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L X Cubeddu

Publications and source records attributed to L X Cubeddu.

At least 73 records · Page 4Linked to original sources
PubMed1988

New alpha 1-adrenergic receptor antagonists for the treatment of hypertension: role of vascular alpha receptors in the control of peripheral resistance.

The pharmacology, clinical efficacy and safety of new alpha-adrenergic receptor antagonists for the treatment of hypertension was reviewed (Table XIV). Although all these agents block alpha 1 receptors, some of them have additional effects on histamine, serotonin, dopamine, and alpha 2 receptors. These other actions account for the differences in the side effect profiles observed, i.e., increased incidence of central nervous system side effects found with indoramin, ketanserin, and urapidil, as well as for some additional beneficial effects of ketanserin (i.e., antiplatelet aggregation activity). The magnitude of BP reduction observed with antagonists of alpha 1-adrenergic receptors is modest. In most studies, the degree of BP reduction is comparable to that of prazosin, but less than that achieved with thiazide diuretics, beta-receptor antagonists, or methyldopa. Studies on the comparative efficacy and safety of new alpha 1 antagonists with converting enzyme inhibitors or calcium-channel blockers are not available. In general, alpha 1 antagonists produce greater reductions in standing than in supine BP, an effect due to the venodilatory action of these drugs. New alpha 1 antagonists appear to have equal efficacy in black and white hypertensive individuals. Their comparative efficacy and safety in young vs elderly hypertensive individuals requires further investigation. No information about the possible development of tolerance during treatment with new alpha 1 blockers was encountered. The effects of alpha 1 antagonists on HR are variable and depend on how long after the oral dose the measurements were obtained. In most studies, no significant HR changes are noticed for readings obtained 24 hours post dose; whereas tachycardia has been observed at the time of peak hypotension. Since alpha 1 antagonist-induced tachycardia is most likely of reflex nature, i.e., mediated to an increase in sympathetic activity, the increased HR may be associated with increases in myocardial contractility and in myocardial oxygen consumption. Consequently, a 24-hour HR monitoring during treatment with alpha 1 antagonists should be required for evaluation of new agents. The hemodynamic, humoral, and hormonal effects of the newer alpha 1-receptor antagonists are comparable to those of prazosin. The most consistent finding is a reduction in total peripheral resistance associated with either no change or with only small increases in cardiac index. These agents have been shown either not to change or to increase renal blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1988

Effect of doxazosin monotherapy on blood pressure and plasma lipids in patients with essential hypertension.

The efficacy and safety of doxazosin (DOX) for the treatment of hypertension was investigated. A multicenter, double-blind, placebo-controlled, parallel design was employed. A 4-week placebo runin period was followed by a 9-week double-blind period during which patients were randomly assigned to placebo or 2, 4, or 8 mg doxazosin. Blood pressures (BP) and heart rates (HR) were measured 24 hours postdose. The mean changes in standing BP (mmHg) were -6.2/-6.9 (2-mg regimen), -5.7/-5.8 (4-mg regimen), -8.5/-7.7 (8-mg regimen) for DOX patients and 0.7/-2.9 for placebo patients. The mean changes in supine BP (mmHg) were -3.2/-4.7 (2-mg regimen), -4.0/-5.1 (4-mg regimen), -4.6/-5.6 (8-mg regimen) for DOX patients and -0.5/-3.3 for placebo patients. There was no evidence of a dose-response relationship for DOX; however, DOX serum levels were linearly related to the dose. Responder rate for the combined DOX patients was 38% (32/84) and for the placebo patients 27% (8/30). HR (24 hours postdose) was not modified by DOX. Patients in the 8-mg regimen had a significantly higher gain in mean body weight (+ 1.3 +/- 0.3 kg; P less than 0.05) compared to the 2-mg regimen, 4-mg regimen, and placebo groups. Plasma norepinephrine was not significantly modified by DOX. DOX had a favorable effect on plasma lipids. DOX lowered LDL cholesterol (P less than 0.05), total cholesterol, and apoprotein B and increased HDL/(LDL + VLDL) ratio (0.05 less than or equal to P less than 0.1) compared to placebo. Dropout rate and treatment-related side effects were equally distributed among the DOX and placebo groups. No patients had the dose of medication reduced because of side effects. Three DOX patients were withdrawn because of postural dizziness.

Blood Pressure↗
PubMed1988

Monoamine release by compound 48/80 from nonmast cell compartments in mouse brain slices.

In the present study we investigated the specificity of the releasing effects of compound 48/80 (48/80) for mast cell vs. neuronal histamine (HA) from hypothalamic slices. In addition, we investigated the selectivity of the releasing effects of 48/80 for HA compared to other neurotransmitters. Brain slices from W/W mice, a genetic mutant devoid of mast cells, and +/+ mice, its normal counterpart, were used. Hypothalamic slices were labeled with [3H]HA or [3H]histidine. 48/80 elicited similar degrees of release of [3H]HA from both mouse strains, irrespective of the label used. In addition, 48/80 produced marked increases in the efflux of dopamine (DA), serotonin (5-HT), norepinephrine (NE) and modest increases in the efflux of acetylcholine (ACh). These effects were concentration-dependent and the magnitude of release varied with the transmitter examined (DA greater than NE greater than 5-HT much greater than ACh = HA). Transmitter efflux induced by 48/80 was not altered by low calcium concentrations or by tetraethylammonium; whereas, release evoked by electrical stimulation was reduced and increased, respectively, by these treatments. In mouse striatal slices preloaded with [3H]DA, 48/80 induced an initial increase in [3H]DA efflux, followed by a marked increase in the efflux of its metabolite, [3H]-3,4-dihydroxyphenylacetic acid. Nomifensine failed to inhibit, whereas reserpine pretreatment reduced 48/80-induced efflux of 3H. In summary, these results indicate that the incubation of hypothalamic slices with [3H]HA or [3H]histidine labels HA neurons selectively and that 48/80 (10-100 micrograms/ml) releases HA from nonmast cell compartments.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

Effects of amiloride and 5-(N,N-hexamethylene)amiloride on dopaminergic and cholinergic neurotransmission.

In order to establish the role of the Na+/H+ exchange transport on neurotransmission, we investigated the effects of amiloride and of 5-(N,N-hexamethylene)amiloride (HMA) on dopamine (DA) and acetylcholine (ACh) release and on receptor-mediated modulation of DA and ACh release. Superfused rabbit striatal slices prelabeled with [3H]DA and [14C]choline were stimulated electrically in the presence and absence of several concentrations of these agents. Amiloride (3-10 microM) and HMA (0.3-10 microM) reduced the basal efflux and the stimulation evoked overflow of total 3H and of [3H]-3,4-dihydroxyphenylacetic acid and inhibited monoamine oxidase activity. The inhibition of stimulation evoked overflow of total 3H was blocked by pretreatment with nomifensine but not by sulpiride. Amiloride had no effect on the basal efflux and the stimulation evoked overflow of ACh or it did modify apomorphine-induced inhibition of DA and ACh release. However, at 3 to 10 microM, HMA enhanced the basal efflux of 3H; this effect was not prevented either by uptake inhibition with nomifensine or by low extracellular calcium. These results suggest that amiloride-sensitive Na+ transport and the amiloride and HMA-sensitive Na+/H+ antiporter play no role on the secretion of DA and ACh, or on the mechanisms by which activation of pre- and postsynaptic DA receptors lead to inhibition of neurotransmitter release. Amiloride- and HMA-induced monoamine oxidase inhibition accounts for the effects of amiloride and HMA on DA efflux and overflow. The guanidine moiety present in the amiloride and HMA molecules is most likely responsible for these effects.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding.

We quantified the effects amphetamine (AMPH), phenylethylamine (PEA), tyramine (TYR), octopamine (OCT) and DA, on initial rates of DA uptake (striatal minces), binding of [3H]mazindol to the neuronal uptake (NU) site (striatal membranes) and on DA and dihydroxyphenylacetic acid (DOPAC) efflux (striatal slices). In general, the order of potency for the three paradigms was: AMPH less than DA = TYR = PEA less than OCT. The Km values for uptake were positively correlated with the Ki values for inhibition of mazindol binding (r = 0.91; P less than .01) and with the potencies to induce DA efflux (r = 0.96; P less than .005). Potencies for inhibition of mazindol binding and for eliciting DA efflux also were highly correlated (r = 0.92; P less than .01). Correlations were lost if data for nomifensine (NOM), a NU inhibitor, were included in the analysis. Despite the significant correlations, AMPH, TYR, PEA and OCT Despite the significant correlations, AMPH, TYR, PEA, and OCT were 10 to 20 times more potent in inhibiting NU than in eliciting efflux or inhibiting mazindol binding. Conversely, the potency of NOM to inhibit mazindol binding was 10 and 800 times greater than that required to inhibit NU or to elicit DA release, respectively. NOM inhibited competitively AMPH-induced DA release. These results suggest that: 1) AMPH-like drugs bind to and are likely to be transported by the NU carrier, and 2) inward transport of these agents appears to have multiple effects (e.g., an increase in intracellular Na+ and Cl-) that act cooperatively to increase Vmax and reduce Km for the outward, carrier-mediated DA transport. AMPH, TYR, PEA and OCT had qualitatively similar effects on endogenous DA and [3H]DA release. Monoamine oxidase inhibition potentiated these effects. All these agents released more endogenous DA from control than from reserpine-treated slices. In control slices, TYR and OCT increased DA and DOPAC efflux; whereas AMPH and PEA increased DA and reduced DOPAC efflux, except at high concentrations in which DOPAC efflux also was increased. After reserpine, these agents reduced DOPAC efflux in proportion to the increased DA efflux. In summary, we propose that AMPH-like drugs increase DA efflux from a single cytoplasmic pool maintained by DA synthesis and spontaneous and drug-induced efflux of DA from storage vesicles.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Sustained high release at rapid stimulation rates and reduced functional autoreceptors characterize prefrontal cortex dopamine terminals.

The release of dopamine (DA) from mesocortical and nigrostriatal nerve terminal fields, as well as its modulation by auto- and heteroreceptors was investigated. Rabbit brain slices obtained from medial prefrontal cortex (PFC) and nucleus caudate (striatum) were prelabeled with [3H]DA in the presence of 0.3 microM desipramine. Neuronal depolarization was elicited by electrical stimulation. Higher stimulation-evoked overflow of [3H]DA (release) was observed from PFC than from striatal slices. At 0.3 Hz (120 pulses) release from the PFC was 60% higher than from the striatum, and at higher frequencies (10 Hz and 120 or 1200 pulses) the fraction of tissue radioactivity released from the PFC was 550% greater than that released from the striatum. These differences were not eliminated by blockade of autoreceptors with haloperidol, or by inhibition of neuronal uptake with nomifensine. These results suggest that the coupling between neuronal depolarization and DA release is more efficient in the PFC than in the striatum. This may allow the PFC terminals to sustain neurotransmission under continuous fast firing. Selective D2 agonists, as well as nonselective DA agonists, inhibited DA release in a concentration-dependent fashion from the PFC and the striatum. Their effects were blocked by l-sulpiride or haloperidol. SKF 38393, a selective D1 agonist, produced a small facilitation of release from both regions; its effects were blocked by SCH 23390 (a selective D1 antagonist). The latter was ineffective on its own. The maximal degree of inhibition of release produced by apomorphine, bromocriptine and LY-171555 was lower in the PFC than in the striatum; these differences were accentuated greatly at high stimulation rates. When the slices were stimulated at frequencies comparable to the "in vivo" firing rates for each neuronal group, apomorphine and LY-171555 were much weaker in inhibiting DA release from the PFC (10 Hz) than from the striatum (3 Hz). In the striatum, strong modulation of DA release by endogenous DA was observed; whereas little modulation was seen in the PFC. Nomifensine produced larger increases in the stimulation-evoked overflow of DA from PFC and there was no synergistic interaction between nomifensine and haloperidol in this structure. In the striatum, marked facilitation of DA overflow was observed when nomifensine and haloperidol were given together. Furthermore, haloperidol per se facilitated DA release from both brain regions; however, the degree of facilitation was frequency dependent in the striatum, but not in the PFC.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Clinical pharmacology of doxazosin in patients with essential hypertension.

Doxazosin is a new quinazoline derivative that, like prazosin, has selectivity for alpha 1-receptors. A three-way crossover, randomized, open study in 18 patients with essential hypertension was conducted to investigate the clinical pharmacokinetics of 2, 4, and 8 mg doxazosin at steady state. The pharmacokinetics of the initial 2 mg dose was also studied. Doxazosin showed linear pharmacokinetics. Increases in doses from 2 to 8 mg (steady state) produced proportional increases in doxazosin serum levels (maximum plasma drug concentration [Cmax] minimum plasma drug concentration [C min], and O-24-hour area under the curve [AUC(p-24)], whereas half-life (t1/2) (19.4, 18.7, and 19.7 hours, respectively), volume of distribution (3.4, 3.4, and 3.6 L/kg, respectively), clearance from serum (2.2, 2.2, and 2.1 ml/min/kg, respectively), and degree of protein binding (1.2%, 1.0%, and 1.0% unbound, respectively) were dose independent. Similar t1/2 and time to reach peak concentration (tmax) were obtained with 2 mg initial dose and 2 mg steady state. alpha 1-Acid glycoprotein levels were unchanged during doxazosin treatment. Doxazosin lowered supine and standing systolic and diastolic blood pressure. The blood pressure reduction was associated with an increase in heart rate. Peak hypotensive and tachycardic effects occurred 5.7 +/- 0.1 hours after administration, whereas Cmax was achieved at 2.4 +/- 0.7 hours (tmax). Greater decreases in systolic blood pressure and increases in heart rate were seen in standing than in supine position. The reduction in standing systolic and diastolic blood pressure with 8 mg was greater than with 2 mg (P less than 0.05); however, the increases in heart rate were not different. Dizziness, headaches, and dry mouth were the most frequent side effects. This study indicates that doxazosin shows linear pharmacokinetics between 2 and 8 mg and that because of its long t1/2, once-a-day administration should be adequate for the treatment of hypertension.

Adult↗
PubMed1987

Clinical pharmacology of carvedilol in normal volunteers.

The mechanism of the vasodilatory action of carvedilol (BM 14190), a new antihypertensive agent, was investigated in normal volunteers. Intra-arterial blood pressure and ECG were monitored continuously. Carvedilol (1 mg/min for 15 minutes) produced a rapid reduction in blood pressure and a transient increase in heart rate. At the end of infusion, systolic and diastolic blood pressure were reduced by 23% (-32.3 mm Hg) and 18% (-13.6 mm Hg), respectively, whereas heart rate was not different from baseline. At the doses used, the hypotensive effect of carvedilol was greater than that of labetalol (36 and 72 mg in 15 minutes). Carvedilol and labetalol antagonized isoproterenol-induced hypotension and tachycardia, at serum levels greater than or equal to 8 and 20 mg/ml, respectively. Both drugs antagonized phenylephrine pressor effects. A similar degree of inhibition (25% of control) of pressor effects was observed for carvedilol and labetalol when their respective serum concentrations were 23 ng/ml and 80 ng/ml. Neither carvedilol nor labetalol had any effect on AII pressor responses. Carvedilol serum levels as high as 150 ng/ml failed to inhibit AII-induced pressor responses. Our results suggest that at the doses used in this study, carvedilol has both alpha 1-and nonselective beta-receptor blocking properties. Moreover, carvedilol is approximately three to five times more potent than labetalol in blocking alpha 1-and beta-receptors and in reducing blood pressure.

Adult↗
PubMed1987

Mechanism of the vasodilatory effect of carvedilol in normal volunteers: a comparison with labetalol.

In a single blind parallel design, saline (n = 9), labetalol i.v. (40 mg n = 4, 80 mg n = 3), and carvedilol i.v. (15 mg n = 8) were given to volunteers with blood pressure (BP) recorded intraarterially. The effect of these treatments on the response to challenge doses of angiotensin II (to give a rise in mean BP of 20-25 mm Hg), isoproterenol (to give an increase in heart rate of 30-35 beats/min), and phenylephrine (to give a rise in mean BP of 20-25 mm Hg) were studied. The dose of i.v. carvedilol employed gave a greater fall in BP than the dose of labetalol used. Carvedilol appeared to be about four times more potent than labetalol in inhibiting the tachycardia to isoprenaline. Likewise, from inhibition of the pressor response to phenylephrine, it is concluded that carvedilol is four times more effective at the alpha receptor than labetalol. Neither drug was found to antagonize the pressor effects of angiotensin. Calculation of the half-life of carvedilol gave values of 2.2 to 9 h. The volume of distribution was found to be 1.54 l/kg and the total body clearance was 0.521 l/h/kg.

Adrenergic beta-Antagonists↗
PubMed1987

Cerebrospinal fluid norepinephrine levels in essential hypertension: effects of drug treatment and withdrawal.

Measurements of cerebrospinal fluid (CSF) catecholamines (CA) were made in an attempt to estimate the activity of central CA neurons in essential hypertension (EHT). CSF norepinephrine (NE), epinephrine (EPI), and dopamine (DA) levels were measured in 12 normotensive (age 36 +/- 3 years; SBP = 116 +/- 4 and DBP = 79 +/- 4 mm Hg) and in 12 EHT (age 41 +/- 2 years; CSF NE levels were twofold higher in EHT (240 +/- 23 pg/ml) than in normotensive subjects (127 +/- 28 pg/ml). Very low EPI and DA levels were observed in both groups of patients. The results suggest that central (spinal?) noradrenergic activity is increased in patients with EHT. In a second study we evaluated the effects of clonidine treatment for 2 weeks (150 micrograms t.i.d.) on CSF NE in EHT. Clonidine reduced pretreatment BP and CSF NE levels by 27% (p less than 0.05) and 39% (p less than 0.01), respectively. The results of the study indicate that central noradrenergic activity is reduced during clonidine treatment. A third group of experiments was designed to compare the effects of clonidine with those of propranolol treatment in patients with EHT. CSF NE measurements were made after 1 month of treatment with 0.36 +/- 0.07 mg of clonidine daily or 160 mg of propranolol daily. CSF NE levels were significantly lower in the clonidine group (p less than 0.01). Seventy-two hours after abrupt discontinuation of clonidine or propranolol treatment, BP returned to pretreatment levels. However, CSF NE showed a threefold increase after clonidine withdrawal, and no change after propranolol withdrawal. CSF EPI was not affected by either treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Comparative dopamine-cholinergic mechanisms in the olfactory tubercle and the striatum: effects of metoclopramide.

The olfactory tubercle (OT) is a limbic structure containing high dopamine (DA) and acetylcholine (ACh) concentrations. We performed a comparative study of the DA-ACh interactions, the efficacy of autoreceptor control and the effects of metoclopramide in the OT and the nucleus caudate (striatum). Rabbit brain slices from both regions of the same animal were prelabeled with radioactive DA and/or choline and then superfused. Comparable magnitude of DA and ACh release was evoked by electrical stimulation from both regions. DA release was unaltered, whereas ACh release was inversely related to the stimulation frequency, both in OT and striatum. Apomorphine (APO), a D1-D2 agonist, an LY-171555 (LY), a D2 agonist, inhibited DA and ACh release from OT and striatum with similar EC50 and Emax (maximal percentage of inhibition). However, the maximal degree of inhibition of ACh release achieved with APO, LY or DA in the OT was only one-half that observed in the striatum. In both regions, the inhibitory effects of DA agonists on DA and ACh release were reduced markedly when the number of electrical pulses and/or the frequency of stimulation were increased. l-Sulpiride, a DA D2 antagonist, increased the evoked release of DA and ACh from OT in direct relationship with the frequency of stimulation. In the OT, increases in synaptic DA achieved by administration of amphetamine or by blockade of the neuronal uptake pump with nomifensine inhibited the evoked release of ACh. Again these drug treatments produced only a 40 to 50% inhibition of ACh release. SKF 38393, a D1 agonist, had no effect per se on DA or ACh release in OT slices from control or from reserpine-treated animals (2 mg/kg s.c. for 3 or 7 days). With the exception of one specific dose combination, coadministration of SKF 38393 and LY produced no additive or synergistic effects on DA or ACh release from OT. APO- and LY-induced inhibition of DA and ACh release were antagonized by l-sulpiride. However, 300 nM SCH 23390, a D1 antagonist, reduced APO inhibition of DA and ACh release without affecting the inhibitory action of LY on DA and ACh release. Metoclopramide, "a DA antagonist with poor limbic activity", had a similar affinity for OT (pA2: 7.59) and striatal (pA2: 7.59) DA autoreceptors. Its antidopaminergic efficacy on DA receptors modulating ACh release from OT and striatum was also compared.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1987

Ionic mechanism of dopaminergic and muscarinic auto- and heteroreceptor activation in superfused striatal slices: role of extracellular chloride.

The Cl dependency of agonist-induced ionic mechanisms involved in the receptor-mediated modulation of electrically stimulated release of dopamine (DA) and acetylcholine (ACh) was examined in superfused rabbit striatal slices prelabeled with [3H] DA (3,4-[8-3H]dihydroxyphenylethylamine) and [14C]choline ([ methyl-14C]choline Cl). Cl- was substituted in the superfusion medium to varying degrees with the impermeant anions isethionate, methanesulfonate or gluconate. The sodium concentration was held constant. Apomorphine (30 nM), a DA receptor agonist, inhibited the stimulation-evoked (1 Hz, 2 min) release of both DA and ACh in Krebs-Ringer-bicarbonate medium (KRB; 125.4 mM Cl-). The inhibitory effects of the agonist were not altered significantly in media containing 66.4 mM Cl-. In 7.4 mM Cl- medium (isethionate replacement), apomorphine-induced inhibition of DA release was reduced (40% inhibition vs. 67% inhibition in KRB). Similarly, apomorphine inhibition of ACh release was lowered from 38% in KRB to 25% in 7.4 mM Cl-. The muscarinic receptor agonist carbachol (10 microM) inhibited the stimulation-evoked release of ACh while enhancing the evoked release of DA in normal Cl- (125.4 mM) medium. Inhibition of ACh release was not altered in 66.4 mM Cl- media but was increased in 7.4 mM Cl- (63% inhibition in low Cl- vs. 50% in KRB). The enhancing effects of carbachol on stimulated DA release were potentiated in 66.4 mM Cl- (88% enhancement vs. 57% in KRB), whereas no change in the agonist effect was observed in the lower Cl- medium (7.4 mM Cl-).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1987

Pharmacologic characterization and functional role of muscarinic autoreceptors in the rabbit striatum.

The objectives of the present studies were 1) to pharmacologically characterize the muscarinic autoreceptors in the striatum and 2) to examine their role in the regulation of physiologic acetylcholine (ACh) release. Schild plots were generated for atropine and pirenzepine against oxotremorine-induced inhibition of [3H]ACh release. Atropine, a nonselective antagonist, yielded a pA2 of 8.92. The pA2 for pirenzepine, a purported M1-selective antagonist, was 7.14. Both Schild plots had slopes not significantly different from one. Four agonists [oxotremorine, carbachol (CARB), McN-A-343 and pilocarpine] were tested for their effectiveness in inhibiting [3H]ACh release. McN-A-343 and pilocarpine have been reported to be selective for M1 receptors. Oxotremorine and carbachol were effective and potent inhibitors of [3H] ACh release, whereas McN-A-343 and pilocarpine were weak. Although the existence of muscarinic receptor subtypes remains an open question, these data are consistent with the "low" pirenzepine affinity (M2) subtype. Chronic treatments (14 days) with several agents were carried out (in vivo) to assess the role of muscarinic autoreceptors in the regulation of physiologic ACh release. Scatchard analyses of binding studies with [3H]quinuclidinyl benzilate were also performed to assess changes in the muscarinic receptor population in the striatum. Chronic treatment with scopolamine caused a 100% increase in the Bmax for [3H]quinuclidinyl benzilate binding but had no effect on the sensitivity of [3H]ACh release to inhibition by CARB. Fourteen-day treatment with physostigmine (3 mg/kg) produced a decrease in the sensitivity of [3H]ACh release to CARB plus a 42% decrease in Bmax and a 48% decrease in Kd for [3H]quinuclidinyl benzilate binding. Chronic haloperidol treatment caused an increase in the sensitivity of [3H]ACh release to CARB accompanied by a 46% increase in Bmax for 3H quinuclidinyl benzilate binding. These data suggest that muscarinic autoreceptors in the striatum do not regulate physiologic ACh release in the presence of intact acetylcholinesterase and that the interaction of dopaminergic and cholinergic neurons in the striatum may not be simple trans-synaptic inhibition.

Acetylcholine↗
PubMed1986

Effects of propranolol, clonidine and hydrochlorothiazide treatment and abrupt discontinuation on central and peripheral noradrenergic activity in essential hypertension.

This study was undertaken to investigate further the CNS actions of commonly employed antihypertensive drugs. Measurements of cerebrospinal fluid (CSF) and plasma catecholamines (CA) were made in an attempt to estimate the activity of central and peripheral noradrenergic neurons during treatment with or after abrupt discontinuation of treatment with clonidine (CLO), propranolol (PRO), hydrochlorothiazide (HCTZ) or placebo, in patients with essential hypertension. A randomized, parallel, placebo-controlled, single-blind design was employed. BP reductions equal to or greater than 10 mmHg were observed with CLO (0.36 +/- 0.07 mg daily), PRO (160 mg +/- 0 mg daily) or HCTZ (70 +/- 12 mg daily). CLO reduced plasma norepinephrine (NE) by 64% and PRO increased it by 25%. Neither HCTZ nor placebo modified plasma NE. Plasma renin activity (PRA) was reduced by PRO (51%, P less than 0.01) and CLO (35%, P less than 0.05). CSF-NE levels (pg/ml) were significantly lower in the CLO group (CLO: 175 +/- 23; PRO: 278 +/- 35; HCTZ: 255 +/- 34; placebo: 203 +/- 7).

Adrenergic Fibers↗
PubMed1986

Interaction between antidepressants and alpha 1-adrenergic receptor antagonists on the binding to alpha 1-acid glycoprotein.

alpha 1-Receptor antagonists and antidepressant agents are basic (cationic) drugs that are known to bind to alpha 1-acid glycoprotein (AAG). Since these drugs are frequently co-administered and since they bind to the same protein, this investigation was designed to evaluate the "in vitro" ability of antidepressants, alpha 1-receptor antagonists, and propranolol to displace [3H]imipramine and [3H]prazosin from the AAG binding site(s). Equilibrium dialysis was employed. Of the drugs studied, the following order of potency in displacing [3H]prazosin was found: trazodone greater than prazosin greater than doxazosin greater than propranolol greater than doxepin = amoxapine = trimazosin = amitriptyline greater than imipramine greater than nortriptyline = desipramine = nomifensine greater than bupropion = maprotiline. [3H]lmipramine binding from AAG was displaced with the following potency order: prazosin greater than imipramine greater than propranolol greater than doxazosin greater than nortriptyline greater than desipramine greater than trimazosin. Tricyclic antidepressants produced similar degrees of displacement of both [3H]imipramine and [3H]prazosin from AAG; whereas, alpha 1-receptor antagonists were more effective displacers of [3H]prazosin than of [3H]imipramine. Furthermore, the demethylated metabolites of imipramine and amitriptyline were less potent displacers than their parent compounds. These results suggest that more than a single binding site may be available for binding to AAG and that hydrophobic bonding is important in the binding of drugs to AAG.

Adrenergic alpha-Antagonists↗
PubMed1986

Liquid chromatographic assay and disposition of carvedilol in healthy volunteers.

Quantitative determination of serum concentrations of carvedilol [(+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl) amino]-2-propanol], a combined alpha- and beta-adrenergic receptor antagonist, was obtained using HPLC with spectrofluorometric detection. Carvedilol was extracted from alkalinized serum with ether and was subsequently back extracted with diluted phosphoric acid. This method proved to be sensitive and reproducible (mean coefficient of variation of 6.1% for 0.25 to 150 nanograms per milliliter of serum). A single dose of carvedilol (5, 10, or 15 mg) was given as an intravenous infusion to three healthy volunteers. Carvedilol serum concentration-time profiles were fitted best to a three-compartment model and the pharmacokinetic data revealed the following mean values: Vdss of 1.97 L/kg, mean residence time (MRT) of 4.66 h, and CL of 0.437 L X h-1 X kg-1.

Antihypertensive Agents↗