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At least 883 records · Page 49Linked to original sources
PubMed1988

A two-state model for the 5-HT2 receptor: effects of alpha-adrenoceptor ligands.

The mode of interaction of some alpha-adrenoceptor ligands with the 5-HT2-receptor system was investigated in the calf coronary artery. Isometric contractions caused by 5-hydroxytryptamine (5-HT) were studied on strips without endothelium. Phentolamine antagonized competitively (pKB = 7.4) the effects of 5-HT. Phentolamine also prevented the methysergide-induced depression of contractions elicited by 5-HT. The alpha 1-selective ligand 127I-HEAT depressed the responses to 5-HT. Both phentolamine and ketanserin prevented the depressant effects of I-HEAT on 5-HT-induced contractions. These and previous experiments are consistent with the existence of the 5-HT2 receptor in two interconvertible states R in equilibrium with R'. Interconversions between the high affinity state R and low affinity state R' (for 5-HT) appear to be modulated by an allosteric site A. The present and previous data suggest four possible modes of interaction of alpha-adrenoceptor ligands with the 5-HT2-receptor system: (a) ligands that compete with 5-HT for the 5-HT2 receptor in the R state (examples are nonselective phentolamine, alpha 1-selective ketanserin and corynanthine, and alpha 2-selective yohimbine and rauwolscine); (b) ligands such as I-HEAT that through binding to A depress the response to 5-HT by favouring the R' state; (c) ligands, such as ketanserin and phentolamine, that through binding to A favour the R state; and (d) ligands, such as phenoxybenzamine, that cause a covalent modification of the R state but not of the R' state. Qualitative and quantitative considerations suggest that in the calf coronary artery the described features are unrelated to alpha 1- and alpha 2-adrenoceptors.

Animals↗
PubMed1987

Effects of nonselective and selective alpha 1-adrenergic blockade on coronary blood flow during exercise.

This study was made to evaluate the relative importance of alpha 1- and alpha 2-adrenergic vasoconstrictor influences in opposing the increase in coronary blood flow that occurs during exercise. The effects of selective alpha 1-adrenergic blockade with prazosin were compared with nonselective alpha-adrenergic blockade with phentolamine on coronary hemodynamics during exercise in chronically instrumented dogs. During control conditions, graded treadmill exercise resulted in progressive increases of myocardial oxygen consumption; this was associated with increased coronary blood flow as well as with increased myocardial oxygen extraction. Although prazosin and phentolamine caused similar reductions of arterial pressure, phentolamine increased heart rate, myocardial oxygen consumption, and coronary blood flow at equivalent exercise levels, and prazosin did not significantly alter these variables. These effects of phentolamine appeared to result from blockade of presynaptic alpha 2-adrenergic receptors, which normally modulate norepinephrine release, that resulted in increased sympathetic effects on the heart. However, at comparable levels of myocardial oxygen consumption, prazosin and phentolamine resulted in similar significant increases of coronary venous PO2 and decreases of coronary vascular resistance. These data support a modest role for alpha 1-adrenergic coronary vasoconstriction during exercise but fail to document an additional role for postsynaptic alpha 2-adrenergic coronary vasoconstriction during exercise.

Animals↗
PubMed1987

[Effect of fentolamin on the resistance of the coronary vessels and on the frequency of the heart rate].

The effects of phentolamine on coronary resistance and heart rate, as well as the influence of beta 1-adrenoceptor blockade on phentolamine effects were studied on the isolated cat hearts. Phentolamine reduced coronary resistance in 100% of cases (-25.9 +/- 4.4%; p less than 0.001) and increased heart rate only in 31.6% of cases (+9.1 +/- 1.4%); on average the alterations of heart rate were nonsignificant (p less than 0.1). After beta 1-blockade with Cordanum the rate of coronary dilation reduced (p less than 0.001), the changes in coronary resistance being nonsignificant (p greater than 0.1). Basal coronary resistance and tone during phentolamine infusion without or after beta 1-blockade were identical (p greater than 0.1). Thus, the reduction of coronary resistance during phentolamine infusion was due to beta 1-adrenomimetic activity of the drug.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

[Mechanism of action of fentolamin on the gastric secretion].

Thirty-three experiments were made on mongrel dogs operated on according to Basov, with the use of phentolamine, pilocarpine, atropine, histamine and their combinations. It was established that administration of histamine gives rise to an increase in gastric secretion, provided the animals are pretreated with phentolamine or with combined pilocarpine and phentolamine. Histamine-induced gastric secretion considerably decreases, provided the animals are pretreated with atropine and ceases almost completely after administration of combined atropine and phentolamine. It is concluded that the stimulating effect of phentolamine on gastric secretion is caused by an increase in the sensitivity of H2-receptors and cholinoreceptors under blockade of the alpha-adrenoreactive systems.

Animals↗
PubMed1982

Adrenergic regulation of distention-induced gastrin release in humans.

To investigate the possible role of adrenergic nerves in neurally mediated gastrin release, we evaluated the effect of selective adrenergic blockade on the serum gastrin response to gastric distention in healthy human subjects. On separate days, 2 mg of propranolol (beta-adrenergic antagonist), 5 mg of phentolamine (alpha-adrenergic antagonist), or saline (control) was injected intravenously just before distending the stomach with 700 ml of isotonic saline. For 30 min following distention, intragastric pH was kept constant at 5.0 by in vivo titration. Propranolol reduced distention-induced gastrin release by approximately 90% (p less than 0.02), whereas phentolamine had no significant effect on the gastrin response to distention. In additional experiments, we evaluated the effect of the same doses of propranolol or phentolamine on the exaggerated gastrin response to gastric distention that occurred during cholinergic blockade with atropine. In the presence of atropine (2.3 microgram/kg i.v.), propranolol significantly (p less than 0.01) reduced distention-induced gastrin release, whereas phentolamine significantly enhanced the gastrin response to distention (p less than 0.01). We conclude that: (1) distention-induced gastrin release was reduced by propranolol, suggesting that gastric distention releases gastrin by a beta-adrenergic mechanism and (2) distention-induced gastrin release was enhanced by phentolamine, but only in the presence of atropine. Thus, adrenergic nerves appear to regulate the gastrin response to gastric distention in humans: beta-adrenergic pathways stimulate gastrin release, and alpha-adrenergic pathways may inhibit gastrin release under certain circumstances.

Adrenergic alpha-Antagonists↗
PubMed1984

Neurogenic and myogenic contractile responses of dog mesenteric arteries to reduced K+ concentration and their interactions with ouabain.

Maintained reduction in extracellular K+ concentrations [( K]e) of isolated canine mesenteric arteries produced two contractions separated by a period of several hours. The mechanisms for respective early and late contractions were investigated. First, early responses to reduced [K]e were examined quantitatively over a period of 2 hr. Critical [K]e for initiating the contraction was 0.14 mM. Early contractions induced by K-free solution were abolished by phentolamine (10(-6) M) or reserpine pretreatment (0.5 mg/kg) but were not inhibited by cocaine (3 X 10(-6) M) or bretylium (2 X 10(-5) M). Treatment with ouabain at a low concentration of 2 X 10(-7) M potentiated markedly the phentolamine-sensitive contractile response to reduced [K]e. In contrast, contractile responses to norepinephrine, tyramine and transmural electrical stimulation were not potentiated by ouabain. Second, the late contraction, that occurred 4 to 5 hr after K-free substitution, also occurred in arteries pretreated with phentolamine or reserpine. The phentolamine-resistant late contraction was not inhibited by atropine, chlorpheniramine, cimetidine, saralasin, aspirin or methysergide. Ouabain potentiated the late contractile response to reduced [K]e in the presence of phentolamine. Thus, in canine mesenteric arteries, reduction in [K]e causes an early contraction due to norepinephrine release from adrenergic nerves and a late contraction that appears to be of myogenic origin. Ouabain may enhance both neurogenic and myogenic derived contractions in response to reduced [K]e by exaggerating the inhibition of the Na+,K+ exchange pump in the membranes of adrenergic nerves and vascular smooth muscle.

Animals↗
PubMed1980

Adrenergic modulation of human pancreatic polypeptide (hPP) release.

Serum human pancreatic polypeptide (hPP) responses to adrenergic modulation were measured in 24 normal subjects. Epinephrine (6 microgram/min) was infused to stimulate adrenergic alpha- and beta-receptors. Beta-receptor stimulation was achieved by infusing epinephrine and selectively blocking alpha- receptors with phentolamine, and alpha-receptor stimulation was achieved by infusing epinephrine and blocking beta-receptors with propranolol. Combined alpha- and beta-receptor stimulation caused a small but insignificant rise in hPP concentration. Phentolamine alone caused a twofold rise in hPP concentration, which was abolished by simultaneous atropine infusion. Propranolol alone had no effect. Adrenergic beta-receptor stimulation with epinephrine plus phentolamine caused a sevenfold rise from 45 +/- 10 to 351 +/- 60 pM (P < 0.05), whereas adrenergic alpha-receptor stimulation caused a significant fall from 100 +/- 25 pM (the rise in hPP concentration induced by epinephrine) to 44 +/- 7.8 pM. The changes in hPP concentration did not correlate with changes in serum insulin, glucose, or free fatty acid (FFA) concentrations. The pattern of the response was quite different from insulin, while reached a peak within 1 min of phentolamine administration, whereas hPP levels rose slowly to a peak at 45 min. The rise induced by adrenergic beta-receptor stimulation with epinephrine plus phentolamine was equivalent to the rise from 40 +/- 11 to 280 +/- 48 pM caused by an insulin-induced fall in serum glucose of about 50% and that induced by isoproterenol infusion, which caused a fourfold rise from 69 +/- 3 to 271 +/- 84 pM. These data suggest that the adrenergic system may be important in the regulation of hPP release.

Adult↗
PubMed1996

The sympathetic nervous system contributes to capsaicin-evoked mechanical allodynia but not pinprick hyperalgesia in humans.

The contribution of the sympathetic nervous system (SNS) to pain, mechanical allodynia (MA), and hyperalgesia in humans is controversial. A clearer understanding is crucial to guide therapeutic use of sympatholytic surgery, blocks, and drug treatments. In rats, capsaicin-evoked MA, and to some extent, pinprick hyperalgesia (PPH), can be blocked with alpha-adrenoreceptor antagonists. In this study, we examined the contribution of the SNS to MA and PPH in normal human subjects by blocking alpha-adrenoreceptors with intravenous phentolamine. In a double-blinded, placebo-controlled, crossover study, subjects were given IV saline or phentolamine, 1 mg/kg over 20 min. Ten minutes after the start of the infusion, subjects received 100 micrograms of intradermal capsaicin on the foot dorsum with the temperature of the injected site clamped at 36 degrees C. The temperature of the uninjected foot was used to monitor the degree of alpha-adrenoreceptor blockade produced by phentolamine. Ongoing pain and MA and PPH areas were measured every 5 min for 60 min. A significantly greater increase in temperature on the uninjected foot was seen during the phentolamine infusion compared with the saline infusion, indicating alpha-adrenergic blockade. Significantly less MA was observed with the phentolamine infusion 10-25 min after capsaicin injection than with the saline infusion. No significant differences in ongoing pain or PPH areas were seen between the two infusions at any time. Our results suggest that capsaicin-evoked MA and PPH have different mechanisms, with the SNS having a role in MA but not in PPH or ongoing pain.

Capsaicin↗
PubMedDate not supplied

Interaction of cholecystokinin (CCK-33) and its C-terminal fragments: CCK-8 and CCK-4 with alpha- and beta-adrenoceptor agonists and antagonists in the cardiovascular system of rats. Part A.

The goal of the present study was to examine the interaction of cholecystokinin (CCK-33) and its fragments: C-terminal octapeptide (CCK-8) and C-terminal tetrapeptide (CCK-4) with alpha- and beta-adrenoceptor agonists and antagonists. The effect of this interaction on arterial blood pressure and function of isolated heart was studied in rats. The results indicate that: 1) CCK-33 enhances the influence of catecholamines: noradrenaline and isoprenaline, mainly on the function of isolated heart. This peptide does not change cardiovascular effects of alpha-adrenoceptor antagonist--phentolamine. CCK-33 diminishes the influence of propranolol on the function of isolated heart. The hypotensive effect of beta-adrenoceptor antagonist is not affected by CCK-33. 2) CCK-8 does not alter cardiovascular effects of noradrenaline and isoprenaline. The peptide diminishes the hypotensive effect of phentolamine and reverses the hypotensive effect of propranolol. CCK-8 enhances the influence of propranolol and does not change the influence of phentolamine on the function of isolated heart. CCK-8 enhances bradycardia evoked by propranolol. 3) CCK-4 does not change the influence of noradrenaline and isoprenaline on arterial blood pressure and diminishes the hypotensive effect of phentolamine and propranolol. The peptide does not change cardiac effects of noradrenaline and diminishes the effects of isoprenaline, phentolamine and propranolol. On the basis of the present study, we concluded that CCK-33 and its fragments CCK-8 and CCK-4 modify the cardiovascular action of alpha- and beta-adrenoceptor agonists and antagonists. We suggest that effects we have observed correlate with the activation of the CCK-A receptors (CCK-33, CCK-8) or CCK-B receptors (CCK-4). CCK-related peptides may increase or reduce the effects of catecholamines indirectly through activation of alpha-adrenoceptors. We can not exclude direct action of the peptides on the heart.

Adrenergic Agents↗
PubMed1986

Examination of spinal monoamine receptors through which brainstem opiate-sensitive systems act in the rat.

The microinjection through stereotaxically implanted guide cannulae of morphine (5 micrograms/0.5 microliter) into the periaqueductal gray, the n. raphe magnus or the n. reticulogigantocellularis results in a significant elevation in the latency of a thermally evoked, spinally mediated reflex (tail-flick) and a supraspinally organized response (hot-plate). Spinal serotonin, noradrenalin, opiate and dopamine receptors were antagonized by the injection through chronically implanted intrathecal catheters of methysergide, phentolamine, naloxone and cis-flupenthixol, respectively. After a significant elevation of the tail-flick response latencies with intracerebral injections of morphine into the periaqueductal gray, the magnitude of the reversal produced by the intrathecally administered antagonists was phentolamine = methysergide much greater than naloxone = cis-flupenthixol = 0. After a significant elevation of the tail-flick response latency with intracerebral injections of morphine into the n. raphe magnus, the magnitude of the reversal produced by the intrathecally administered antagonist was methysergide greater than phentolamine greater than naloxone much greater than cis-flupenthixol = 0. After a significant elevation of the tail-flick response latency was produced by the microinjection of morphine into the n. reticulogigantocellularis, the magnitude of the reversal produced by intrathecal antagonists was phentolamine greater than naloxone much greater than methysergide = cis-flupenthixol = 0. None of the intrathecal antagonists reversed the elevation of the hot-plate response latencies produced by morphine injections into the n. raphe magnus and n. reticulogigantocellularis injections. A significant, but clearly subtotal reversal of the elevated hot-plate response latencies produced by periaqueductal gray morphine was produced by intrathecal phentolamine and methysergide. It is concluded that discrete populations of brain opiate receptors in the periaqueductal gray, n. raphe magnus and n. reticulogigantocellularis differentially activate spinal monoamine and opioid receptors to modulate thermally evoked spinally mediated reflexes. The general failure of treatments which reverse the segmental reflex inhibition to reverse the hot-plate effects suggests that: other spinopetal pathways are operative; that descending pathways activated by these manipulations do not contribute to the analgesic effects of brainstem morphine; and/or that in addition to spinopetal modulation, brainstem opiate receptors modulate nociceptive transmission at the brainstem level.

Animals↗
PubMed2002

Biochemical and functional characterization of alpha-adrenergic receptors in the rabbit vagina.

Vascular and non-vascular smooth muscle within the vagina mediate important physiological changes during sexual arousal in women. In this study, we have characterized alpha-adrenergic receptors (AR) in rabbit vagina by assessment of radioligand binding, contractility of isolated tissue strips and genital hemodynamics. [3H]Prazosin and [3H]RX821002 (alpha-1 and alpha-2 AR selective antagonists) bound to rabbit vaginal membrane preparations with high affinity and limited capacity. Competition binding assays using both non-selective and subtype selective ligands for AR (phentolamine, prazosin, delequamine, rauwolscine and UK14304) further confirmed the presence of alpha-1 and alpha-2 AR in vaginal tissue. In organ bath preparations of vaginal tissue strips, norepinephrine-induced contraction was attenuated by alpha-1 and alpha-2 AR antagonists (prazosin, tamsulosin, delequamine and phentolamine). In anesthetized rabbits, intravaginal injection of the alpha-1 AR selective antagonist REC 15/2615 (50 and 100 microg/kg) caused a 2 to 3-fold increase in genital tissue oxyhemoglobin (OHb) concentration. Similar increases in tissue OHb were observed with intravaginal injection of phentolamine (500 microg/kg) or a tri-mixture of vasodilators (PGE1, papaverine, phentolamine). REC 15/2615, phentolamine or the tri-mixture also enhanced the amplitude and/or duration of change in genital tissue OHb after pelvic nerve stimulation. Thus, vaginal tissue expresses functional alpha-1 and alpha-2 AR, which modulate vaginal smooth muscle contractility and genital engorgement.

Administration, Intravaginal↗
PubMed1996

Effect of dose on the nasal absorption of epinephrine during cardiopulmonary resuscitation.

Delay in epinephrine administration during cardiopulmonary resuscitation (CPR) due to technical difficulties in obtaining an access site may be detrimental. To avoid this potential delay, we have previously shown that intranasal administration of phentolamine and epinephrine is a rapidly obtainable and feasible route of administration during CPR. A randomized blinded dose ranging study was performed in a controlled laboratory environment. Thirty mongrel dogs were randomized to one of the following dosage regimens: phentolamine, 0.25 or 2.5 mg/kg/nostril; epinephrine, 0.075, 0.75, or 7.5 mg/kg/nostril. Phentolamine was administered intranasally 1 minute before the intranasal administration of epinephrine to improve absorption. Each dog underwent 3 minutes of ventricular fibrillation followed by 7 minutes of closed chest CPR. Epinephrine was administered was administered at 3 minutes of CPR. Data from 26 dogs were included for analysis. Treatment B (0.25 and 7.5 mg/kg/nostril of phentolamine and epinephrine, respectively) produced the greatest elevation in coronary perfusion pressure (17 +/- 11 vs. 4 +/- 3 mm Hg for the next highest group, P < .003) and in epinephrine plasma concentrations (1,403 +/- 1,400 vs 290 +/- 182 ng/mL for the next highest group, P > .05). In addition, treatment B had the highest resuscitation rate, 100% (5/5) versus 0% to 50% for the other groups (P < .05). These data show that there is a dose response effect, with 0.25 and 7.5 mg/kg/nostril of phentolamine and epinephrine being the optimal dose studied. In addition, when administered in appropriate doses, intranasal epinephrine reaches the systemic circulation and increases coronary perfusion pressure and successful resuscitation during CPR in this canine model.

Absorption↗
PubMed1975

The effect of pregnancy on the control of lipolysis in fat cells isolated from human adipose tissue.

1. Lipolysis has been estimated by measuring the release of glycerol in isolated adipose tissue cells obtained from women in early prognancy, late pregnancy and 1 - 3 days post partum and from non-pregnant women. 2. Adipocytes of women at the end of pregnancy exhibited higher rates of lipolysis in response to adrenaline (1.5 - 15 muM) plus phentolamine (13 muM) than those of non-pregnant women or those in early pregnancy. 3. Lipolysis in response to adrenaline plus phentolamine in fat cells from women 1 - 3 days post partum was reduced compared to that at the end of gestation but was enhanced relative to that in the non-pregnant or early pregnant state. 4. Basal lipolysis also tended to be greatest at term. 5. Under conditions where the production of cyclic AMP was not rate limiting for the stimulation of lipolysis, that is in the presence of dibutyryl cyclic AMP (1 mM) or adrenaline (15 muM) plus phentolamine (13 muM) plus caffeine (1 mM), the release of glycerol in cells from women at term and in the puerperium was greater than that in women in the non-pregnant or early pregnant state. 6. Cell levels of cyclic AMP rose after incubation with adrenaline (6 muM) plus phentolamine or adrenaline (15 muM) plus phentolamine plus caffeine (1 mM) but were similar in all four groups of women. 7. It is concluded that the observed enhancement of lipolysis demonstrated in fat cells from women at the end of pregnancy reflects an increase in hormone-sensitive lipase activity rather than a modification of hormone receptor site sensitivity or of the rates of synthesis or breakdown of cyclic AMP. 8. This increase in adipose tissue lipolysis at the end of gestation could contribute to the reported rise in plasma nonesterified fatty acids in the final weeks of pregnancy.

Adipose Tissue↗
PubMed1982

Inhibitory actions of catecholamines on electrically induced contractions of the submucous plexus-longitudinal muscularis mucosae preparation of the guinea-pig oesophagus.

1 The submucous plexus-longitudinal muscularis mucosae preparation of the guinea-pig oesophagus was used to study the actions of catecholamines on the twitch responses to electrical stimulation.2 When the preparation was stimulated coaxially (0.1 Hz, 0.5 ms, supramaximal voltage), stable twitch-like contractions were obtained. These were abolished by tetrodotoxin (0.1 muM) and atropine (0.1 muM), potentiated by physostigmine (0.1 muM), and were mediated presumably by stimulation of intramural cholinergic nerves.3 The twitch contractions of the muscularis mucosae were inhibited by catecholamines, in a concentration-dependent manner. The order of potency was isoprenaline > adrenaline > noradrenaline > dopamine.4 The inhibitory actions of noradrenaline (1 muM) and adrenaline (1 muM) were partly reversed by phentolamine (1 muM) or by propranolol (1 muM), and completely abolished by both antagonists together. The inhibitory effect of dopamine (300 muM) was largely reversed by phentolamine (1 muM), but not by propranolol (1 muM), while the inhibitory action of isoprenaline was competitively antagonized only by propranolol (pA(2) of 7.6).5 The contraction of the muscularis mucosae to exogenously applied acetylcholine (ACh, 20 nM) which was comparable in magnitude with that to electrical stimulation was also inhibited by isoprenaline (0.1 muM), adrenaline (1 muM) and noradrenaline (1 muM), but not by dopamine (300 muM). In the presence of propranolol (1 muM), noradrenaline, adrenaline and dopamine potentiated the ACh-induced contraction, while the effect of isoprenaline was mainly antagonized. The potentiating effects were antagonized by further treatment with phentolamine (1 muM).6 Adrenaline, noradrenaline and dopamine but not isoprenaline, produced a weak contraction of the longitudinal muscularis mucosae in the presence of propranolol (3 muM). The contractile responses were completely inhibited by phentolamine (3 muM). Tone in the muscularis mucosae induced by carbachol (3 muM) in the presence of phentolamine (10 muM) was inhibited by catecholamines, in a concentration-dependent manner, an effect that was competitively antagonized by propranolol.7 In the submucous plexus-longitudinal muscularis mucosae preparation of the guinea-pig oesophagus there are three types of adrenoceptor, inhibitory prejunctional alpha-adrenoceptors, excitatory postjunctional alpha-adrenoceptors and inhibitory postjunctional beta-adrenoceptors, and cholinergic neurotransmission is inhibited by catecholamines acting at both prejunctional alpha- and postjunctional beta-adrenoceptors.

Animals↗
PubMed1986

Prejunctional beta-adrenoceptors in rabbit pulmonary artery and mouse atria: effect of alpha-adrenoceptor blockade and phosphodiesterase inhibition.

In rabbit isolated pulmonary artery previously incubated with [3H]-noradrenaline, isoprenaline (0.3 microM) had no effect on the stimulation-induced outflow of radioactivity. However, if the phosphodiesterase inhibitor ICI 63,197 (30 microM) or the alpha-adrenoceptor blocker phentolamine (1 microM) was present, then isoprenaline significantly enhanced the stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). ICI 63,197 (30 microM) but not phentolamine significantly enhanced the stimulation-induced outflow of radioactivity. In mouse isolated atria previously incubated with [3H]-noradrenaline and stimulated at a frequency of 10 Hz, isoprenaline had no effect on the stimulation-induced outflow of radioactivity; this is in contrast to its release-enhancing effects at stimulation frequencies of 4 Hz and 2 Hz. The facilitation of stimulation-induced outflow by isoprenaline at 4 Hz was blocked by propranolol (0.08 microM) which, by itself, had no effect on the stimulation-induced outflow. At a stimulation frequency of 2 Hz in mouse atria the facilitatory effect of isoprenaline (0.01 microM) was significantly greater in the presence of ICI 63,197 (30 microM) which, by itself, had no effect on the stimulation-induced outflow. Similarly, the facilitatory effect of isoprenaline was significantly greater in the presence of phentolamine (1 microM) but, in this case, phentolamine significantly enhanced the stimulation-induced outflow. These results suggest that facilitatory prejunctional beta-adrenoceptors are present in both rabbit pulmonary artery and mouse atria. The effects of the phosphodiesterase inhibitor ICI 63,197 suggest that they are linked to adenylate cyclase in both tissues and we propose that the ability of phentolamine to facilitate the release and enhance the effect of isoprenaline may be due to the blockade of alpha-adrenoceptor inhibition of adenylate cyclase. This latter proposition needs further investigation.

Adenylyl Cyclases↗
PubMed1988

Effect of chlorpromazine on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta.

1. The effects of chlorpromazine on sympathetic neuroeffector transmission have been studied in the rabbit isolated pulmonary artery and aorta. 2. Chlorpromazine (10(-8)-10(-5) M), prazosin (10(-9)-10(-7) M) and phentolamine (3 x 10(-8)-3 x 10(-5) M) decreased the contractions of pulmonary artery evoked by electrical field stimulation (150 pulses; 3 Hz). The rank order of inhibitory potency (ID50) was prazosin greater than chlorpromazine greater than phentolamine. 3. Rauwolscine (3 x 10(-9) M-4 x 10(-6) M) enhanced the neurogenic response by up to 201%. However, higher concentrations (6 x 10(-6)-3 x 10(-5) M) reduced the contractions evoked by transmural stimulation. 4. The inhibitory effect of prazosin (10(-6) M) was reversible, while that of chlorpromazine (10(-8) M) was not. 5. Chlorpromazine (10(-8)-10(-4) M), desmethylimipramine (3 x 10(-9)-10(-5) M), cocaine (10(-7)-3 x 10(-4) M) and phentolamine (10(-5)-3 x 10(-4) M) reduced the accumulation of [3H]-noradrenaline ([3H]-NA, 10(-8) M) by aorta. The rank order of inhibitory potency (ID50) was: desmethylimipramine greater than chlorpromazine greater than cocaine greater than phentolamine. Prazosin (10(-7)-10(-5) M) and rauwolscine (10(-8)-10(-4) M) did not reduce [3H]-NA accumulation. 6. Chlorpromazine (10(-8)-10(-6) M) and prazosin (3 x 10(-9)-10(-7) M) antagonized the contractions of aorta evoked by exogenous noradrenaline (10(-9)-3 x 10(-4) M) and phenylephrine (10(-9)-3 x 10(-3) M). The pA2 values for chlorpromazine on the alpha 1-adrenoceptors were 8.24 (noradrenaline) and 8.27 (phenylephrine). The corresponding values for prazosin were 8.64 and 8.57, respectively. 7. It is concluded that chlorpromazine and prazosin are potent inhibitors of postsynaptic alpha 1-adrenoceptors. Chlorpromazine and phentolamine, unlike prazosin and rauwolscine, are also inhibitors of Uptake.

Adrenergic alpha-Antagonists↗
PubMed1986

Dopamine, noradrenaline and isoprenaline: secretory and electrophysiological effects in vitro on mouse pancreas.

The amylase release from mouse pancreatic fragments was studied after dopamine (DA), and alpha- or beta-sympathomimetic agonist application. The electrical parameters of the acinar cell membrane were also monitored. Both DA (from 5 X 10(-6) to 10(-4) M) and beta-stimulants (isoprenaline from 5 X 10(-6) to 5 X 10(-5) M; noradrenaline from 3 X 10(-4) to 10(-3) M) evoked an increase in amylase release, while noradrenaline in alpha-receptor stimulating doses failed to have any effect. The stimulatory effect of DA was blocked by ganglion blockers (Arfonad 10(-5) M; pentamethonium 3 X 10(-5) M) in a competitive manner and a dual antagonism was observed with atropine (10(-7) M, 10(-9) M). An alpha-receptor antagonist (phentolamine 10(-5) M) and a beta-receptor antagonist (propranolol 10(-5) M) had no influence on the dopamine response. Moreover, the DA-induced stimulation was dependent on the presence of extracellular calcium. Perfusion with 10(-4) and 10(-3) M-DA or local application (from 77 micrograms to 4.3 mg), resulted in marked membrane depolarization with diminution of the input resistance. This effect was blocked by atropine (10(-5) M) and pentamethonium (10(-4) M), but not by propranolol (10(-5) M) or phentolamine (10(-5) M). The isoprenaline- (IP) and noradrenaline- (NA) induced increase in amylase release was competitively blocked by propranolol (10(-5) M) but not by phentolamine (10(-5) M). Atropine caused a dose-dependent (10(-7) M, 10(-6) M) decrease in the maximal response (non-competitive antagonism), while the ganglion blocker pentamethonium (10(-4) M) was without effect. NA caused membrane depolarization accompanied by a decrease in the input resistance after local application (from 77 micrograms to 1.6 mg). This effect persisted in the presence of 10(-5) M-phentolamine but was abolished by 10(-5) M-propranolol. IP perfusion (10(-4) and 10(-3) M) or local application (0.3 M; from 32 to 130 micrograms) caused the same electrical changes as those induced by NA and DA. The effect of IP persisted in the presence of 10(-5) M-phentolamine, 10(-4) M-pentamethonium and 10(-4) M-domperidone, but was abolished by propranolol (10(-5) M) and tetrodotoxin (5 X 10(-6) M) and markedly diminished by atropine (10(-5) M).(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed2004

Evidence of sustained forearm vasodilatation after brief isocapnic hypoxia.

Healthy subjects exposed to 20 min of hypoxia increase ventilation and muscle sympathetic nerve activity (MSNA). After return to normoxia, although ventilation returns to baseline, MSNA remains elevated for up to an hour. Because forearm vascular resistance is not elevated after hypoxic exposure, we speculated that the increased MSNA might be a compensatory response to sustained release of endogenous vasodilators. We studied the effect of isocapnic hypoxia (mean arterial oxygen saturation 81.6 +/- 4.1%, end-tidal Pco2 44.7 +/- 6.3 Torr) on plethysmographic forearm blood flow (FBF) in eight healthy volunteers while infusing intra-arterial phentolamine to block local alpha-receptors. The dominant arm served as control. Forearm arterial vascular resistance (FVR) was calculated as the mean arterial pressure (MAP)-to-FBF ratio. MAP, heart rate (HR), and FVR were reported at 5-min intervals at baseline, then while infusing phentolamine during room air, isocapnic hypoxia, and recovery. Despite increases in HR during hypoxia, there was no change in MAP throughout the study. By design, FVR decreased during phentolamine infusion. Hypoxia further decreased FVR in both forearms. With continued phentolamine infusion, FVR after termination of the exposure (17.47 +/- 6.3 mmHg x min x ml(-1) x 100 ml of tissue) remained lower than preexposure baseline value (23.05 +/- 8.51 mmHg x min x ml(-1) x 100 ml of tissue; P < 0.05). We conclude that, unmasked by phentolamine, the vasodilation occurring during hypoxia persists for at least 30 min after the stimulus. This vasodilation may contribute to the sustained MSNA rise observed after hypoxia.

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