Search PubMed⌕ Search

Biomedical subjects

J A Bevan

Publications and source records attributed to J A Bevan.

At least 127 records · Page 7Linked to original sources
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↗
PubMed1986

Alpha adrenoceptor antagonists selectively reduce thrombin-stimulated contraction in rabbit arteries.

Thrombin-induced contractions and the influence on them of alpha adrenoceptor antagonists were studied in the rabbit femoral and central ear artery using in vitro methods. Maximum contraction with thrombin represented between 50 and 66% of the maximum arterial response to norepinephrine (NE). The thrombin dose-response relationship was complex and did not have a classic sigmoidal shape, whether the endothelium was functional or not. In the femoral artery, the nonselective alpha adrenoceptor antagonist phentolamine (10(-6) M) and the selective alpha-1 adrenoceptor antagonist prazosin (10(-8) and 10(-7) M) significantly reduced the contractions induced with concentrations of thrombin greater than 6 U X ml-1, and increased the concentration of thrombin required to produce maximal contraction. The selective alpha-2 adrenoceptor antagonist rauwolscine (10(-7) M) did not alter the contraction initiated by thrombin or by NE. In the rabbit ear artery, contraction to thrombin and NE could also be reduced with prazosin but not rauwolscine. Reserpine pretreatment did not alter the magnitude of the thrombin-induced contraction in the femoral and central ear artery, indicating that the response and its sensitivity to alpha adrenoceptor blockade was not related to the release of NE from nerve stores. Neither thrombin (0.1-16 U X ml-1) nor NE (10(-9)-10(-5) M) produced any significant relaxation in partially contracted rabbit femoral arteries, whether or not the endothelium was functional, i.e., exhibiting a 50 to 100% maximum relaxation with methacholine or when either alpha-1, alpha-2 or beta adrenoceptor antagonists were present.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1986

Norepinephrine-sensitive, phenoxybenzamine-resistant receptor sites associated with contraction in rabbit arterial but not venous smooth muscle: possible role in adrenergic neurotransmission.

The possibility that not all contractions of rabbit blood vessels to norepinephrine (NE) are mediated through alpha adrenoceptors sensitive to phenoxybenzamine (PBZ) was investigated. Dose-response curves (DRCs) to NE were made in the absence and presence of PBZ pretreatment which minimized the contribution of alpha adrenoceptors. In all arteries studied (saphenous, renal, femoral and central ear arteries), after PBZ-treatment, NE produced biphasic DRCs. The initial component of these DRCs corresponded to doses of NE which in the absence of PBZ were supramaximal. Under conditions of our experimentation the plateau-phase usually occurred at between 5 and 40% of the pre-PBZ maximal response to NE. The second phase occurred with further additions of NE, and achieved a mean of 72 (+/- 4)% of the pre-PBZ maximal contraction to NE. The latter component presumably represented contractions mediated through low-affinity sites for NE which were insensitive to doses of PBZ sufficient to alkylate alpha adrenoceptors. In veins (saphenous and inferior vena cava), we found no evidence for such sites. Our results are discussed in light of current ideas of adrenergic neurotransmission in vascular smooth muscle as proposed by Hirst and Neild (1980a) and others who suggest that response to high concentrations of neuronally released NE occur through PBZ-resistant receptors termed gamma adrenoceptors located exclusively at the postsynaptic membrane. We were able to demonstrate PBZ-resistant, low-affinity sites for NE contractions in the femoral artery, a vessel with very sparse adrenergic innervation, and conclude that such sites for NE are present in a number of arteries (and not veins) irrespective of their innervation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Prazosin selectively antagonizes norepinephrine contractions at low-affinity, non-alpha adrenoceptor sites (extraceptors) in arterial muscle.

The characteristics of a low-affinity site activated by norepinephrine (NE), which is demonstrable in arterial smooth muscle pretreated with phenoxybenzamine (PBZ) to alkylate most alpha adrenoceptors were studied. Treatment with PBZ resulted in biphasic dose-response curves to NE. The initial phase associated with concentrations of NE up to 10(-5) M was due to its action in tissues where alpha adrenoceptors have been reduced to a number that would not support a maximum contraction. The second phase occurred with higher doses of NE. We postulate that this latter PBZ-resistant phase or contraction, which can represent more than 60% of the control maximal response, occurs at low-affinity sites for NE "extraceptors" distinct from alpha adrenoceptors in arterial smooth muscle. These residual responses to NE after PBZ treatment were inhibited selectively by prazosin and protected by prazosin from further inhibition by additional doses of PBZ. Effects due to prazosin at low-affinity sites were observed only with doses in excess of those required to competitively inhibit responses through alpha adrenoceptors in smooth muscle. The response to NE occurring through PBZ-resistant adrenoceptors was not dependent on the presence of the endothelium. This low-affinity site for NE was also evident after alkylation of alpha adrenoceptors with other irreversibly acting antagonists (e.g., benextramine and dibenamine). These observations are discussed in relation to the suggestion for a new adrenoceptor, the gamma-adrenoceptor. Differences and similarities of the extraceptor with this proposed adrenoceptor are discussed. Both sites have a high threshold to NE, and both may be influenced by prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1985

Evidence for functional alpha-adrenoceptors in rabbit basilar arteries.

The contractile response of rabbit basilar arteries to 1-norepinephrine was studied both in the absence and in the presence of prazosin (10 nM and 1 microM). Prazosin produced a parallel shift to the right of the norepinephrine, but not the histamine, dose-response curves indicating the presence of prazosin-sensitive alpha-adrenoceptors in this vessel. The alpha-adrenoceptor-mediated contractile responses to norepinephrine in rabbit basilar arteries were much more sensitive to the deleterious effects of storage (for 18 h at 4 degrees C) than those to histamine. It is suggested that the low number of alpha-adrenoceptors in the rabbit basilar artery combined with their low sensitivity to alpha-adrenoceptor agonists, and detrimental effects associated with tissue storage may explain some inconsistent reports in the literature regarding the presence of functional alpha-adrenoceptors in rabbit basilar arteries, particularly ligand binding studies.

Acetylcholine↗
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↗
PubMed1985

Acetylcholine induced endothelial-dependent vasodilation increases as artery diameter decreases in the rabbit ear.

Isolated resistance vessels in the rabbit ear preconstricted with histamine were relaxed by acetylcholine by a proportionately greater amount than the central ear artery. The relaxation was antagonized by atropine and also by endothelium removal. Our studies represent the first direct evidence that endothelium-dependent dilation can occur in resistance vessels.

Acetylcholine↗
PubMed1985

Responses of rabbit aorta to tyramine in relation to the surface of drug entry.

The contraction elicited by submaximally effective concentrations of tyramine in the rabbit aortic strip occurs after a shorter latency and increases at a higher initial velocity to a greater steady-state level when drug entry is limited to the adventitial than when it is limited to the intimal surface. The reverse was true for noradrenaline. Both amines elicited equal maximum responses with independence of the surface of entry into the vascular wall. Differences between steady-state contractions disappear when the intramural disposition pathways of tyramine are blocked pharmacologically by a combination of pargyline and semicarbazide. Incubation with cocaine and pretreatment with reserpine resulted in a reversal of the surface of entry related differences between steady-state contractions to tyramine related to differences of the surface of entry. This reflected the unmasking of the direct component of the action of tyramine. Thus, the technique of limited drug entry into the vascular wall together with blockade of disposition pathways allows us to characterize the pre- and postsynaptic components of the action of tyramine.

Animals↗
PubMed1985

Vascular myogenic or stretch-dependent tone.

Myogenic tone is an important source of vascular resistance, which appears to depend upon stretch of the vessel wall. It contributes to autoregulation, is dependent upon external calcium, and may involve a calcium-entry mechanism different from that associated with the action of agonists and changes in the membrane potential.

Animals↗
PubMed1985

Phentolamine-resistant neurogenic constriction occurs in small arteries at higher frequencies.

The effect of the alpha 1, alpha 2-antagonist phentolamine (PTA) on neuromuscular transmission and exogenous norepinephrine (NE) was assessed in arteries of diminishing diameter possessing a substantial adventitiomedial junction adrenergic innervation in the rabbit ear, i.e., central ear artery (CEA), unstretched lumen diameter (ULD) approximately equal to 300 microns; main side branch (MSB) off the CEA (ULD approximately equal to 150 microns); and terminal branch (TB) off the MSB (ULD approximately equal to 75 microns). With increasing PTA concentrations, contractile responses to transmural nerve stimulation (TNS) were decreased proportionately less in TB than in MSB and CEA. PTA (4 X 10(-6) M, a competitive antagonist concentration) blocked the tetrodotoxin-sensitive TNS-induced contractions of CEA segments at 2, 4, and 8 Hz. The response at 8 Hz was reduced at least 98% in MSB and 86% in TB. However, responses to 8 Hz were not abolished in MSB and TB until 2 X 10(-5) and 3 X 10(-5) M PTA, respectively. PTA (3 X 10(-5) M) possessed nonspecific depressant properties in addition to its alpha-antagonist properties. We conclude that the sympathetic nervous system influences tone through alpha-adrenoceptors in the CEA and in the MSB and TB at lower frequencies. Responses in the MSB and TB at higher frequencies of nerve stimulation are mediated predominately through alpha-receptors. If the possibility of a nonadrenergic transmitter is discounted, the possibilities that the small PTA-resistant component of the neurogenic response is due to a high concentration of NE acting on alpha-adrenoceptors and/or a high threshold site cannot be distinguished.

Animals↗
PubMed1985

Neurogenic muscarinic vasodilation in the cat. An example of endothelial cell-independent cholinergic relaxation.

Nerve-mediated and acetylcholine-induced dilator behavior of feline posterior auricular arteries was studied in vitro. We evaluated the muscarinic nature and endothelial cell-dependence of the vasodilations and attempted to determine if there are inhibitory muscarinic receptors located directly on the smooth muscle cells in this artery. Transmural nerve stimulation of arteries which were pretreated with guanethidine (5 X 10(-6)M) and constricted with prostaglandin F2 alpha (3 X 10(-6)M) caused a frequency-dependent, tetrodotoxin-sensitive relaxation of up to 50% of induced tone. Atropine (10(-7)M) blocked more than 95% of this response at all frequencies. Removal of the endothelium by rubbing the intimal surface did not affect the magnitude of the response, but prolonged it slightly. Neurogenic relaxations in rubbed preparations were atropine-sensitive, although less so than control at higher stimulation frequencies. Relaxation of this artery to the calcium ionophore A23187 was completely endothelial cell-dependent. However, exogenous acetylcholine caused dose-dependent relaxations both in control and rubbed preparations. We conclude that the posterior auricular artery is an example of a blood vessel which has muscarinic receptors located directly on its smooth muscle cells which, when activated by acetylcholine released from perivascular nerves, mediate a smooth muscle cell relaxation. This finding contrasts with models of the vascular smooth muscle cell which indicates an excitatory role for muscarinic receptors.

Acetylcholine↗
PubMed1985

Effect of diltiazem on experimental chronic cerebral vasospasm in the monkey.

The influence of diltiazem on chronic cerebral vasospasm was studied following subarachnoid hemorrhage (SAH) in a primate model. The model mimics the human experience including the production of neurological deficits. Six monkeys were pretreated with diltiazem (25 mg/kg twice daily) for 2 days prior to surgical production of an SAH and for 5 days after the hemorrhage. This group was compared with six untreated monkeys that also sustained an SAH. The mean diameter of cerebral arteries measured at six angiographic sites was 60.6% of the pre-SAH diameter for the untreated group and 99.7% for the diltiazem-treated group. These values are significantly different (p less than 0.0005). There was no neurological deficit in the pretreated animals. The mean diameter of the "most constricted vessel" in each experiment was 22% of the prehemorrhage diameter for the untreated and 84% for the treated group (p less than 0.0005). Arterial pressure was unaffected by the dosage regimen. These experiments with this primate model of chronic cerebral vasospasm demonstrate that vascular narrowing and neurological deficit can be markedly attenuated by diltiazem pretreatment.

Animals↗
PubMed1985

The human adrenergic neurovascular mechanism.

The major features of adrenergic neurotransmission established in animals have been observed in one blood vessel or another from the human. However, the detailed mechanism in one particular human blood vessel or vascular sample from a particular regional bed has not yet been carefully compared with a corresponding vessel from nonhuman species. There is probably more known about cerebral blood vessels than others, and if our knowledge of this bed is at all representative of what occurs elsewhere, then any projections regarding the human from animal studies are potentially very misleading. The little evidence that is available suggests that generalization regarding human vessels is going to be difficult. Yet this very difficulty emphasizes the need for study, not only from the normal and healthy subject, but from the diseased. The human circulation represents a source of vascular tissue whose analysis will reveal much more about the circulation and its change with circumstances, including disease, of interest to the scientist and the physician than can ever be achieved by experimentation with animal tissues.

Aging↗
PubMed1985

Alpha adrenoceptor number limits response of some rabbit arteries to norepinephrine.

Some properties of the receptor population mediating contraction to I-norepinephrine (NE) were studied in rabbit aorta and the intrapulmonary and basilar arteries. The constrictor effect of NE in isolated vessel ring segments were recorded, both in the absence and presence of concentrations of phenoxybenzamine which depressed the maximal contractions to NE. Dose-response curves to NE were biphasic in the basilar artery. In the basilar artery and in medium-sized intrapulmonary arteries, the response to maximally effective concentrations of NE were always lower than responses to other agents. In the larger intrapulmonary artery segments and aorta the responses to NE and serotonin were of similar magnitude. The ED50 for NE did not change with vessel size in intrapulmonary arteries, whereas that of the basilar artery was considerably greater than in the pulmonary and aorta segments. The NE dissociation constant (KA) and the receptor occupation-response relationship was calculated in all vessel segments. The KA for NE was similar in part I of the basilar artery, aorta and both sizes of pulmonary artery. The KA for NE in part II of the basilar artery dose-response curves was 8 to 10 times greater. Half-maximal responses by NE were produced by occupation of 10% of receptors in the aorta and the large intrapulmonary artery and of 40 to 50% receptors in the basilar and medium-sized intrapulmonary artery. It is concluded that in some smaller arteries the small NE response may be limited by receptor number, and that whereas this may not be a phenomenon common to all vessels of this size, it may reflect specialization of certain vascular beds.

Animals↗