SEARCH · Search PubMed

Results for “PHENTOLAMINE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 847 records · Page 47Linked to original sources

PubMed2001

Desensitization of insulin secretory response to imidazolines, tolbutamide, and quinine. I. Secretory and morphological studies.

The desensitization of pancreatic B-cells against stimulation by insulin secretagogues that inhibit ATP-dependent K(+) channels (K(ATP) channels) was investigated by measuring insulin secretion of perifused pancreatic islets. Additionally, the islet insulin content and the number of secretory granules per B-cell were determined. Prior to the measurement of secretion, islets were cultured for 18 h in the presence or absence of the test agents in a cell-culture medium containing 5 mM glucose. The effects of three imidazolines, phentolamine, alinidine, and idazoxan (100 microM each) were compared with those of the well-characterized sulfonylurea, tolbutamide (500 microM), and those of the ion channel-blocking alkaloid, quinine (100 microM). Insulin secretion was strongly reduced upon re-exposure to phentolamine, alinidine, tolbutamide, and quinine, whereas idazoxan, which stimulated secretion only weakly, had no significant effect. The imidazoline secretagogues phentolamine and alinidine induced a cross-desensitization against the stimulatory effect of tolbutamide and quinine. A long-term depolarization with 40 mM KCl was also able to induce a significant reduction of the secretory response to all of the above secretagogues. The insulin content of cultured islets was moderately, but significantly reduced by alinidine, whereas the reduction by phentolamine, tolbutamide, and quinine was not significant. In contrast to these observations, the ultrastructural examination revealed that tolbutamide-treated B-cells had a high degree of degranulation, whereas the other test agents and 40 mM KCl produced only a partial degranulation, except for phentolamine, which produced no significant degranulation at all. These results suggest that the desensitization of insulin secretion is a common property of all agents that stimulate insulin secretion by depolarisation of the plasma membrane. Depending on the specific secretagogue, additional mechanisms, proximal and distal to Ca(2+) influx, appear to contribute to the desensitization (see Rustenbeck et al., pages 1695-1703, this issue).

Animals↗

PubMed1987

Effect of alpha-adrenergic and serotonergic blockers on the acute irritative response in the rabbit eye.

The effect of alpha-adrenergic and serotonergic (5-HT) blockers on the acute irritative response in the rabbit eye elicited by topical, neutral formaldehyde (1%), was studied. In the control animals, the peak rise in the intraocular pressure (delta IOP) after irritation was 29.5 +/- 5.7 mm Hg, and the perfusion pressure of the eye at 1 min after irritation was 50.1 +/- 2.8 mm Hg. The peak rise in the IOP was inhibited by phentolamine (alpha- and 5-HT-antagonist, delta IOP = 6.6 +/- 2.1 mm Hg, P less than 0.01), methysergide (5-HT-antagonist, delta IOP = 10.6 +/- 4.4 mm Hg, P less than 0.05), and prazosin (alpha 1-antagonist, delta IOP = 12.8 +/- 3.7 mm Hg, P less than 0.05). Perfusion pressures of the eyes were decreased after pretreatment with phentolamine or prazosin, and were 35.2 +/- 4.8 mm Hg (P less than 0.05) and 25.7 +/- 3.7 mm Hg (P less than 0.01), respectively. Perfusion pressure in the methysergide group remained unchanged (75.4 +/- 14.2 mm Hg). Yohimbine (alpha 2-antagonist) and ketanserin (5-HT2-antagonist) did not inhibit the IOP response. None of the antagonists could inhibit the miosis or disruption of the blood-aqueous barrier induced by topical neutral formaldehyde. In the contralateral eyes, the changes in the IOP, in the integrity of the blood-aqueous barrier, and also in the pupil size, were enhanced by ketanserin. The present study demonstrates the inhibitory actions of methysergide, phentolamine, and prazosin on the neurally mediated, acute irritative response in the rabbit eye. Methysergide seems to inhibit the response, probably acting via the 5-HT1-receptors. A part of the effect of phentolamine might be explained by an inhibitory action via 5-HT1-receptors. The effect of phentolamine and prazosin on the alpha 1-receptors seems to create an inhibitory action on the irritative response by lowering the perfusion pressure of the eye.

Adrenergic alpha-Antagonists↗

PubMed2001

Depletion of brown fat norepinephrine content by acute cold exposure and adrenoceptor blockade.

Experiments were conducted to characterize the effects of acute cold exposure, with and without adrenoceptor blockade, on intrascapular brown adipose tissue (IBAT) and adrenal catecholamine content in male Sprague-Dawley rats. Groups of animals with indwelling temperature transmitters were tested following treatment with saline, the alpha-adrenoceptor blocker phentolamine, the beta-adrenoceptor blocker propranolol, combined blockade with phentolamine plus propranolol, and the ganglionic blocker chlorisondamine. IBAT norepinephrine (NE) content was not affected in animals tested at 22 degrees C, but was reduced in 4 degrees C-exposed animals treated with phentolamine (-57%), phentolamine plus propranolol (-97%), and chlorisondamine (-42%). Adrenal NE and epinephrine (EPI) content were not altered by the treatments at 4 degrees C or 22 degrees C. None of the treatments affected the temperature of animals at 22 degrees C, but significant hypothermia occurred at 4 degrees C after chlorisondamine (-2.3+/-0.3 degrees C) and the combination of phentolamine and propranolol (-1.5+/-0.4 degrees C). These results suggest that cold exposure alone did not affect IBAT NE content, but when cold exposure was combined with adrenoceptor blockade, the sympathetic activation was sufficient to cause a reduction in IBAT NE content. In addition, alpha- and beta-adrenoceptor-mediated mechanisms contribute to the maintenance of core temperature. However, both alpha- and beta-receptor mechanisms had to be interrupted before a deficit in body temperature was detected.

Adipose Tissue, Brown↗

PubMed2000

Interaction between AVP and sympathetic system in subtotal nephrectomy-saline hypertension: role of alpha and V1 receptors.

The development process of subtotal nephrectomy-salt hypertension is still unclear. The aim of the present study was to determine the role of the interaction between vasopressin and sympathetic system in the development of this hypertension by using AVP V1 antagonist and alpha blocker phentolamine under anesthesia condition. For this purpose, we carried out about 73% subtotal nephrectomy on male Wistar rats. One group of these rats (normotensive group) was given a low-salt diet and the other group (hypertensive group) was given a high-salt diet for 4 weeks. Finally, eight groups of rats were formed according to the kind(s) of the injected drug(s): (1) normotensive and hypertensive groups injected only V1 antagonist, (2) normotensive and hypertensive groups injected only phentolamine, (3) normotensive and hypertensive groups injected first V1 antagonist and then phentolamine, (4) normotensive and hypertensive groups injected first phentolamine and then V1 antagonist. Either V1 or alpha blockage separately led to a higher reduction in the mean blood pressure (MAP) of the hypertensives than, of the normotensives (p < 0.05). The combined blockage of V1 and alpha receptors, also caused a higher decrease in the MAP of hypertensive group than, of normotensive group, not depending on the order of the injections (p < 0.01). The heart rate increase recorded as a response to the phentolamine injection in normotensive group, did not develop in hypertensive group (p < 0.05). There was no significant difference between the two groups with regard to plasma electrolytes and osmolality. A positive correlation was found between systolic blood pressure and plasma osmolality in hypertensive group (r = 0.40, p < 0.05), but not in normotensive group. We conclude that the increase in V1 and alpha pressor activities contributes to the subtotal nephrectomy-saline hypertension and the augmentation of alpha pressor activity by vasopressin may participate in this contribution.

Adrenergic alpha-Antagonists↗

PubMed1995

Role of alpha-adrenoceptors in the maintenance of core temperature in humans.

1. Although alpha-adrenoceptor antagonists have been shown to induce core hypothermia in animals, it is unclear whether the primary mechanism is increased heat loss or decreased heat production. Furthermore, studies have not been performed in humans to determine the role of alpha-adrenoceptors in the maintenance of core temperature. 2. alpha-Adrenoceptor blockade was achieved with three doses of phentolamine given by random assignment on three different study days in five male and five female healthy subjects. Core temperature, mean skin-surface temperature, fingertip capillary blood flow and metabolic heat production were measured. Dose-response curves were plotted for all measured variables, and males and females were compared to identify potential gender differences. 3. Core temperature decreased with all doses of phentolamine. At the completion of the phentolamine infusion, the decrease in core temperature was more significant with high-dose (0.3 +/- 0.1 degrees C, P = 0.03) and with medium-dose (0.2 +/- 0.0 degrees C, P = 0.05) phentolamine than with low-dose phentolamine (0.1 +/- 0.0 degrees C). The maximum core temperature decrease during the study was more significant with high dose (0.6 +/- 1 degrees C) than with medium (0.3 +/- 1 degrees C, P = 0.04) or low (0.3 +/- 1 degrees C, P = 0.005) doses. Mean skin-surface temperature was increased with all doses. Fingertip blood flow was increased (approximately 60% above baseline) with the medium and high doses, but was unchanged with the low dose. Total body oxygen consumption was unchanged regardless of dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1977

New detection of brain dopamine receptors with (3H)dihydroergocryptine.

Because dihydroergocryptine (DHE) and closely related ergots are dopamine-mimetic agonists, we tested [3H]DHE as a possible ligand for [3H]dopamine receptors in the calf caudate. In order to avoid [3H]DHE from tagging alpha-adrenergic receptors, an excess of 500 nM phentolamine was used to block these sites, permitting the dopamine receptors to be measured separately. Specific binding of [3H]DHE was defined as total binding minus that occurring in the presence of 1 muM (+)-butaclamol. Excess phentolamine reduced the specific binding of [3H]DHE from 328 down to 138 fmol/mg, the difference presumably representing alpha-receptors. The KD for [3H]DHE was 0.55 nM (with or without phentolamine), and this high affinity site was blocked (in the presence of phentolamine) by 250nM apomorphine, 650 nM dopamine, and 1200 mM (minus)-norepinephrine, indicating that[3H]DHE was binding to dopamine receptors. All neuroleptics blocked specific [3H]DHE binding in direct relation to the clinical potency of the neuroleptic. The displacement of specific [3H]DHE binding by dopamine or by norepinephrine (in the presence of phentolamine) revealed two subsets of dopamine receptors.

Animals↗

PubMed1989

Urodynamic effect of acute alpha-receptor blockade in patients with bladder neck dysfunction.

Forty-nine male patients, median age 35 years (range 16-59) with bladder neck dysfunction (BND) were investigated before and after intravenous administration of phentolamine to evaluate the effect of acute alpha-blockade on micturition parameters and to identify patients, who might benefit from alpha-blocking therapy. Under the influence of phentolamine we found a significant decrease in the mean values of maximal urethral closure pressure (MUCP), pressure at the bladder neck and prostatic profile length (PPL), a decreased bladder capacity, a more complete bladder emptying, and a small but significant improvement in peak flow rate (PFR). However, according to a flow-rate nomogram analysis with correction for voided volume, only two patients significantly improved their PFR. A subgroup of 20 "responders", defined as patients with any improvement of PFR after phentolamine, not caused by increased detrusor pressure was characterized by significantly longer opening time and lesser maximal flow rate before phentolamine (more severe BND). All other pressure-flow parameters as well as the static pressure at bladder neck niveau were not different. We conclude that it is not possible before phentolamine administration to select a group of patients, which might benefit from alpha-blockade and it is suggested that this procedure might be included in the evaluation of patients with suspected BND.

Adult↗

PubMedDate not supplied

Interaction of imidazoline alpha-adrenergic receptor antagonists with histamine receptors.

Because the alpha-adrenergic receptor antagonists phentolamine and tolazoline are similar in structure to histamine, it is possible that the vasodilatation caused by these drugs may be due in part to stimulation of histamine receptors. The vascular effects of these agents were studied in the hindquarters of rats and the gracilis muscle of dogs. To eliminate interruption of sympathetic vasoconstrictor tone as a mechanism of vasodilatation, all animals were treated with the alpha-adrenergic receptor antagonist, dibozane. After dibozane, histamine caused vasodilatation in the rat, whereas both tolazoline and phentolamine caused vasoconstriction. It is concluded that phentolamine and tolazoline do not stimulate vascular histamine receptors in the rat. In the dog, after alpha-receptor blockade, phentolamine and tolazoline caused vasodilatation, as did histamine. Responses to histamine were partially attenuated by mepyramine and greatly attenuated by the combination of mepyramine and metiamide, indicating the participation of both H1- and H2-histamine receptors. Vasodilatation caused by phentolamine was not reduced by antihistamines and does not appear to involve histamine receptors. Vasodilatation following tolazoline was blocked by metiamide but not mepyramine. It is concluded that in addition to blockade of alpha-adrenergic receptors, tolazoline can cause vasodilatation by stimulation of histamine H2-receptors.

Adrenergic alpha-Antagonists↗

PubMed1995

Role of the sympathoadrenal axis in the cardiovascular response to cocaine in conscious unrestrained rats.

We investigated the role of peripheral sympathetic neurons and the adrenal medulla in the cardiovascular responses to cocaine in conscious, unrestrained Sprague-Dawley rats. Surgical adrenal demedullation (ADM) and/or chemical peripheral sympathectomy was used to eliminate one or both components of the sympathoadrenal axis. Phentolamine (5 mg/kg i.v.) was used to evaluate whether cocaine elicited epinephrine (EPI) release from the adrenal medulla. Significant EPI release by cocaine would result in "epinephrine reversal" after phentolamine pretreatment. Cocaine (2.5 mg/kg i.v.) was used in all experiments except the dose-response relationship study. In normal rats, cocaine caused a transient increase in mean blood pressure (MBP). Pretreatment with phentolamine reversed this BP response and this depressor effect was blocked by propranolol (2 mg/kg i.v.) suggesting that the pressor effect of cocaine was mediated by EPI. Chemical sympathectomy alone partially inhibited the pressor effect of cocaine, but pretreatment with phentolamine still reversed the residual action of cocaine on MBP at this time. Two weeks after ADM, the effect of cocaine on MBP was not significantly different from that of the sham-operated rats. However, pretreatment with phentolamine inhibited but did not reverse the effect of cocaine on MBP at that time. In rats with both ADM and chemical sympathectomy, cocaine caused only a decrease in MBP that was not blocked by propranolol or atropine methylnitrate, presumably because of its direct depressive actions. Results of this study suggest that both peripheral sympathetic neurons and the adrenal medulla play important roles in the cardiovascular actions of cocaine.

Adrenal Medulla↗

PubMed1971

Effect of catecholamines and angiotensin on extracellular water and cation movements and the effect of alpha and beta-adrenoceptor blockade.

1. The extracellular fluid volume (ECFV), as raffinose space, and its content of Na, K and Ca were measured in anaesthetized dogs in acute experiments before and during the vascular response to intravenous injections and infusions of noradrenaline, adrenaline, isoprenaline and angiotensin.2. In male dogs the effect of noradrenaline was unpredictable, the ECFV might increase or decrease. In female dogs noradrenaline caused an increase in the ECFV. The difference between the responses of the two sexes was statistically significant (P<0.001). After phentolamine, noradrenaline exerted no effect at all in either sex. After bretylium the results were like those in normal animals.3. In both males and females adrenaline generally induced an increase in the ECFV. After phentolamine, adrenaline decreased the ECFV in males and caused little change in females. The differences before and after blockade were statistically significant (P<0.001). After bretylium the results in both sexes were like those in normal animals.4. In both male and female dogs isoprenaline induced an increase in the ECFV and the results were the same as in the normal animals after both phentolamine and bretylium.5. In male dogs there was no change in the ECFV as a result of administering angiotensin, either alone or in the presence of phentolamine or bretylium. In normal females angiotensin induced a decrease in ECFV and the difference between the responses of the males and females was statistically significant (P<0.005). In females which had received either phentolamine or bretylium the results were indistinguishable from those in the males.6. Blockade of the beta-adrenoceptors with pronethalol in a few animals did not change the response to the drugs from those seen in normal animals.7. The cation content of the ECF changed in the same direction and to about the same extent as the water, except after noradrenaline when in some experiments the proportionate change in potassium concentration was considerably greater than that of the other substances.8. The inulin space and its Na and K content were measured in several dioestrous, oestrous and pro-oestrous rats and in normal and stilboestrol treated males before and after giving an intravenous injection of angiotensin. There was little difference between the results of control injections of 0.9% saline solution and of angiotensin in dioestrous and oestrous females and normal males. On the other hand, pro-oestrous females and stilboestrol treated males responded alike to angiotensin in the form of a decrease in ECFV which was statistically different from the responses in the other three groups (P<0.0005).9. It is suggested that the various results depend on two factors: the site of action of the drug-for example, whether it increases or decreases capillary pressure and therefore, fluid transfer-and also the sex of the animal. The ground substance of the small blood vessels is probably important in taking up and releasing fluid, and its capacity for so doing may well vary with the amount of available oestrogen. It appears that the effect of oestrogens and events at the alpha-adrenoceptor site are connected in some way.

Adrenergic alpha-Antagonists↗

PubMed1980

Effects of clonidine on canine cardiac neuroeffector structures controlling heart rate.

1 In intact dogs anaesthetized with pentobarbitone, clonidine (10 mug/kg, i.v.) produced a sustained decrease in heart rate. This effect was significantly smaller in vagotomized dogs in which the sympathetic drive to the heart was either left intact or experimentally created by continuous electrical stimulation of the decentralized cardioaccelerator nerve. In the latter preparation, the negative chronotropic action of clonidine was reversed by an intravenous injection of phentolamine, whereas in the former experimental situation it was antagonized only by an intravenous plus an intravertebral artery injection of phentolamine.2 In dogs with denervated hearts the tachycardia produced by electrical stimulation of the cardioaccelerator nerve was accompanied by a rise in noradrenaline overflowing into the coronary sinus plasma. Clonidine inhibited both these effects and phentolamine restored them to pre-clonidine levels.3 Clonidine decreased heart rate in dogs with an intact parasympathetically innervated heart and decentralized stellate ganglia. When the low basal heart rate of this preparation was elevated by electrical stimulation of the cardioaccelerator nerve, clonidine had a negative chronotropic effect, the degree of which was similar to that observed in intact dogs.4 Clonidine neither modified baseline heart rates of dogs with denervated hearts nor the levels of heart rate which in this preparation were reduced by a sustained electrical stimulation of the right vagus or increased by intravenous infusions of either isoprenaline or noradrenaline.5 These findings indicate that in the intact dog, bradycardia induced by clonidine resulted both from a reduction of sympathetic drive and from a concomitant increase in parasympathetic tone. The latter action did not occur at the level of cardiac neuroeffector structures since it was observed only in the presence of centrally connected vagal pathways. The inhibition of cardiac sympathetic tone was of both peripheral and central origin. Clonidine, in fact, diminished the quantity of noradrenaline overflowing into the coronary sinus plasma in cardiac denervated dogs with a tachycardia elicited by electrical stimulation of the decentralized cardioaccelerator nerve. This peripheral effect was probably due to an activation of alpha-adrenoceptors located on sympathetic nerve terminals since it was antagonized by phentolamine. However, in vagotomized dogs (intact sympathetic pathways) intravenous phentolamine failed to antagonize the heart rate effects of clonidine which were abolished by a subsequent injection of phentolamine into the vertebral artery. Thus, the clonidine-induced inhibition of both the peripheral and central sympathetic drive to the heart would appear to be mediated via alpha-adrenoceptors.

Animals↗

PubMed1980

The effect of prazosin on the guinea-pig ileum.

1 The alpha-adrenoceptor blocking activity of prazosin was compared with that of phentolamine, yohimbine and phenoxybenzamine in the guinea-pig isolated ileum. 2 Phentolamine (2.56 X 10(-8) to 2.56 X 10(-6) M) and yohimbine (5.12 X 10(-8) to 5.12 X 10(-6) M) antagonized the sympathetic inhibition of twitches induced by transmural stimulation, whereas prazosin (5.28 X 10(-8) to 5.28 X 10(-6) M) and phenoxybenzamine (4.2 X 10(-9) to 4.2 X 10(-7) M) had no effect. 3 Phentolamine, yohimbine, prazosin and phenoxybenzamine antagonized the relaxant response of the ileum to periarterial nerve stimulation and to exogenous noradrenaline in the absence of transmural stimulation. 4 The pA2 value for phentolamine against noradrenaline in the transmurally-stimulated gut (presynaptic alpha-adrenoceptor site; 8.17 +/- 0.04) was significantly different from that in the non-stimulated gut (postsynaptic alpha-adrenoceptor site; 6.88 +/- 0.12). 5 Phentolamine and prazosin probably block noradrenaline responses at the same alpha-adrenoceptor site on the postsynaptic membrane.

Adrenergic alpha-Antagonists↗

PubMed1982

Presynaptic effect of clonidine antagonized by the tetramine disulphide, benextramine.

1 The presynaptic alpha-adrenoceptor blocking activity of the newly synthesized alpha-adrenoceptor blocking drug, benextramine, was evaluated in the isolated left atrium of the guinea-pig heart. 2 High-voltage stimulation increased the force of contraction of electrically driven atrial strips, presumably by releasing noradrenaline from sympathetic nerve endings. Like phentolamine, benextramine increased the effect of high-voltage stimulation, presumably by blocking presynaptic alpha-adrenoceptors. 3 Clonidine reduced the effect of high-voltage stimulation, presumably by stimulating presynaptic alpha-adrenoceptors. The inhibitory effect of clonidine was antagonized noncompetitively by benextramine and competitively by phentolamine. 4 Combined administration of benextramine and phentolamine only resulted in the competitive phentolamine antagonism. Thus phentolamine protected the presynaptic alpha-adrenoceptors against benextramine blockade.

Adrenergic alpha-Antagonists↗

PubMed1985

Interaction between the inhibitory action of acetylcholine and the alpha-adrenoceptor autoinhibitory feedback system on release of [3H]-noradrenaline from rat atria and rabbit ear artery.

Stimulation-induced increases in the efflux of radioactivity (S-I efflux) were measured in the bathing medium following labelling of the noradrenergic transmitter pools of rat atria and rabbit artery preparations with [3H]-noradrenaline. In atria stimulated with trains of 16 or 60 pulses at 2 Hz, phentolamine enhanced, whereas acetylcholine inhibited S-I efflux. With trains of 16 pulses phentolamine had a smaller enhancing effect than with trains of 60 pulses, whereas the inhibitory effect of acetylcholine was more pronounced with 16 pulses of stimulation. The inhibitory effect of acetylcholine was markedly enhanced by phentolamine when stimulation was with 60 pulses. With 16 pulses of stimulation the effect of acetylcholine was unaltered by phentolamine and abolished by the alpha 2-adrenoceptor agonist 3,4-dihydroxyphenylimino-2-imidazolidine (DPI). Phentolamine had no effect on the negative inotropic effect of acetylcholine on driven left atrial preparations. In arterial preparations stimulated with trains of 30 pulses at 1 Hz, both acetylcholine and clonidine inhibited S-I efflux, whereas yohimbine and idazoxan enhanced S-I efflux. Combining acetylcholine with clonidine did not alter the inhibitory effect of clonidine but the combination of acetylcholine with yohimbine or idazoxan abolished the marked enhancing effects of yohimbine or idazoxan on S-I efflux. These findings indicate that there may be a reciprocal interaction between prejunctional alpha-adrenoceptors and prejunctional muscarinic cholinoceptors.

Acetylcholine↗

PubMed1990

Characterization of responses to cromakalim and pinacidil in smooth and cardiac muscle by use of selective antagonists.

1. In dog isolated coronary artery (precontracted with endothelin, 10 nM) cromakalim (0.1-30 microM) and pinacidil (1-30 microM) produced concentration-dependent vasorelaxant responses. The effects of these compounds could be blocked by glibenclamide (3 microM), phentolamine (30 microM) or alinidine (30 microM) to a similar extent, indicating that both agents alter vascular tone through the same mechanism in this preparation. 2. The ability of the antagonists glibenclamide, phentolamine and alinidine to block the response to cromakalim in a number of smooth muscle types from the guniea-pig was determined. Cromakalim (0.1-30 microM) produced concentration-dependent relaxant responses in thoracic aorta (precontracted with endothelin, 30 nM), ileum (precontracted with K+, 25 mM) and trachea (spontaneously contracted). Responses to cromakalim in all tissues could be blocked by the three antagonists. However, significantly higher concentrations of the antagonists were required to block responses in the thoracic aorta than in the ileum or trachea. Given that the rank order of potency of the antagonists was similar in all tissues (i.e. glibenclamide greater than phentolamine = alinidine), this result may suggest vascular K+ channels opened by cromakalim are quantitatively but not qualitatively different in vascular compared with non-vascular smooth muscle. Glibenclamide was approximately 10 times more potent than phentolamine or alinidine. 3. Cromakalim had minimal functional effects on the rat spontaneously beating right atrial (rate) or electrically driven left ventricular strip (force) preparations. Similarly the three antagonists studied failed to alter force generation in the right ventricular strip. However alinidine and phentolamine did produce a dose-related bradycardia in the spontaneously beating right atria. This effect appears to be unrelated to blockade of the K+ channel opened by cromakalim since glibenclamide, the most potent K+ channel antagonist studied, failed to produce the same response. 4. It would appear that the K+ channel opened by cromakalim is present in a number of vascular and non-vascular smooth muscle. Based on the potency of the three antagonists studied, there appears to be little heterogeneity in the process activated by cromakalim in vascular and non-vascular smooth muscle.

Animals↗

PubMed1999

Imidazolines and the pancreatic B-cell. Actions and binding sites.

Stimulation of insulin secretion by imidazoline compounds displays variable characteristics. Phentolamine (10-100 microM) increased secretion of perifused mouse islets at nonstimulatory glucose concentrations (5 mM) and even in the absence of glucose. Idazoxan (20-100 microM) elicited a moderate increase in insulin secretion, which required the presence of a stimulatory glucose concentration (10 mM). Phentolamine is therefore a stimulator of secretion in its own right, whereas idazoxan may be termed an enhancer of secretion. Both compounds inhibited the activity of ATP-dependent K+ channels in inside-out patches from B-cells; however, idazoxan achieved only an incomplete block. Both compounds depolarized the B-cell plasma membrane to an extent that permitted the opening of voltage-dependent Ca2+ channels (-40 to -30 mV). An increase in cytoplasmic Ca2+ concentration was induced by phentolamine and much less so by idazoxan. Activation of protein kinase C, a possible mechanism to amplify Ca(2+)-induced secretion, could not be verified for phentolamine. It thus appears that stimulation of insulin secretion by phentolamine is due to its blocking effect on KATP channels, which may be the correlate of non-adrenergic imidazoline binding sites which were characterized in insulin-secreting HIT cells. Whether incomplete closure of KATP channels by idazoxan or additional effects are responsible for the requirement of high glucose to stimulate secretion remains to be clarified.

Adenosine Triphosphate↗

PubMed1968

Shivering and non-shivering therogenesis during summit metabolism in young lambs.

1. Summit metabolism of lambs declined steadily from about 3.5 l. O(2)/kg.hr during the first day of life, to about 2.0 l. O(2)/kg.hr at 2 months of age.2. The contributions of shivering and non-shivering thermogenesis to these changes were estimated by three independent methods; non-shivering thermogenesis was stimulated by catecholamines in a thermoneutral environment, shivering was suppressed by curariform drugs during summit metabolism, and an attempt was made to suppress non-shivering thermogenesis during summit metabolism by use of the sympatholytic drugs phentolamine and propranolol. Drugs were given by intravenous infusion during measurement of oxygen consumption in a closed circuit respiration chamber.3. ;Resting' metabolic rate of lambs during the first day of life was increased two to three-fold, from 1 l. O(2)/kg.hr, by either adrenaline or noradrenaline infused at 1-10 mug/kg.min. The increase declined with increasing age of lamb and was virtually absent by 3 weeks. The response to catecholamines appeared maximal at the dose levels used.4. Muscular paralysis induced by suxamethonium or gallamine reduced summit metabolism by about 2 l. O(2)/kg.hr in all lambs examined within the first 2 months of life. The residual metabolic rate, and the metabolic response to catecholamines under thermoneutral conditions, declined with age in the same manner, and their magnitudes were similar.5. Summit metabolism in lambs aged up to 2 months was depressed to varying degrees by the sympathetic inhibitors phentolamine, propranolol and hexamethonium. The depression with propranolol was greater, and the decline with age clearer, than with phentolamine. Hexamethonium and phentolamine depressed blood pressure, propranolol decreased heart rate and phentolamine and propranolol each suppressed shivering in some experiments.6. In 1 day-old lambs estimates of non-shivering thermogenesis, by the various methods, ranged from 0.8 to 1.4 l. O(2)/kg.hr (mean 1.1 l. or 31% of summit metabolism), and the estimates of shivering ranged from 1.3 to 1.9 l. O(2)/kg.hr (mean 1.6 l. or 46% of summit metabolism). However, in lambs 1-month old, estimates of non-shivering thermogenesis from sympathetic inhibition (0.6 and 0.8 l. O(2)/kg.hr) were considerably higher than estimates from muscular paralysis or stimulation by catecholamines (0.2 and 0.1 l. O(2)/kg.hr). It is suggested that the depression of summit metabolism by the sympathetic inhibitors is not solely due to specific inhibition of non-shivering thermogenesis, at least in the older lambs.7. The possession of a non-shivering thermogenic mechanism in addition to shivering is of clear survival value to new-born lambs.

Age Factors↗

PubMed1981

Neuromuscular transmission and smooth muscle membrane properties in the guinea-pig ear artery.

Effects of noradrenaline and alpha-adrenoceptor blocking agents on neuromuscular transmission of the guinea-pig ear artery were assessed using the micro-electrode method.1. The mean membrane potential, and length and time constants of the longitudinally oriented muscle cells were -64.5 +/- 5 mV (n = 150), 1.03 +/- 0.16 mm (n = 15) and 410 +/- 40 msec (n = 7) respectively. From the current-voltage relationship, weak outward current pulses produced an anomalous rectification of the membrane while stronger intensities produced a normal rectification of the membrane with a depolarization over 10-15 mV.2. Brief stimulation (0.1-0.5 msec) of the tissue produced an excitatory junction potential (e.j.p.). Facilitation produced by repetitive stimulation was evident only on very rare occasions. Higher stimulus intensities caused a stepwise increase of the amplitude of e.j.p.s.3. Spontaneously generated miniature excitatory junction potentials (m.e.j.p.s) were recorded from the muscle membrane. In many cells, the interval and amplitude histograms of m.e.j.p.s showed skew curves. On rare occasions, a bell-shaped amplitude distribution (quantal release of packeted noradrenaline (NA)) was observed.4. NA (> 3 x 10(-7)m) depolarized the membrane and increased the membrane resistance, as measured from the amplitude of the electrotonic potential. Phentolamine suppressed the NA-induced depolarization. However, high concentrations of phentolamine (> 10(-5)m) depolarized the membrane and increased the membrane resistance.5. NA (10(-8)m) caused no change in membrane potential though it suppressed the amplitude of an e.j.p. produced by a single stimulus, but did not suppress the amplitude of the subsequent e.j.p.s evoked by repetitive stimulation (0.2-2.0 Hz). A higher concentration of NA (3 x 10(-7)m) depolarized the membrane and markedly suppressed the amplitude of e.j.p.s. On the other hand, NA (10(-8) or 2 x 10(-8)m) generated burst discharges of m.e.j.p.s between silent periods or random generation.6. Phentolamine (10(-6)m) markedly enhanced the amplitude of e.j.p.s and caused a smooth facilitation in response to a train of stimuli with no effect on the membrane potential. A stepwise change in the amplitude of e.j.p.s was no longer observed at any given stimulus frequency and intensity.7. Phenoxybenzamine (10(-7)m) suppressed the amplitude of e.j.p.s with no change in the membrane potential.8. The results led to the conclusion that, at a concentration which has no effect on the post-junctional muscle membrane, NA and phentolamine seemed to be more effective on prejunctional adrenoceptors, while phenoxybenzamine seemed to have a greater effect on post-junctional adrenoceptors. NA depresses adrenergic transmission by negative feed-back, while the enhancing action of phentolamine can be explained partly by blocking of prejunctional adrenoceptors and, in addition, by an increase of NA release.

Animals↗