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Biomedical subjects

R D Bevan

Publications and source records attributed to R D Bevan.

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↗
PubMed1991

Longitudinal in vivo and in vitro time-course study of chronic cerebrovasospasm in the rabbit basilar artery.

Subarachnoid hemorrhage (SAH) was induced by multiple injections of autologous blood into the prepontine cistern in the rabbit. Long-lasting angiographic narrowing was recorded over a period of nine days after SAH. Papaverine (PPV) reversed angiographic narrowing in the first three days after SAH. Vasospasm was refractory to PPV from day five to day nine after SAH. PPV - refractoriness (in vivo) was positively correlated with decreased vessel wall distensibility (in vitro). Arterial segments showed spontaneous increases in tone in the first two days after SAH. Other alterations observed include a marked gradual reduction in the capacity of the vessel wall to contract, reduction in constrictor nerve influences on vascular tone, and impaired acetylcholine - induced vasorelaxation. Tonic contraction to the maximum dose of serotonin was increased in acute spasm and decreased in chronic spasm. It is suggested that the initial cause of arterial narrowing after SAH is the action of vasoactive substances released in the close vicinity of the arterial wall; this then leads to abnormal tone, tissue damage, and structural changes.

Acetylcholine↗
PubMed1991

Effects of postnatal growth and denervation on characteristics of the saphenous artery in SHR and WKY rats between 3 and 6 weeks of age: an in vitro study.

Thigh vessels of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were unilaterally surgically denervated at 10 days of age by femoral nerve section. Denervated and contralateral control segments of saphenous arteries from 3- and 6-week-old rats were mounted in a small vessel myograph for study. Both strains showed growth changes in blood pressure, but there was no significant difference between WKY and SHR. Both strains also had significant growth changes in vessel dimensions and the in vitro measurements suggested that SHR vessels had a thicker wall. Denervation did not affect vessel size. Transmural nerve stimulation indicated loss of innervation due to the surgical procedure. In the denervated vessels, both norepinephrine (NE) and 5-hydroxytryptamine (5-HT) dose response curves were shifted to the left, indicating a postjunctional increase in sensitivity. Maximum tension developed was in the order K+ greater than 5-HT greater than NE. In comparing the two strains, vessels from 6-week-old SHR were less sensitive to 5-HT. Relaxation to acetylcholine was significantly decreased in denervated arteries from WKY, whereas in SHR the significant decrease occurred only at 3 weeks. Denervated vessels from both rat strains at 3 weeks showed greater relaxation to beta-receptor activation, but not at 6 weeks of age. Therefore, the absence of functional innervation resulted in altered function of the saphenous artery wall.

Aging↗
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

Two indices of functional damage of the artery wall parallel the time course of irreversible narrowing in experimental vasospasm in the rabbit.

Autologous blood placed around the basilar artery caused angiographic narrowing with a biphasic time course. The first immediate phase was reversed by intraarterial papaverine; the second exhibited an increasing component of narrowing which was papaverine-resistant. In vitro studies showed that vessels became increasingly stiffer, less capable to develop active tone, and less responsive to vasoconstrictors and vasodilators. The papaverine-resistant component of angiographic narrowing (in vivo) could be directly correlated with loss of contractility and increased artery wall stiffness (in vitro).

Animals↗
PubMed1991

Clentiazem protects against chronic cerebral vasospasm in rabbit basilar artery.

BACKGROUND AND PURPOSE: Experiments were carried out in rabbits to determine whether clentiazem (8-chlorodiltiazem), a cerebrovascular-selective calcium channel blocker, administered 24 hours before subarachnoid hemorrhage influenced the subsequent cerebral vasospasm. METHODS: Subarachnoid hemorrhage was induced by multiple injections of blood into the prepontine cisterns of 35 male New Zealand White rabbits, and clentiazem (5 mg/kg) was administered 4 times daily until sacrifice. Cerebral artery diameter was assessed in vivo by angiography. Functional features of basilar arteries were measured using conventional in vitro methodology. RESULTS: Clentiazem reduced the angiographic narrowing seen on days 2 and 5 from 35% and 34%, respectively (sham control, 1.42 +/- 0.31 mm [n = 22]), to 8% and 11%, respectively, and prevented the narrowing (32%) that occurred on day 9. Narrowing in the untreated rabbits was only partly reversed by papaverine; all narrowing in clentiazem-treated animals was papaverine sensitive. Clentiazem prevented or reduced many of the changes in the basilar artery caused by the subarachnoid hemorrhage. Of particular relevance to arterial narrowing were the increased wall stiffness, the transient spontaneous changes in wall force, and the reduction in relaxation to acetylcholine. Reduction of the changes in wall force induced by agonists and by stimulation of intramural sympathetic nerves was observed. CONCLUSIONS: The vascular damage associated with chronic cerebral vasospasm is related to calcium entry into the smooth muscle and endothelial cells, and possibly sympathetic nerve terminals, through calcium channels sensitive to clentiazem, which suggests that clentiazem may be of value in the management of chronic cerebral vasospasm.

Acetylcholine↗
PubMed1991

Longitudinal time course of reversible and irreversible components of chronic cerebrovasospasm of the rabbit basilar artery.

Multiple injections of autologous blood were made around the basilar artery of rabbits through a silicone catheter placed into the prepontine cistern. The total blood injected was 3 ml/kg in aliquots of 0.5 to 0.8 ml over a 4-hour period. Control angiograms were obtained 7 days before this procedure. Groups of animals were examined by angiography on each of 9 days after the injections of blood. An angiogram was obtained 15 minutes after the first injection of blood, 20 seconds after the intra-arterial injection of a maximum dilating dose of papaverine. All surviving animals showed basilar artery narrowing, which was greatest 24 hours after the hemorrhage, when the vessel diameter was reduced to 54% of the control value. The narrowing then decreased to a reduction of about 30%, which was maintained throughout the rest of the study period. A papaverine-resistant component of narrowing was not seen until the 3rd day. It increased progressively to Day 9 when it represented 63% of the total. This model has a number of features that are reminiscent of human cerebrovasospasm, including the fact that there is an initial phase of narrowing that is completely reversed by an intra-arterially administered vasodilator, and a second phase beginning on Day 3 which exhibits a progressively increasing papaverine-resistant component.

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

Pharmacologic irreversible narrowing in chronic cerebrovasospasm in rabbits is associated with functional damage.

We studied isolated basilar artery segments from a rabbit model of chronic cerebrovasospasm. Autologous blood placed around the basilar artery of rabbits killed 1, 2, 3, 4, 5, 6, 7, or 9 days later caused narrowing of the segments with a biphasic time course. The first (immediate) phase was reversed by intra-arterial papaverine; the second phase exhibited an increasing component of narrowing that was papaverine-insensitive. Based on the passive force/length curves, basilar artery segments became increasingly stiff over 9 days. By contrast, the segments' contractility decreased. Responses of the basilar artery segments were greater over the first few days, but then became less than that of saline-injected controls. Contractions in response to norepinephrine and potassium were reduced. Endothelium-based acetylcholine-induced vasodilation progressively diminished, as did the response to sympathetic nerve stimulation. There was a negative correlation between artery wall stiffness and contractility. The papaverine-insensitive component of angiographic narrowing correlated directly with loss of contractility and with artery wall stiffness. These results are consistent with the conclusion that increased artery wall stiffness is a primary determining factor in the arterial narrowing of chronic cerebrovasospasm.

Acetylcholine↗
PubMed1989

Variable receptor affinity hypothesis.

Measurements of the contractile response to norepinephrine (NE) of a variety of arteries of three mammalian species that are commonly used in the laboratory provide evidence that tissue sensitivity and affinity of the alpha 1-adrenoceptor for NE covary over a range of several orders of magnitude. The quantitative relationship suggests that variation in affinity can, to a great extent, account for the variation in sensitivity found in a number of circumstances. Furthermore, it is argued that the variation in affinity appears to be continuous and thus does not provide a basis for receptor type subdivision. There is also evidence that adrenergic antagonist affinity can vary significantly in tissues. The factors that might account for this variation include differences in receptor chemical structure, in the local membrane microenvironment, and in a number of intracellular processes. A hypothesis of variable receptor affinity has been proposed. If it is correct, then variation in receptor affinity is an important functionally relevant variable that could account for selectivity of tissue responses to circulating hormones and may represent a mechanism of change in the intact organism and in disease.

Adrenergic alpha-Antagonists↗
PubMed1989

Influence of adrenergic innervation on vascular growth and mature characteristics.

Sympathetic nerve control of systemic and pulmonary vasculatures is discussed. The effect of removal of the nerve influence postnatally and subsequent development of arterial structure and function is contrasted with denervation in the adult, with reference to the rabbit ear and rat mesenteric arterial vasculature. Evidence is given that sympathetic nerves exert a trophic effect on vascular structure and function, particularly during growth that is associated with nerve activity.

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↗
PubMed1988

Diltiazem protects against functional changes in chronic cerebrovasospasm in monkeys.

Diltiazem given 48 hours before experimental subarachnoid hemorrhage protects the cerebral vasculature of monkeys against the widespread cerebrovascular spasm seen on angiography after 5-6 days and against associated neurologic defects. In vitro examination of the cerebral arteries from treated monkeys shows that compared with untreated animals, the functional changes in the vascular smooth muscle cells, the increase in arterial wall stiffness, and the decrease in contractility, all of which were prominent in untreated monkeys, were relatively small. Other changes such as abnormal spontaneous myogenic tone, decreased responsiveness to constrictor and dilator nerve activation, and other indexes of neuronal function were little influenced by the drug. We suggest that chronic cerebrovasospasm may be initiated by the combined action of exceptionally high concentrations of a number of putative spasmogens causing injury to the larger cerebral arteries. However, the later development of intractable spasm is related to the location of blood clot and to the involvement of the vascular wall in an inflammatory process. The combined insult results in pathologic changes in the artery wall resulting in increased thickness and stiffness. Diltiazem acts on cerebrovascular smooth muscle in lower concentrations than on smooth muscle in other vascular beds, interfering with calcium entry through receptor-operated and potential-sensitive channels, and may protect against calcium-induced cell death through these and additional actions. Protection against early events presumably prevents the genesis of the subsequent chronic state.

Animals↗
PubMed1988

Early treatment with diltiazem reduces delayed cerebral vascular narrowing after subarachnoid hemorrhage.

Using a primate model of subarachnoid hemorrhage, we have demonstrated the ability of diltiazem to reduce delayed, experimental narrowing of cerebral vessels under clinically realistic conditions. Twelve monkeys were treated identically, except that six received oral diltiazem (20 mg/kg t.i.d.) starting 24 hours after a subarachnoid hemorrhage (SAH) and continuing for 5 days. Neurological examination showed that all untreated monkeys were hyperreflexic and hypotonic on the side contralateral to the SAH. Only two of the six of the diltiazem-treated monkeys had a similar deficit. Control angiograms taken before the SAH were compared with those taken 5 days later. The average vessel diameter at six standard sites in monkeys without diltiazem was 61% of control, whereas the average diameter at the same positions in the diltiazem-treated monkeys was 92% of control (P less than 0.01). In each group, the diameter of the most narrowed artery of each monkey was compared with values at the same site before SAH. The average diameter in the untreated group was 22% of control, significantly smaller than the corresponding value from the diltiazem-treated group, which was 68% (P less than 0.005). Delaying diltiazem treatment until 24 hours after hemorrhage still provides some protection, but less than that given by pretreatment with the drug. This suggests that the processes that eventually result in chronic cerebral vascular narrowing are initiated during the 24-hour period immediately after SAH. We propose that there is initially an acute, severe, calcium-dependent contraction of vascular smooth muscle and associated injury to the vessel wall, including its innervation.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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↗