Amidephrine

Abstract: l-Norepinephrine and l-phenylephrine were full agonists and cirazoline, SKF d-89748, Sgd 101/75 and SKF l-89748 were partial agonists in contracting rat isolated aortic rings. Clonidine, l-amidephrine and St 587 were found ineffective. Nifedipine (10(-8)-10(-6) M) abolished the contractions to Sgd 101/75 and to high K+ with similar potency but only partially inhibited the contractions to the other alpha adrenoceptor agonists. Norepinephrine, phenylephrine, cirazoline and Sgd 101/75 were full agonists in stimulating 45Ca++ influx, which amounted to 50% of the maximal influx produced by high K+. SKF d- and l-89748 behaved as partial agonists, whereas St 587, amidephrine and clonidine were virtually inactive. Nifedipine was equally effective in blocking the influx of 45Ca++ produced by K+ and the alpha adrenoceptor agonists. Norepinephrine stimulated 45Ca++ efflux to an extent similar to that for high K+. In the following order of decreasing efficacy, phenylephrine, cirazoline and SKF d- and l-89748 caused significant stimulation of 45Ca++ efflux. Sgd 101/75, amidephrine, clonidine and St 587 were without effect. However, Sgd 101/75 (10(-5) M) antagonized the 45Ca++ efflux of norepinephrine. Nifedipine (3 X 10(-7) M) completely suppressed the K+-induced 45Ca++ efflux but only partly affected the 45Ca++ efflux caused by the alpha adrenoceptor stimulants. A highly significant (r = 0.975) linear relationship was found between the nifedipine-resistant contractile response and the 45Ca++ efflux obtained in the presence of nifedipine. The data suggest that the stimulation of alpha-1 adrenoceptors in rat aorta can activate two distinct processes of Ca++ utilization for contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: 1 Experiments have been made to identify the kinds of receptors concerned in the actions of catecholamines in increasing potassium efflux, membrane potential and glucose release in tissue slices prepared from guinea-pig liver2 Glucose release could be accelerated by activation of either of two distinct receptors, one of which resembles the alpha receptor of Ahlquist's classification, the other being beta-like Thus both amidephrine and isoprenaline (sympathomimetic amines which selectively activate alpha and beta receptors respectively) elicited the response3 The effect of isoprenaline on glucose release was inhibited by the beta blocking agent propranolol (1 muM) but not by the alpha blocker phentolamine (10 muM), whereas the converse held for amidephrine However, the degree of antagonism observed with phentolamine was less than found in smooth muscle, suggesting that the alpha-like receptor in the liver may differ somewhat from that in other tissues, or be less accessible to the antagonist4 Amidephrine, like noradrenaline, increased the efflux of (42)K from the slices and caused hyperpolarization, suggesting that the increase in potassium permeability underlying these responses is alpha-mediated This conclusion was supported by the finding that the effect of amidephrine on membrane potential was inhibited by phentolamine but not propranolol (1 muM)5 In keeping with this interpretation, low concentrations (20-50 nM) of isoprenaline, although sufficient to activate the beta receptors (as judged by the effect on glucose release) had little effect on the ionic composition of the tissue, and caused only a small increase in (42)K efflux Thus the ;ion movement' and ;glucose' responses could be largely dissociated6 Larger concentrations (1-6 muM) of isoprenaline increased (42)K efflux to a greater extent, although the effect was always less than with the same concentration of noradrenaline7 Activation of the beta-receptors caused a small and inconsistent hyperpolarization which became more pronounced and also more reproducible on replacing the chloride content of the bathing fluid by the larger anion isethionate8 Although these results show that activation of either of two distinct adrenergic receptors in guinea-pig liver can cause the same end-response (eg an increase in glucose release, or, under some circumstances, hyperpolarization of the cell membrane), the underlying mechanisms cannot be assumed to be identical This is discussed

Abstract: 1. The present study characterizes and classifies alpha 1-adrenoceptor-mediated vasoconstriction in the isolated perfused kidney of rat using quantitative receptor pharmacology and compares the results to radioligand binding studies (made in cloned alpha 1-adrenoceptor subtypes, native alpha 1A-adrenoceptors in submaxillary gland of rat, and alpha 1A-adrenoceptors in several other tissues of rat). 2. Concentration-effect curves to noradrenaline in the presence of 5-methyl-urapidil were biphasic, indicating alpha 1-adrenoceptor heterogeneity. The alpha 1-adrenoceptor subtype mediating the first phase (low affinity for 5-methyl-urapidil) could not be 'isolated' for detailed pharmacological characterization but was defined by a sensitivity to inhibition by chloroethylclonidine and an inability of methoxamine to activate the site. Additionally, vasoconstriction mediated by this alpha 1-adrenoceptor subtype or subtypes was abolished by nitrendipine (1 microM), thereby allowing characterization of the second, high affinity site for 5-methyl-urapidil. 3. The following antagonists interacted competitively with noradrenaline at the alpha 1-adrenoceptor for which 5-methyl-urapidil exhibits high affinity (pKB value): WB 4101 (10.3) > prazosin (9.5) approximately HV 723 (9.3) approximately 5-methyl-urapidil (9.2) > phenotolamine (8.6) > spiperone (pA2 = 8.1) approximately oxymetazoline (7.9). In contrast, insurmountable antagonism was seen with S(+)- and R(-)-niguldipine, the S(+)-isomer being approximately 30 fold more potent than the R(-)-isomer. Receptor protection experiments indicated that S(+)-niguldipine interacted directly with alpha 1-adrenoceptors. Dehydroniguldipine acted as a competitive antagonist (pKB = 9.0). Thus, the results with antagonists define the alpha 1-adrenoceptor as an alpha 1A-adrenoceptor. 4. An agonist 'fingerprint' was constructed in the presence of nitrendipine to define further the alpha 1A-adrenoceptor. The following order and relativity of agonist potency was obtained: cirazoline (1) approximately adrenaline (2) > noradrenaline (5) > phenylephrine (23) approximately amidephrine (31) > methoxamine (71) >> isoprenaline (1456) approximately dopamine (2210). 5. A high correlative association was shown between the affinity of antagonists obtained functionally in the isolated perfused kidney of rat and pKi values obtained from binding experiments with the cloned bovine alpha 1C-adrenoceptor (R2 = 0.85), native alpha 1A-adrenoceptors in submaxillary gland of rat (R2 = 0.79), and alpha 1A-adrenoceptors from several other tissues of rat (values taken from the literature, R2 = 0.89). 6. The present study demonstrates that the alpha 1A-adrenoceptor is the predominant alpha 1-adrenoceptor subtype mediating vasoconstrictor responses to exogenously administered noradrenaline in the isolated perfused kidney of rat. More importantly, alpha 1A-adrenoceptors mediating vasoconstrictor responses to noradrenaline exhibited a pharmacological equivalency to the cloned bovine alpha 1 c-adrenoceptor. Thus,definitive functional pharmacological data are provided for equating the two receptors and support results derived recently from molecular and radioligand binding studies.