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J A Bevan

Publications and source records attributed to J A Bevan.

At least 91 records · Page 5Linked to original sources
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

Aminergic histofluorescence and contractile responses to transmural electrical field stimulation and norepinephrine of human middle cerebral arteries obtained promptly after death.

The responses of cerebral arteries to catecholamines and sympathetic nerve stimulation show wide variation between animal species. We examined the catecholaminergic histofluorescence and the contractile responses elicited by transmural electrical field stimulation and norepinephrine (NE) in proximal segments of human middle cerebral artery (MCA) obtained during autopsy. Twenty-four percent of the specimens were obtained within 2 hours and 76% within 4 hours of death. A moderately dense catecholaminergic histofluorescence was seen in all segments of human MCA using the glyoxylic acid technique, counterstained with pontamine sky blue. However, only seven of 35 (20%) MCA segments tested showed tetrodotoxin-blocked transmural electrical field stimulation contractions, and all of these were harvested within 4 hours of death. The responses were mostly seen in the most proximal MCA segments and, at 32 Hz, only achieved 6 +/- 1% of the maximal tissue contraction. NE caused two distinct responses in human MCA segments. At low concentrations, it acts via an alpha-like adrenoreceptor to cause contractions 20 +/- 3% of the maximal tissue response. The NE ED50s for the three successive segments were not different from each other; the value for the most-proximal segment was 7.9 +/- 0.2 x 10(-7) M. At concentrations above 10(-5) M, this catecholamine acts on low-affinity sites resistant to alpha-adrenergic antagonists causing contractions that at 10(-3) M reach 52 +/- 5% of the maximal tissue response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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↗
PubMed1989

Pharmacology of TA-3090 (8-chloro diltiazem) related to its cerebrovascular protective properties.

TA-3090 (8-chloro diltiazem) has been shown in three experimental circumstances to have cerebrovascular protective properties. In vitro investigation of its pharmacology was undertaken to determine the foundation of this effect. Based on contractile responses of rabbit arteries to high potassium and norepinephrine, TA-3090 has some selectivity for cerebral and renal artery potential-sensitive and cerebral receptor-operated calcium-dependent mechanisms. It has no effect on arterial contraction to sympathetic nerve stimulation. It prevents the increase in uptake of 45Ca2+ in response to K+ (80 mM) in rabbit thoracic aorta and antagonizes the contractile effect of the putative cerebrovascular spasmogen alpha-thrombin on the femoral artery. All these effects take place in concentrations below those that significantly depress the action of the rabbit atrium. TA-3090 has little or no effect on other factors known to regulate cerebral blood flow (e.g., stretch-induced contraction and flow-induced contraction and dilation). This spectrum of pharmacologic activity suggests that TA-3090 would selectively block Ca2+ entry into cerebrovascular smooth muscle through potential-sensitive and receptor-operated Ca2+ channels that would be expected to increase in subarachnoid hemorrhage and cerebral ischemia. The action would occur using doses that have little effect on other factors that contribute to the control of cerebral blood flow.

Animals↗
PubMed1989

Antiresorptive dose-response relationships across three generations of bisphosphonates.

The first generation of bisphosphonates was discovered in the late 1960s and is characterized by short alkyl or halide side-chains. Well known representatives of this class are 1-hydroxyethane-1,1-bisphosphonate (etidronate) and dichloromethane bisphosphonate (clodronate). The antiresorptive activity of these and other analogues was measured in an assay in which a drug was administered for 7 days to growing rats, followed by a morphological assessment of bone volume. In this model, the first generation analogues have antiresorptive activity at dose levels from 0.1 to 10 mg P/kg. Some first generation analogues are now used to treat metabolic bone disease but, when given orally, their efficacy in aggressive resorptive disease may be limited because of low potency. A second generation of bisphosphonates, characterized by an amino terminal group and a higher antiresorptive potency, includes 3-amino-1-hydroxypropane-1,1-bisphosphonate (pamidronate) and 4-amino-1-hydroxybutane-1,1-bisphosphonate. Their antiresorptive activity in growing rats ranges from 0.01 to 1 mg P/kg. In the 1980s a third generation of bisphosphonates, characterized by a cyclic chain, was synthesized. It includes series of pyridinyl ethane bisphosphonates, pyridinyl aminomethane bisphosphonates, indan bisphosphonates, cyclopentane bisphosphonates, piperidyl ethane bisphosphonates, pyridinyl and piperidyl hydroxyethane bisphosphonates, piperidinylidene aminomethane bisphosphonates, and pyridinyl oxa- and thiomethane bisphosphonates. Several of these show antiresorptive activity in growing rats as low as 0.001 mg P/kg. Many of the first-, second- and third-generation bisphosphonates have been tested in a model of retinoid-induced bone resorption, and in this model the rank ordering of potency is similar, though somewhat larger doses of bisphosphonate are required to block the resorption induced by the retinoid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Stretch of vascular smooth muscle activates tone and 45Ca2+ influx.

A number of blood vessels develop and maintain an active tone when stretched in vitro. The magnitude of this tone is related to the concentration of extracellular Ca2+. We propose that stretch-induced tone is primarily associated with 45Ca2+ influx, and is minimally affected by the release of intracellular stores of Ca2+. The characteristics of stretch-induced 45Ca2+ influx and tone are distinct from those due to depolarization with K+ and are not dependent on the endothelium. Stretch-induced tone was not altered by increases in the extracellular concentration of K+ nor by removal of the endothelium. Activators of protein kinase C increased, while inhibitors of the enzyme attenuated, stretch-induced tone. We propose that in some blood vessels, stretch per se allows the Ca2+ influx that leads to tone. Stretch-induced tone may be regulated by protein kinase C.

Animals↗
PubMed1988

Increased alpha-adrenergic receptor affinity in resistance vessels from hypertensive rats.

alpha-Adrenergic receptor-related properties, specifically, norepinephrine affinity, occupancy and reserve during contraction, were determined in segments of rat resistance arteries. These were obtained from the superior mesenteric bed of spontaneously hypertensive rats and Wistar-Kyoto strain controls. Receptor affinity for norepinephrine in the spontaneously hypertensive rats was significantly greater than that for the Wistar-Kyoto controls. There were no differences in the estimates of receptor occupancy and reserve. This finding taken together with other studies is consistent with the conclusion that increased alpha-adrenergic receptor-mediated sensitivity of vascular smooth muscle of the spontaneously hypertensive rat reflects differences in the agonist site on the alpha-adrenergic receptor.

Animals↗
PubMed1988

Stretch-dependent calcium uptake associated with myogenic tone in rabbit facial vein.

Many blood vessels possess stretch-dependent myogenic tone. This tone contributes to the active resistance in small arteries, which regulates blood flow in the body. In this report we describe results indicating that stretch-dependent myogenic tone in the rabbit facial vein, a vascular preparation with useful experimental properties, is accompanied by an increased uptake of 45Ca2+. This influx may not occur through voltage-gated Ca2+ channels, since neither the extent of myogenic tone nor 45Ca2+ influx is affected by a concentration of 1,4-dihydropyridine (PN 200-110, 10 nM) that reduces tone and 45Ca2+ influx due to the depolarization by K+. These results indicate that in myogenically active vessels a stretch-activated influx of Ca2+ may occur through distinct Ca2+-entry pathways.

Animals↗
PubMed1988

Flow-dependent dilation in a resistance artery still occurs after endothelium removal.

Infusion of physiological saline solution into the lumen of a tonically contracted resistance artery in vitro caused active relaxation. After endothelium removal by rubbing, confirmed by scanning electron microscopy and loss of the relaxation response to acetylcholine (1 microM), flow relaxation was reduced from a mean of 70% to 37%. The latter change was significant (p less than 0.01). It is concluded that flow-relaxation in the resistance artery of the rabbit originates from both the tunica intima and the media.

Acetylcholine↗
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

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↗