximum effect did not occur until 5-6 h, even after intravenous administration. The blood pressure reduction produced by doxazosin was associated in the young with a significant increase in heart rate to 108 beats min-1 (placebo, 82 beats min-1) but this increase was significantly attenuated in the elderly at 91 beats min-1 (placebo, 77 beats min-1). Pressor response studies in the young subjects confirmed the alpha 1-adrenoceptor antagonist activity of doxazosin with significant rightward shifts of the dose-response curves for the selective alpha 1-adrenoceptor agonist phenylephrine. Using the technique of concentration-effect analysis, both the degree of alpha 1-adrenoceptor antagonism and the hypotensive effect can be correlated with the concentration of doxazosin in the 'effect compartment'.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adrenergic alpha-Antagonists; Adult; Aged; Aging; Antihypertensive Agents; Blood Pressure; Doxazosin; Female; Half-Life; Humans; Kinetics; Male; Prazosin
PubMed: 2871854
DOI: 10.1111/j.1365-2125.1986.tb02850.x -
Indian Journal of Pharmacology 2013Capsaicin is used to evoke pulmonary C reflexes and produces complex pressure responses along with apnea/tachypnea, and bradycardia. In the present study, the mechanisms...
OBJECTIVES
Capsaicin is used to evoke pulmonary C reflexes and produces complex pressure responses along with apnea/tachypnea, and bradycardia. In the present study, the mechanisms involved in capsaicin-induced pressure responses were explored.
MATERIALS AND METHODS
Tracheal, jugular venous, and femoral artery cannulations were performed in anesthetized adult rats. Blood pressure, respiratory excursions, and electrocardiogram were recorded. Cardiorespiratory reflex changes evoked by jugular venous injection of capsaicin (10 μg/kg) were recorded in vagotomized and antagonist pretreated animals.
RESULTS
Capsaicin produced triphasic pressure response exhibiting immediate hypotension, intermediate recovery, and delayed hypotension. Time-matched respiratory changes showed apnea, bradypnea, and tachypnea, respectively. Bradycardia occurred at immediate and intermediate phases. After vagotomy, immediate hypotension was abolished; the intermediate recovery was potentiated as hypertensive response; and the delayed hypotension persisted. In case of respiration, the immediate bradypnea persisted and delayed tachypnea was abolished; while heart rate changes at immediate and intermediate phases were abolished. Antagonists of α1-adrenoceptor (prazosin or terazosin, 0.5 mg/kg), β-adrenoceptor (propranolol, 1 mg/kg), AT1 receptor (losartan, 10 mg/kg) and Ca(2+) channel (diltiazem, 1 mg/kg) failed to block the capsaicin-induced intermediate hypertensive response in vagotomized animals.
CONCLUSIONS
These observations implicate the existence of mechanisms other than adrenergic, angiotensinergic, or Ca(2+) channel-dependent mechanisms for mediating the capsaicin-induced intermediate hypertensive response in vagotomized animals.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Animals; Calcium Channel Blockers; Capsaicin; Diltiazem; Female; Hypertension; Losartan; Prazosin; Propranolol; Rats; Vagotomy
PubMed: 24014912
DOI: 10.4103/0253-7613.115019 -
British Journal of Clinical Pharmacology Nov 1983We report the results of an observer blind crossover trial in 31 patients with essential hypertension comparing the hypotensive effect of four doses of prazosin and of... (Clinical Trial)
Clinical Trial
We report the results of an observer blind crossover trial in 31 patients with essential hypertension comparing the hypotensive effect of four doses of prazosin and of hydralazine used as the third step of triple therapy and additional data on the efficacy of low dose combinations of these two drugs. Both drugs had an appreciable antihypertensive effect, 1 mg of prazosin being equivalent to 12.5 mg of hydralazine. Increasing the dose of prazosin from 4 to 8 mg twice daily and hydralazine from 50 to 100 mg twice daily did not consistently reduce blood pressure. The combination of the two drugs at low doses resulted in the blood pressure of more patients being controlled (diastolic blood pressure 90 mm Hg or below) than when either drug was used alone at high dose. The symptoms reported by patients were similar for both drugs. The combination did not lead to an increased reporting frequency. The trial demonstrates one of the problems of a crossover study, namely a treatment/period interaction.
Topics: Adult; Aged; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Female; Heart Rate; Humans; Hydralazine; Hypertension; Male; Middle Aged; Prazosin; Quinazolines
PubMed: 6357257
DOI: 10.1111/j.1365-2125.1983.tb02212.x -
British Journal of Pharmacology Mar 19951. The alpha 1-adrenoceptor subtypes of rat heart were characterized in binding experiments performed with [3H]-prazosin as the radiolabel. The specific binding to the...
1. The alpha 1-adrenoceptor subtypes of rat heart were characterized in binding experiments performed with [3H]-prazosin as the radiolabel. The specific binding to the alpha 1-adrenoceptors was determined with 0.3 microM prazosin, because phentolamine (10 microM) was insufficient to inhibit completely the specific binding of high concentrations of [3H]-prazosin. 2. In saturation experiments, [3H]-prazosin bound to two distinct affinity sites (pKD = 10.39 and 8.19). The proportion of the low affinity sites was approximately 84% of total specific binding. Membranes pretreated with chloroethylclonidine (CEC, 10 microM) also showed two distinct affinity sites for [3H]-prazosin, although the maximum numbers of high and low affinity sites were reduced by 86 and 64%, respectively. 3. In competition experiments, [3H]-prazosin (100 pM) binding was inhibited by WB4101 (2-(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane) and 5-methylurapidil. The inhibition curves displayed shallow slopes which could be subdivided into high and low affinity components (pKi = 10.43 and 8.36 for WB4101, 8.62 and 6.61 for 5-methylurapidil). However, unlabelled prazosin or HV723 (alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)-ethyl)amin o) propyl)benzeneacetonitrile fumarate) competed for [3H]-prazosin binding monophasically (pKi = 10.34 and 8.28, respectively). In CEC-pretreated membranes, prazosin, WB4101, 5-methylurapidil and HV723 antagonized the [3H]-prazosin (100 pM) binding monophasically (pKi = 9.70, 9.56, 8.60 and 8.82, for each antagonist). 4. On the other hand, 1000 pM [3H]-prazosin binding was inhibited by unlabelled prazosin biphasically (pKi = 10.49 and 8.49). HV723 did not discriminate both prazosin-high and low affinity sites (pKi = 8.18). 5. These results suggest the presence of at least three distinct alpha1-adrenoceptor subtypes in rat hearts(two prazosin-high affinity sites and one prazosin-low affinity site). According to the recent alpha l-adrenoceptor subclassifications, one of the former two sites corresponds to the alpha 1B subtype with low affinities for WB4101 and 5-methylurapidil and sensitive to CEC, while another site with relatively high affinities for WB4101 and 5-methylurapidil may be classical alpha 1A, cloned alpha 1c, alpha 1D subtypes or their mixture. The prazosin-low affinity site corresponds to putative alpha 1L subtype with low affinity for HV723,which may be predominantly involved in the positive inotropic response to phenylephrine.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Binding, Competitive; Clonidine; Heart; Heart Ventricles; In Vitro Techniques; Kinetics; Male; Myocardium; Prazosin; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1
PubMed: 7780636
DOI: 10.1111/j.1476-5381.1995.tb13308.x -
The Chinese Journal of Physiology 2022Bilateral nucleus tractus solitarii (NTS) lesions, possibly caused by enterovirus 71 infection, cause severe neurogenic hypertension, leading to acute heart failure...
Bilateral nucleus tractus solitarii (NTS) lesions, possibly caused by enterovirus 71 infection, cause severe neurogenic hypertension, leading to acute heart failure (HF), pulmonary edema, and death within hours. Alpha-adrenergic blockers attenuate blood pressure and ameliorate HF and pulmonary edema, thereby prolonging survival time. However, the molecular mechanisms of these blockers are not clear. In this study, we investigated these mechanisms in a rat model of 6-hydroxydopamine (6-OHDA)-induced HF. Sprague-Dawley rats were treated with prazosin 10 min after the microinjection of 6-OHDA into the NTS. Immunohistochemistry and dihydroethidium (DHE) staining were used for analysis. In the cardiac tissue of 6-OHDA-induced HF, in situ expression of tumor necrosis factor-alpha (TNF-α), fibroblast growth factor-23 (FGF23), and FGF receptor 1 (FGFR1) increased, but in situ expression of Vitamin D receptor (VDR) decreased. DHE staining revealed several heart cells with high reactive oxygen species production. Prazosin treatment decreased TNF-α, FGF23, and FGFR1 expression in the heart of rats with 6-OHDA-induced HF. It also prevented cardiomyopathy caused by 6-OHDA-induced bilateral NTS lesions by inhibiting the FGF23-FGFR1 pathway and downregulating TNF-α expression. In situ, FGF23, FGFR1, VDR, superoxide, and TNF-α in the heart were found to be involved in acute HF in our rat model of 6-OHDA-induced bilateral NTS lesions. These findings are potentially useful for treating fatal enterovirus 71 infection-induced NTS lesions and HF.
Topics: Animals; Down-Regulation; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heart Failure; Oxidopamine; Prazosin; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha
PubMed: 36073566
DOI: 10.4103/cjp.cjp_9_22 -
British Journal of Pharmacology Apr 2008In addition to alpha1A, alpha1B and alpha1D-adrenoceptors (ARs), putative alpha1L-ARs with a low affinity for prazosin have been proposed. The purpose of the present...
BACKGROUND AND PURPOSE
In addition to alpha1A, alpha1B and alpha1D-adrenoceptors (ARs), putative alpha1L-ARs with a low affinity for prazosin have been proposed. The purpose of the present study was to identify the alpha1A-AR and clarify its pharmacological profile using a radioligand binding assay.
EXPERIMENTAL APPROACH
Binding experiments with [3H]-silodosin and [3H]-prazosin were performed in intact tissue segments and crude membrane preparations of rat cerebral cortex. Intact tissue binding assays were also conducted in rat tail artery.
KEY RESULTS
[3H]-silodosin at subnanomolar concentrations specifically bound to intact tissue segments and membrane preparations of rat cerebral cortex at the same density (approximately 150 fmol mg(-1) total tissue protein). The binding sites in intact segments consisted of alpha1A and alpha1L-ARs that had different affinities for prazosin, while the binding sites in membranes showed an alpha1A-AR-like profile having single high affinity for prazosin. [3H]-prazosin also bound at subnanomolar concentrations to alpha1A and alpha1B-ARs but not alpha1L-ARs in cerebral cortex; the binding densities being approximately 200 and 290 fmol mg(-1) protein in the segments and the membranes, respectively. In the segments of tail artery, [3H]-silodosin only recognized alpha1A-ARs, whereas [3H]-prazosin bound to alpha1A and alpha1B-ARs.
CONCLUSIONS AND IMPLICATIONS
The present study clearly reveals the presence of alpha1L-ARs as a pharmacologically distinct entity from alpha1A and alpha1B-ARs in intact tissue segments of rat cerebral cortex but not tail artery. However, the alpha1L-ARs disappeared after tissue homogenization, suggesting their decomposition and/or their pharmacological profile changes to that of alpha1A-ARs.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Arteries; Binding Sites; Cerebral Cortex; Indoles; Male; Prazosin; Radioligand Assay; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Tail
PubMed: 18223667
DOI: 10.1038/sj.bjp.0707679 -
British Journal of Pharmacology Feb 19881. The effect of chronic prazosin pretreatment (3 days) on the ability to excrete a modest saline load (i.v. saline, 0.097 ml min-1) was studied in the anaesthetized...
1. The effect of chronic prazosin pretreatment (3 days) on the ability to excrete a modest saline load (i.v. saline, 0.097 ml min-1) was studied in the anaesthetized rat. Three days before the experiment, the drinking water was replaced with 0.5% dextrose (control), 0.015 mg ml-1 prazosin in 0.5% dextrose (low dose) or 0.15 mg ml-1 prazosin in 0.5% dextrose (high dose). 2. The selectivity of the prazosin for alpha 1-adrenoceptors was evaluated in pithed rats. The pressor response to phenylephrine was partially attenuated by the low dose of prazosin and completely attenuated by the high dose of prazosin. The pressor response to clonidine was slightly decreased by the 3 day prazosin pretreatment indicating a selectivity for alpha 1-adrenoceptors. 3. In rats pretreated with the low dose of prazosin, there was a significant decrease in sodium and water, but not potassium excretion as compared to the control group. Captopril failed to alter these effects of the low dose of prazosin. Blood pressure and creatinine clearance were the same in both groups. In rats pretreated with the high dose of prazosin, there was a further decrease in sodium and water but not potassium excretion. However, this dose of prazosin also significantly decreased blood pressure and increased creatinine clearance. A decrease in renal perfusion pressure with an aortic clamp to the same level as that observed with the high prazosin dose also decreased sodium and water but not potassium excretion. The decrease in sodium and water excretion was not as great as that observed with the high dose of prazosin. 4. The results indicate that chronic a,-adrenoceptor blockade with prazosin attenuates the ability to excrete a saline load in a dose-related manner. Whether this inability to excrete a saline load is analogous to the sodium and water retention observed with the clinical use of prazosin remains to be determined.
Topics: Adrenergic alpha-Antagonists; Anesthesia; Animals; Blood Pressure; Clonidine; Kidney; Natriuresis; Phenylephrine; Prazosin; Rats; Rats, Inbred Strains; Sodium Chloride
PubMed: 2896036
DOI: 10.1111/j.1476-5381.1988.tb11452.x -
British Medical Journal Nov 1976
Clinical Trial Comparative Study
Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Hypotension, Orthostatic; Male; Prazosin; Quinazolines
PubMed: 791450
DOI: 10.1136/bmj.2.6046.1257-b -
Nature Chemical Biology Jan 2015Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely...
Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely marketed α1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline's ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multistress resistance. Our studies demonstrate that TZ has a new protein target, Pgk1, and reveal its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatments for diseases including stroke and sepsis.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Apoptosis; Cells, Cultured; Cytokines; HSP90 Heat-Shock Proteins; Infarction, Middle Cerebral Artery; Mice; Models, Molecular; Phosphoglycerate Kinase; Prazosin; Protein Conformation; Rats; Sepsis; Stress, Physiological; Stroke
PubMed: 25383758
DOI: 10.1038/nchembio.1657 -
Biological Psychiatry Mar 2008Prazosin, a central nervous system (CNS) active alpha-1 adrenoreceptor antagonist, has reduced nightmares and sleep disturbance in placebo-controlled studies of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Prazosin, a central nervous system (CNS) active alpha-1 adrenoreceptor antagonist, has reduced nightmares and sleep disturbance in placebo-controlled studies of combat-related posttraumatic stress disorder (PTSD). We evaluated objective sleep parameters and PTSD symptoms in a placebo-controlled prazosin trial for civilian trauma-related PTSD.
METHODS
Thirteen outpatients with chronic civilian trauma PTSD, frequent nightmares, and sleep disturbance participated in a randomized placebo-controlled crossover trial of prazosin. Sleep parameters were quantified at home with the REMView (Respironics, Pittsburgh, Pennsylvania). The PTSD symptoms were quantified with the Clinician Administered PTSD Scale (CAPS) "recurrent distressing dreams" and "disturbed sleep" items, a non-nightmare distressed awakenings scale, the PTSD Dream Rating Scale (PDRS), the PTSD Checklist-Civilian (PCL-C), and the Clinical Global Impression of Improvement (CGI-I).
RESULTS
Prazosin compared with placebo significantly increased total sleep time by 94 min; increased rapid eye movement (REM) sleep time and mean REM period duration without altering sleep onset latency; significantly reduced trauma-related nightmares, distressed awakenings, and total PCL scores; significantly improved CGI-I scores; and changed PDRS scores toward normal dreaming.
CONCLUSIONS
Prazosin reductions of nighttime PTSD symptoms in civilian trauma PTSD are accompanied by increased total sleep time, REM sleep time, and mean REM period duration in the absence of a sedative-like effect on sleep onset latency.
Topics: Adrenergic alpha-Antagonists; Adult; Cross-Over Studies; Dreams; Female; Humans; Male; Middle Aged; Polysomnography; Prazosin; Sleep; Sleep Initiation and Maintenance Disorders; Sleep, REM; Stress Disorders, Post-Traumatic; Wakefulness
PubMed: 17868655
DOI: 10.1016/j.biopsych.2007.07.001