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Predominance in the urethra and prostate of the alpha(1A)-adrenoceptor subtype, which is believed to be the receptor mediating noradrenaline induced smooth muscle contraction in these tissues, led to the preparation of alpha(1A)-selective antagonists to be tested as uroselective compounds for the treatment of benign prostatic hyperplasia. Thus, a number of selective alpha(1A)-adrenoceptor antagonists were synthesized and assayed in vitro for potency and selectivity. Dog pharmacokinetic parameters of 12 (RO700004) and its metabolite 40 (RO1104253) were established. The relative selectivity of intravenously administered 12, 40 and standard prazosin to inhibit hypogastric nerve stimulation-induced increases in intraurethral prostatic pressure versus phenylephrine-induced increases in diastolic blood pressure in anesthetized dogs was 76, 71 and 0.6, respectively.
After treatment, there were 5 cured cases, 13 markedly effective cases, 9 effective cases, 1 ineffective case, and 2 eliminated cases in the experimental group, as compared with 2 cured cases, 8 markedly effective cases, 10 effective cases, 7 ineffective cases, and 3 eliminated cases in the control group. The total effectiveness rate was obviously higher in the former (96.4%) than in the latter (74.1%). IPSS, Qmax, and CSS were improved in both of the groups after medication, even more significantly in the experimental than in the control group (IPSS: 15.22 ± 2.98 vs 18.15 ± 5.88, P <0.05; Qmax: [13.56 ± 2.26] ml/s vs [11.78 ± 2.97] ml/s, P <0.05; CSS: 6.18 ± 2.13 vs 9.52 ± 3.15, P <0.05). Because of the difference in the QOL score between the two groups at the baseline (P = 0.038 <0.05), no more comparison was made in this aspect after treatment.
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Losartan, an AT1 angiotensin II (ANG II) receptor non-peptide antagonist, induces an increase in mean arterial pressure (MAP) when injected intracerebroventricularly (icv) into rats. The present study investigated possible effector mechanisms of the increase in MAP induced by icv losartan in unanesthetized rats. Male Holtzman rats (280-300 g, N = 6/group) with a cannula implanted into the anterior ventral third ventricle received an icv injection of losartan (90 micro g/2 micro l) that induced a typical peak pressor response within 5 min. In one group of animals, this response to icv losartan was completely reduced from 18 +/- 1 to 4 +/- 2 mmHg by intravenous (iv) injection of losartan (2.5-10 mg/kg), and in another group, it was partially reduced from 18 +/- 3 to 11 +/- 2 mmHg by iv prazosin (0.1-1.0 mg/kg), an alpha1-adrenergic antagonist (P<0.05). Captopril (10 mg/kg), a converting enzyme inhibitor, injected iv in a third group inhibited the pressor response to icv losartan from 24 +/- 3 to 7 +/- 2 mmHg (P<0.05). Propranolol (10 mg/kg), a beta-adrenoceptor antagonist, injected iv in a fourth group did not alter the pressor response to icv losartan. Plasma renin activity and serum angiotensin-converting enzyme activity were not altered by icv losartan in other animals. The results suggest that the pressor effect of icv losartan depends on angiotensinergic and alpha1-adrenoceptor activation, but not on increased circulating ANG II.
Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS) has been investigated as a tool for accurate determination of the molecular mass of synthetic analogues of prazosine, a molecule used for the treatment of hypertension. Samples were dissolved in methanol, mixed with mass calibration standards, and crystallised on the target with alpha-cyano-4-hydroxycinnamic acid as matrix. Acquisition of spectra was rapidly completed in reflectron mode, allowing high resolution (6000-10000) and sensitive (about 1-10 pmol of sample on target) determination of the synthetic products. The results show the effectiveness of MALDI-TOFMS for accurate mass determination of these fairly large molecules, which are otherwise difficult to analyse by other high-resolution mass spectrometric techniques.
After bilateral superior cervical ganglionectomy (SCGx) of adult male rats, norepinephrine (NE) content of the medial basal hypothalamus (MBH) decreased significantly by 39-47% from 16 h to 7 days after surgery. During this time the levels of serum growth hormone (GH) and prolactin (PRL) and of MBH GH-releasing hormone (GRH), thyrotropin-releasing hormone (TRH) and somatostatin were measured by RIA. In sham-operated controls, serum PRL increased and serum GH decreased 16-24 h after surgery, attaining pre-surgical levels later on. In SCGx rats, significantly lower serum GH and PRL and higher MBH GRH and TRH content as compared to controls was observed 16-24 h after surgery, during the wallerian degeneration phase after SCGx. MBH somatostatin concentration decreased in SCGx rats 20 h after surgery. Two injections of the alpha 1-adrenoceptor blocker prazosin 45 and 90 min before sacrifice, alone or together with the beta-blocker propranolol, prevented the changes in MBH hypophysiotropic hormone content, as well as in serum GH and PRL levels, found in SCGx rats 20 h after surgery. Propranolol treatment did not affect hormone levels. Neither drug modified the decrease in MBH NE content observed after SCGx. The results argue in favor of the existence of physiologically relevant projections from superior cervical ganglion neurons to the MBH controlling hypophysiotropic hormone release.
After a 2-year combination therapy, discontinuation of either one drug induced benign prostatic hyperplasia progression in either group. Greater risk of resuming medication and needing TURP were noted in patients who discontinued 5ARI.
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We have synthesized and examined some of the pharmacological properties of 6-[N,S-dimethyl-N'-cyanoisothioureidomethyl]-6,11-dihydro-5H- dibenz(b,e)azepine hydrochloride (Fran 12), a derivative of 6-methylaminomethyl-6,11-dihydro-5H- dibenz[b,e,]azepine. In the guinea-pig isolated ileum, Fran 12 (10(-7)-10(-5) M) caused parallel rightward shifts of the concentration-response curves to histamine. A Schild plot gave a pA2 of 7.48, with a slope not significantly different from -1.0. In the rat stomach fundus strip and in endothelium-denuded aortic rings, Fran 12 inhibited contractile responses to 5-hydroxytryptamine in a non-competitive manner. In both chloralose-anaesthetized and pithed rats, it inhibited pressor responses to 5-hydroxytryptamine. It had no effect on depressor responses to 5-hydroxytryptamine in anaesthetized rats. In pithed rats, Fran 12 (0.25-2 mg/kg, i.v.) produced dose-dependent increases in blood pressure. These were not inhibited by i.v. phentolamine, prazosin, yohimbine, propranolol, methysergide, pentolinium or atropine but were inhibited by verapamil. These results indicate that Fran 12 is a histamine and 5-hydroxytryptamine antagonist which also exerts pressor effects via a peripheral action. The pressor action does not appear to be mediated via effects on alpha 1- or alpha 2-adrenoceptors, muscarinic or nicotinic cholinoceptors or 5-hydroxytryptamine receptors, although calcium channel activation may play a role.
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The induction of complex bilateral leg muscle activation combined with coordinated stepping movements is demonstrated in patients with complete paraplegia. This was achieved by partially unloading patients who were on a moving treadmill. In comparison to healthy subjects, the paraplegic patients displayed a less dynamic mode of muscle activation. In all other respects leg muscle electromyographic activity was modulated in a similar manner to that in healthy subjects. However, the level of electromyographic activity in the gastrocnemius (the main antigravity muscle during gait) was considerably lower in the patients. During the course of a daily locomotor training program, the amplitude of gastrocnemius electromyographic activity increased significantly during the stance phase, while inappropriate tibialis anterior activation decreased. Incompletely paraplegic patients benefited from the training with respect to performance of unsupported stepping movements on solid ground. In about half of completely paraplegic patients with low muscle tone, no beneficial effect of the training was seen. This may be due to an inhibitory effect on spinal neuronal activity by drugs patients were taking (e.g., prazosin, clonidine, cannabinoids). In this study intrathecal application of clonidine drastically reduced, while epinephrine enhanced locomotor muscle electromyographic activity. The results of this study promise to be significant in the treatment of paraplegic patients.
Long-term treatment with (±)doxazosin produces potent hypotensive action in conscious rats that seems to result from synergic interaction of the two enantiomers.
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To explore the efficacy of levofloxacin, terazosin, and their combination in patients with category III chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).
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Methamphetamine (2-15 mg/kg, i.p.) has been shown to induce interleukin-1 beta (IL-1 beta) mRNA in the rat hypothalamus. The induction of IL-1 beta mRNA was blocked by intraperitoneal pretreatment with beta-blockers propranolol (0.1-1 mg/kg, but not 0.01 mg/kg) and pindolol (0.3 and 1 mg/kg). Prazosin (1 and 5 mg/kg) and yohimbine (1 and 5 mg/kg), alpha-blockers and haloperidol (1 mg/kg), a dopamine antagonist, produced partial and little suppression, respectively. When injected intracerebroventricularly (i.c.v.), propranolol, but neither prazosin nor yohimbine, significantly suppressed the methamphetamine-induced expression of IL-1 beta mRNA at a dose of 1 nmol/rat. An i.c.v. injection of the beta-adrenoceptor agonist isoproterenol (1 and 3 micrograms/rat) dose-dependently increased the hypothalamic level of IL-1 beta mRNA. The present results suggest that the induction of hypothalamic IL-1 beta mRNA by methamphetamine is mediated by beta-adrenoceptors in the brain.
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Nerve terminals obtained from rat brain cortex and hippocampus, were labelled with 0.04 microM of [3H]noradrenaline ([3H]NA). Thereafter the basal release of [3H]NA was measured in a Brandel superfusion apparatus, in the presence of alpha 1-adrenoceptor agonists (phenylephrine or noradrenaline) or these alpha 1-adrenoceptor agonists along with prazosin, an alpha 1-adrenoceptor antagonist. In cortical synaptosomes both alpha 1-adrenoceptor agonists increased the basal release of [3H]NA in a concentration-dependent manner (EC50 = 0.15 microM for phenylephrine and 12.6 microM for noradrenaline). Effects were reversed by 0.01 microM prazosin (EC50 = 2.46 and 130.1 microM, respectively). In synaptosomes from rat brain hippocampus, phenylephrine (EC50 = 1.28 microM) and noradrenaline (EC50 = 33.7 microM) also increased the [3H]NA release and prazosin (0.01 microM) shifted the corresponding concentration-response curves to the right (EC50 = 7.38 and 264.0 microM, respectively). Events produced by noradrenaline acting as alpha 1-adrenoceptor agonist did not show Ca2+ dependence. These results suggest (1) the presence of functional alpha 1-adrenoceptors in nerve terminals from rat brain cortex and hippocampus, (2) that these receptors seem to play a role in the presynaptic modulation of [3H]NA release, and (3) that intraterminal Ca2+ may be involved.
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Canine uterine arteries are innervated by adrenergic, vasoconstrictor and nitroxidergic vasodilator nerves, and the neurogenic vasodilation is evidently more marked than that in other canine arteries, including the iliac artery.
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After 4 years, women who were randomized to lifestyle intervention only were less likely to be receiving step 1 therapy alone (placebo) than men who were randomized to placebo therapy (46% vs 66%, respectively, P < .01). There were significantly greater decreases in the mean systolic blood pressure in both men and women who were assigned to treatment with active drugs compared with those participants who were receiving placebo therapy; differences among treatments with active drugs were similar between men and women. Men experienced larger falls in their total and low-density lipoprotein cholesterol and triglyceride levels regardless of the treatment assignment than did women; however, there were no significant sex-by-treatment interactions. Quality-of-life indexes were generally improved with active drug treatment compared with placebo therapy in both sexes; there was a sex-by-treatment interaction for the general health index. The relative risk (RR) for combined clinical events was similar in women (RR, 0.64; 95% confidence interval [CI], (0.36 to 1.16) and in men (RR, 0.67; 95% CI, 0.40 to 1.14) who were assigned to treatment with all active drugs combined, compared with those who were receiving placebo therapy.
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This study investigated mechanisms involved in the maintenance of the functional response pattern of the postjunctional alpha(1)-adrenoceptor in vas deferens isolated from rats submitted to acute swimming stress. The plasma corticosterone levels increased approximately three times after the swimming stress in the nontreated rats as well as after swimming stress in the rats pretreated with desipramine (DMI), yohimbine (YO), or DMI with YO. No alteration was detected in the sensitivity to norepinephrine (NE) in the vasa deferentia from the stressed rats or stressed rats treated with DMI or DMI with YO, in relation to their respective control. However, when the vasa deferentia were previously incubated with DMI, a reduction in sensitivity to NE in organs from stressed rats was observed. Vasa deferentia excised from rats pretreated with YO before the swimming stress showed an increase in postjunctional alpha(1)-response that was abolished by prazosin (PZ). Thus, the neuronal uptake, the prejunctional alpha(2)-adrenoceptors (mediating prejunctional inhibition), the occupancy and functional response of the postjunctional alpha(1)-adrenoceptors, and the emotional stress component were very important for the determination of the noradrenergic response pattern in vas deferens from rats submitted to acute swimming stress.
Vasoconstriction of carotid arteriovenous anastomoses may be involved in the therapeutic action of acutely acting anti-migraine agents, including the triptans and ergot alkaloids. While 5-HT1B/1D receptors mediate the effect of triptans, ergotamine and dihydroergotamine also interact with alpha-adrenoceptors. In the present study, we investigated the potential role of alpha1- and alpha2-adrenoceptors in mediating vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Ten minute intracarotid infusions of phenylephrine (1, 3 and 10 microg kg(-1) min(-1)) or BHT 933 (3, 10 and 30 microg kg(-1) min(-1)) produced dose-dependent decreases in total carotid and arteriovenous anastomotic conductances; no changes were observed in the capillary fraction. The carotid vascular effects of phenylephrine and BHT 933 were selectively abolished by prazosin (100 microg kg(-1), i.v.) and rauwolscine (300 microg kg(-1), i.v.), respectively. The responses to phenylephrine and BHT 933 were not affected by the selective 5-HT1B/1D receptor antagonist GR127935 (500 microg kg(-1), i.v.). These results show that both alpha1- and alpha2-adrenoceptors can mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Since vasoconstrictor activity in this in vivo model is predictive of anti-migraine activity, an agonist activity at particularly the alpha2-adrenoceptor subtypes, in view of their less ubiquitous nature, could provide migraine abortive potential. Thus, the present results may aid further understanding of the mode of action of some current anti-migraine agents and may eventually be helpful in the development of future treatment in migraine.
A prejunctional mechanism involving an alpha 1-adrenergic receptor may exert control on the release of acetylcholine from parasympathetic nerve endings in the heart. To test this hypothesis in vivo, rats were prepared for electrical stimulation of the vagus nerves. Blood pressures and heart rates were monitored, and the animals were treated with alpha-agonists and alpha-antagonists. The alpha 1-selective agonist phenylephrine significantly attenuated vagally induced bradycardia in a dose-dependent fashion (ED50 = 19 micrograms/kg). This is consistent with the hypothesis that there is alpha-adrenergic inhibition of ACh release. In contrast, the alpha 2-selective agonist, BHT-920, caused no change in heart rate during vagal stimulation. The effects of phenylephrine to raise heart rate and blood pressure during vagal stimulation were blocked by the alpha 1-selective antagonist prazosin (ID50 approximately 1 microgram/kg) but not by the alpha 2-selective antagonists yohimbine and rauwolscine. This further supports an alpha 1 assignment to the prejunctional adrenergic receptor mechanism, which can regulate the release of acetylcholine from cardiac parasympathetic neurons.
The effects of prazosin HCl treatment on several variables were determined in 16 patients suffering from micturition disturbances associated with benign prostatic hypertrophy. After administration of the drug in doses of 1-2 mg/day, subjective symptoms improved in 11 patients (68.8%). Urine retention rate, maximum urine flow rate, and average urine flow rate exhibited statistically significant improvement, but voided urine volume did not. Urethral pressures declined significantly in the bladder neck and prostatic urethra but not in the pressure at the external sphincter. The results suggest prazosin HCl may be effective in small doses in symptomatic treatment of benign prostatic hypertrophy.
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The present study evaluated the effects of melatonin on the discharge rate of tonically active medial vestibular nucleus (MVN) neurons in an in vitro slice preparation of the rat dorsal brainstem. The results demonstrated that, when melatonin was applied to the slice for a period of 7-10 min, a decrease in MVN neuron firing rate was observed in 21/58 (36%) of the cells sampled. The inhibitory effects of melatonin were present in synaptic uncoupling condition and were mimicked by 2-iodomelatonin, a non-selective agonist with high affinity for melatonin membrane receptor subtypes (MT(1), MT(2), MT(3)). The MT(2) receptor antagonists luzindole and 4-phenyl-2-propionamidotetraline and the MT(3) receptor antagonist prazosin did not, however, antagonise the inhibitory effects of melatonin, indicating that melatonin may act on MVN neurons through an MT(1) receptor-mediated mechanism.
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Pinacidil is an orally administered antihypertensive drug that acts via direct relaxation of vascular smooth muscle to produce peripheral vasodilatation and a reduction in blood pressure without significant direct effects on cardiac electrophysiology. Pinacidil is unrelated to other antihypertensive drugs in clinical use, either in structure or mechanism of action. It belongs to a new class of agents called 'potassium channel openers' which act via potassium efflux to hyperpolarize cell membranes, indirectly causing a net reduction in intracellular calcium that leads to relaxation of vascular smooth muscle. Pinacidil is indicated in the management of essential hypertension. In clinical trials of up to 1 year duration, pinacidil administered twice daily in a controlled release capsule formulation has been shown to achieve adequate blood pressure control both in previously untreated patients and in those with blood pressure inadequately controlled by beta-adrenoceptor blocking drugs or thiazide diuretics. In long term (up to 1 year) comparative studies pinacidil was at least as effective as hydralazine, prazosin or nifedipine in maintaining blood pressure control. Pinacidil may also have a potential use in the treatment of patients with secondary renal hypertension. Clinical trials to date have usually allowed the addition of a thiazide diuretic and/or beta-adrenoceptor blocking drug to enhance the efficacy of pinacidil and/or to reduce the incidence of adverse effects. The main adverse effects of pinacidil treatment, which result from its peripheral vasodilator activity, are headache, oedema, palpitations and tachycardia. Although the overall incidence of adverse effects is quite high, they are usually mild, transient in nature and respond to a reduction in dose. Nevertheless, these effects may occasionally be severe, necessitating withdrawal from therapy. Thus, pinacidil is an effective antihypertensive drug for the treatment of mild to moderate essential hypertension. Despite its novel mechanism of action pinacidil causes adverse effects typical of peripheral vasodilators; during long term use with twice daily administration of the controlled release capsule formulation, the addition of a diuretic is often necessary to attenuate peripheral oedema and maintain adequate control of blood pressure. Further long term controlled trials are needed to determine the precise role of pinacidil relative to that of the angiotensin converting enzyme (ACE) inhibitors and calcium channel blocking drugs.