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PubMed1982

Characterization of adrenergic control of glucagon secretion from isolated perfused rat pancreas.

In order to characterize the adrenergic control of the pancreatic A cell the effect on glucagon secretion of three sympathomimetic substances - epinephrine, isoproterenol and phenylephrine - and two adrenergic blocking agents - propranolol and phentolamine - were tested separately in the basal state and during glucagon hypersecretion induced by arginine infusion or glucopenia, using the isolated perfused rat pancreas. Epinephrine and isoproterenol infusion caused a prompt and sustained glucagon release in the basal state and potentiated glucagon response to metabolic stimuli. Insulin secretion was suppressed by epinephrine and slightly stimulated by isoproterenol. The stimulatory effect on glucagon secretion observed during phenylephrine infusion was abolished by concomitant propranolol infusion and potentiated by phentolamine. Insulin secretion was markedly depressed by phenylephrine: this effect was reserved by concomitant phentolamine infusion, while no effect was observed by concomitant propranolol infusion. Propranolol caused a suppression of both glucagon and insulin secretion, while phentolamine slightly enhanced glucagon and insulin production. In conclusion, beta-adrenergic receptor stimulation markedly increased pancreatic glucagon secretion and slightly enhanced pancreatic beta-cell activity; conversely, alpha-adrenergic agents markedly depressed insulin secretion while scarcely influencing glucagon production.

Animals↗
PubMedDate not supplied

Interactions between sympathomimetic agonists and blocking agents: cardiac effects of phenylephrine and isoproterenol.

In the isolated rat atria the effects of phenylephrine (alpha-agonist) and isoproterenol (beta-agonist) on the contractile force and heart rate were studied either in presence or not of alpha- and/or beta-blockade. Phentolamine 10(-6) M and propranolol 10(-8) M were used as alpha- and beta-antagonists, respectively. The chronotropic dose-response curves were made in both spontaneously beating atria while inotropic effects were derived from left atria driven at 1 Hz, 5 msec and voltage about 20 percent above threshold. Both agonists induced an inotropic effect that could be significantly blocked by phentolamine, propranolol and both antagonists given together. The chronotropic dose-response curve of isoproterenol (pD2 = 10.70 +/- 0.11) was blocked by phentolamine (pD2 = 9.27 +/- 0.08, p less than 0.001) and propranolol (pD2 = 9.21 +/- 0.19, p less than 0.001). Contrarily, pentolamine was unable to shift to the right the chronotropic dose-response curve for phenylephrine (pD2 = 6.48 +/- 0.07 and 6.63 +/- 0.10, respectively). This action of phenylephrine on the heart rate was significantly blocked by propranolol (pD2 = 6.21 +/- 0.13, p less than 0.05) and by propranolol plus phentolamine (pD2 = 6.07 +/- 0.04, p less than 0.001). From the present results it is concluded that in the rat's atrial myocardium there exist alpha- and beta-adrenoceptors mediating the positive inotropic effect of isoproterenol and phenylephrine. Yet, the chronotropic action seems to behave in a different way: while isoproterenol triggered either type of receptors; phenylephrine is only mediated by beta-adrenoceptors.U

Animals↗
PubMed1980

Transcriptional and translational control of nafenopin-induced ornithine decarboxylase activity in rat liver.

The induction of liver ornithine decarboxylase activity by nafenopin was studied in rats. The alpha-adrenergic antagonist, phentolamine, injected 0.5 hr before nafenopin, greatly potentiated the response. Actinomycin D, injected before nafenopin, did not affect nafenopin-induced ornithine decarboxylase activity whereas the potentiating effect of phentolamine was inhibited. In contrast, administration of actinomycin D 5.0 hr after nafenopin markedly enhanced nafenopin-induced activity. The induction of ornithine decarboxylase activity by nafenopin, as well as the potentiating effect of phentolamine was inhibited by 1,3-diaminopropane and cycloheximide, implying a requirement for synthesis of new enzyme protein for both effects. These results suggest that nafenopin induced ODC through a posttranscriptional mechanism whereas the potentiating effect of phentolamine requires transcription of new messenger RNA.

Animals↗
PubMed1998

The role of epidermal growth factor in platelet-endothelium interactions.

The objective of this study was to determine whether endogenous EFG released after submaximal physical exercise, affects platelet-endothelium interactions. Sixteen healthy male volunteers, aged 23-26 years, were submitted to a submaximal bicycle ergometry test. Blood for determination of EGF concentrations, platelet function studies (concentrations of beta-TG, PF4 and TXB2) and endothelium activity (LTC4 and endothelin-1,2 concentrations) was taken via an intravenous catheter before starting exercise and 15, 30 and 60 min after. A similar scheme was followed to investigate changes in the same parameters induced by a slow intravenous infusion of 0.3 mg/kg b.w. phentolamine (an alpha-adrenergic blocker) before exercise. Plasma concentrations of EGF and the markers of platelet function-beta-TG and PF4 as well as LTC4 concentrations increased only 15 min following exercise. The concentrations of TXB2, and endothelium-1,2 were almost unchanged 15 min after the submaximal bicycle ergometry test. Phentolamine markedly decreased the EGF concentrations in plasma (15 min following exercise) while at 30 and 60 min after exercise it had no effect on this parameter. No significant changes in concentrations of beta-TG, PF6, LTC4 and endothelin-1,2 after phentolamine infusion were found. These results show that increase of plasma EGF following exercise was accompanied with increase of beta-TG, PF4 and LTC4 concentrations. Inhibition of alpha-adrenergic receptors with phentolamine abolished the exercise-induced increase in plasma EGF concentration. The findings suggest that endogenous EGF may affect the platelet function and changes the reactivity of the vascular endothelium.

Adult↗
PubMed1976

The ability of pimozide to prevent inhibition by dopamine analogs of cardioaccelerator nerves in cat hearts.

The dopamine receptor blocking agent, pimozide, antagonized inhibitory actions of apomorphine, N,N-dimethyldopamine and 5,6-dihydroxy-2-dimethyl-aminotetralin (M-7) on stimulation-induced positive chronotropic responses of cat hearts in both in vivo and in vitro experiments. Pimozide did not antagonize the inhibitory effect of clonidine in vitro experiments. Phentolamine, an alpha-adrenergic blocking agent, antagonized the inhibitory actions of dopamine analogs at 1.10 mug/ml concentration in in vitro experiments. Phentolamine, 0.3 mug/ml, only attenuated the response of N, N-dimethyldopamine but did not antagonize the effects of apomorphine and M-7. Lower concentration of phentolamine, 0.1 mug/ml, showed marked inhibition to the inhibitory effect of clonidine. Both phentolamine and pimozide potentiated stimulation-induced positive chronotropic responses of cat right atria. Possibility of the presence of dopaminergic inhibitory system near the alpha-adrenergic inhibitory system in cardioaccelerator nerve terminal is discussed.

Animals↗
PubMed1990

Inhibitory prejunctional muscarinic receptors at sympathetic nerves do not operate through a cyclic AMP dependent pathway.

In mouse atria previously incubated with [3H]-noradrenaline, carbachol (1.0 mumo1/l) significantly inhibited the fractional stimulation-induced (S-I) outflow of radioactivity. The inhibitory effect of carbachol was greater in the presence of the alpha-adrenoceptor antagonist phentolamine (1.0 mumol/l), which by itself significantly increased the S-I outflow of radioactivity. In both cases the inhibitory effect of carbachol was blocked by atropine (0.3 mumol/l), suggesting that the effect was mediated through muscarinic receptors. 8-Bromo cyclic AMP (270 mumol/l) in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 100 mumol/l), was used to maximally enhance the S-I outflow of radioactivity through the cyclic AMP mechanism. The inhibitory effect of carbachol either in the presence or in the absence of phentolamine, was not reduced in the presence of 8-bromo cyclic AMP and IBMX. Similar results with carbachol in the presence of 8-bromo cyclic AMP and IBMX were also found in rat right atrial strips which had been incubated with [3H]-noradrenaline. These results suggest that the effects through inhibitory prejunctional muscarinic receptors are not mediated by cyclic AMP. The protein kinase inhibitor, staurosporine (0.1 mumol/l), significantly blocked the enhancing effects of 8-bromo cyclic AMP (270 mumol/l) plus IBMX (100 mumol/l) on the S-I outflow of radioactivity from rat atrial strips. The inhibitory effect of carbachol (1.0 mumol/l) however, was not reduced in the presence of staurosporine, suggesting that protein kinases affected by staurosporine (protein kinase A, protein kinase C) are not involved in the post-receptor mechanism for inhibitory prejunctional muscarinic receptors. This finding further rules out the involvement of cyclic AMP in muscarinic inhibition. The inhibitory effect of carbachol either by itself or in the presence of phentolamine, was not reduced in atria from mice that had been pretreated with pertussis toxin (1.5 or 3.0 micrograms). Furthermore, in rat atrial strips, the inhibitory effect of carbachol either in the presence or in the absence of phentolamine, was also not altered by pretreating the rats with pertussis toxin (8.4 micrograms). The results suggest that in both tissues the major mechanism for inhibition of noradrenaline release through muscarinic receptors does not involve a pertussis toxin sensitive G protein.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Effects of imidazoline-related compounds on the mechanical response to nicorandil in the rat portal vein.

The purpose of this study was to investigate the interactions of compounds structurally related to imidazoline at K+ channels located in the rat portal vein. Nicorandil, a K+ channel activator, dose dependently inhibited spontaneous contractions of the isolated rat portal vein. Glibenclamide (0.1-1 microM), an ATP-sensitive K+ channel blocker, competitively antagonized the response to nicorandil, whereas methylene blue (10 microM), a guanylate cyclase inhibitor, did not. Phentolamine, antazoline, tolazoline, and midaglizole also shifted the dose-response curve for nicorandil to the right in the dose range of 1-100 microM. The rank order of potency was glibenclamide much greater than phentolamine = antazoline = midaglizole greater than tolazoline. In contrast, clonidine, idazoxan, imidazole, 1-benzylimidazole, and yohimbine were ineffective. In addition, cromakalim (1-100 nM), a selective K+ channel activator, also inhibited spontaneous contractions of the rat portal vein, and this effect was antagonized by phentolamine in a similar way to that found with nicorandil. These results suggest that some 2-substituted imidazolines, including phentolamine, possibly act as K+ channel blockers, like glibenclamide, in vascular smooth muscle.

Animals↗
PubMed1984

Neurotransmitter-blocking agents influence antinociceptive effects of carbamazepine, baclofen, pentazocine and morphine on bradykinin-induced trigeminal pain.

The influence of naloxone (a narcotic antagonist), bicuculline (a GABA antagonist), phentolamine (an alpha-blocking agent), propranolol (a beta-adrenergic blocking agent), haloperidol (a dopaminergic blocking agent), methysergide (a serotonergic blocking agent) and atropine (a muscarinic blocking agent), on the antinociceptive effects induced by carbamazepine, baclofen, pentazocine and morphine, were investigated with a new antinociception test, using the trigeminal pain induced by application of bradykinin onto the tooth pulp of the rat. The antinociceptive effect of carbamazepine was significantly inhibited by bicuculline, phentolamine, propranolol and haloperidol but not by naloxone, methysergide and atropine. The effect of baclofen was significantly reduced by naloxone, bicuculline, propranolol and atropine but not by phentolamine, haloperidol and methysergide. The antinociceptive actions of pentazocine and morphine on trigeminal pain were significantly reduced by naloxone and phentolamine, and by naloxone alone, respectively. These results suggest the involvement of different neurotransmitters in the antinociceptive effects of the four analgesic drugs on trigeminal pain induced by bradykinin.

Analgesics↗
PubMed1994

Prejunctional action of the venom from the Indian red scorpion Mesobuthus tamulus on adrenergic transmission in vitro.

Venom (RSV) from the Indian red scorpion, Mesobuthus tamulus (Buthus tamulus), can cause increased peripheral sympathetic activity with consequent enhancement of adrenergic responses. We have therefore investigated the effects of RSV on adrenergic transmission in the rat isolated anococcygeus muscle. The effects of phentolamine (5 microM), tetrodotoxin (2 microM), guanethidine (5 microM), desipramine (1 microM) and reserpine pretreatment in vivo (5 mg/kg s.c. x 24 hr and 5 mg/kg i.p. x 3 hr) on the contractile responses of the rat anococcygeus muscle to RSV (1.5 microgram/ml), field stimulation, noradrenaline (NA, 1 microM or 3 microM) and tyramine (15 microM) were compared. The contractile responses to RSV and to field stimulation were completely blocked by phentolamine, tetrodotoxin, guanethidine and reserpine pretreatment, but the responses were potentiated by desipramine. The contractile responses to tyramine were completely blocked by phentolamine, reserpine pretreatment as well as desipramine. The responses to NA were completely blocked by phentolamine, but were potentiated by guanethidine, desipramine and reserpine. Relatively low concentrations (0.1 microgram/ml x 4) of RSV which did not produce any observable increase in tone of the anococcygeus muscle, potentiated the contractile response of the anococcygeus muscle to field stimulation, but not the responses to exogenous NA; 4-aminopyridine (25 microM x 2) also potentiated the muscle responses to field stimulation. HPLC measurements revealed only very low concentrations (0.10 +/- 0.03 mumol/g venom) of NA in RSV. Thus, the adrenergic agonist action of RSV in the rat isolated anococcygeus muscle can be attributed to the involvement of some prejunctional mechanism(s) of action that stimulates the release of neurotransmitter which differs from the indirect action mediated by tyramine.

Animals↗
PubMed1988

Inhibitory effects of atropine and adrenergic antagonists on the changes in autonomic receptors and cyclic nucleotides of rat parotid and submandibular glands caused by sympathetic nerve stimulation.

The changes in cyclic AMP (cAMP) concentration and density of beta-adrenoceptors caused by electrical stimulation of the sympathetic innervation to parotid and submandibular glands of rat did not occur when the alpha- and beta-adrenergic antagonists, phentolamine, and propranolol were administered 20 min prior to initiation of stimulation. They also did not occur when phentolamine, the beta-adrenergic antagonist, was administered alone prior to nerve stimulation, indicating that beta-adrenoceptors mediate these effects. Simultaneous administration of the alpha- and beta-antagonists also prevented the changes in densities of muscarinic receptors and cGMP concentrations usually induced by sympathetic nerve stimulation. Also, the changes in muscarinic receptors and cGMP did not occur when atropine was administered prior to nerve stimulation, nor did they occur with simultaneous administration of atropine, phentolamine + propranolol; with phentolamine alone, or propranolol alone, the effects were blocked to a large extent. Secretion was inhibited completely when both adrenergic antagonists were present during nerve stimulation, but flow rate was unchanged when atropine was present. The changes in both beta-adrenoceptors and muscarinic receptors reflect a desensitization caused by prolonged exposure to neurotransmitters released when the sympathetic nerve is stimulated. The changes are prevented when either atropine or adrenergic antagonists are present during nerve stimulation.

Adrenergic beta-Antagonists↗
PubMed2005

Effects of Ya-hom on blood pressure in rats.

The effects of Ya-hom, a traditional Thai herbal formulation, on blood pressure were evaluated to verify its use for fainting treatment. Ya-hom has several recipes, which are composed of different medicinal plants in varying ratio. We have selected the most popular commercial preparation to determine the effect on the blood pressure in rats. The water extract of Ya-hom at doses of 0.2, 0.4, 0.6 and 0.8 g/kg initially transiently decreased pressure and over time, increased blood pressure. The duration of the Ya-hom effect on decreasing and increasing blood pressure was dose dependent. The time to maximal effect of Ya-hom on increasing blood pressure was also dose dependent. Phentolamine attenuated the blood pressure decreasing effect but did not affect the blood pressure increasing effect of Ya-hom. Ya-hom was previously shown to increase aortic ring contraction, which was partially inhibited by phentolamine, and increased atrial contraction. It is possible that phentolamine inhibits the effect of Ya-hom on vascular smooth muscle contraction resulting in a prominent positive inotropic effect. This may be the same reason that phentolamine does not influence the effect of Ya-hom on increasing blood pressure. The dominant effect of Ya-hom on increasing blood pressure supports the use of Ya-hom for the treatment of fainting.

Animals↗
PubMed1997

Dopamine constricts porcine pial veins.

Dopamine has been shown to induce pial arterial relaxation and constriction in several species. Its mode of action on pial veins, however, remains unclarified. The vasomotor effect of dopamine on porcine pial veins was, therefore, examined using an in vitro tissue bath technique. The results indicated that dopamine constricted exclusively isolated ring segments of pial veins in the presence or absence of active muscle tone. The constriction induced by dopamine was not affected by N(omega)-nitro-L-arginine (L-NNA, 2 x 10(-5) M) or indomethacin (10(-5) M). Only in few preparations was the constriction induced by maximum concentration of dopamine potentiated by L-NNA, suggesting that dopamine at high concentrations may release NO or a NO-related substance. In the presence of L-NNA (2 x 10(-5) M), dopamine-induced constriction was inhibited by phentolamine and yohimbine (but not prazosin) in a concentration-dependent manner with maximum inhibition at 10(-6) M. SKF38393 and 6-bromo-APB (selective dopamine D1 receptor agonists) and LY171555 (a selective dopamine D2 receptor agonist) also induced pial venous constriction exclusively in the presence of L-NNA. The constriction was not affected by phentolamine (10(-6) M). The order of potency for these agonists in the presence of phentolamine, propranolol, guanethidine and L-NNA was: 6-bromo-APB > SKF38393 > dopamine > LY171555. The dopamine-induced constriction in the presence of phentolamine was further inhibited by both SCH23390 (a selective dopamine D1 receptor antagonist) and sulpiride (a selective dopamine D2 receptor antagonist), but was not affected by dopamine D3 or D4 receptor antagonists. These results indicate that dopamine at low and high concentrations induces exclusively constriction of isolated porcine pial veins. The constriction is mediated by postsynaptic alpha2-adrenoceptors, and dopamine D1 and D2 receptors.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1998

Role of adrenergic nervous system in cigarette smoke-induced bronchoconstriction in guinea pigs.

The goal of this study was to clarify the role of the adrenergic nervous system in bronchoconstriction induced by exposure to cigarette smoke in guinea pigs. Artificially ventilated animals were exposed to 160 puffs of smoke for 8 min. Bronchoconstriction was assessed as a percentage of the baseline total pulmonary resistance (RL). The effects of pretreatment with phentolamine (0.1 mg/kg, i.v.), propranolol (1 mg/kg, i.v.), and/or atropine (1 mg/kg, i.v.) were evaluated. Exposure to cigarette smoke caused significant bronchoconstriction. Phentolamine, an alpha-adrenoceptor antagonist, significantly inhibited cigarette smoke-induced bronchoconstriction, while propranolol, a beta-adrenoceptor antagonist, significantly enhanced it. Combined use of these compounds further enhanced the bronchoconstriction. All of modulations of the bronchoconstriction by adrenoceptor antagonists were completely abolished by pretreatment with atropine. Phentolamine and/or propranolol had no effect on the bronchoconstriction induced by inhaled acetylcholine. Pretreatment with yohimbine (0.5 mg/kg, i.v.), a selective alpha2-adrenoceptor antagonist, showed modulatory effects similar to those of phentolamine on cigarette smoke-induced bronchoconstriction. These results suggest that cigarette smoke-induced bronchoconstriction is regulated by the prejunctional modulation of the cholinergic system via alpha- and beta-adrenoceptors. This mechanism may be modulated by the autoregulation of adrenergic nerves via the alpha2-autoreceptor.

Acetylcholine↗
PubMed1998

Postischemic left ventricular dysfunction is abolished by alpha-adrenergic blocking agents.

OBJECTIVES: We sought to evaluate the efficacy of alpha-adrenergic blocking agents in counteracting left ventricular (LV) dysfunction occurring after transient ischemia in humans. BACKGROUND: The mechanisms underlying postischemic LV dysfunction are largely unknown. METHODS: Percutaneous transluminal coronary angioplasty (PTCA) provides a clinical model of ischemia and reperfusion. In 50 patients undergoing coronary stenting for 77+/-5% stenosis, LV function was monitored by transesophageal echocardiography during and 30-min after PTCA. Fifteen minutes after stenting, 15 patients received 12 microg/kg body weight of the alpha-blocker phentolamine intracoronarily, 15 patients received 600 microg/kg of the alpha1-blocker urapidil intravenously, 10 patients received the combination of phentolamine and 1.2 mg of propranolol intracoronarily, and 10 patients received saline. RESULTS: Fifteen minutes after successful coronary dilation, significant contractile dysfunction occurred in previously ischemic and nonischemic myocardium. LV dysfunction was accompanied by an increase in coronary resistance and diffuse vasoconstriction. Alpha-blockers counteracted LV dysfunction and coronary resistance and the increase in vasoconstriction. Phentolamine and urapidil increased global LV shortening from 34+/-9% to 45+/-8% and to 49+/-8%, respectively (p < 0.05). After the administration of propranolol combined with phentolamine, LV dysfunction remained unchanged (34+/-6%), as in control subjects. CONCLUSIONS: LV dysfunction occurs after PTCA, as described in animal models after ischemia. Alpha-blockers abolished LV, macrocirculatory and microcirculatory dysfunction, whereas the alpha-blocker effect was prevented by combining alpha- and beta-blockers. The evidence of diffuse rather than regional dysfunction, together with the opposite effects of alpha- and beta-blockade, supports the hypothesis of neural mechanisms eliciting postischemic LV dysfunction.

Adrenergic alpha-Antagonists↗
PubMed1993

Dopamine DA2-receptor activation inhibits noradrenaline release in human kidney slices.

Dopamine receptor modulation of noradrenaline release from renal sympathetic nerves was investigated. Human kidney slices were incubated with 3H-noradrenaline, placed into superfusion chambers between two platinum electrodes and field-stimulated at 5 Hz. The slices accumulated radioactivity. Pretreatment of the kidney slices with 6-hydroxy-dopamine (1.2 mM) prior to the 3H-noradrenaline incubation reduced the accumulation of radioactivity. The stimulation induced (S-I) outflow of radioactivity was mainly composed of intact 3H-noradrenaline. The sodium channel blocker tetrodotoxin (1 microM), 6-hydroxy-dopamine pretreatment and omission of calcium from the superfusion solution abolished S-I outflow of radioactivity. The DA1-receptor agonist fenoldopam (SKF 82526; 0.01 and 0.1 microM) did not alter but fenoldopam (1 microM) increased S-I outflow of radioactivity. However, in the presence of either the non-selective alpha-adrenoceptor antagonist phentolamine (1 microM) or the selective alpha 2-adrenoceptor antagonist idazoxan (1 microM) fenoldopam (1 microM) had no effect. The DA2-receptor agonist quinpirole (LY 171555; 1 microM) inhibited S-I outflow of radioactivity, an effect blocked by the selective DA2-receptor antagonists S(-)-sulpiride (10 microM) and domperidone (0.3 microM) but unaltered either by the DA1-receptor antagonist SCH 23390 (1 microM) or by phentolamine (1 microM). The alpha 2-adrenoceptor agonist UK 14304 (0.1 microM) inhibited S-I outflow of radioactivity, and this effect was blocked by phentolamine (1 microM) and idazoxan (1 microM) but unaltered by S(-)-sulpiride (10 microM). Phentolamine and idazoxan, in contrast to S(-)-sulpiride, domperidone and SCH 23390, enhanced S-I outflow of radioactivity by themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Up-regulation of the levels of expression and function of a constitutively active mutant of the hamster alpha1B-adrenoceptor by ligands that act as inverse agonists.

The alpha1-adrenergic agonist phenylephrine stimulated phospholipase D (PLD) activity in Rat 1 fibroblasts transfected to express either the wild-type hamster alpha1B-adrenoceptor or a constitutively active mutant (CAM) form of this receptor. The EC50 for agonist stimulation of PLD activity was substantially lower at the CAM receptor than at the wild-type receptor as previously noted for phenylephrine stimulation of phosphoinositidase C activity. Sustained treatment of cells expressing the CAM alpha1B-adrenoceptor with phentolamine resulted in a marked up-regulation in levels of this receptor with half-maximal effects produced within 24 h and with an EC50 of approx. 40 nM. Such an up-regulation could be produced with a range of other ligands generally viewed as alpha1-adrenoceptor antagonists but equivalent treatment of cells expressing the wild-type alpha1B-adrenoceptor was unable to mimic these effects. After sustained treatment of the CAM alpha1B-adrenoceptor expressing cells with phentolamine, basal PLD activity was increased and phenylephrine was now able to stimulate PLD activity to greater levels than in vehicle-treated CAM alpha1B-adrenoceptor-expressing cells. The EC50 for phenylephrine stimulation of PLD activity was not altered, however, by phentolamine pretreatment and the associated up-regulation of the receptor. After phentolamine-induced up-regulation of basal PLD activity, a range of alpha1-antagonists were shown to possess the characteristics of inverse agonists of the CAM alpha1B-adrenoceptor as they were able to substantially decrease the elevated basal PLD activity.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1990

Modulation of adrenoceptor-mediated cardiovascular effects by short-term in vivo infusion of isoproterenol in rats.

After a 16-h in vivo infusion period of isoproterenol (400 micrograms/kg/h) from a minipump implanted subcutaneously (s.c.) in rats, we observed an increase in heart weight due to tissue edema. In isolated perfused heart preparations, the EC50s of isoproterenol to induce positive inotropy and increase in coronary flow were increased approximately 7 and 4 times, respectively. Isoproterenol dose-response curves performed in trachea preparations, were shifted to the right by about fivefold as compared with the control group. In the presence of phentolamine, the isoproterenol induced maximal relaxation in the isolated aorta from isoproterenol-pretreated animals was reduced from 46.5 to 9.2% as compared with saline-pretreated rats. In the absence of phentolamine, the epinephrine (EPI) and norepinephrine (NE) cumulative dose-response curves in this preparation were not affected by isoproterenol pretreatment with respect to EC50 and maximal effect. However, in the presence of phentolamine, the contractile response to a supramaximal dose of NE (10 microM) amounted to 30 and 70% in the saline- and isoproterenol-pretreated rats, respectively. In the presence of both phentolamine and propranolol, a similar response of 70% was observed by this supramaximal dose of agonist in the saline-pretreated rats as well. In anesthetized rats, 120 min after removal of the minipumps, sodium nitroprusside induced increase in heart rate (HR) was reduced after isoproterenol pretreatment, whereas for salbutamol the decrease in diastolic blood pressure (DBP) was also reduced. As compared with salbutamol, a marked increase was observed in the ratio of mean arterial blood pressure (MAP) to HR for SNP after isoproterenol pretreatment. The phenylephrine-induced increase in MAP was increased after isoproterenol pretreatment. We conclude that in the pathogenesis of heart failure the beta-adrenoceptor-mediated effects of catecholamines are attenuated and alpha-adrenoceptor-mediated effects become progressively important.

Animals↗
PubMedDate not supplied

Dual effects of clonidine on rat prejunctional alpha-adrenoceptors.

1. The effects of clonidine (1.0 mumol/l) and phentolamine (3.0 mumol/l) on the stimulation-induced efflux of radioactivity were assessed in rat isolated atria and tail arteries in which transmitter stores had been labelled with (3H)-noradrenaline. 2. In atria, clonidine did not affect transmitter release when stimulation was for 10 s periods at frequencies of 1, 2 or 5 Hz, whereas at 10 Hz there was a significant 1.2-fold enhancement of release. Phentolamine enhanced release with stimulation at 5 Hz and 10 Hz by 1.5- and 2.5-fold respectively. 3. In tail arteries, clonidine reduced release when stimulation was for 30 s periods at a frequency of 1 Hz, but did not affect release at 2 Hz or 5 Hz. Phentolamine in each case produced an approximately 1.5-fold enhancement of release. 4. In the pithed rat, spinal stimulation of cardioaccelerator fibres produced a tachycardia, the magnitude of which depended on the frequency and duration of stimulation. Clonidine (10 micrograms/kg, i.v.) caused either a reduction or an enhancement of the response depending on the frequency and duration of stimulation; in the presence of phentolamine (2 mg/kg, i.v.), clonidine had no effect. 5. The results are consistent with partial agonistic actions of clonidine at prejunctional alpha-adrenoceptors in the rat cardiovascular system; such effects may be of relevance to the mechanism of the clonidine withdrawal syndrome.

Animals↗