G protein and alpha-adrenoceptor classification.
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GTP-Binding Proteins↗
Biomedical subjects
I F Musgrave
Publications and source records attributed to I F Musgrave.
Effect of phorbol ester and pertussis toxin on the enhancement of noradrenaline release by angiotensin II in mouse atria.
1. Mouse atria were incubated with [3H]-noradrenaline, and the outflow of radioactivity due to electrical field stimulation (5 Hz, 60 s) was used as an index of noradrenaline release. Angiotensin II (0.01 and 0.1 microM) significantly enhanced the stimulation-induced (S-I) outflow of radioactivity. 2. Phorbol 12-myristate 13-acetate (0.001, 0.03, 0.1 and 1.0 microM), a protein kinase C activating phorbol ester, significantly enhanced the S-I outflow of radioactivity. When angiotensin II (0.1 microM) was present with the concentration of phorbol 12-myristate 13-acetate that was maximally effective in increasing the S-I outflow (0.1 microM), the enhancement of S-I outflow produced by angiotensin II was maintained. 3. Polymyxin B (70 microM), an inhibitor of protein kinase C, significantly inhibited the S-I outflow. Polymyxin B also inhibited the enhancement of the S-I outflow produced by angiotensin II (0.1 microM). 4. In another series of experiments mice were injected with pertussis toxin (1.5 micrograms per mouse), 4 days before their atria were removed. The effectiveness of pertussis toxin pretreatment was determined indirectly using carbachol. Carbachol caused a concentration-dependent fall in both the rate and force of beating of isolated spontaneously beating atria from mice pretreated with vehicle. This effect of carbachol was not seen with atria from mice pretreated with pertussis toxin. 5. Pertussis toxin pretreatment did not alter the enhancement of the S-I outflow of radioactivity produced by angiotensin II (0.01 and 0.1 microM). 6. These results suggest that angiotensin II receptor modulation of noradrenaline release is not mediated through either a pertussis toxin sensitive guanine nucleotide-binding protein or activation of protein kinase C.
Angiotensin II↗
Do phorbol myristate and phorbol dibutyrate enhance noradrenaline release by the same mechanisms?
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Animals↗
Involvement of cyclic nucleotides in prejunctional modulation of noradrenaline release in mouse atria.
1 In mouse isolated atria previously incubated with [3H]-noradrenaline, 8-bromo-cyclic AMP (3-270 microM) produced a concentration-dependent increase in the fractional stimulation-induced outflow of radioactivity. 8-Bromo-cyclic GMP induced a lesser increase in the stimulation-induced outflow. 2 The phosphodiesterase inhibitors: M&B 22948 (90 microM); ICI 63197 (30 and 90 microM) and 3-isobutyl-1-methylxanthine (90 microM) increased the fractional stimulation-induced outflow. Together these results indicate that cyclic AMP may have a modulatory effect on noradrenaline release. 3 The inhibition of the stimulation-induced outflow produced by clonidine (0.03 microM) and its facilitation produced by phentolamine (1 microM) were unaltered in the presence of 8-bromo-cyclic AMP (90 microM). However, in the presence of 8-bromo-cyclic AMP (270 microM), the facilitatory effect of phentolamine was enhanced, but the inhibitory effect of clonidine (0.03 microM) was unaltered. In the presence of ICI 63197 (30 microM) the inhibitory effect of clonidine (0.03 microM) was unaltered, but the facilitatory effect of phentolamine (1 microM) was slightly enhanced. 4 Isoprenaline (0.003-0.1 microM) enhanced the fractional stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). In the presence of 8-bromo-cyclic AMP (90 microM), the facilitatory effect of isoprenaline (0.01 microM) was blocked. In the presence of ICI 63197 (30 microM) the facilitatory effect of isoprenaline (0.003 microM) was potentiated. 5 These results suggest that whereas beta-adrenoceptor-mediated enhancement of noradrenaline release is linked to the stimulation of adenylate cyclase and enhanced formation of cyclic AMP, alpha-adrenoceptor-mediated inhibition of noradrenaline release is not linked to inhibition of adenylate cyclase activity.
8-Bromo Cyclic Adenosine Monophosphate↗
A comparison of cardiovascular and catecholamine responses to three stimuli in mild hypertension.
In five males with mild essential hypertension, simultaneous hemodynamic and arterial and venous plasma catecholamine responses to three stimulation tests (mental arithmetic, isometric handgrip exercise, and cold) were studied. Plasma norepinephrine (NE), epinephrine (EPI), and dopamine (DA) were measured radioenzymatically. Isometric exercise was the best stimulus for systolic and diastolic blood pressure and NE. Mental arithmetic produced the highest levels of plasma EPI, but there was great intersubject variability. Dopamine levels did not increase with any of these stimuli. Consistent arterio-venous differences across the forearm were seen for EPI but not NE, consistent with local production of NE. Isometric exercise produced the closest correlations between peripheral plasma catecholamine levels, blood pressure, and heart rate. Good correlations were seen with mental arithmetic, but with the stimulus of cold correlation was poor.
Adult↗
Increased plasma noradrenaline during adrenaline infusion in man.
Arterial and venous plasma noradrenaline in recumbent mild hypertensives, and in normotensives with one adrenal gland, increased significantly during infusion of adrenaline to achieve levels similar to those seen during mental arithmetic stress. Although decreased noradrenaline clearance has not been excluded as an explanation of increased plasma levels, these results are consistent with the hypothesis that physiological concentrations of adrenaline are capable of facilitating noradrenaline release in man.
Adrenalectomy↗
Effect of phorbol esters and polymyxin B on modulation of noradrenaline release in mouse atria.
Phorbol 12-myristate 13-acetate (PMA; 0.03, 0.1 and 1.0 mumol/l), a protein kinase C activating phorbol ester, significantly enhanced the stimulation-induced (S-I) outflow of radioactivity at 5 Hz stimulation in mouse atria preincubated with [3H]-noradrenaline, whereas a phorbol ester which does not activate protein kinase C, phorbol 13-acetate (0.1 mumol/l), had no effect. This suggests that protein kinase C may have a role in modulating sympathetic neurotransmission. Polymyxin B (7 and 21 mumol/l), an inhibitor of protein kinase C, had no effect on the S-I outflow of radioactivity. However, it had a significant inhibitory effect in a concentration of 70 mumol/l. Polymyxin B (21 mumol/l) reduced the facilitation of the S-I outflow of radioactivity produced by PMA (0.03 mumol/l), 8-bromo-cyclic AMP (90 mumol/l), tetraethylammonium chloride (300 mumol/l), and idazoxan (0.1 mumol/l). Furthermore, when a higher frequency of stimulation was applied (10 Hz rather than 5 Hz), polymyxin B (21 mumol/l) by itself inhibited the S-I outflow of radioactivity. In the presence of a concentration of PMA (0.1 mumol/l) that was maximally effective in enhancing the S-I outflow of radioactivity, both idazoxan (0.1 mumol/l) and 8-bromo-cyclic AMP (90 mumol/l) still enhanced the S-I outflow. This suggests that these agents are not operating through protein kinase C and further suggests that the inhibitory effect of polymyxin B on these agents cannot be due to inhibition of protein kinase C. The effects of clonidine on the S-I outflow were not affected by a maximally effective concentration of PMA (0.1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)
8-Bromo Cyclic Adenosine Monophosphate↗
Increased plasma noradrenaline during low dose adrenaline infusion in resting man and during sympathetic stimulation.
Both resting and stimulated (straight-leg raising and head-up tilt) levels of arterial and venous plasma noradrenaline were significantly higher during low-dose adrenaline infusion in five mild hypertensive and four normotensive patients with one adrenal. Repeat adrenaline infusions in the five hypertensive patients while measuring noradrenaline clearance (3H-noradrenaline constant infusion) achieved similar levels of plasma adrenaline, and similar increases in plasma noradrenaline, within five min of achieving target infusion rate. Increased plasma noradrenaline was not explained by reduced clearance. These results are consistent with the hypothesis that physiological concentrations of adrenaline are capable of facilitating noradrenaline release in man.
Epinephrine↗
Imidazoline binding sites and signal transduction pathways.
1. Discrete, non-adrenergic binding sites for imidazolines have been characterized in the brain and periphery. The I1 clonidine-preferring site is mainly distributed in the brain and brain stem, while the I2 idazoxan-preferring site is more widely distributed. 2. The I1 site appears to be associated with modulation of blood pressure. Imidazolines act within the rostral ventrolateral medulla to produce hypotension. The underlying signal transduction mechanism is poorly understood. 3. The imidazolines clonidine and cirazoline inhibited nicotine-stimulated calcium entry into rat phaeochromocytoma (PC-12) cells by a non-adrenergic mechanism. This effect was not attributable to the stimulation of protein kinases. 4. Similarly, clonidine and cirazoline inhibited nicotine-stimulated inward currents into PC-12 cells. This inhibitory action was not altered by inhibitors of signal transducing G-proteins. 5. Clonidine and cirazoline displaced the ion channel ligand [3H]-phencyclidine from nicotinic acetylcholine receptors, suggesting that these drugs act by direct blockade of the intrinsic ion channel of the nicotinic acetylcholine receptor. 6. This ion channel-blocking activity represents a novel action of these imidazolines and may underlie some of the proposed physiological actions of I1 sites.
Animals↗
Facilitation of noradrenaline release by isoprenaline is not mediated by angiotensin II in mouse atria and rat tail artery.
The hypothesis that facilitation of noradrenaline release by prejunctional beta-adrenoceptors is linked to the local generation of angiotensin II was investigated in rat tail artery and mouse atria which were incubated with [3H]-noradrenaline. The outflow of radioactivity induced by electrical field stimulation of the tissues was taken as an index of noradrenaline release. In mouse atria, angiotensin II (0.01 microM) enhanced the stimulation-induced (S-I) noradrenaline release and this was blocked by saralasin (0.1 microM). Isoprenaline (0.01 microM) also enhanced the S-I release of noradrenaline, but this was not blocked by either saralasin (0.1 microM and 0.3 microM) or captopril (5 microM). Furthermore, the facilitatory effects of angiotensin II (0.1 microM) and isoprenaline (0.1 microM) were additive. In rat tail artery, the facilitatory effect of angiotensin II (0.01 microM) on noradrenaline release was blocked by saralasin (0.1 microM). The facilitatory effect of isoprenaline (0.1 microM) was blocked by propranolol (1 microM) but not by saralasin (0.1 microM) nor captopril (5 microM). These results indicate that beta-adrenoceptor-mediated facilitation of noradrenaline release occurs independently of angiotensin II in mouse atria and rat tail artery.
Angiotensin II↗