Biomedical subjects

L C Rump

Publications and source records attributed to L C Rump.

At least 73 records · Page 4Linked to original sources

PubMed1994

A study of ATP as a sympathetic cotransmitter in human saphenous vein.

1. Strips of human saphenous veins were superfused with Krebs-Henseleit solution at either 25 degrees C or 37 degrees C. Constrictor responses to electrical stimulation (10 Hz, 40 s) but not to exogenous noradrenaline (0.1, 1 microM) were abolished by guanethidine (10 microM) and tetrodotoxin (1 microM). Hence, responses to electrical stimulation are due to action potential-induced release of sympathetic neurotransmitters. 2. Constrictor responses to electrical stimulation and noradrenaline were reduced by the alpha 1-adrenoceptor antagonist, prazosin (0.3 microM) as well as by the alpha 2-adrenoceptor antagonist, rauwolscine (1 microM). The combination of prazosin and rauwolscine abolished constrictor responses to noradrenaline at 25 degrees C and 37 degrees C. However, constrictor responses to electrical stimulation were partly resistant to alpha-adrenoceptor blockade by prazosin and rauwolscine (at 25 degrees C about 30%). Residual constrictor responses to electrical stimulation were also observed in the presence of the combination of prazosin (3 microM) and rauwolscine (10 microM) as well as in the presence of phenoxybenzamine (10 microM). 3. Veins, incubated with [3H]-noradrenaline, released tritium upon electrical stimulation (10 Hz, 40 s). Moreover, electrical stimulation also induced an overflow of ATP amounting to 4.8 +/- 1.5 pmol g-1 at 25 degrees C and 2.0 +/- 0.5 pmol g-1 at 37 degrees C. Both tritium and ATP overflow were abolished by tetrodotoxin (0.5 microM). The combination of prazosin (0.3 microM) and rauwolscine (1 microM) increased tritium overflow at either 25 degrees C or 37 degrees C by about 120%, but reduced ATP overflow by about 70%. Hence, a significant percentage of the electrically evoked ATP overflow seems to be released from non-neuronal cells upon activation of alpha-adrenoceptors by endogenous noradrenaline. The remaining ATP overflow, which was resistant to alpha-adrenoceptor blockade, may reflect neuronally released ATP.4. ATP (300 MicroM) and alpha,Beta-methylene-ATP (1, 10 MicroM), both induced constrictor responses. The P2-purinoceptor antagonist, suramin (300 MicroM) markedly inhibited constrictor responses to ATP and alpha, beta-methylene-ATP, but not those to electrical stimulation and to noradrenaline. Moreover, suramin(300 MicroM) failed to diminish the alpha-adrenoceptor blockade-resistant constrictor response to 10 Hz.5. In conclusion, constrictor responses to sympathetic nerve stimulation in human saphenous veins are mainly but not exclusively mediated by neuronally released noradrenaline. There is a concomitant release of ATP and noradrenaline. P2-purinoceptors which mediate vasoconstriction are present; however,a role of neuronally released ATP in constrictor responses to electrical stimulation could not be established. Therefore, the nature of the sympathetic transmitter responsible for alpha-adrenoceptor blockade-resistant constrictor responses remains unknown.

Action Potentials↗

PubMed1994

Beta 2-adrenergic receptor and angiotensin II receptor modulation of sympathetic neurotransmission in human atria.

The aim of the present study was to investigate beta-adrenergic receptor and angiotensin II (Ang II) receptor modulation of norepinephrine release in human atria. Slices of human atrial appendages were incubated with [3H]norepinephrine, superfused with Krebs-Henseleit solution, and electrically stimulated in superfusion chambers. Pretreatment of the tissue with 6-hydroxydopamine (1.2 mmol/L) before the [3H]norepinephrine incubation to destroy sympathetic nerves reduced the uptake of radioactivity and abolished the stimulation-induced (S-I) outflow of radioactivity. Furthermore, S-I outflow of radioactivity was prevented by the addition of tetrodotoxin (1 mumol/L) to and omission of extracellular Ca2+ from the superfusion solution. Separation of [3H]norepinephrine from its metabolites revealed that the S-I outflow of radioactivity was mainly composed of intact [3H]norepinephrine. Thus, the S-I outflow of radioactivity was taken as an index of norepinephrine release. Isoproterenol (0.001 to 0.1 mumol/L) dose-dependently enhanced the S-I outflow of radioactivity. The concentration-response curve of isoproterenol was shifted to the right by the selective beta 2-adrenergic receptor antagonist ICI 118551 (0.01 and 0.1 mumol/L) but not by the beta 1-adrenergic receptor-selective antagonist atenolol (0.3 and 30 mumol/L). Ang II (0.001 to 1.0 mumol/L) also dose-dependently enhanced S-I outflow of radioactivity. The facilitatory effect of Ang II was blocked by either the peptide Ang II receptor antagonist saralasin (1.0 mumol/L) or EXP 3174 (0.1 mumol/L), the in vitro active form of the nonpeptide Ang II receptor antagonist losartan. The cell-permeable cAMP analogue 8-bromo-cAMP (30 to 300 mumol/L) dose-dependently enhanced S-I outflow of radioactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1994

Alpha 2-adrenergic receptors of the alpha 2c subtype mediate inhibition of norepinephrine release in human kidney cortex.

The pharmacological properties of the alpha 2-adrenergic receptors regulating the release of norepinephrine were investigated in human kidney cortex. Slices were preincubated with [3H]norepinephrine, superfused in the presence of desipramine, and stimulated electrically. Two procedures were used to estimate the affinity of alpha-adrenergic antagonists at the autoreceptors. First, pEC30 values (negative logarithms of antagonist concentrations that increased the electrically evoked overflow of tritium by 30%) were determined. Second, antagonist pKd values were determined against the overflow-inhibiting effect of the alpha 2 receptor-selective agonist UK 14,304. Antagonist pEC30 values correlated well with the respective pKd values (r = 0.96, p < 0.01). The site of action of the phenylethylamine norepinephrine, as well as of the imidazoline derivative UK 14,304, is an alpha 2-adrenergic receptor. Neither the cyclooxygenase inhibitor indomethacin nor the adenosine receptor antagonist 8-sulfophenyltheophylline changed the concentration-inhibition curve of UK 14,304. When compared with binding data from the literature, the pEC30 values correlated best with the antagonist affinities at alpha 2c binding sites in an opossum kidney cell line and rat brain cortex (r > or = 0.95, p < 0.001) and at the affinities of alpha 2c sites obtained in COS cells transfected with either the human alpha 2-C4 or rat RG10-alpha 2 gene (r > or = 0.95, p < 0.01). In contrast, the correlations with alpha 2A, alpha 2B, and alpha 2D sites were not as good. Moreover, the alpha 2-autoreceptors in human kidney cortex were very similar to the alpha 2C-adrenergic receptors mediating prostaglandin synthesis in rabbit aorta but differed from alpha 2A- and alpha 2D-autoreceptors in rabbit and rat tissues. It is concluded that in human kidney cortex prejunctional autoreceptors are alpha 2C.

Adrenergic alpha-Agonists↗

PubMed1993

Methoxamine inhibits noradrenaline release through activation of alpha 1- and alpha 2-adrenoceptors in rat isolated kidney: involvement of purines and prostaglandins.

The effects of the alpha 1-adrenoceptor agonist methoxamine and the alpha 2-adrenoceptor agonist bromoxidine (UK 14034) on the stimulation induced (S-I) outflow of radioactivity at 100 Hz/6 pulses from rat isolated kidney preincubated with 3H-noradrenaline were investigated. Methoxamine (0.3-30 mumol/l) inhibited S-I outflow of radioactivity to a maximum of 83% with a pEC50 of 5.85 (5.71-5.94). UK 14304 (0.0003-0.3 mumol/l) inhibited S-I outflow of radioactivity to a maximum of 99% with a pEC50 of 8.35 (8.26-8.47). alpha-Adrenoceptor antagonist affinities (pKD) against methoxamine and UK 14304 at prejunctional alpha-adrenoceptors were determined. The concentration response curve of methoxamine was shifted to the right by the alpha 1/alpha 2B-adrenoceptor antagonist prazosin (0.1 mumol/l) with a pKD of 7.41 and that of UK 14304 by prazosin (0.3 mumol/l) with a pKD of 6.24. The alpha 2-adrenoceptor antagonist rauwolscine (0.1 mumol/l) shifted the concentration response curve of UK 14304 potently to the right with a pKD of 8.34. The concentration response curve of methoxamine was shifted also to the right by rauwolscine (0.1 mumol/l) and the alpha 2-adrenoceptor antagonist idazoxan (0.1 mumol/l), however, both antagonists suppressed the maximum response of methoxamine to 46% and 56%, respectively. A ten times lower concentration of rauwolscine (0.01 mumol/l) did not shift the concentration response curve of methoxamine but the inhibitory effect of methoxamine still reached only a maximum of 59%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1993

Dopamine receptor modulation of noradrenaline release by carmoxirole in human cortical kidney slices.

The effect of the dopamine D2-receptor agonist carmoxirole on noradrenaline release was investigated in human and rat cortical kidney slices. After preincubation with 3H-noradrenaline, the slices were electrically stimulated at 5 Hz in superfusion chambers, and the stimulation-induced (S-I) outflow of radioactivity was taken as the index of noradrenaline release. In human but not in rat cortical kidney slices, carmoxirole (0.03 microM) inhibited the S-I outflow of radioactivity. Carmoxirole (0.3 microM) also failed to inhibit the S-I outflow of radioactivity from human kidney slices. When alpha-adrenoceptors were blocked by the non-selective alpha-adrenoceptor antagonist phentolamine (1 microM), carmoxirole (0.03 microM, 0.3 microM) inhibited S-I outflow to a similar extent. The inhibitory effect of carmoxirole (0.03 microM) was prevented by the D2-receptor antagonist (-)-sulpiride (10 microM) but not by the D1-receptor antagonist SCH 23390 (1 microM) in human kidney slices. Phentolamine (1 microM) by itself induced a five-fold greater enhancement of the S-I outflow of radioactivity in rat than in human cortical kidney slices. The data suggest that activation of prejunctional D2-receptors by carmoxirole inhibits noradrenaline release from human renal sympathetic nerves. Carmoxirole in higher concentrations (0.3 microM) blocks inhibitory prejunctional alpha-autoreceptors, which seems to mask the inhibitory D2-receptor mediated effect. The different effects of phentolamine and carmoxirole in human and rat kidney may indicate a difference of the prejunctional alpha-autoreceptor mechanism in the two species.

Animals↗

PubMed1993

Dopamine DA2-receptor activation inhibits noradrenaline release in human kidney slices.

Dopamine receptor modulation of noradrenaline release from renal sympathetic nerves was investigated. Human kidney slices were incubated with 3H-noradrenaline, placed into superfusion chambers between two platinum electrodes and field-stimulated at 5 Hz. The slices accumulated radioactivity. Pretreatment of the kidney slices with 6-hydroxy-dopamine (1.2 mM) prior to the 3H-noradrenaline incubation reduced the accumulation of radioactivity. The stimulation induced (S-I) outflow of radioactivity was mainly composed of intact 3H-noradrenaline. The sodium channel blocker tetrodotoxin (1 microM), 6-hydroxy-dopamine pretreatment and omission of calcium from the superfusion solution abolished S-I outflow of radioactivity. The DA1-receptor agonist fenoldopam (SKF 82526; 0.01 and 0.1 microM) did not alter but fenoldopam (1 microM) increased S-I outflow of radioactivity. However, in the presence of either the non-selective alpha-adrenoceptor antagonist phentolamine (1 microM) or the selective alpha 2-adrenoceptor antagonist idazoxan (1 microM) fenoldopam (1 microM) had no effect. The DA2-receptor agonist quinpirole (LY 171555; 1 microM) inhibited S-I outflow of radioactivity, an effect blocked by the selective DA2-receptor antagonists S(-)-sulpiride (10 microM) and domperidone (0.3 microM) but unaltered either by the DA1-receptor antagonist SCH 23390 (1 microM) or by phentolamine (1 microM). The alpha 2-adrenoceptor agonist UK 14304 (0.1 microM) inhibited S-I outflow of radioactivity, and this effect was blocked by phentolamine (1 microM) and idazoxan (1 microM) but unaltered by S(-)-sulpiride (10 microM). Phentolamine and idazoxan, in contrast to S(-)-sulpiride, domperidone and SCH 23390, enhanced S-I outflow of radioactivity by themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

Alpha 2-autoreceptor subclassification in rat isolated kidney by use of short trains of electrical stimulation.

1 Rat kidneys were perfused with Krebs-Henseleit solution and incubated with [3H]-noradrenaline. The renal nerves were electrically stimulated at either 1 Hz for 30 s or 100 Hz for 0.06 s. The stimulation induced (S-I) outflow of radioactivity was taken as an index of endogenous noradrenaline release. 2 At a frequency of 1 Hz for 30 s the alpha-adrenoceptor antagonists BRL 44408 (0.01, 0.1 microM) and imiloxan (0.1, 1.0 microM) enhanced S-I outflow of radioactivity. However, at a frequency of 100 Hz for 0.06 s the alpha-adrenoceptor antagonists, idazoxan (0.1, 1.0 microM), imiloxan (0.1, 1.0 microM), BRL 44408 (0.1, 1.0 microM), BRL 41992 (0.1, 1.0 microM) and prazosin (0.01 microM) failed to enhance S-I outflow of radioactivity. 3 Thus, the rat isolated kidney stimulated at 100 Hz for 0.06 s, avoids autoinhibition by endogenous noradrenaline and alpha-adrenoceptor antagonist affinities (pKB) at the prejunctional alpha-autoreceptor were estimated without disturbance by the endogenous activator. 4 The alpha 2-adrenoceptor agonist, clonidine, inhibited the S-I outflow of radioactivity with a maximum of 90% and an EC50 of 7.2 nM. 5 All alpha-adrenoceptor antagonists used caused parallel shifts of the concentration-response curve for clonidine to the right. The rank order of potencies was: rauwolscine (alpha 2A/B) > idazoxan (alpha 2A/B) > phentolamine (alpha 2A/B) > WB 4101 (alpha 2A) > BRL 44408 (alpha 2A) > BRL 41992 (alpha 2B) > prazosin (alpha 2B) = imiloxan (alpha 2B).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

Effects of the novel dopamine DA2-receptor agonist carmoxirole (EMD 45609) on noradrenergic and purinergic neurotransmission in rat isolated kidney.

The effects of the classical dopamine DA2-receptor agonist quinpirole (LY 171555) and the recently characterized DA2-receptor agonist, carmoxirole (EMD 45609), on neurotransmission in rat isolated kidney were investigated. After preincubation with 3H-noradrenaline, the renal nerves were electrically stimulated. The stimulation induced (S-I) outflow of radioactivity was taken as an index of noradrenaline release. Quinpirole (0.3 mumol/l) inhibited S-I outflow of radioactivity and pressor-responses to renal nerve stimulation (RNS) at 1 Hz. Both effects of quinpirole were blocked by the DA2-receptor antagonist S(-)-sulpiride (10 mumol/l). The alpha 1, alpha 2-adrenoceptor antagonist phentolamine (1 mumol/l) did not block the inhibitory effect of quinpirole. Carmoxirole (0.003 and 0.03 mumol/l) did not alter and carmoxirole (0.3 mumol/l) even enhanced S-I outflow of radioactivity, however, pressor responses to RNS were markedly reduced by carmoxirole (0.003-0.3 mumol/l). Pressor responses to RNS were also markedly reduced by the alpha 1-adrenoceptor antagonist prazosin (0.1 mumol/l). Carmoxirole (0.3 mumol/l), prazosin (0.1 mumol/l) and phentolamine (1 mumol/l) totally abolished pressor responses to exogenous noradrenaline (0.05 mumol/l). In contrast, quinpirole (0.3 mumol/l) did not alter pressor responses to exogenous noradrenaline (0.05 mumol/l). Furthermore, carmoxirole (0.003-0.3 mumol/l) markedly reduced pressor responses induced by the alpha 1-adrenoceptor agonist methoxamine (1 mumol/l) but even the highest concentration of carmoxirole (0.3 mumol/l) had no effect on pressor responses induced by bolus injections of either neuropeptide Y (1.5 ng) or angiotensin II (1 ng). Phentolamine (1 mumol/l) by itself markedly enhanced S-I outflow of radioactivity and pressor responses to RNS were virtually unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1992

Activation of beta 2-adrenoceptors by isoprenaline and adrenaline enhances noradrenaline release in cortical kidney slices of young spontaneously hypertensive rats.

The aim of the present study was to investigate beta-adrenoceptor modulation of noradrenaline release from sympathetic nerves in superfused cortical kidney slices of 4-week-old spontaneously hypertensive rats (SHR) and age-matched controls (WKY). After preincubation with 3H-noradrenaline the kidney slices were electrically stimulated in superfusion chambers. The stimulation induced (S-I) outflow of radioactivity was mainly composed of unmetabolized 3H-noradrenaline in both strains and thus taken as an index of noradrenaline release. There was a frequency-dependent (1.25-20 Hz) increase in the S-I outflow of radioactivity. At all stimulation frequencies tested S-I outflow of radioactivity was similar or even slightly lower in SHR than in WKY kidney slices in either the absence or presence of cocaine (10 mumol/l). The non-selective beta-adrenoceptor agonists isoprenaline (0.1 mumol/l) and adrenaline (0.01 and 0.1 mumol/l) enhanced S-I outflow of radioactivity. The facilitatory effects of isoprenaline (0.1 mumol/l) and adrenaline (0.1 mumol/l) were blocked by the selective beta 2-adrenoceptor antagonist ICI 118551 (0.1 mumol/l) but not by the selective beta 1-adrenoceptor antagonist atenolol (0.3 mumol/l). The cell-permeable cAMP analogue 8-bromo-cAMP (300 mumol/l) enhanced S-I outflow of radioactivity to a similar extent in both SHR and WKY kidney slices. A combination of 8-bromo-cAMP (300 mumol/l) and adrenaline (0.1 mumol/l) did not enhance S-I outflow of radioactivity to a greater extent than 8-bromo cAMP (300 mumol/l) alone in both strains.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1992

Activation of alpha 1- and alpha 2-adrenoceptors inhibits noradrenaline release in rabbit renal arteries: effects of pertussis toxin and N-ethylmaleimide.

1. The effects of selective alpha 1- and alpha 2-adrenoceptor agonists and antagonists on the stimulation-induced (S-I) outflow of radioactivity at 2 Hz were investigated in superfused rabbit renal arteries incubated with [3H]-noradrenaline. 2. The alpha 1-adrenoceptor agonist methoxamine (10 microM) inhibited S-I outflow of radioactivity and this effect was abolished by the alpha 1-adrenoceptor antagonist prazosin (0.1 microM) but not by the alpha 2-adrenoceptor antagonist rauwolscine (1 microM). Neither the prostaglandin synthesis inhibitor indomethacin (10 microM) nor the adenosine receptor antagonist 8-phenyl-theophylline (1 microM) prevented the inhibitory effect of methoxamine. 3. The alpha 2-adrenoceptor agonists clonidine (0.1 microM) and UK 14304 (0.1 microM) both inhibited S-I outflow of radioactivity. The inhibitory effect of clonidine was blocked by rauwolscine but not by prazosin. The inhibitory effect of UK 14304 was markedly reduced by rauwolscine. 4. Prazosin (0.1 microM) alone did not enhance the S-I outflow of radioactivity at 2 Hz and slightly enhanced S-I outflow at 4 Hz. Rauwolscine (1 microM) alone markedly enhanced S-I outflow of radioactivity at 2 and 4 Hz. 5. Pretreatment of the arteries with pertussis toxin (1 microgram ml-1) did not significantly alter the inhibitory effects of methoxamine or UK 14304 or the potentiation by rauwolscine. However, pretreatment of the arteries with a higher concentration of pertussis toxin (5 micrograms ml-1) prevented the inhibitory effect of methoxamine but still did not affect the responses to UK 14304 and rauwolscine. 6. Pretreatment of the arteries with N-ethylmaleimide (NEM, 10 microM) for 30 min did not alter the inhibitory effect of methoxamine but markedly attenuated the inhibitory effect of UK 14304 and the facilitatory effect of rauwolscine. 7. The results suggest that both alpha 1- and alpha 2-adrenoceptors take part in the modulation of noradrenaline release from sympathetic nerves in rabbit renal arteries. Alpha 1-adrenoceptor mediated inhibition may be coupled to G-proteins which are pertussis toxin sensitive and alpha 2-adrenoceptor mediated inhibition to G-proteins which are NEM-sensitive.

Adrenergic alpha-Agonists↗

PubMed1991

Alpha 2-adrenoceptor activation inhibits noradrenaline release in human and rabbit isolated renal arteries.

The aim of the present study was to investigate alpha 2-adrenoceptor modulation of noradrenaline release in superfused strips of human and rabbit renal arteries. The arteries were field-stimulated after incubation with [3H]noradrenaline. The stimulation-induced outflow of radioactivity was taken as an index of noradrenaline release. At a high stimulation frequency (4 Hz), the alpha 2-adrenoceptor agonist clonidine (0.1 mumol/l) failed to inhibit stimulation-induced outflow of radioactivity in human and rabbit renal arteries whereas the alpha 2-adrenoceptor agonist UK 14304 (0.1 mumol/l) did inhibit stimulation-induced outflow. The inhibitory effect of UK 14304 in human renal arteries was blocked by the alpha 2-adrenoceptor blocking drug rauwolscine (1 mumol/l). At a lower stimulation frequency (2 Hz), both clonidine and UK 14304 inhibited stimulation-induced outflow of radioactivity from rabbit renal arteries; both effects were blocked by rauwolscine. Rauwolscine by itself enhanced stimulation-induced outflow of radioactivity in both preparations. The results suggest that activation of prejunctional alpha 2-adrenoceptors in human and rabbit renal arteries inhibits noradrenaline release. Neuronally released noradrenaline exerts inhibitory feed-back modulation of its own release through activation of prejunctional alpha 2-adrenoceptors. At a higher stimulation frequency most of the prejunctional alpha 2-adrenoceptors are already occupied by endogenous noradrenaline and clonidine fails to inhibit noradrenaline release since it seems to act as a partial agonist at these prejunctional alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1990

Prostaglandin E2 inhibits noradrenaline release and purinergic pressor responses to renal nerve stimulation at 1 Hz in isolated kidneys of young spontaneously hypertensive rats.

The effects of prostaglandin E2 (PGE)2 and the thromboxane A2 (TxA2) receptor agonist U-46619 on noradrenaline release and pressor responses to renal nerve stimulation (RNS) at 1 Hz were investigated in isolated kidneys of spontaneously hypertensive rats (SHR; 5-7 weeks) and age-matched Wistar-Kyoto rats (WKY). After incubation with 3H-noradrenaline, the renal nerves were stimulated. The stimulation-induced (S-I) outflow of radioactivity was taken as an index of noradrenaline release. Absolute S-I outflow of radioactivity was lower in SHR than in WKY but pressor responses to RNS were greater in SHR than in WKY. Tetrodotoxin (1 mumol/l) abolished S-I outflow of radioactivity and pressor responses to RNS in both strains. PGE2 (0.06 mumol/l) inhibited S-I outflow of radioactivity in SHR but not in WKY kidneys. PGE2 (0.6 mumol/l) inhibited S-I outflow of radioactivity in both strains. In SHR, PGE2 (0.6 mumol/l) decreased pressor responses to RNS, but increased them in WKY. In WKY, but not in SHR kidneys, pressor responses to RNS were markedly reduced by the alpha 1-adrenoceptor antagonist prazosin (0.1 mumol/l). The prazosin-resistant pressor responses to RNS were blocked by alpha, beta-methylene adenosine triphosphate (ATP; 1 mumol/l). In kidneys of SHR, pretreated with 6-OH-dopamine (50 mg/kg intravenously, 24 and 48 h before isolation of the kidneys) to destroy sympathetic nerve endings, pressor responses to RNS and S-I outflow of radioactivity were almost abolished. U-46619 (0.1 mumol/l) increased perfusion pressure in SHR and WKY kidneys and this effect was blocked by the TxA2 receptor antagonist daltroban (BM 13505; 3 mumol/l). U-46619 did not significantly modulate S-I outflow of radioactivity. The results suggest that activation of prejunctional PGE2 receptors in kidneys of SHR and WKY inhibits noradrenaline release. The prejunctional inhibitory PGE2 receptor mechanism on renal sympathetic nerves seems to operate more effectively in SHR than in WKY. There is no evidence for prejunctional TxA2 receptors in the kidneys of SHR or WKY. Pressor responses to RNS at 1 Hz in SHR kidneys seem to be due entirely to release of a purinergic co-transmitter from renal sympathetic nerves, and PGE2 possibly reduces pressor responses to RNS by inhibiting release of this purinergic co-transmitter.

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

PubMed1990

Prostaglandin E2 inhibits and indomethacin enhances noradrenaline release in isolated kidneys of adult spontaneously hypertensive rats.

Renal neurotransmission and its modulation by prostaglandin (PG) E2 (0.06 microM) and indomethacin (10 microM) was investigated in isolated kidneys of adult spontaneously hypertensive (SHR) and normotensive control (WKY) rats. After preincubation with [3H]-noradrenaline the renal nerves were stimulated. The stimulation induced (S-I) outflow of radioactivity was taken as an index of noradrenaline release. The S-I outflow of radioactivity from SHR and WKY kidneys was similar but S-I pressor responses were enhanced in kidneys of SHR. PGE2 inhibited and indomethacin enhanced the S-I outflow of radioactivity in kidneys of WKY and SHR to a similar extent. This inhibitory effect of PGE2 is due to activation of inhibitory prejunctional PGE2 receptors. Neuronally released noradrenaline stimulates a local formation of PGE2 which then transjunctionally inhibits noradrenaline release. Renal noradrenaline release in the adult SHR and its modulation by PGs is not altered. An enhanced postjunctional responsiveness of the renal vasculature may contribute to the maintenance of hypertension in the adult SHR.

Animals↗

PubMed1990

Modulation of noradrenaline release from rat cortical kidney slices: effects of angiotensin I and II.

Rat kidney slices were incubated with [3H]-noradrenaline and placed into a superfusion chamber between two platinum electrodes. The kidney slices accumulated and stored radioactivity. In kidney slices taken from rats whose sympathetic nerve terminals were destroyed by pretreatment with 6-hydroxydopamine accumulation of radioactivity was abolished. The alpha 2-adrenoceptor antagonist idazoxan (0.1-1 microM) enhanced but tetrodotoxin (TTX, 1 microM) or omission of calcium from the superfusion solution abolished the stimulation induced (S-I) outflow of radioactivity. Angiotensin (A) I (3-300 nM) and AII (1-100 nM) enhanced S-I outflow of radioactivity. The effect of AI was markedly attenuated by the angiotensin converting enzyme inhibitor captopril (3 microM) and that of AII was blocked by the AII receptor antagonist saralasin (1 microM). These results suggest that the kidney slice preparation is a valid technique to study modulation of renal noradrenaline release. Endogenous noradrenaline released from sympathetic nerves in rat kidney slices activates prejunctional alpha 2-adrenoceptors to inhibit its own release. AII, which can also be formed locally from AI in these kidney slices, activates prejunctional AII receptors to facilitate renal noradrenaline release.

Angiotensin I↗

PubMed1989

[Modulation of renal transmitter release by presynaptic receptors].

Renal sympathetic nerve varicosities possess a variety of receptors which when activated by appropriate agonists can modulate noradrenaline release at the local level of the kidney. Thus, activation of prejunctional alpha 1- and alpha 2-adrenoceptors, prostaglandin (PG), dopamine, adenosine and serotonin receptors inhibits, whereas activation of prejunctional beta 2-adrenoceptors and angiotensin (A) II receptors enhances renal noradrenaline release. Moreover, neuronally released noradrenaline itself activates prejunctional inhibitory alpha 1- and alpha 2-adrenoceptors forming a "negative feedback loop" of its own release (autoinhibition). PGE2 and adenosine locally formed in the kidney by renal nerve stimulation inhibits noradrenaline release through activation of their specific prejunctional receptor system (transjunctional inhibition).

Adenosine↗

PubMed1989

Effects of endogenous and synthetic prostanoids, the thromboxane A2 receptor agonist U-46619 and arachidonic acid on [3H]-noradrenaline release and vascular tone in rat isolated kidney.

1. Rat kidneys were perfused with Krebs-Henseleit solution and the perfusion pressure was monitored. After incubation with [3H]-noradrenaline the renal nerves were stimulated. The stimulation-induced (S-I) outflow of radioactivity was taken as an index of noradrenaline release. The effect of prostaglandins on perfusion pressure, pressor responses to renal nerve stimulation (RNS) and S-I outflow of radioactivity was assessed. 2. Prostaglandin E2 (PGE2, 0.06 and 0.6 microM), PGF2 alpha (0.6 microM), PGI2 (0.6 and 3 microM) and iloprost (0.6 microM) increased perfusion pressure and enhanced pressor responses to RNS. These facilitatory effects of the prostaglandins were not a result of an enhanced transmitter release. In contrast, PGE2 dose-dependently inhibited, whereas the other prostaglandins failed to modulate S-I outflow of radioactivity. PGE2 (0.6 microM) also enhanced pressor responses to exogenous noradrenaline. 3. Arachidonic acid (1 microM) increased perfusion pressure and enhanced pressor responses to RNS. These effects were abolished in the presence of indomethacin (10 microM) suggesting that local production of prostaglandins from exogenous arachidonic acid was responsible for this facilitation. However, arachidonic acid (1 microM) did not modulate S-I outflow of radioactivity. Arachidonic acid (10 microM), despite causing a marked increase in perfusion pressure, failed to alter pressor responses to RNS and only slightly inhibited S-I outflow of radioactivity. 4. The thromboxane A2 (TxA2) receptor agonist U-46619 (0.1 microM) increased vascular tone and enhanced pressor responses to RNS. These effects were blocked by the newly developed selective TxA2 receptor antagonist, daltroban (BM 13505; 3 microM), suggesting that these facilitatory effects of U-46619 were due to activation of TxA2 receptors. However, U-46619 failed to alter the S-I outflow of radioactivity from rat isolated kidney. 5. The alpha 1-adrenoceptor agonist methoxamine (1 microM) also increased perfusion pressure and enhanced pressor responses to RNS without affecting the S-I outflow of radioactivity in the presence of the prostaglandin synthesis inhibitor indomethacin (10 microM). 6. The results suggest that PGE2 modulates noradrenaline release through an inhibitory prejunctional receptor mechanism. There is no evidence for prejunctional PGF2 alpha, PGI2 or TxA2 receptors in the rat isolated kidney. All prostaglandins increased vascular tone in the rat isolated kidney and this alone may provide a condition for enhanced pressor responses to RNS since methoxamine also enhanced pressor responses to RNS without affecting S-I outflow of radioactivity. It is probable that postjunctionally active PGF2 and PGI2 is formed locally from exogenous arachidonic acid, but not enough prejunctionally active PGE2 is synthesized to modulate renal transmitter release.

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

PubMed1987

Modulation of norepinephrine release through alpha 1- and alpha 2-adrenoceptors in rat isolated kidney.

The aim of this study was to investigate alpha-adrenoceptor modulation of norepinephrine (NE) release from sympathetic nerves in rat isolated perfused kidney. After preincubation with [3H]NE, the renal nerves were stimulated. The stimulation-induced (S-I) outflow of radioactivity was used as an index of NE release. Clonidine (0.1 mumol/L) decreased the S-I outflow of radioactivity. This effect was abolished by the alpha 1-adrenoceptor antagonist idazoxan (0.1 mumol/L) but not by the alpha 2-adrenoceptor antagonist prazosin (0.1 mumol/L). Methoxamine (10 mumol/L) also had an inhibitory effect; this was abolished by prazosin (0.1 mumol/L), but not by idazoxan. Individually, these alpha-blocking drugs and the alpha 1-adrenoceptor antagonist corynanthine (0.3 mumol/L) enhanced S-I outflow of radioactivity. In the presence of indomethacin (10 mumol/L), the inhibitory effect of methoxamine was abolished but clonidine still inhibited S-I outflow of radioactivity. The facilitatory effect of prazosin was also unaltered by indomethacin. These results suggest the existence of inhibitory prejunctional alpha 1- and alpha 2-adrenoceptors in the kidney. The inhibitory effect of methoxamine seems to be mediated through prostaglandin inhibition of NE release. However, the evidence for inhibitory prejunctional alpha 1-adrenoceptors rests solely on the facilitatory effects of prazosin and corynanthine.

Adrenergic alpha-Agonists↗

PubMed1987

Modulation of renal noradrenaline release by prejunctional receptor systems in vitro.

1. The amount of noradrenaline released per nerve impulse from renal sympathetic nerves can be modulated through specific prejunctional receptors. 2. Under in vitro conditions activation of alpha 1-, alpha 2-, prostaglandin, adenosine, dopamine and serotonin receptors inhibits noradrenaline release from the kidney. 3. Stimulation of prejunctional beta-adrenoceptors, probably of the beta 2-subtype, as well as stimulation of prejunctional angiotensin II receptors facilitates noradrenaline release. Moreover, neuronally released noradrenaline inhibits its own release through activation of both prejunctional alpha 1- and alpha 2-adrenoceptors. 4. Locally produced PGE2, which is formed and released via stimulation of postjunctional alpha 1-adrenoceptors, as well as adenosine, released from postjunctional sites by renal nerve stimulation (RNS), seems to inhibit noradrenaline release through their specific prejunctional receptor systems.

Adenosine↗