Biomedical subjects

J R Docherty

Publications and source records attributed to J R Docherty.

At least 37 records · Page 2Linked to original sources

PubMed1997

Alpha 2C-adrenoceptors mediate contractile responses to noradrenaline in the human saphenous vein.

We have investigated the subtype of alpha 2-adrenoceptor mediating isometric contractions of human saphenous vein in comparison with alpha 2-adrenoceptor ligand binding sites. Postjunctional alpha 2-adrenoceptors in the human saphenous vein were investigated in terms of the ability of alpha 2-adrenoceptor antagonists to shift the contractile potency of noradrenaline. The following antagonists were employed (potencies, pKB, in human saphenous vein in parentheses): chlorpromazine (6.98 +/- 0.24), BDF 8933 (7.60 +/- 0.06), prazosin (6.62 +/- 0.15), ARC 239 (7.19 +/- 0.15), yohimbine (7.23 +/- 0.09), HV 723 (7.52 +/- 0.14), WB 4101 (7.90 +/- 0.06), SKF 104078 (6.55 +/- 0.08), BRL 44408 (5.72 +/- 0.21). Antagonist potency at postjunctional alpha 2-adrenoceptors was correlated with antagonist affinity at alpha 2-adrenoceptor ligand binding sites in membranes of human platelet (alpha 2A), rat kidney (alpha 2B) and Sf9 cells expressing human recombinant receptors (alpha 2C), labelled with [3H]yohimbine. The correlation with the postjunctional alpha 2-adrenoceptor mediating contraction of the human saphenous vein was best for the human recombinant alpha 2C-adrenoceptor ligand binding site (r = 0.92, n = 8, P < 0.001), as compared to correlations with the alpha 2B-adrenoceptor ligand binding site of rat kidney (r = 0.62, n = 8, n.s.) and with the alpha 2A-adrenoceptor ligand binding site of human platelet (r = 0.23, n = 8, n.s.). It is concluded that the functional postjunctional alpha 2-adrenoceptor mediating contractions of the human saphenous vein closely resembles the human recombinant alpha 2C-adrenoceptor ligand binding site.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1997

Comparison of the effects of nitric oxide synthase inhibition and guanylate cyclase inhibition on vascular contraction in vitro and in vivo in the rat.

We have investigated the differences between the nitric oxide synthase inhibitor (NOSI), L-NMMA, and the guanylate cyclase inhibitors (GCI), methylene blue and LY 83583, in their abilities to increase vasoconstrictor responses in vitro and in vivo. In rat small mesenteric arterial rings, 1 h exposure to the NOSI, L-NMMA (100 microM), and the GCI, methylene blue (10 microM), alone or in combination with L-NMMA, caused a significant reduction in the maximum relaxation to ACh in mesenteric arteries pre-contracted with the thromboxane mimetic U46619 (10 microM). Hence, both NOSI and GCI inhibit endothelium-dependent relaxations to ACh in rat small mesenteric artery. However, 1 h exposure to L-NMMA and L-NNA (both 100 microM), but not methylene blue (10 microM), significantly increased the contractile response to U-46619 (10 microM) in rat small mesenteric artery. It was decided to investigate further this difference between NOSI and methylene blue. In rat small mesenteric arterial rings, L-NMMA (10 microM) and LY 83583 (1-10 microM) significantly increased the contractile response to KCl (40 mM) or to noradrenaline (10 microM), when administered during the contraction. However, methylene blue (1-10 microM) increased the contractile response to KCl but not noradrenaline. In rat aortic rings, L-NMMA (100 microM), methylene blue (1-10 microM) and LY 83583 (1-10 microM) significantly increased the contractile response to KCl (40 mM) or to noradrenaline (1 microM). In the pithed rat preparation, L-NMMA (40.3 micromol kg(-1), i.v.) significantly increased the pressor response both to bolus injection of noradrenaline (3.13 nmol kg[-1]) and to spinal pressor nerve stimulation. However, methylene blue (3.13-15.6 micromol kg[-1]) or LY 83583 (4.0-40.0 micromol kg[-1]), failed to affect pressor responses to either NA or pressor nerve stimulation. Hence, there are differences between NOSI and GCI in their abilities to increase vasoconstrictor responses, especially when comparing responses in vitro and in vivo. This suggests that nitric oxide has actions in addition to activation of guanylate cyclase to modulate vasoconstrictor responses, presumably by membrane hyperpolarisation, and that this action may be more important in vivo.

Acetylcholine↗

PubMed1997

The alpha-adrenoceptor-mediated actions of chloroethylclonidine.

1. Chloroethylclonidine (CEC) has an affinity for all 6 subtypes of alpha-adrenoceptor, but binds irreversibly particularly to alpha 1B-, alpha 1D-, alpha 2C-, and alpha 2A/D-adrenoceptors. 2. Functionally, CEC behaves as an irreversible alpha 1-adrenoceptor antagonist, reducing the maximum response to noradrenaline (NA), and shows subtype selectivity in that alpha 1A-adrenoceptors are relatively insensitive to CEC. CEC also behaves as an irreversible alpha 2-adrenoceptor agonist, both prejunctionally in the rat vas deferens and postjunctionally in the dog saphenous vein. 3. In the rat aorta, CEC does not produce direct contractions, but following exposure to CEC concentrations of NA of 10 microM and above produce contractions resistant to alpha 1- and alpha 2-adrenoceptor blockade. We have investigated this phenomenon in detail. 4. Receptor protection experiments were carried out in the rat aorta, in which the protecting agent was present prior to and during exposure to CEC. The component of the contraction to NA resistant to alpha-blockade was still present following receptor protection with the alpha 1-adrenoceptor antagonist prazosin, but absent following receptor protection with NA and reduced following receptor protection with alpha 2-adrenoceptor antagonists. The resistant response may represent an irreversible agonist interaction between CEC, NA, and normally silent alpha 2-adrenoceptors, that cannot be affected by subsequent competitive antagonism, but that can be prevented by receptor protection with the agonist NA prior to CEC. 5. CEC has two major classes of action at alpha-adrenoceptors: irreversible antagonism at alpha 1-adrenoceptors, and irreversible agonism at alpha 2-adrenoceptors. Both actions can be demonstrated in the rat aorta.

Adrenergic alpha-Antagonists↗

PubMed1997

Vascular actions of octreotide in the portal hypertensive rat.

1. We have investigated the actions of the somatostatin analogue octreotide in the portal hypertensive Wistar rat in vivo and in rat small mesenteric artery and aorta in vitro. 2. In small mesenteric artery, octreotide (0.1-0.3 microM) failed to produce any direct contraction, nor did it affect contractions to noradrenaline (NA, 10 microM) or endothelium-dependent relaxations to acetylcholine. 3. In rat aorta, octreotide (0.3 microM) and somatostatin (1 microM) failed to affect contractions to NA (1 microM), or concentration-contractile response curves to NA. 4. In rat vas deferens, octreotide and somatostatin significantly reduced contractile responses to electrical stimulation with pD2 values (-log IC50) of 8.19 +/- 0.10 (n = 4) and 8.16 +/- 0.26 (n = 4), respectively. Hence, the lack of effect of these agents in aorta or mesenteric artery was not due to lack of efficacy or inappropriate choice of concentration. 5. In the anaesthetized portal hypertensive rat, intravenous injection of octreotide (1-100 microg kg[-1]) did not significantly affect systemic blood pressure, nor did it affect mesenteric vascular conductance as measured by laser doppler flow probes. However, octreotide (100 microg kg[-1]) significantly reduced vascular conductance to 74.2 +/- 7.7% of control (n = 6) in porto-systemic shunt vessels as measured by laser doppler flow probes. 6. Phenylephrine (1 microg kg[-1]) significantly raised blood pressure and significantly decreased vascular conductance in both mesenteric (66.6 +/- 3.7% of control) and porto-systemic shunt vessels (58.7 +/- 10.0% of control). 7. It was concluded that octreotide has selective effects on porto-systemic shunt vessles in vivo in the portal hypertensive rat.

Animals↗

PubMed1996

Investigation of the subtype of alpha 2-adrenoceptor mediating pressor responses in the pithed rat.

We have investigated the subtype of alpha 2-adrenoceptor mediating postjunctional pressor responses in the pithed rat in comparison with alpha 2-adrenoceptor ligand binding sites. In pithed rats, postjunctional alpha 2-adrenoceptors were investigated in terms of the ability of alpha 2-adrenoceptor antagonists to shift the pressor potency of the alpha 2-adrenoceptor agonist xylazine. Antagonist potency at postjunctional alpha 2-adrenoceptors in the pithed rat was correlated with antagonist affinity at alpha 2-adrenoceptor ligand binding sites in membranes of rat kidney (alpha 2B), Sf9 cells expressing human recombinant receptors (alpha 2C) and rat submandibular gland (alpha 2D) labelled with [3H]yohimbine. The correlation with the postjunctional alpha 2-adrenoceptor mediating pressor responses in the pithed rat was better for the alpha 2D-adrenoceptor ligand binding site of rat submandibular gland (r = 0.95, n = 9, P < 0.0001) and the alpha 2B-adrenoceptor ligand binding site of rat kidney (r = 0.90, n = 9, P < 0.001) than with the human recombinant alpha 2C-adrenoceptor ligand binding site (r = 0.81, n = 9, P < 0.01). When the pressor potencies of three additional antagonists were included in the correlations for alpha 2B- and alpha 2D-sites only, the correlation with alpha 2D-adrenoceptor ligand binding site of rat submandibular gland (r = 0.91, n = 12, P < 0.0001) was much better than with the alpha 2B-adrenoceptor ligand binding site of rat kidney (r = 0.77, n = 12, P < 0.01). It is concluded that the functional postjunctional alpha 2-adrenoceptors mediating pressor responses in the pithed rat most closely resemble the alpha 2D-adrenoceptors subtype.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1996

Effects of aging on prejunctional control of neurotransmission in the rat.

In this study, we have looked in detail at the effects of aging on neurotransmission in isolated atria and intact heart in anesthetized rats, examining adult and aged animals. There was a diminished ability of the norepinephrine reuptake blocker cocaine to increase stimulation-evoked release of norepinephrine in aged rats and in terms of increasing the norepinephrine-evoked tachycardia in anesthetized rats, suggesting that the function of the reuptake process is diminished by aging. The ability of the alpha 2 adrenergic receptor agonist xylazine to inhibit release of norepinephrine neurotransmitter was also diminished in aged rats both in isolated tissues and in vivo in anesthetized animals. In further studies, the ability of the beta-adrenergic receptor agonists isoproterenol (beta 1 and beta 2 agonist) and procaterol (selective beta 2 agonist) to increase stimulation-evoked release of norepinephrine was examined. Both agonists produced a concentration-dependent facilitation of norepinephrine release in rats atria. Although isoproterenol and procaterol increased release in tissues from young and old animals, the magnitude of the increase was significantly reduced in tissues from old rats, so that beta-adrenergic receptor mediated facilitation was diminished. In summary, aging is associated with a decline in prejunctional modulation of neurotransmission, in terms of diminished norepinephrine reuptake, diminished prejunctional alpha 2 adrenergic receptor mediated inhibition and diminished prejunctional beta 2 adrenergic receptor mediated facilitation. TABLE 2 summarizes the possible effects of aging on noradrenergic neurotransmission. Overall, neurotransmission at rest may be little changed by aging, given that postjunctional responsiveness may fall, but scope for modulation may be diminished.

Adrenergic Fibers↗

PubMed1995

Prejunctional actions of K+ channel blockers in rat vas deferens.

In studies of isometric contractions in prostatic portions of rat vas deferens evoked by single pulse electrical stimulation, the K+ channel blockers 4-aminopyridine, tetraethylammonium and charybdotoxin, but not apamin, significantly reduced the prejunctional inhibitory potency and the maximum inhibitory effect of the alpha 2-adrenoceptor agonist xylazine. The protein kinase C activator phorbol dibutyrate had similar effects to 4-aminopyridine against xylazine. However, 4-aminopyridine, tetraethylammonium, charybdotoxin and phorbol dibutyrate, but not apamin, significantly increased the magnitude of the isometric contraction to a single stimulus. 4-Aminopyridine and phorbol dibutyrate significantly reduced, while tetraethylammonium did not affect, isometric contractions to noradrenaline, and 4-aminopyridine failed to affect contractions to alpha,beta-methylene-ATP, so that the effects of these agents on the isometric contraction to a single stimulus were presumably by a prejunctional action. The Ca2+ entry facilitator Bay K 8644 (1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyrid ine carboxylic acid methylester) increased stimulation-evoked contractions by a postjunctional action and reduced the inhibitory effects of xylazine. When the isometric contraction following 4-aminopyridine was reduced by decreasing the stimulation voltage or by reducing the Ca2+ concentration from 2.5 to 0.9 mM, 4-aminopyridine significantly reduced the potency of xylazine. However, tetraethylammonium and Bay K 8644 failed to affect the inhibitory potency of xylazine in low Ca2+. It is concluded that the K+ channel blocker 4-aminopyridine reduces the prejunctional inhibitory potency of xylazine, and this action is independent of increased neurotransmitter release. These results suggest that prejunctional alpha 2-adrenoceptor-mediated inhibition in rat vas deferens involves K+ channels sensitive to block by 4-aminopyridine.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1995

Effects of portal hypertension on responsiveness of rat mesenteric artery and aorta.

1. We have examined the effects of pre-hepatic portal hypertension on the responsiveness of rat small mesenteric arteries and aorta. Rats were made portal hypertensive by creating a calibrated portal vein stenosis, or sham-operated. 2. In rat mesenteric arteries, there was no significant difference between portal hypertensive and sham-operated animals in the contractile potency of noradrenaline (NA), but the maximum contractile responses to NA, U46619 and KCl were significantly increased in vessels from portal hypertensive animals. This altered maximum contractile response was not due to alterations in smooth muscle mass. 3. In rat mesenteric arteries, there were no significant differences between portal hypertensive and sham-operated animals in endothelium-dependent relaxations to acetylcholine (ACh). The difference between portal hypertensive and sham-operated rats in the maximum response to U46619 was maintained following a combination of methylene blue (1 microM) and NG-monomethyl-L-arginine (100 microM), suggesting that any differences in endothelial function do not explain differences in the response to vasoconstrictors. 4. In rat aorta, there were no significant differences between portal hypertensive and sham-operated animals in the contractile response to NA or KCl or in the endothelium-dependent relaxations to ACh. 5. In pithed rats, there was no difference between portal hypertensive and sham-operated animals in the pressor potency of NA. 6. It is concluded that portal hypertension produces an increase in the contractile response to the vasoconstrictors NA, U46619 and KCl in rat mesenteric arteries but not in the aorta. This suggests that the diminished responsiveness to vasoconstrictors reported in portal hypertensive rats in vivo is not due to a diminished responsiveness at the level of the vascular smooth muscle.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

Investigation of the subtype of alpha 2-adrenoceptor mediating prejunctional inhibition of cardioacceleration in the pithed rat heart.

1. We have investigated the subtype of alpha 2-adrenoceptor mediating prejunctional inhibition of cardioacceleration in the pithed rat heart in comparison with alpha 2-adrenoceptor ligand binding sites. 2. In pithed rats, prejunctional alpha 2-adrenoceptors were investigated in terms of the ability of alpha 2-adrenoceptor antagonists to shift the inhibitory potency of the alpha 2-adrenoceptor agonist, xylazine, against the tachycardia to a single electrical stimulus given via the pithing rod. 3. Antagonist potency at prejunctional alpha 2-adrenoceptors in pithed rat heart was correlated with antagonist affinity at alpha 2-adrenoceptor ligand binding sites in membranes of rat kidney and submandibular gland labelled with [3H]-yohimbine. 4. The correlation with the prejunctional alpha 2-adrenoceptor in pithed rat heart was best for the alpha 2D-adrenoceptor ligand binding site of rat submandibular gland (r = 0.98, n = 10, P < 0.0001), as compared to correlations with the alpha 2A-adrenoceptor ligand binding site of human platelet (r = 0.90, n = 9, P < 0.001), the alpha 2B-adrenoceptor ligand binding site of rat kidney (r = 0.82, n = 10, P < 0.01) and with published results for the alpha 2C-adrenoceptor ligand binding site (r = 0.48, n = 6, NS). 5. It is concluded that the functional prejunctional alpha 2-adrenoceptor of pithed rat heart closely resembles the alpha 2D-adrenoceptor ligand binding site of rat submandibular gland.

Adrenergic alpha-Agonists↗

PubMed1995

Investigation of the actions of chloroethylclonidine in rat aorta.

1. The interaction between chloroethylclonidine (CEC) and noradrenaline (NA) has been examined at alpha-adrenoceptors mediating contractions of rat aorta. 2. In rat aorta, the competitive antagonist prazosin, over the concentration-range 0.01-10 microM, produced concentration-dependent shifts in the contractile potency of NA, so that there was no component of the NA contraction resistant to prazosin. 3. The irreversible alpha 1-adrenoceptor antagonists, phenoxybenzamine (PBZ) (1-10 microM) and benextramine (10 microM) produced shifts in potency of NA and reduced the maximum response in a concentration-dependent manner. 4. The irreversible alpha 1-adrenoceptor antagonist, CEC (100 microM), produced a non-parallel shift in the NA concentration-response curve so that low concentrations of NA produced relatively small contractions but relatively high concentrations produced further contractions, so that the maximum response was not significantly reduced. 5. The combination of CEC pretreatment and subsequent prazosin (0.1 microM) produced a parallel shift in the potency of NA. However, prazosin (10 microM) failed to produce any further effect on the response to high concentrations of NA following CEC pretreatment. Hence, a component of the contraction to NA in the presence of CEC was resistant to subsequent prazosin. Likewise, this component was resistant to a combination of prazosin (10 microM) and yohimbine (10 microM). 6. Receptor protection experiments were carried out in which tissues were exposed to NA (100 microM), yohimbine (10 microM) or prazosin (0.1 microM) prior to and during exposure to CEC. Receptor protection with NA, yohimbine or prazosin (0.1 microM), followed by washout prevented the shift in potency of NA produced by CEC. 7. Further experiments examined the effects of prazosin (10 microM) on responses to NA following receptor protection with NA (100 microM), yohimbine (10 microM), prazosin (10 microM), or xylazine (100 microM). In receptor protection studies with NA, subsequent prazosin (10 microM) produced a shift in response to NA following CEC which was not signficantly different from the shift produced by prazosin alone in the absence of receptor protection. In receptor protection studies with prazosin, yohimbine or xylazine, subsequent prazosin (10 microM) produced shifts in the response to NA following CEC which were significantly less than the shift produced by prazosin alone in the absence of receptor protection.8. It is concluded that CEC has two actions in the rat aorta. Firstly, it behaves as an irreversible a,-adrenoceptor antagonist, reducing the response to low concentrations of NA (up to 10 microM). However,after exposure to CEC, concentrations of NA of 10 microM and above produced contractions resistant toprazosin. This resistant component was still present following receptor protection with alpha1,- or alpha2-adrenoceptor antagonists, but absent following receptor protection with NA. Hence, the latter response may represent an irreversible agonist interaction between CEC, NA and alpha-adrenoceptors which cannot be affected by subsequent competitive antagonism, but which can be prevented by receptor protection with the agonist NA prior to CEC.

Adrenergic alpha-Antagonists↗

PubMed1995

Investigations of the function of the vascular endothelium in portal hypertensive rats.

There were no differences between mesenteric arteries from sham or 14-day portal hypertensive (PH) rats in the potency of or maximum endothelium-dependent relaxations (EDR) to acetylcholine. There were no differences between sham-operated and PH rats in the effects of the combination of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (100 mumol/l) and methylene blue (10 mumol/l) in causing a significant reduction in the EDR to acetylcholine. The degree of portal-systemic shunting, as measured by 57Co-labeled microspheres, was unaffected by acute administration of NG-monomethyl-L-arginine (50 mg/kg) or methylene blue (5 mg/kg). In conclusion, nitric oxide is the main mediator of EDR in rat mesenteric artery, and no evidence was found for an increased role for endothelial-derived nitric oxide in PH rats.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1994

Prejunctional actions of N-ethyl-maleimide and phenoxybenzamine in rat vas deferens.

In studies of electrically evoked isometric contractions of rat vas deferens, N-ethyl-maleimide (30 microM) pretreatment significantly reduced the prejunctional inhibitory potencies of xylazine and 5-hydroxytryptamine but failed to affect the potency of the alpha 1-adrenoceptor agonist amidephrine. Phenoxybenzamine (1 microM) or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (10 microM) produced significant shifts in the potency of xylazine and significantly reduced the maximum inhibition, but the combination of phenoxybenzamine or EEDQ and N-ethyl-maleimide (30 microM) produced no further alteration in the effects of xylazine. In displacement studies, N-ethyl-maleimide displaced the binding of [3H]MK 912 ((2S,12bS)1',3'-dimethylspiro- (1,3,4,5',6,6',7,12b-octahydro-2H-benzo[b]furo[2,3-a]quinazoline)- 2,4'- pyrimidin-2'one) to rat renal cortex membranes with a Ki of 466 +/- 133 microM (n = 5), and so does not bind to alpha 2-adrenoceptors in the concentration range in which it affects prejunctional receptor mediated responses. This may suggest that N-ethyl-maleimide has actions other than inactivation of G-proteins or that the irreversible alpha 2-adrenoceptor antagonists phenoxybenzamine and EEDQ inactivate G-proteins sensitive to N-ethyl-maleimide in concentrations at which they bind to alpha 2-adrenoceptors.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed1994

Aging and vasoconstrictor responses mediated by alpha 2-adrenoceptors and 5-HT1 and 5-HT2 receptors.

The potencies of noradrenaline (NA) at producing alpha 2-adrenoceptor mediated contractions, and of 5-hydroxytryptamine (5-HT) at producing 5-HT1 and 5-HT2 receptor mediated contractions were investigated in rings of human saphenous vein obtained from varicose vein surgery. There was a significant negative correlation between agonist potency and age for NA at alpha 2-adrenoceptors (r = 0.52, n = 21, p < 0.05) and for 5-HT at both 5-HT1 (r = 0.47, n = 19, p < 0.05) and 5-HT2 (r = 0.54, n = 19, p < 0.05) receptors, so that both agonists were less potent with increasing age. This demonstrates an age-related decrease in alpha 2-adrenoceptor and 5-HT1 and 5HT2 mediated contractile responsiveness in the human saphenous vein.

Adult↗

PubMed1993

Investigation of the subtypes of alpha 1-adrenoceptor mediating contractions of rat aorta, vas deferens and spleen.

1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) or phenylephrine in rat vas deferens, spleen and aorta, and mediating contractions to endogenous NA in rat vas deferens have been examined. 2. In rat vas deferens, the competitive antagonists prazosin, WB 4101, benoxathian and 5-methyl-urapidil inhibited contractions to NA with pA2 values of 9.26, 9.54, 9.02 and 8.43, respectively. The irreversible antagonist chloroethylclonidine (CEC) (100 microM) failed to affect contractions to NA. 3. In rat vas deferens in the presence of nifedipine (10 microM), contractions to NA were significantly attenuated and under these conditions, CEC (100 microM) significantly reduced the maximum response to NA. 4. In rat spleen, the competitive antagonists prazosin, WB 4101 and benoxathian inhibited contractions to phenylephrine with pA2 values of 9.56, 8.85 and 7.60, respectively, and 5-methyl-urapidil had a KB of 6.62. CEC (100 microM) significantly reduced the maximum contraction to phenylephrine. 5. In rat aorta, the competitive antagonists, prazosin, WB 4101, benoxathian and 5-methyl-urapidil inhibited contractions to NA with pA2 values of 9.45, 9.21, 8.55 and 8.12, respectively. CEC (100 microM) produced an approximately parallel shift in the potency of NA, without significantly reducing the maximum response. 6. In epididymal portions of rat vas deferens in the presence of nifedipine (10 microM), the isometric contraction to a single electrical pulse was significantly reduced by CEC (100 microM), and by the competitive antagonists prazosin, WB 4101, benoxathian and 5-methyl-urapidil at concentrations of 1 nM. 7. In prostatic portions of rat vas deferens, the alpha l-adrenoceptor agonist, amidephrine, produced concentration-dependent increases in the isometric contraction to a single electrical stimulus and the maximum increase in the evoked response produced by amidephrine was unaffected by CEC (100 microM).8. Contractions of rat vas deferens produced by NA (and amidephrine) are mediated predominantly by alpha lA-adrenoceptors as shown by the high potency of alpha lA-adrenoceptor selective antagonists and the lack of effect of CEC. A small CEC-sensitive response, particularly in epididymal portions, was revealed in the presence of nifedipine. Contractions of rat spleen are mediated by alpha lB-adrenoceptors since alpha 1A selective antagonists showed low potency and CEC significantly reduced the maximum contraction to phenylephrine. Contractions of rat aorta to NA are mediated by non-alpha lA, non-alpha lB-adrenoceptors, due to the high potency of the aMA-selective antagonists and sensitivity to CEC.9. The noradrenergic contraction of epididymal portions of rat vas deferens in the presence of nifedipine is CEC-sensitive, but the alpha 1 A-selective antagonists showed high potency, suggesting that this response is mediated by non-alpha lA, non-alpha 1B-adrenoceptors.10. In conclusion, at least three subtypes of functional alpha 1-adrenoceptors have been demonstrated in these studies.

Adrenergic alpha-Agonists↗

PubMed1992

Are the prejunctional alpha 2-adrenoceptors of the rat vas deferens and submandibular gland of the alpha 2A- or alpha 2D-subtype?

We have investigated the effects of antagonists at functional prejunctional alpha 2-adrenoceptors of rat was deferens and rat submandibular gland and compared potencies with affinities for the alpha 2A-, alpha 2B- and putative alpha 2D-ligand binding sites of human platelet, rat kidney, and rat submandibular gland, respectively. Prejunctional potency of antagonists was expressed as an EC30 (concentration producing a 30% increase in stimulation-evoked release of tritium in tissues pre-incubated with [3H]noradrenaline) in rat vas deferens and submandibular gland, and also as a pA2 (antagonist concentration producing a 2-fold shift in the inhibition by the alpha 2-adrenoceptor agonist xylazine of the electrically-evoked isometric twitch) in rat vas deferens. The functional prejunctional alpha 2-adrenoceptors of rat vas deferens and submandibular gland are alpha 2A-like since there was a good correlation between affinity for the alpha 2A-ligand binding site in human platelet and prejunctional potency in rat vas deferens (r = 0.90, n = 7, P less than 0.001), and submandibular gland (r = 0.84, n = 7, P less than 0.05). However, there was a better correlation between affinity for the alpha 2-ligand binding site of rat submandibular gland and prejunctional potency in rat vas deferens (r = 0.95, n = 7, P less than 0.001), and submandibular gland (r = 0.97, n = 7, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

Investigations of prejunctional alpha 2-adrenoceptors in rat atrium, vas deferens and submandibular gland.

We have examined the effects of a series of alpha 2-adrenoceptor antagonists on the stimulation-evoked release of tritium from rat atrium, vas deferens and submandibular gland pre-incubated with [3H]noradrenaline, and correlated these potencies with affinities for the alpha 2A-ligand binding site of human platelet and the alpha 2B-ligand binding site of rat kidney. The alpha 2B-selective adrenoceptor antagonists prazosin and ARC 239 showed significantly higher, and the alpha 2A-selective antagonist BRL 44408 showed significantly lower, potency in atrium than in vas deferens and submandibular gland. Yohimbine and BDF 8933 failed to distinguish between prejunctional alpha 2-adrenoceptors or between ligand binding sites. It is concluded that the prejunctional alpha 2-adrenoceptor of rat atrium resembles the alpha 2B-ligand binding site, and differs from the prejunctional alpha 2-adrenoceptors of rat vas deferens and submandibular gland, which resemble the alpha 2A-ligand binding site.

Adrenergic alpha-Antagonists↗

PubMed1992

Investigations of the subtype of alpha 2-adrenoceptor mediating contractions of the human saphenous vein.

1. We have examined the effects of a series of alpha 2-adrenoceptor antagonists against isometric contractions to noradrenaline in human saphenous vein, and correlated these potencies with affinities for the alpha 2A-ligand binding site of human platelet and the alpha 2B-ligand binding site of rat kidney. 2. The alpha 2B-selective adrenoceptor antagonists, prazosin, ARC 239 and HV 723 showed high, and the alpha 2A-selective antagonist BRL 44408 showed low, potency in human saphenous vein. 3. Potency in human saphenous vein correlated better with affinity for the alpha 2B-ligand binding site (r = 0.71, n = 12, P less than 0.01) than with affinity for the alpha 2A-ligand binding site (r = 0.56, n = 12, non significant). 4. It is concluded that the postjunctional alpha 2-adrenoceptor of human saphenous vein resembles an alpha 2B-ligand binding site more than an alpha 2A-ligand binding site.

Adrenergic alpha-Antagonists↗

PubMed1991

Actions of 8-hydroxy-2-(N-dipropylamino) tetralin (8-OH-DPAT) at alpha 2-adrenoceptors.

1 We have examined the actions of the 5-HT1A-receptor ligand 8-OH-DPAT at alpha 2-adrenoceptor ligand binding sites in human platelet and rat kidney membranes and at functional pre- and postjunctional alpha 2-adrenoceptors in rat atrium and human saphenous vein, respectively. 2 8-OH-DPAT had low affinity for the alpha 2A ligand binding site of human platelet but showed 10 times higher affinity for the alpha 2B ligand binding site of rat kidney (K1 of 6.41, -log M). 3 In functional studies, 8-OH-DPAT had low potency as an antagonist of noradrenaline-induced contractions in human saphenous vein, with a KB of 5.40 (-log M). 4 In rat atria preincubated with [3H]-noradrenaline, 8-OH-DPAT potentiated stimulation-evoked overflow of tritium with an EC30 (concentration producing 30% increase in the stimulation-evoked overflow) of 6.37 (-log M). 5 It is concluded that 8-OH-DPAT shows selectively for the alpha 4B ligand binding site of rat kidney and for the functional prejunctional alpha 2-adrenoceptor of rat atrium, which resembles the alpha 2B ligand binding site.

8-Hydroxy-2-(di-n-propylamino)tetralin↗