Epinephrine and norepinephrine (1-10 microM) stimulated the release of prostacyclin (PGI2) from the rabbit aorta in vitro. The stimulation was maintained for at least 2 h in the continuous presence of epinephrine. Phenylephrine mimicked this effect, whereas the selective alpha 2-agonist UK-14,304 was completely ineffective. The action of epinephrine was abolished by prazosin (1 microM) and was maintained in the presence of yohimbine. Epinephrine or phenylephrine neither increased the basal release of PGI2 from bovine aortic endothelial cells nor potentiated the stimulatory action of adenine nucleotides, which is mediated by P2-purine receptors. The response to epinephrine was lost in freshly deendothelialized strips of rabbit aorta, possibly because of cyclooxygenase self-inactivation. The response recovered however following overnight incubation of these strips in a cell culture medium. The response to epinephrine was mimicked by neither phorbol 12-myristate,13-acetate nor ionophore A23187. It was not inhibited by pretreatment with pertussis toxin. It is concluded that adrenergic agents stimulate the vascular production of PGI2, by activating alpha 1-receptors located on smooth muscle cells.
The number of membrane-bound beta-adrenoceptors is reduced in the myocardium of spontaneously hypertensive rats, and this decline may account for the decreased inotropic responsiveness to beta-agonists. It is not known, however, whether the total complement of cellular beta-receptors is lower in hypertensive animals. This issue was examined using two different approaches: acid elution of cell surface-bound beta-receptor ligands and comparison of the number of receptors in the plasma membrane and a postcytosolic vesicular fraction. Approximately 30% of the total beta-receptors were located intracellularly in Wistar-Kyoto rats compared with 42% for spontaneously hypertensive rats. Similarly, a decline in membrane-bound beta-receptors in hypertensive rats was balanced by a rise in receptors associated with the vesicular fraction. In contrast, alpha 1-adrenoceptors were higher in the membrane and lower in the vesicular fraction of hypertensive rats without a significant difference in total alpha-receptors compared with normotensive animals. Differences in adrenergic responsiveness in this, and perhaps other, models of cardiac hypertrophy reflect altered intracellular distribution of adrenoceptors, which may be under the control of the sympathetic nervous system.
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The purpose of this study was to evaluate the effects of carvedilol, a beta 1&2-adrenergic blocker and vasodilator, on cirazoline-mediated changes in arterial blood pressure and isoproterenol-mediated changes in heart rate after acute and chronic administration. Conscious, chronically instrumented male Sprague-Dawley rats were injected with carvedilol (1 mg/kg, IV), prazosin (0.3 mg/kg, IV), or propranolol (1 mg/kg, twice daily for 8 days. After administration of the first dose of carvedilol on day 1, the vasopressor response to cirazoline (60 +/- 3 mmHg predrug) and the isoproterenol-induced tachycardia (152 +/- 13 beats/min predrug) were blocked (e.g., 7 +/- 4 mmHg postdrug and 11 +/- 3 beats/min postdrug, respectively). After the administration of carvedilol on day 8, the cirazoline vasopressor response was 2 +/- 1 mmHg and the isoproterenol-induced tachycardia was 4 +/- 3 beats/min, indicating effective alpha 1- and beta-adrenergic blockade after chronic dosing with carvedilol. Prazosin blocked the cirazoline-induced vasopressor response on both days 1 and 8 but had no effect on the isoproterenol-induced tachycardia. Propranolol blocked the isoproterenol-induced tachycardia on both days 1 and 8 but had no effect on the cirazoline vasopressor response. These data indicate that only carvedilol effectively blocked both alpha- and beta-adrenergic hemodynamic responses and that the antagonism of these responses with carvedilol was not diminished after chronic dosing of twice-a-day treatment for 8 days.
We investigated the effects of intraperitoneal administration of adrenoceptor antagonists to the hyperthermia and hyperglycemia induced by prostaglandin F2 alpha (50 micrograms) injected into the third cerebral ventricle in anesthetized rats. Phentolamine inhibited the hyperthermia and hyperglycemia induced by prostaglandin F2 alpha. Prazosin inhibited the hyperthermia induced by prostaglandin F2 alpha, while enhancing the hyperglycemia. Yohimbine inhibited the prostaglandin F2 alpha-induced hyperglycemia without an effect on the hyperthermia. Propranolol had no effect on either prostaglandin F2 alpha-induced hyperglycemia or hyperthermia. These observations suggest that the hyperglycemia induced by prostaglandin F2 alpha is regulated by alpha 2-adrenoceptor systems while the hyperthermia is regulated by alpha 1-adrenoceptor systems in rats.
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Adult female rats were treated with prazosin, a selective alpha 1-adrenoceptor inhibitor, for 60 days in doses of 0.5 mg/kg/day or 0.5 mg/kg/8 h. Prolonged prazosin administration lowered the gain of body weight and significantly decreased systolic blood pressure and heart weight. Prazosin administered every 8 h also lowered serum triglycerides but did not change the total cholesterol level. Selective alpha 1-inhibitor treatment increased the adrenal gland weight and decreased the number of adrenocortical cells; in every 8 h treated group this effect being connected with a marked cell hypertrophy (in all adrenocortical zones). Our results suggest that prazosin induced changes in the structure of the rat adrenal cortex depend on activation of the hypothalamo-pituitary-adrenocortical axis and possibly on the small inhibition of the proliferative activity of rat adrenocortical cells.
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CT (25 and 50 mg/kg) increased swimming activity (P<0.05) by 92.73% and attenuated immobility time by 35.72%, similar to anti-immobility effect of imipramine (33.87%) in FST. In addition, CT (50 mg/kg) significantly (P<0.01) reduced immobility time by 30.24% in TST. -However, the antidepressant-like effect elicited by CT was reversed by metergoline, cyproheptadine, and sulpiride (40.81, 45.93, and 48.52%, respectively) pretreatment but prazosin, and yohimbine failed to reverse this antidepressant-like effect. Similar to diazepam, CT (25 mg/kg) increased duration of open arms exploration (P<0.05) by 43.73% in EPM, number of head-dips (HBT) (90.32%), and time spent in the light compartment by 45.77% in light/dark test indicating anxiolytic-like effect. The anxiolytic-like effect of CT was reversed by flumazenil pretreatment.
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These cases are discussed with reference to the known effects of KB220Z including enhanced dopamine homeostasis and functional connectivity of brain reward circuitry in rodents and humans. Their understanding awaits intensive investigation involving large-population, double-blinded studies.
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In patients not responsive to antihypertensive treatment and concomitantly affected by impaired glucose metabolism, achievement of target BP was obtained in more than one third of cases after 16-week add-on treatment with doxazosin. Changes in glyco-lipidic parameters and reduction of 10-year CHD risk observed during the study, although of moderate extent, confirm the overall favourable effect of antihypertensive combinations including doxazosin.
Bradykinin (100 pM to 1 microM) contracted the rabbit urinary detrusor in vitro. The sensitivity to bradykinin was about 1000 times higher than that to acetylcholine (ACh) on a molar basis. The contractile response to bradykinin was unaffected by atropine, diphenhydramine, FPL-55712, methysergide, prazosin or tetrodotoxin, indicating that the contraction was not mediated via the release of ACh, histamine, peptide leukotrienes, serotonin or catecholamine. The bradykinin-induced contraction was, however, inhibited by indomethacin (5 microM), a cyclooxygenase inhibitor. Caffeic acid (10 microM), a lipoxygenase inhibitor, did not affect the contraction. Bradykinin (1 nM to 100 nM) stimulated the release of prostaglandin E2 from the detrusor in a concentration-dependent manner, and the release was abolished by treatment with indomethacin (5 microM). Prostaglandin (PG) E2 contracted the urinary detrusor with an EC50 of about 0.1 microM. Adenosine 5'-triphosphate (ATP), a stimulator of PG synthesis, also contracted the muscle with an EC50 of about 100 microM. [14C]Arachidonic acid was converted to PGE2 and F2 alpha when it was incubated with the 700 X g supernatant of the muscle homogenate. However, neither bradykinin nor ATP stimulated the PG synthesis in the supernatant. These results showed that bradykinin and ATP did not affect the cyclooxygenase and/or PG degradation system. On the other hand, when the intact detrusor muscle was incubated with [14C]arachidonic acid, bradykinin and ATP stimulated the PG synthesis, and the stimulated synthesis was inhibited by indomethacin. Mepacrine, a phospholipase A2 inhibitor, more potently inhibited the bradykinin- and ATP-induced contractions than the ACh-induced one.(ABSTRACT TRUNCATED AT 250 WORDS)
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The PATHWAY-2 study, funded by the British Heart Foundation, randomised 335 patients with resistant hypertension (already treated according to guidelines) to sequentially receive 12 weeks of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin (4-8 mg modified release) and placebo. The study design allowed drug comparisons in each patient, with 230 patients completing all cycles. Results showed that spironolactone reduced home systolic BP by 8.70 mm Hg more than placebo (<0.001), 4.26 mmHg more than bisoprolol/doxazosin (<0.001), 4.03 mm Hg more than doxazosin (<0.001), and by 4.48 mm Hg more than bisoprolol. By the end of the trial, there would only be 15 patients considered eligible for renal denervation trials in uncontrolled hypertension. PATHWAY-2 will have significant implications for patient recruitment in to other trials.
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The alpha-1 adrenergic innervation of the human prostate has been studied using radioligand receptor binding methods and in vitro contractile experiments. The density of alpha-1 adrenergic binding sites is of the same order of magnitude as alpha-2 adrenergic and muscarinic-cholinergic (MCh) receptors in the human prostate adenoma. The contractile response of human prostate adenomas to selective alpha-1, alpha-2, and MCh agonists indicated that smooth muscle contraction of the human prostate is mediated by alpha-1 adrenoceptors. The selective affinities of terazosin for alpha-1 and alpha-2 binding sites were determined using competitive displacement assays. Terazosin was shown to have a four hundred-fold greater affinity for alpha-1 binding sites. The concentration of terazosin-inhibiting phenylephrine-induced contractions suggested that terazosin inhibits prostate smooth muscle contraction via alpha-1 adrenoceptors.
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We prospectively studied the effect of terazosin on bladder compliance in 12 spinal cord injured patients. All study patients had demonstrated previously poor compliance despite clean intermittent catheterization and maximum anticholinergic therapy. Patients were started on 5 mg. terazosin nightly for 4 weeks. They were evaluated with a history, physical examination, symptom score, and synchronous cystoscopy and cystometry before, during and after terazosin therapy. Detrusor compliance improved in all patients during the treatment phase. The change in bladder pressure and the safe bladder volume were statistically and clinically significant. Patients also reported fewer episodes of incontinence and dysreflexia. The improvement in compliance and continence suggests that in the spinal cord injured patient terazosin may have an effect on alpha receptors in the detrusor muscle or central effects and that improved compliance is not due to decreased outlet resistance.
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The adrenoceptor mechanism that mediates the reduction of urinary sodium (UNa V) and bicarbonate (UHCO3 V) excretion during 1.0-Hz renal nerve stimulation (RNS) was evaluated in 21 anesthetized dogs. In each animal RNS decreased UNa V and UHCO3 V without changing mean arterial pressure, renal blood flow, or glomerular filtration rate. After these initial responses, dogs were administered phentolamine [2.0 micrograms.kg-1.min-1 intrarenal artery (ira); n = 7], prazosin (0.7 micrograms.kg-1.min-1 ira; n = 5), (+/- )-propranolol (2.0 micrograms.kg-1.min-1 ira; n = 4), or atenolol (50 mg/kg iv; n = 5) and the renal responses to RNS were again tested. Both the antinatriuretic response and reduction of UHCO3 V during RNS were abolished by alpha 1/alpha 2-adrenoceptor blockade with phentolamine and by alpha 1-adrenoceptor antagonism with prazosin. beta-Adrenoceptor blockade with (+/- )-propranolol (beta 1/beta 2) or atenolol (beta 1) did not alter either the decrease in UNa V or UHCO3 V after RNS. These results provide further evidence that, during low-frequency RNS, reduction of UNa V is mediated in part by carbonic anhydrase-dependent bicarbonate reabsorption. These antinatriuretic responses and decreases in UHCO3 V during 1.0-Hz RNS are mediated by adrenergic neurotransmitter stimulation of alpha 1-adrenoceptors.
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Recent evidences from molecular biology, radioreceptor binding and functional studies indicate that the alpha 1-adrenoceptor population is heterogeneous and can at least be divided into two subclasses named alpha 1A and alpha 1B. The present study was designed to obtain, a selective enrichment of rat brain cortical membranes with each subtype of alpha 1-adrenoceptor using alkylating agents. [3H]prazosin binding to rat cortical membranes was saturable and of high affinity (KD = 0.11 +/- 0.02 nM; Bmax = 132.5 +/- 7.2 fmol/mg protein). All ligands competed for specific [3H]prazosin binding in a statistically significant biphasic manner (%Rhigh = 30-40%; %Rlow = 60-70%). These sites meet generally accepted and recently described pharmacologic criteria for their identification as the alpha 1A- and alpha 1B-adrenoceptors. After pretreatment of membranes with benextramine (1 microM) in the presence of clonidine (1 microM), the antagonists, WB4101, (+)-niguldipine and phentolamine, displaced the radioligand with an inhibition curve steeper than in control membranes and with Ki values that agree with those obtained for the low affinity site present in control membranes. On the other hand, after pretreatment with chloroethylclonidine (10 microM) in the presence of WB4101 (1 nM), Hill coefficients for the displacement of the radioligand by WB4101, (+)-niguldipine, and phentolamine, were also increased, but in contrast to the situation described above, the Ki values agree with those obtained for the high affinity site present in control membranes. In conclusion, this method of partial alkylation of receptors could be a valuable tool for separately studying the pharmacological characteristics of the alpha 1-adrenoceptor subtypes in native membranes of cerebral tissue.
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Consumption of cardiovascular drugs oscillated between 324 DDD/1000p/Day for drugs with action on the renin-angiotensin system, and 6.5 DDD/1000p/Day for anti-aldosterone diuretics. Variation in consumption for areas in the 5th and 95th percentiles went from 1.8 times (digitalics) to 17.2 times (flavonoids), although most of the groups showed an extremal quotient of around 5. Variation in average prices was lower than in consumption (1.1 times for doxazosin and 3.7 for flavonoids) and variations in pharmaceutical expenditure was similar to variation in consumption (from 2.0 timesfor digitalics to 13.0 times for flavonoids).
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An alkylating analog of prazosin, SZL49 [1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-bicyclo[2.2.2]octa-2,5- diene-2-carbonyl)-piperazine], was synthesized and its pharmacological properties examined. SZL49 competed with nanomolar potency at [3H]prazosin binding sites of rat tissues. Pretreatment of membranes with SZL49 (10 nM) followed by washing led to a reduction in [3H]prazosin binding without a change in the Kd of the remaining sites. However, preincubation even at a concentration of 1 microM, led to only a 50% reduction in binding. Higher concentrations of SZL49 in the preincubation mixtures increased the Kd of the remaining sites. Pretreatment of membranes with phenoxybenzamine led to greater than 80% reduction in these sites. Preincubating membranes with SZL49 together with prazosin prevented the loss of binding caused by SZL49 alone. Utilizing different buffers or altering the ratio of absolute amounts of SZL49 and receptors in the preincubations failed to increase the blockade of [3H]prazosin binding sites. SZL49 was injected i.p. into rats and 16 hr later membranes were prepared from tissues and [3H]prazosin saturation experiments were performed. Whereas Kd values in brain and heart were no different from controls, the Kd value of the remaining kidney binding sites was increased approximately 5-fold in test animals in contrast to in vitro experiments. Maximum binding values of heart were reduced significantly by approximately 42%. Maximum binding values of kidney and brain were reduced about 21 and 36%, respectively. In functional studies with isolated rat aorta, pretreatment with SZL49, followed by a 1.5 hr washout, shifted to the right in a dose-dependent manner the dose-response curves for phenylephrine and norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
A comparative study of cholinergic and adrenergic mechanisms was performed on isolated circular muscle strips of the canine ileum, ileocolonic junction and colon. Cholinergic agonists evoked atropine sensitive contractions, which were most prominent in the colon. The presence of neostigmine to inhibit acetylcholinesterase did not alter the relative sensitivities of the tissues to acetylcholine. The different maximal contraction to cholinergic agents discriminates the colon from the ileum and the ileocolonic junction. Alpha adrenoceptor agonists produced greater contractions in the ileocolonic junction and only marginal contractions in the colon. Phentolamine completely and prazosin and yohimbine partially blocked the response of the ileocolonic junction to norepinephrine, suggesting the involvement of both alpha-1 and alpha-2 adrenoceptors. As in other sphincteric gut smooth muscle, the contractile effects of alpha adrenergic agents are more important than the inhibitory ones. The different effects of cholinergic and adrenergic agents on the ileocolonic junction, as compared sphincteric properties in the canine ileocolonic junction. sphincteric properties in the canine ileocolonic junction.
The effect of a newly synthesized irreversible blocker of the alpha-1 receptor [1-(4-amino-6,7-dimethoxy-2-quinazolnyl)-4-(2-bicyclo[2,2,2] octa-2,5-dienylcarbonyl)-piperazine; SZL-49] has been evaluated in contractile studies in rabbit aorta and binding studies in aorta and brain. SZL-49 produced long lasting inhibition of norepinephrine-induced contractions which was apparent 21 hr after drug washout. The inhibition, which was dose and time dependent, was characterized by progressive shift to the right in the norepinephrine dose-response curve. The ED50 for norepinephrine was shifted from 10(-7) M to 8 X 10(-7), 3 X 10(-6), 1 X 10(-5) and 5 X 10(-4) M after incubation (30 min) and washout of increasing concentrations of SZL-49. Surprisingly, SZL-49, irrespective of the dose or incubation time, did not decrease the maximal response of aortic rings to norepinephrine. This resulted in a norepinephrine dose-response curve after SZL-treatment that is parallel to the control. SZL-49 had no effect on the spasmogenic actions of histamine, serotonin, KCl or CaCl2. In contrast to the inhibitory pattern seen with SZL-49, incubation with 10(-7) M phenoxybenzamine shifted the norepinephrine dose-response curve to the right in a nonparallel manner and significantly depressed the maximal response obtainable with norepinephrine. Incubation with 10(-6) M phenoxybenzamine for 30 min virtually abolished the response to norepinephrine. Phenoxybenzamine (10(-7) M) was without effect on aortic rings treated with a maximally effective dose of SZL-49. Prazosin weakly antagonized the contractile actions of norepinephrine observed after SZL-49 treatment, whereas yohimbine was without effect on these norepinephrine-induced contractions. In control binding studies [3H]prazosin bound to two classes of sites in both aorta and brain preparations. Affinities and densities for these sites were K1 = 67.5 pM, K2 = 309 pM; R1 = 38.2 fmol/mg, R2 = 46.47 fmol/mg in aorta and K1 = 29.6 pM, K2 = 182 pM; R1 = 6.6 fmol/mg and R2 = 30.4 fmol/mg in brain. Treatment with increasing amounts of SZL-49 (10(-10) to 10(-8) M) progressively reduced the number of [3H]prazosin sites without altering the affinity of the sites remaining. At 10(-7) M, SZL-49 eliminated completely all specific [3H]prazosin binding. Our results indicate that the site mediating norepinephrine contraction after treatment with SZL-49 does not possess the characteristics of an alpha-1 receptor and supports the hypothesis that a low affinity site for norepinephrine and prazosin exists in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)
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The main objective of this study was to characterize the alpha 1-adrenoceptors expressed in adult rat brown adipocytes. For this purpose, membrane fractions were prepared from brown adipose tissue as well as from isolated brown adipocytes. The following are major findings: (i) BAT membranes were considerably enriched in alpha 1-adrenoceptors (specific [3H]prazosin binding, Bmax, 79.49 +/- 16.77 fmol/mg protein; KD, 0.24 +/- 0.04 nM); (ii) among the cells that comprise brown adipose tissue, brown adipocytes were enriched in alpha 1-adrenoceptors; (iii) > 95% of total alpha 1-adrenoceptors were resistant to inactivation by 20 microM chloroethylclonidine, which readily and essentially completely inactivated alpha 1B-adrenoceptors in rat liver membranes; (iv) brown adipose tissue membrane alpha 1-adrenoceptors showed high affinity towards 5-methyl urapidil (KD 7.23 +/- 2.49 nM) and WB 4101 (KD 0.66 +/- 0.30 nM) and low affinity towards BMY 7378 (KD 0.34 +/- 0.03 microM); essentially similar affinities for these drugs were seen for membranes prepared from brown adipocytes; and (v) EBDA/LIGAND analysis of 5-methyl urapidil, WB 4101, and BMY 7378 competition curves revealed the presence of a single binding site for these drugs. Recent work has documented that 5-methyl urapidil and WB 4101 interact with high affinity with alpha 1A-adrenoceptors, while BMY 7378 interacts with high affinity with alpha 1D-adrenoceptors. Taken together, these findings are consistent with the view that alpha 1-adrenoceptors expressed in adult rat BAT are mainly of the alpha 1A subtype.
Melatonin, the major secretory product of pineal gland has been suggested to play a regulatory role in the circadian rhythm of body activities including the pain sensitivity. Three subtypes of melatonin receptors, i.e. ML1, ML2 and ML3 have been identified.
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In order to characterize the hemodynamic actions of urotensin I, a vasodilator peptide with selectivity for the mesenteric vascular bed, we studied its hypotensive effects and interference with alpha-1 and alpha-2 adrenergic vasoconstrictor responses in the rat. After i.v. administration in anesthetized rats, urotensin I (0.06-6 nmol/kg) produced a dose-dependent lowering of arterial blood pressure. At hypotensive doses, urotensin I was about 3 times more potent in antagonizing systemic pressor responses to the selective alpha-1 adrenoceptor agonist, phenylephrine, than responses to the nonselective adrenoceptor agonist, norepinephrine. Additional studies were performed on the blood-perfused mesenteric bed of the anesthetized rat and on the isolated rat superior mesenteric artery, using as tools phenylephrine, norepinephrine and the relatively selective alpha-2 adrenoceptor agonist, alpha-methylnorepinephrine. The selectivity of the three agonists for vascular alpha-1 and alpha-2 adrenoceptors in the blood-perfused mesenteric bed was confirmed using prazosin and yohimbine as selective antagonists of alpha-1 and alpha-2 adrenoceptors, respectively. Urotensin I diminished the maximum increase in perfusion pressure and shifted the log dose-response curves to the right for all three agonists. A marked selectivity of urotensin I for alpha-1 adrenoceptor-mediated responses was observed: IC30 values of the peptide for pressor responses to phenylephrine, norepinephrine and alpha-methylnorepinephrine were 0.05, 0.83 and greater than 6 nmol/kg, respectively. A less pronounced selectivity of urotensin I for alpha-1 adrenoceptor-mediated contractions could be demonstrated in isolated strips of the superior mesenteric artery of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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Alpha1-adrenergic receptors were quantified by radioligand binding assays, employing [3H]-prazosin as the radioligand in association with compounds displaying different degrees of selectivity for alpha1A-, alpha1B- and alpha1D-adrenergic receptor subtypes.
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Clonidine, an alpha 2-agonist, had a significant (P < 0.05) anti-secretory effect, while yohimbine, an alpha 2-antagonist, significantly (P < 0.05) increased net fluid secretion. Phenylephrine, an alpha 1-agonist, and prazosin, an alpha 1-antagonist, lacked significant effects on net fluid transport. Similarly, prenalterol, a beta 1-agonist, and metoprolol, a beta 1-antagonist, had no significant effect on the net fluid transport. The beta 2-agonist salbutamol significantly (P < 0.001) decreased net fluid secretion, while the beta-antagonist propranolol significantly (P < 0.001) decreased net fluid secretion.
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Naftopidil, an alpha 1-adrenergic antagonist, was orally tested in comparison with prazosin, in a rat cystomanometric model to evaluate the effect on the bladder volume capacity (BVC), the micturition pressure (MP) and the mean arterial blood pressure (MAP), contemporaneously recorded to evaluate the selectivity of action. Naftopidil induced a clearcut increase of BVC and a decrease of MP without lowering MAP at 6.25 mg kg-1 p.o.. Prazosin was inactive on BVC, decreased MP and induced a significant decrease of MAP at 1.56 mg kg-1 p.o. Naftopidil could offer an advantage when compared with prazosin.
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We have shown that, within therapeutic plasma concentrations, the unbound fraction of furosemide changes in direct proportion to the reciprocal of the plasma albumin concentration (correlation coefficient 0.99). Changes in the albumin concentration were produced by ultrafiltration of human plasma using a haemofiltration filter. Thus, we propose that, when studying changes in the pharmacokinetics of a highly protein bound drug, calculated changes in the unbound fraction offer an alternative to actual measurement of the unbound concentration, which is often difficult. Nine healthy volunteers receiving a continuous furosemide infusion were studied in normovolaemia and after dehydration (-1.4 kg), with and without pretreatment with an angiotensin converting enzyme inhibitor (captopril) or an a1-adrenoceptor blocking agent (prazosin). Significantly larger changes in the renal clearance of furosemide were found that could be explained by changes in the unbound fraction. Following dehydration, the unbound fraction of furosemide was decreased by about 5%, while its renal clearance fell by 27%, 33% and 13% after pretreatment with placebo, captopril and prazosin, respectively. The secretory clearance of the unbound furosemide changed substantially and in parallel with changes in the renal blood flow. It is suggested that changes in the renal clearance and excretion of furosemide and its t1/2 are much more dependent on changes in renal blood flow than on changes in its unbound fraction.
All the patients got complete volume expansion after taking phenoxybenzamine with tachycardia occurring in 23 of them and postural hypotension in 13 patients. In the 25 cases mainly with increase of norepinephrine before medical treatment doxazosin mosylate was completely effective in 18 cases with their blood pressure < 180/140 mm Hg; and was partially effective in the other 7 cases with their blood pressure > 180/140 mm Hg of which 2 suffered from postural hypotension. Doxazosin mosylate was partially effective in the other 13 cases mainly with increase of both norepinephrine and epinephrine. The total efficiency rate of these two medicines was not significantly different (chi(2) = 18.05, P > 0.05). The side-effect rate of doxazosin mosylate was significantly lower than that of phenoxybenzamine (chi(2) = 324, P < 0.01).
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The present study was undertaken to investigate the effect of the ethanolic extract of Allium sativum L. (Family: Lilliaceae), commonly known as garlic, on depression in mice.
The aim of the present study was to investigate dopamine receptor- and alpha-adrenergic receptor-mediated modulation of norepinephrine release in human atria. Right atrial appendages were incubated with 3H-norepinephrine, placed in superfusion chambers, and field-stimulated by platinum electrodes at a frequency of 5 Hz. The stimulation-induced (S-I) outflow of radioactivity was taken as an index of norepinephrine release. The dopamine D2-receptor agonist quinpirole (0.03-3 microM) concentration dependently inhibited the S-I outflow of radioactivity with an EC50 of 0.03 microM. The concentration-response curve of quinpirole was potently shifted to the right by the D2-receptor antagonists domperidone (0.003 microM, pKB approximately 9.2) and S(-)-sulpiride (0.1 microM, pKB approximately 8.6). The D1-receptor antagonist SCH 23390 (1 microM) slightly (pKB approximately 6.9) shifted the concentration-response curve of quinpirole, whereas the alpha 2-adrenergic antagonist rauwolscine (0.01 microM) and the alpha 1-adrenergic antagonist prazosin (1 microM) had no effect. The D1-receptor agonist did not affect fenoldopam (0.03 and 0.3 microM), but fenoldopam (3 microM) enhanced the S-I outflow of radioactivity. The facilitatory effect of fenoldopam (3 microM) was unaltered by SCH 23390 (0.1 microM) but prevented by rauwolscine (0.01 microM). The alpha 2-adrenergic agonist UK 14304 (0.01-1 microM) (EC50: 0.06 microM), but not the alpha 1-adrenergic agonist methoxamine (0.3-30 microM), inhibited S-I outflow of radioactivity. The concentration-response curve of UK 14304 was shifted to the right by rauwolscine (0.01 microM, pKB approximately 8.6).(ABSTRACT TRUNCATED AT 250 WORDS)