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Biomedical subjects

R D Bevan

Publications and source records attributed to R D Bevan.

At least 37 records · Page 2Linked to original sources
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↗
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

Altered endothelium-mediated relaxation after denervation of growing rabbit ear artery.

The relaxation response to methacholine and sodium nitroprusside was examined in ring segments from the posterior auricular artery and its continuation the central ear artery in growing rabbits 2, 4, 6 and 8 weeks following unilateral adrenergic and sensory denervation. The maximal relaxation achieved by methacholine (endothelium-dependent) was significantly depressed in the denervated arteries compared with the contralateral controls. Sodium nitroprusside (endothelium-independent relaxant agent) elicited the maximal relaxation in all tissues. These results demonstrated impaired arterial endothelium-dependent relaxation to methacholine after chronic denervation.

Animals↗
PubMed1986

Proliferation of arteriovenous anastomoses in the developing rabbit ear is enhanced after denervation.

The innervation of the rabbit ear vasculature by noradrenergic and substance P-immunoreactive (SP-IR) nerves was investigated in both young and adult animals. All vascular segments were supplied by both noradrenergic and SP-IR nerves. In the ear margins, the arteriovenous anastomoses (AVAs) were more densely innervated than other vessels. In general, the density of both noradrenergic and SP-IR nerves increased with age until 10-12 weeks postnatum. The ear vasculature was denervated in young rabbits to test whether the normal proliferation of AVAs in the growing ear was altered in the absence of nerves. Surgical resection of all auricular nerve trunks except the auricular branch of the auriculo-temporal nerve, and removal of the ipsilateral superior cervical ganglion in 10- to 12-day-old rabbits left the ear devoid of both noradrenergic and SP-IR nerves for at least four weeks. Repeated administration of 6-hydroxydopamine (6-OHDA) to young rabbits produced degeneration of noradrenergic terminal axons, but preterminal nerve trunks survived. SP-IR nerves did not appear to be affected by 6-OHDA. These denervation regimes resulted in a 1.5- to 2-fold increase in the number of AVAs formed in the growing ear. Surgical denervation and 6-OHDA treatment also led to retarded growth of the media of the central ear artery, but this effect of 6-OHDA was probably not due to a specific action on vascular smooth muscle. Surgical resection of most of the dorsal auricular nerves in adult rabbits did not affect AVA density. Large differences in AVA density were apparent between groups of control animals from different parts of the country, or groups examined at different times of the year. These results demonstrate that the labile nature of AVAs in the rabbit ear can result in considerable variability in the absolute number of AVAs and suggest that both intrinsic and extrinsic factors may influence development of the microvasculature.

Animals↗
PubMed1986

Denervation increases myogenic tone in a resistance artery in the growing rabbit ear.

The effect of chronic sympathetic and sensory denervation of the growing rabbit ear vasculature on myogenic tone in a resistance artery was studied. Unilateral superior cervical ganglionectomy and section of greater and anterior auricular nerves were performed at 4 wk of age. Compared with the contralateral control, 2 and 6 wk later, the denervated artery developed greater stretch-dependent myogenic tone. This phenomenon may partially account for the return of tone described in the denervated ear vasculature.

Animals↗
PubMed1986

Changes in postjunctional alpha-adrenoceptors during postnatal growth in rabbit arteries.

The pharmacological characteristics of the postjunctional alpha-adrenoceptors of vascular smooth muscle were studied in ring segments of thoracic aorta, superior mesenteric, and central ear arteries of 4- and 8-week-old, and young adult (12- to 16-week-old) rabbits. Norepinephrine (alpha 1, alpha 2-agonist), phenylephrine (alpha 1-agonist), and UK 14,304-18 (alpha 1-agonist) caused a concentration-dependent contraction of all three arterial segments from 4- and 8-week-old animals. Norepinephrine and phenylephrine but not UK 14,304-18 contracted the young adult thoracic aorta and superior mesenteric artery, whereas all the agonists contracted the central ear artery. The effects of the alpha 1-adrenoceptor antagonists, prazosin and thymoxamine, and the alpha 2-adrenoceptor antagonists, rauwolscine and yohimbine, on these responses were studied. In the 4-week-old rabbits, responses to norepinephrine, phenylephrine, and UK 14,304-18 were reduced by all four antagonists with nominal pA2 values in the range of 7-8.5. The action of the antagonists was competitive. Between 4 and 8 weeks, there was a significant decrease in the pA2 values of rauwolscine against norepinephrine and UK 14,304-18 in the aorta and between rauwolscine and UK 14,304-18 on the superior mesenteric artery. The pA2 values of rauwolscine and yohimbine, but not prazosin and thymoxamine, were lower in the young adult compared with values from the 8-week-old rabbit. In the interpretation of these results, there are two possibilities.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1985

Experimental chronic cerebrovascular spasm in the monkey: an assessment of the functional changes in the cerebral arteries and their protection by diltiazem.

The structure and function of cerebral arteries obtained from a monkey model of chronic cerebral vascular spasm 5 days after hemorrhage have been examined. Narrowing of the larger cerebral arteries demonstrated by angiography at all sites of measurement seems to be due primarily to an increased wall rigidity associated with cellular damage, the resultant inflammatory response and large, long-lasting spontaneous increases in muscle tone. Changes in agonist sensitivity were extremely variable. The reduction of contractility of the vessel wall to a mean of 30% of control diminished the consequence of any changes in active tone characteristics. Neurogenic control on the side of the lesion was remarkably depressed. When treated with diltiazem, beginning 1 day before induction of hemorrhage and continuing to the time of sacrifice, arterial diameter was reduced at only 1 of the 6 standard sites of measurement and then by only a small amount. Neurologic effects invariably seen in the untreated monkeys were prevented by diltiazem. Many of the changes in the artery wall, including structural alterations, were diminished by the drug. Abnormal spontaneous myogenic tone was present but was less in the diltiazem-treated group; however, nerve damage and its functional consequences were not prevented. It is concluded that diltiazem, presumably by preventing the accumulation of intracellular calcium within the cell, prevents the initial events in the evolution of chronic cerebrovasospasm or narrowing. This is probably achieved by a diminishing of the direct vasoconstrictor effects and the toxicity of putative spasmogens released from blood clots, nerves and the brain on the vascular smooth muscle, thus interrupting the sequence leading to pathologic change.

Animals↗