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M A Oriowo

Publications and source records attributed to M A Oriowo.

At least 19 recordsLinked to original sources
PubMed1992

Vascular alpha-adrenoceptor affinity variation is not due to varying populations of subtypes distinguished by WB 4101 and chlorethylclonidine.

Interaction with chlorethylclonidine has been used to subdivide populations of alpha 1-adrenoceptors in some tissues. WB 4101 can distinguish high and low affinity states of the receptor. The present study was carried out to determine if different populations or affinity states of alpha 1-adrenoceptors distinguished by either of these compounds, could explain the variation in alpha 1-adrenoceptor agonist affinity found amongst rabbit arteries. Five arteries were studied whose affinity for noradrenaline vary between 4.8 and 6.4. These were the thoracic aorta, renal, superior mesenteric, ear and ovarian arteries. WB 4101 was found to be equally effective in antagonizing noradrenaline on all arteries. Chlorethylclonidine caused a 20-fold rightward shift of the noradrenaline dose-contraction curve in the thoracic aorta; but had little or no effect on the other vessels. Thus, the combination of different proportions of subsets of alpha 1-adrenoceptors distinguished by WB 4101 or chlorethylclonidine does not explain the variation in alpha 1-adrenoceptor affinity found in these rabbit arteries.

Adrenergic alpha-Agonists↗
PubMed1992

Activation of a single alpha-1-adrenoceptor subtype in rat aorta mobilizes intracellular and extracellular pools of calcium.

The calcium channel antagonist, nifedipine (0.1 microM), only slightly inhibited the response to the full alpha 1-adrenoceptor agonist, (-)-norepinephrine, in rat aorta, but nearly completely inhibited the response to the partial alpha 1-adrenoceptor agonist, (-)-dobutamine, indicating that (-)-norepinephrine primarily utilizes intracellular stores of calcium to produce vasoconstriction, whereas (-)-dobutamine relies primarily upon the translocation of extracellular calcium. It has been proposed that the different pools of calcium mobilized by (-)-norepinephrine and (-)-dobutamine in rat aorta result from the activation of two different alpha 1-adrenoceptor subtypes by these agonists. Because the irreversible alpha 1-adrenoceptor antagonist, phenoxybenzamine, has been proposed to inactivate an alpha 1-adrenoceptor subtype coupled specifically to the mobilization of intracellular stores of calcium, this compound should selectively inhibit the response of (-)-norepinephrine, and not the response of (-)-dobutamine, if two distinct alpha 1-adrenoceptor subtypes exist in rat aorta. In the present study, phenoxybenzamine produced concentration-dependent, noncompetitive inhibition of the responses to both agonists in rat aorta, and the pA2' values for phenoxybenzamine were 8.12 +/- 0.23 and 7.74 +/- 0.27 against (-)-dobutamine and (-)-norepinephrine, respectively, which are not significantly different from each other (p greater than 0.05). In addition, the phasic and tonic components of the response to (-)-norepinephrine, which are mediated by the mobilization of intracellular calcium and the translocation of extracellular calcium, respectively, are also inhibited to the same extent by phenoxybenzamine. The results do not support the hypothesis of two alpha 1-adrenoceptor subtypes in rat aorta, one of which being coupled to the translocation of extracellular calcium, and the other to the mobilization of intracellular calcium. Rather, the results support our previous hypothesis that a single alpha 1-adrenoceptor subtype exists in vascular smooth muscle, and this alpha 1-adrenoceptor is coupled to two distinct signal transduction processes, one of which elicits the mobilization of intracellular calcium, and the other opens membrane calcium channels to permit the influx of extracellular calcium.

Animals↗
PubMed1992

Receptor protection studies with phenoxybenzamine indicate that a single alpha 1-adrenoceptor may be coupled to two signal transduction processes in vascular smooth muscle.

Full alpha 1-adrenoceptor agonists, such as (-)-norepinephrine, produce vasoconstriction in the rat aorta primarily through the mobilization of intracellular stores of calcium, whereas partial alpha 1-adrenoceptor agonists, such as (-)-dobutamine, produce vasoconstriction primarily through the translocation of extracellular calcium. The different pools of calcium utilized by full and partial alpha 1-adrenoceptor agonists have been proposed to result from the activation of different alpha 1-adrenoceptor subtypes. The irreversible alpha 1-adrenoceptor antagonist, phenoxybenzamine, selectively eliminates only that component of an alpha 1-adrenoceptor-mediated response in the rat aorta that is dependent upon the mobilization of intracellular stores of calcium. In order to determine whether in the rat aorta there exist two distinct alpha 1-adrenoceptor subtypes linked separately to the mobilization of intracellular and extracellular calcium, we utilized the full and partial alpha 1-adrenoceptor agonists, (-)-norepinephrine and (-)-dobutamine, respectively, and the irreversible antagonist, phenoxy-benzamine, as pharmacologic tools in a classical receptor-protection study to probe these alpha 1-adrenoceptor-mediated vasoconstrictor process(es). Our logic was that if the intracellular and extracellular pools of calcium were coupled to different alpha 1-adrenoceptor subtypes, then only (-)-norepinephrine, and not (-)-dobutamine, would protect against alpha 1-adrenoceptor alkylation by phenoxybenzamine, since phenoxybenzamine only eliminates the process that depends on intracellular calcium. Alternatively, if both (-)-norepinephrine and (-)-dobutamine produce a similar degree of alpha 1-adrenoceptor protection against phenoxybenzamine, our results would suggest that a single alpha 1-adrenoceptor subtype exists which activates both the translocation of extracellular calcium and the mobilization of intracellular calcium. Phenoxybenzamine (30 nM) abolished contractions of the rat aorta produced by (-)-norepinephrine, as expected. Pretreatment of the tissues with either (-)-norepinephrine or (-)-dobutamine, at concentrations that produced equivalent degrees of alpha 1-adrenoceptor occupancy, resulted in equal protection against alkylation of alpha 1-adrenoceptors by phenoxybenzamine, arguing against the existence of two distinct alpha 1-adrenoceptor subtypes in the rat aorta. These results are consistent with our previous hypothesis that two different signal-transduction processes may be activated in the rat aorta by a single alpha 1-adrenoceptor population, with the intrinsic efficacy of the agonist determining which signal-transduction process is activated.

Adrenergic alpha-Agonists↗
PubMed1991

Vascular smooth muscle sensitivity to noradrenaline is reduced during an infection with Trypanosoma brucei in rats and rabbits.

alpha 1-adrenoceptor sensitivity to noradrenaline has been studied in some arterial smooth muscles of rats and rabbits infected with T. brucei. In rabbits, a decrease in sensitivity of the arterial smooth muscles to noradrenaline was observed in the thoracic aorta, central ear but not renal arteries. No change in the sensitivity of the smooth muscles to histamine was observed. In rats, noradrenaline potency was reduced in the aorta, renal but not tail arteries. In both species, affinity of noradrenaline for alpha 1-adrenoceptors was significantly (P less than 0.05) reduced in arteries where the potency of noradrenaline was reduced. Prazosin KB values in infected animals were significantly (P less than 0.05) lower than controls. These results are interpreted to suggest either an alteration in the structure of alpha 1-adrenoceptors during an infection, or accumulation of some factor(s) in the receptor microenvironment that modulated binding of agonists and antagonists to the receptors during an infection with T. brucei. The possible role of reduced alpha 1-adrenoceptor affinity in the hypotension observed during an infection with T. brucei is discussed.

Animals↗
PubMed1991

Evidence for heterogeneity of prejunctional alpha-2-adrenoceptors.

The interactions between SK&F 104078 and several selective alpha 2-adrenoceptor agonists at pre- and postjunctional alpha 2-adrenoceptors were investigated in order to assess the previously reported selectivity of SK&F 104078 for postjunctional alpha 2-adrenoceptors and to determine whether or not SK&F 104078 could uncover subtypes of alpha 2-adrenoceptors located prejunctionally as has also been suggested. The alpha 2-adrenoceptor agonists, UK 14,304, xylazine, B-HT 933, B-HT 920, clonidine and M-7, produced concentration-dependent prejunctional alpha 2-adrenoceptor-mediated inhibition of neurogenic responses in the guinea pig atrium and rat vas deferens and produced postjunctional alpha 2-adrenoceptor-mediated contraction of the canine saphenous vein. The alpha 2-adrenoceptor antagonist, rauwolscine, blocked all the agonists at both pre- and postjunctional alpha 2-adrenoceptors without demonstrating preference for any agonist or any synaptic location of alpha 2-adrenoceptors. In marked contrast, SK&F 104078 produced equivalent antagonism of all agonists in the canine saphenous vein but had no significant effect against the same agonists in the guinea pig atrium, suggesting a high degree of selectivity for postjunctional alpha 2-adrenoceptors in these test systems, consistent with our previous observations. In the rat vas deferens, however, SK&F 104078 significantly antagonized the prejunctional alpha 2-adrenoceptor-mediated effects of clonidine and M-7 but did not block the responses to UK 14,304, xylazine, B-HT 933 and B-HT 920. These results indicate that the prejunctional alpha 2-adrenoceptor antagonist effects of SK&F 104078 are tissue and agonist dependent, and that there may be at least two subtypes of prejunctional alpha 2-adrenoceptors that can be discriminated with SK&F 104078 but not with rauwolscine. Both subtypes of prejunctional alpha 2-adrenoceptors may be present in the rat vas deferens, while only the SK&F-104078-insensitive subtype is present in the guinea pig atrium.

Adrenergic alpha-Agonists↗
PubMed1991

Variable receptor affinity and tissue sensitivity.

Vascular smooth muscle sensitivity to norepinephrine (NE), measured by contractile responses in vitro, varied in different arteries of the rabbit and also in the same vessels in other species. There was a good correlation between variation in the affinity of NE for the alpha 1-adrenoceptor and tissue sensitivity. The variation was continuous and probably not indicative of different receptor subtypes. Solubilization of alpha 1-adrenoceptors from the membrane changed the affinity for specific ligands while reconstitution restored it. Taken together, these results suggest the presence of a factor(s) within the receptor microenvironment capable of modulating affinity and hence tissue sensitivity to NE. In some blood vessels, receptor number was correlated significantly with affinity of the alpha 1-adrenoceptor for NE also. In general, the contribution of receptor number was considerably less than the affinity for NE.

Animals↗
PubMed1991

Interaction of vascular alpha-1 adrenoceptors with multiple signal transduction pathways.

In the rat vasculature, a single alpha 1-adrenoceptor may be coupled to two distinct G proteins, one of which regulates phospholipase C activity and is insensitive to pertussis toxin, and another which regulates calcium channel function and is highly sensitive to inhibition by pertussis toxin. alpha 1-Adrenoceptor agonists may in theory activate both pathways, but the efficiency of alpha 1-adrenoceptor coupling to the pertussis-toxin-insensitive pathway is low relative to the other pathway that couples the alpha 1-adrenoceptor to calcium channels. As such, only full agonists with high intrinsic efficacy can activate both pathways, whereas partial agonists, by virtue of their lower intrinsic efficacies, are less able to activate the pertussis-toxin-insensitive pathway, thereby rendering partial alpha 1-adrenoceptor agonists more sensitive than full alpha 1-adrenoceptor agonists to inhibition by calcium channel blockers and pertussis toxin.

Animals↗
PubMed1991

Variation in the interaction of some phenylethylamine and imidazoline derivatives with alpha-1 adrenoceptors in rabbit arteries: further evidence for the variable receptor affinity hypothesis.

This study was undertaken to determine whether the variation in the affinity of the alpha-1 adrenoceptors previously found for norepinephrine and phenylephrine in different arteries is also seen with other alpha-1 adrenoceptor agonists, and if so, if one part of the structure is particularly responsible for the variation. The potency and dissociation constants of eight agonists, both phenylethylamines and imidazolines, were determined in five rabbit arteries. In each artery the rank order of phenylethylamine agonist potency was epinephrine greater than norepinephrine greater than phenylephrine greater than deoxyepinephrine greater than methoxamine greater than dopamine. The same rank order of dissociation constants was found. For the imidazolines, the potency order was oxymetazoline greater than clonidine. For each agonist, there was a linear correlation between artery sensitivity and receptor affinity. None of the regression line slopes differed from each other. For each artery there was a linear correlation between phenylethylamine sensitivity and affinity. With the exception of the ovarian, which was lower, slopes of the regression lines in each group do not differ from each other. There were differences in the spread of the dissociation constants of the phenylethylamine derivatives among the arteries. The range of affinities was most marked with norepinephrine (greater than 40-fold) and least with epinephrine (approximately 4-fold). They suggest that agonist affinity governs the biological activity of at least the phenylethylamines on rabbit arteries mediated by the alpha-1 adrenoceptor. Variation in agonist affinity can explain the extent of the biological response. Differences in range of amine affinities in different arteries suggest that the agonist recognition site, although similar in the different arteries, is not identical and may be related particularly to some variation of the amine attachment site of the molecule. The results provide further support for the variable receptor affinity hypothesis.

Animals↗
PubMed1990

Chloroethylclonidine unmasks a non-alpha-adrenoceptor noradrenaline binding site in the rat aorta.

The effect of chloroethylclonidine on noradrenaline-induced contractions of the rat aorta was studied. Chloroethylclonidine (1-5 X 10(-5) M) shifted noradrenaline dose-response curve to the right approximately 5000-fold without depressing the maximum. The response to noradrenaline after chloroethylclonidine was not antagonized by phenoxybenzamine (10(-7) M), prazosin (10(-7) M), WB 4101 (10(-7) M) nor yohimbine (10(-5) M) and is therefore not mediated via alpha 1-adrenoceptors. These results would suggest that there is a homogenous population of chloroethylclonidine-sensitive alpha 1-adrenoceptors in the rat aorta and that chloroethylclonidine treatment reveals a non-alpha-adrenoceptor noradrenaline binding site in this tissue.

Animals↗
PubMed1989

Variation in sensitivity of six cat and six rat arteries to norepinephrine can be related to differences in agonist affinity and receptor reserve.

The sensitivity of contraction to norepinephrine and alpha-1-adrenoceptor affinity and reserve were measured in six rat and six cat arteries. These were the thoracic and abdominal aorta, superior mesenteric, renal, and femoral arteries of both species, and rat tail and cat splenic arteries. Sensitivity to norepinephrine differed by more than a factor of 30 in the rat and 20 in the cat. Rank order of sensitivities were in general similar in the two species. In rat and cat there was a significant correlation between sensitivity to norepinephrine and alpha-1 adrenoceptor affinity and also between sensitivity and receptor reserve, expressed as -antilog (pD2 - pKA). In the rat the contribution of affinity to these differences in sensitivity was greater than that of receptor reserve. In the cat arteries, receptor reserve is the more important factor. These results support the "variable receptor affinity hypothesis." This proposes that the affinity of a receptor can vary, and this may be due to differences in receptor structure, local membrane microenvironment, and extent of influence of intracellular mechanisms. The hypothesis proposes that variation in affinity can have a significant impact on tissue sensitivity.

Animals↗
PubMed1987

Sympathetic control of cerebral arteries: specialization in receptor type, reserve, affinity, and distribution.

The sympathetic neuroeffector system in the mammalian cerebral circulation has a number of distinctive features that reflect its specialized role in this vascular bed: 1) there is limited alpha-adrenoceptor-mediated contraction in large vessels that becomes progressively less important with branching; 2) contraction is limited by receptor number; small branches often seem to have no functional alpha adrenoceptors; 3) adrenoceptor affinity for norepinephrine is low and so is sensitivity; and 4) the dominant alpha-adrenoceptor subtype differs in different species and may have unique characteristics in some. There is a mechanism of non-alpha-adrenoceptor-mediated contraction involving low-affinity receptor sites--extraceptors--activated by sympathetic nerves. The pig has a seemingly atypical sympathetic mechanism. On the basis of current information the sympathetic neuroeffector mechanisms of the rabbit seem most clearly related to the human. The size, pattern, and distribution of sympathetic control suggest that the role of the sympathetic nerves is to protect the smaller pial arteries against the consequences of sudden increases in sympathetic adrenal discharge. It is not an important mechanism of controlling cerebral blood flow.

Adrenergic alpha-Agonists↗
PubMed1987

Characterization of histamine H1 and H2 receptors in the rabbit isolated ovarian artery and vein.

Histamine H1 and H2 receptors in the rabbit isolated ovarian artery and vein were studied. Histamine (10(-6)-3 X 10(-4) M) and 2-thiazolylethylamine (2ThEA) (10(-5)-3 X 10(-4)) concentration dependently caused contraction of both vessels. The -log EC50 for the artery was 5.20 +/- 0.13 and 4.48 +/- 0.01, and for the vein it was, 5.50 +/- 0.10 and 5.10 +/- 0.27, respectively. Metiamide (10(-5) M) significantly potentiated histamine-induced but not 2ThEA-induced contractions. The pA2 for antagonism by mepyramine against histamine and 2ThEA was 8.80 +/- 0.20 (slope = 0.73) and 9.02 +/- 0.11 (slope = 0.74) in the artery and 9.50 +/- 0.30 (slope = 1.0 +/- 0.2) and 9.00 +/- 0.20 (slope = 1.0 +/- 0.1) in the vein. Histamine and impromidine concentration dependently relaxed the contracted ovarian artery and vein. Impromidine was 300-fold and sixfold more potent than histamine in the artery and vein, respectively. The relaxant potency of histamine was the same in both vessels. The relaxations were antagonized by metiamide (10(-5) M). The KB against histamine and impromidine was similar in both vessels. These results indicate that functional histamine H1 and H2 receptors exist in the ovarian artery and vein. The possible relevance of this to the proposed role of histamine in ovulation is discussed.

Animals↗
PubMed1987

Variation in sensitivity of alpha adrenoceptor-mediated contraction of the vascular smooth muscle of rabbit elastic and muscular arteries is related to receptor affinity.

Norepinephrine sensitivity (pD2) and agonist dissociation constant (pKA) have been determined in the following 12 rabbit arteries: thoracic and abdominal aorta, basilar, ear, common, external and internal iliac, ovarian, large and medium pulmonary, renal and superior mesenteric. They were determined in the presence of beta adrenoceptor blockade and uptake 1 and uptake 2 inhibition to prevent compromising additional actions of norepinephrine and intrinsic processes that influence its concentration at the site of action. In the superior mesenteric artery, determinations were made after endothelial inactivation and in the presence of indomethacin, because in this vessel blockade by these procedures influences norepinephrine sensitivity. In 12 arteries a positive correlation was found between norepinephrine pD2 and pKA (r = 0.74, P less than .01). The slope of the regression line did not differ from unity. Norepinephrine pD2 did not correlate with receptor reserve in these arteries when assessed as antilog pD2-pKA. In three arteries, the ear and common and external iliac, a large receptor reserve was found. If these were excluded from the series, the following correlation would be found: r = 0.9; P less than .001. Here again the slope of the regression line did not differ from unity. The pD2 and pKA were determined for the more selective alpha-1 adrenoceptor agonist, phenylephrine in six of these arteries, and similar results were obtained. The KB for prazosin in this series did not correlate with norepinephrine KA (r = 0.45, P greater than .05), and the slope (0.17) was not significantly different from zero. The pD2 for histamine, determined after H2 receptor blockade, does not differ in the arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Physiological variation in alpha-adrenoceptor-mediated arterial sensitivity: relation to agonist affinity.

Vascular smooth muscle from different arteries of the rabbit varies in sensitivity to norepinephrine, even when factors known to contribute to this variation are excluded. Sensitivity to norepinephrine mediated through the alpha-adrenoceptor is linearly related to the agonist dissociation constant, but is not significantly related to receptor reserve. These results suggest that agonist affinity is the primary determinant of sensitivity to norepinephrine, at least in these arteries, and that this is a locally regulated characteristic which may account for regional sensitivity changes.

Animals↗
PubMed1986

The effect of altering the external Ca++ concentration and TMB-8 on noradrenaline-induced contractions of the rat anococcygeus muscle.

The effect of varying external Ca++ concentration and 8(-N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) on noradrenaline-induced contractions of the rat anococcygeus muscle was studied. The contractile response to NA was not significantly altered when the external Ca++ concentration was reduced by 50% and 75%. The contractions were however reduced to approximately 10% of the control on complete withdrawal of extracellular Ca++. The loss of contractile response to NA in O-Ca++ was time-dependent and the rate was not modified by EGTA (0.1 mM). There was a rapid restoration of NA responses on re-introducing Ca++. NA-induced contractions were concentration-dependently antagonized by TMB-8, an intracellular Ca++ antagonist. The results are interpreted to suggest that alpha 1-adrenoceptor activation in the rat anococcygeus muscle releases Ca++ from intracellular stores.

Animals↗
PubMed1985

Muscarinic receptor agonist-antagonist interaction in the rat rectum: are there ways of activating the same receptors?

The interaction between the muscarinic receptor agonists, carbachol, acetylcholine (ACh) and methacholine, and antagonists, atropine, gallamine, 4-DAMP and pirenzepine, was studied on the rat isolated rectum preparation. ACh (1.93 X 10(-8)-1.95 X 10(-6) M), methacholine (8.7 X 10(-8)-1.1 X 10(-6) M) and carbachol (1.1 X 10(-7)-3.5 X 10(-6) M) induced contractions that were reversibly antagonized by atropine (1.9 X 10(-9)-4.8 X 10(-8) M), 4-DAMP (1.5 X 10(-8)-2.86 X 10(-7) M) gallamine (1.12 X 10(-6)-1.12 X 10(-4) M) and pirenzepine (2.8 X 10(-7)-7.0 X 10(-6) M). The pA2 values were atropine: 8.99 +/- 0.28, 9.29 +/- 0.14 and 8.86 +/- 0.05; 4-DAMP: 8.39 +/- 0.10, 8.66 +/- 0.15 and 8.26 +/- 0.30, gallamine: 5.85 +/- 0.23, 5.73 +/- 0.25 and 5.96 +/- 0.10 and pirenzepine: 6.85 +/- 0.44, 7.17 +/- 0.13 and 7.21 +/- 0.03 against ACh, methacholine and carbachol, respectively. The experimental dose-ratio (atropine + gallamine) was greater than the expected dose-ratio (as predicted by the Paton & Rang rule) for ACh and methacholine while the experimental dose-ratio closely approximates the expected dose-ratio for carbachol. It is suggested that atropine, 4-DAMP pirenzepine and gallamine act on the same receptors but gallamine allosterically altered the binding of the agonists and antagonists to varying extents.

Acetylcholine↗
PubMedDate not supplied

Alpha 1-adrenoceptor subtype mediates norepinephrine-induced contraction of the rabbit isolated ovarian artery.

The interactions between selective alpha-adrenoceptor agonists and antagonists were studied in the rabbit isolated ovarian artery in an attempt to characterize the alpha-adrenoceptor subtype present in the smooth muscle of this vessel. Norepinephrine, epinephrine, and phenylephrine, but not clonidine or BHT-920, contracted the ovarian artery in a concentration dependent manner. The rank order of potency was epinephrine greater than norepinephrine greater than phenylephrine. The contractions were competitively antagonized by prazosin, phentolamine, and yohimbine. However, prazosin and phentolamine were approximately 100-500 times more potent than yohimbine against norepinephrine and phenylephrine. Observations were unchanged when arterial segments were used after endothelial removal. Norepinephrine-induced contractions of the ovarian artery were relatively resistant to blockade by diltiazem. The results suggest that exclusively alpha 1-adrenoceptors are present in vascular smooth muscle cells of the ovarian artery, whose activation operates through a mechanism relatively independent of Ca2+ influx into the smooth muscle cells.

Adrenergic alpha-Agonists↗