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L C Rump

Publications and source records attributed to L C Rump.

At least 55 records · Page 3Linked to original sources
PubMed1997

Angiotensin converting enzyme inhibition unmasks the sympathofacilitatory effect of bradykinin in human right atrium.

OBJECTIVE: To investigate the role of angiotensin converting enzyme (ACE) inhibition in bradykinin-mediated modulation of noradrenaline release in human and rat atrium. METHODS: Human and rat atrial slices were incubated with [3H]-noradrenaline, superfused with Krebs-Henseleit solution and stimulated electrically at 5 Hz. The stimulation-induced outflow of radioactivity was taken as an index of endogenous noradrenaline release. RESULTS: In the absence of ACE inhibition 0.01-1 micromol/l bradykinin failed to alter the release of noradrenaline in human atrium. In contrast, 0.001-0.1 micromol/l bradykinin enhanced the release of noradrenaline in rat atrium. In the presence of 3 micromol/l of the ACE inhibitor captopril, however, bradykinin significantly enhanced the release of noradrenaline in human atrium. The bradykinin B1-receptor agonist (Des-Arg9)-bradykinin (0.01-1 micromol/l) had no effect on the release of noradrenaline in human atrium both in the absence and in the presence of 3 micromol/l captopril. Captopril (3 micromol/l) potentiated the facilitatory effect of bradykinin in rat atrium. The selective bradykinin B2-receptor antagonist D-Arg[Hyp3,Thi5, D-Tic7,Oic8]-bradykinin (Hoe 140, 0.3 micromol/l) and the cyclo-oxygenase inhibitor indomethacin (10 micromol/l) reduced the facilitatory effect of bradykinin significantly in the presence of captopril in rat and human atrium. Prostaglandin F2alpha (0.1 micromol/l), prostaglandin E2 (0.3 micromol/l) and the thromboxane A2 receptor agonist U-46 619 (0.1 micromol/l) enhanced the release of noradrenaline in human atria, whereas 0.1 micromol/l prostaglandin I2 had no effect. CONCLUSION: These data suggest that bradykinin facilitates the release of noradrenaline in human and rat atrium by activation of bradykinin receptors of the B2-subtype and subsequent release of facilitatory prostaglandins. The facilitatory effect of bradykinin in human atrium can only be demonstrated when its enzymatic degradation is prevented by ACE inhibition.

Aged↗
PubMed1997

Prejunctional neuropeptide Y receptors in human kidney and atrium.

The aim of our study was to characterize functionally prejunctional neuropeptide Y (NPY) receptors in human and rabbit renal cortex, as well as in human right atrium. Segments of human atrial appendages and of human and rabbit renal cortex were preincubated with [3H]noradrenaline, superfused with Krebs-Henseleit solution and stimulated electrically in superfusion chambers. The stimulation-induced outflow of radioactivity was taken as an index of endogenous noradrenaline release. The effects of subtype-selective NPY analogs on the stimulation-induced noradrenaline release were studied. NPY, its endogenous analog, peptide YY, and its C-terminal fragment, NPY13-36, but not its analog, [Leu31,Pro34]NPY, concentration dependently (1-100 nM) inhibited [3H]noradrenaline release in all tissues studied. NPY-induced inhibition of [3H]noradrenaline release in human and rabbit kidney was abolished by pretreatment with pertussis toxin. We conclude that prejunctional inhibition of noradrenaline release in human heart and human and rabbit kidney occurs through NPY receptors of the Y2 subtype, which appear to couple to a pertussis toxin-sensitive G protein.

Animals↗
PubMed1997

Determinants of intrarenal Doppler indices in stable renal allografts.

Color Doppler sonography has been introduced for graft monitoring after renal transplantation. Little is known, however, about independent factors that have an impact on intrarenal Doppler indices as indicators for transplant dysfunction. Therefore, in this study, potential determinants of the resistive index (RI) and of the pulsatility index (PI) in 110 patients with stable renal allografts were studied. The mean RI and PI were 0.70 +/- 0.07 (range, 0.53 to 0.88) and 1.36 +/- 0.21 (range, 0.91 to 1.98), respectively. In multivariate regression analysis, RI and PI correlated significantly with age and arterial pulse pressure of the recipient. There was no correlation with donor age, heart rate, mean arterial blood pressure, and cyclosporine trough levels. Furthermore, parameters of kidney function, such as serum creatinine concentration, creatinine clearance rate, 51Cr-ethylenediaminetetraacetate clearance rate, and proteinuria, showed no significant correlation with the Doppler indices. The data indicate that intrarenal Doppler indices of the grafts are hemodynamic indices, primarily depending on the recipient-related vascular compliance rather than on the function of the graft. Therefore, only intraindividual comparison of the Doppler indices may be useful to detect potential changes of graft resistance during long-term follow-up.

Adolescent↗
PubMed1996

Diagnosis of renovascular disease by intra- and extrarenal Doppler scanning.

The purpose of this prospective, angiographically controlled study was to determine the diagnostic value of color Doppler sonography with two differing approaches of scanning in patients with clinical clues for renal artery stenosis (RAS). In 135 hypertensive patients peak systolic velocity in the main renal arteries and the resistive index (RI) of the intrarenal arteries were measured. The RI side-to-side-difference (delta RI) greater than 0.05 or peak systolic velocity greater than 2 m/s were used to discriminate normal from stenotic renal arteries, defined as angiographically confirmed RAS > 50%. In 88 of 135 patients 107 RAS were demonstrated by selective arteriography. Five renal artery occlusions occurred, which were all diagnosed by color Doppler sonography. Seventy-six RAS were detected by increased peak systolic velocity, and an additional 19 stenoses were identified by delta RI. The combined analysis of peak systolic velocity and delta RI resulted in a sensitivity of 89% and specificity of 92%. The positive predictive value was 92% and the negative predictive value was 88%. Our data suggest that only the combination of intra- and extrarenal scanning with color Doppler sonography represents an effective screening method for significant renal artery stenosis in hypertensive patients.

Adult↗
PubMed1996

alpha-Adrenergic regulation of human renal function.

Pharmacological and molecular cloning techniques have identified six human subtypes of alpha-adrenoceptors which are designated alpha 1A, alpha 1D, alpha 2A, and alpha 2C. At the protein level human kidney expresses predominantly alpha 2A-adrenoceptors while other alpha 2-adrenoceptor subtypes or alpha 1-adrenoceptors have not been detected consistently in radioligand binding studies. However, the presynaptic receptors, which inhibit noradrenaline release in the human kidney, appear to belong to the alpha 2C-subtype. Intrarenal infusion of the nonselective alpha-adrenoceptor antagonist, phentolamine, and of the selective alpha 2-adrenoceptor antagonist, yohimbine, but not of the selective alpha 1-adrenoceptor antagonist, doxazosin, increase renal blood flow and renin release in hypertensive patients undergoing diagnostic renal angiography. Thus, alpha 2- but not alpha 1-adrenoceptors appear to mediate a tonic renal vasoconstriction and inhibition of renin release. Effects of systemically given alpha 1-adrenoceptor agonists and antagonists are difficult to interpret on a mechanistic level since direct effects in the kidney and indirect effects due to baroreflex activation and peripheral presynaptic and central sympatholytic actions may at least partially offset each other. Moreover, some of these drugs may additionally act independent of alpha-adrenoceptors, for example, via imidazoline recognition sits. The net result in a given subject may depend on the endogenous sympatho-adrenal tone. Thus, for each target population of interest, effects have to be described empirically for each drug.

Adrenergic alpha-Agonists↗
PubMed1996

Extracellular ATP in the human kidney: mode of release and vascular effects.

1. We have previously shown that ATP is a co-transmitter of noradrenaline in the rat kidney. In the present study the release of ATP and noradrenaline from human kidney cortex was investigated. Vascular effects of ATP and stable analogues were tested in human and rabbit isolated renal blood vessels. 2. Sympathetic nerve stimulation (20 Hz for 1 min) in human kidney slices released 89 +/- 16 fmol noradrenaline per mg wet weight and 99 +/- 20 fmol ATP per mg wet weight in controls (n = 12). The Na+ channel blocker tetrodotoxin (1 microM) abolished ATP and noradrenaline release. 3. In human isolated extrarenal arteries the P2X-purinoceptor agonist beta, gamma-methylene-L-ATP caused almost no constrictor responses, beta, gamma-methylene-L-ATP induced moderate constrictor responses in intrarenal arteries. In preconstricted human intrarenal arteries ATP induced vasodilation. 4. ATP and the P2Y-receptor agonist 2-methyl-thio-ATP (2-MeSATP) dilated preconstricted rabbit renal arteries. The P2Y-receptor antagonist Reactive Blue 2 (3 microM) shifted the concentration response curves of ATP and 2-MeSATP to the right. 5. In conclusion, sympathetic nerve stimulation induces the release of ATP and noradrenaline in human renal cortex. ATP activates vasoconstrictory P2X- and vasodilatory P2Y-receptors in human renal blood vessels. The net vascular response to ATP in vivo will depend on the tissue distribution of these purinoceptors.

Adenosine Triphosphate↗
PubMed1996

Pharmacokinetic profile of cyclosporine A after conversion to Sandimmun Optoral: influence on ambulatory blood pressure in renal transplant patients.

The aim of the present study was to investigate whether the pharmacokinetic profile of cyclosporin A under Sandimmun Optoral compared to Sandimmun has an effect on blood pressure in patients with stable renal allograft function. Twenty-eight patients were randomized into two groups. Two pharmacokinetic profiles (I, II; time interval 7 days) were obtained in each group. One group (n = 18) was switched from Sandimmun to an equal dose (1:1) of Sandimmun Optoral after the first kinetic and the other (n = 10) received Sandimmun for both kinetics. Eight blood samples were taken during each kinetic and cyclosporine values were measured. Ambulatory blood pressure measurement was performed during each kinetic. There were no differences in the pharmacokinetic parameters between kinetics I and II in the control group but significant differences in the switched group with increased Cmax (+64%), AUC (+44%), C0 (+17%) and decreased Tmax (-39%) in kinetic II compared to kinetic I. Correlation of C0 with AUC was stronger for Sandimmun Optoral (r = 0.792) than for Sandimmun (r = 0.718). Correlation of C0 with Cmax was similar for Sandimmun Optoral (r = 0.53) and Sandimmun (r = 0.56). Mean 12 h blood pressure of kinetic II tended to be lower than that of kinetic I in the control group, but the opposite was true for the switched group. When blood pressure levels around Tmax +/- 1 h were analyzed only, RR (syst/diast) in mmHg was 135 +/- 3.7/89 +/- 2.2 (kinetic I) and 130 +/- 2.8/85 +/- 2.8 (kinetic II) for control as compared to 134 +/- 2.4/85 +/- 2.9 and 137 +/- 3.1/86 +/- 2.8 for the switched group, respectively. Sandimmun Optoral shows an improved pharmacokinetic profile. However, higher blood concentrations of cyclosporine under Sandimmun Optoral tend to increase slightly systemic blood pressure as compared to that under Sandimmun.

Adult↗
PubMed1995

Dopaminergic and alpha-adrenergic control of neurotransmission in human right atrium.

The aim of the present study was to investigate dopamine receptor- and alpha-adrenergic receptor-mediated modulation of norepinephrine release in human atria. Right atrial appendages were incubated with 3H-norepinephrine, placed in superfusion chambers, and field-stimulated by platinum electrodes at a frequency of 5 Hz. The stimulation-induced (S-I) outflow of radioactivity was taken as an index of norepinephrine release. The dopamine D2-receptor agonist quinpirole (0.03-3 microM) concentration dependently inhibited the S-I outflow of radioactivity with an EC50 of 0.03 microM. The concentration-response curve of quinpirole was potently shifted to the right by the D2-receptor antagonists domperidone (0.003 microM, pKB approximately 9.2) and S(-)-sulpiride (0.1 microM, pKB approximately 8.6). The D1-receptor antagonist SCH 23390 (1 microM) slightly (pKB approximately 6.9) shifted the concentration-response curve of quinpirole, whereas the alpha 2-adrenergic antagonist rauwolscine (0.01 microM) and the alpha 1-adrenergic antagonist prazosin (1 microM) had no effect. The D1-receptor agonist did not affect fenoldopam (0.03 and 0.3 microM), but fenoldopam (3 microM) enhanced the S-I outflow of radioactivity. The facilitatory effect of fenoldopam (3 microM) was unaltered by SCH 23390 (0.1 microM) but prevented by rauwolscine (0.01 microM). The alpha 2-adrenergic agonist UK 14304 (0.01-1 microM) (EC50: 0.06 microM), but not the alpha 1-adrenergic agonist methoxamine (0.3-30 microM), inhibited S-I outflow of radioactivity. The concentration-response curve of UK 14304 was shifted to the right by rauwolscine (0.01 microM, pKB approximately 8.6).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1995

Vasoconstrictor responses to the P2x-purinoceptor agonist beta, gamma-methylene-L-ATP in human cutaneous and renal blood vessels.

1. Strips of human saphenous veins and of human renal arteries and veins were superfused with Krebs-Henseleit solution at 37 degrees C. Constrictor responses were elicited by exogenous noradrenaline and the P2x-purinoceptor-selective agonist, beta, gamma-methylene-L-ATP. 2. In human saphenous veins, beta, gamma-methylene-L-ATP (0.3-30 microM; EC50 2.2 microM) induced marked constrictor responses. The maximal response to beta, gamma-methylene-L-ATP was similar to the maximal response to noradrenaline. The P2-purinoceptor antagonist suramin (30 microM) shifted the concentration-response curve of beta, gamma-methylene-L-ATP to the right (apparent pKB value 4.8); suramin (100 microM) markedly inhibited the responses to beta, gamma-methylene-L-ATP. The preferential P2x-purinoceptor antagonist, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 3 microM) slightly reduced the response to beta, gamma-methylene-L-ATP. At a ten times higher concentration (30 microM), PPADS almost abolished the responses to beta, gamma-methylene-L-ATP. PPADS (30 microM), in contrast, caused no significant change in the concentration-response curve of noradrenaline. 3. In extrarenal and intrarenal arteries, EC50 values and maximal responses to noradrenaline were similar when compared with responses to noradrenaline in saphenous veins. Noradrenaline also constricted extrarenal veins. However, in contrast to the results obtained on saphenous veins, beta, gamma-methylene-L-ATP caused almost no constrictor responses in extrarenal veins and arteries and only moderate responses in intrarenal arteries. 4. The results demonstrate marked differences in responsiveness of human blood vessels to the selective P2x-purinoceptor agonist, beta, gamma-methylene-L-ATP, suggesting tissue differences in the occurrence or operation of P2x-purinoceptors in human vascular tissues. Moreover, the results indicate that PPADS blocks P2x-purinoceptors in human isolated blood vessels as previously demonstrated in animal blood vessels.

Adenosine Triphosphate↗
PubMed1995

Alpha 2C-adrenoceptor-modulated release of noradrenaline in human right atrium.

1. The aim of the present study was to characterize the presynaptic alpha 2-autoreceptors in human right atrium in terms of the alpha 2A-D system. Segments of atrial appendages were preincubated with [3H]-noradrenaline and then superfused in the presence of cocaine and stimulated electrically. pEC30% values of eight alpha-adrenoceptor antagonists with discriminatory power were determined. pEC30% is the negative logarithm of the antagonist concentration that increased the stimulation-induced overflow of tritium by 30%. For four antagonists, the dissociation constant KD was determined, in addition to pEC30%, against the overflow-inhibiting effect of 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) under autoinhibition-free conditions. 2. pEC30% and KD values yielded identical rank orders of antagonist affinity (rauwolscine > WB 4101 > phentolamine > prazosin) suggesting that both released noradrenaline and the exogenous agonist UK 14,304 activated the same receptor to inhibit release. 3. The eight antagonist pEC30% values obtained in right atrium correlated significantly with their pEC30% values, reported in the literature, at the presynaptic alpha 2C-autoreceptors in human kidney (r = 0.817; slope of the regression line 1.03). No significant correlation was obtained between pEC30% values at atrial autoreceptors and pKD values at previously characterized alpha 2A-autoreceptors in rabbit and alpha 2D-autoreceptors in rat, mouse and guinea-pig tissues. 4. Comparison of antagonist pEC30% values with their pKD values at native alpha 2 binding sites in cells or tissues that express a single subtype only, and with pKD values at alpha 2 binding sites in membranes of COS cells transfected with human alpha 2 subtype genes confirms the alpha 2C character of the atrial autoreceptors: significant correlations were obtained exclusively with the alpha 2C binding sites. 5. Ratios of KD values were computed for alpha 2-autoreceptors in human right atrium and for binding sites in COS cells transfected with human alpha 2 subtype genes. The autoreceptor ratios corresponded well with the respective ratios for the alpha 2C binding sites (maximal three fold deviation) but were, in part, markedly different from ratios calculated for alpha 2A and alpha 2B binding sites (up to 166 fold deviation). This outcome supports the alpha 2C designation of the autoreceptors. 6. In conclusion, the presynaptic alpha 2-autoreceptors in human right atrium are alpha 2C. In this they agree with the previously characterized alpha 2-autoreceptors in human kidney. The alpha 2C classification possibly separates, in general, human alpha 2-autoreceptors from those in lagomorph (rabbit) and rodent (rat, mouse, guinea pig) species that have been proposed to be predominantly alpha 2A or alpha 2D.

Adrenergic alpha-Antagonists↗
PubMed1995

Alpha-adrenoceptor modulation of norepinephrine and ATP release in isolated kidneys of spontaneously hypertensive rats.

The present study investigates sympathetic cotransmission and its alpha-adrenoceptor-mediated modulation in kidneys of spontaneously hypertensive rats (SHR, 12 to 14 weeks) and age-matched normotensive Wistar-Kyoto rats (WKY). In the presence of cocaine and corticosterone, renal nerve stimulation at 1 Hz (30 seconds) induced a greater outflow of norepinephrine in SHR (4.2 +/- 0.2 pmol/g kidney) than in WKY (3.0 +/- 0.2 pmol/g kidney). The alpha 2-adrenoceptor antagonist rauwolscine (0.01 to 1 mumol/L) increased the stimulation-induced norepinephrine outflow to a greater extent in SHR than in WKY. In contrast, the alpha 1-adrenoceptor antagonist prazosin (0.03 to 3 mumol/L) increased the stimulation-induced norepinephrine outflow to a greater extent in WKY than in SHR. This difference was not observed in the presence of the P1-purinoceptor antagonist 8-(p-sulfophenyl)theophylline (100 mumol/L). Stimulation at 4 Hz (30 seconds) induced an outflow of ATP (SHR, 12.7 +/- 3.3 pmol/g kidney; WKY, 16.7 +/- 2.1 pmol/g kidney; perfusion solution without cocaine and corticosterone). Prazosin (0.03 mumol/L) markedly reduced pressor responses to stimulation and inhibited the induced ATP outflow by 60% to 70%. When prazosin (0.03 mumol/L) was present, rauwolscine (0.1 mumol/L) increased the induced outflow of norepinephrine and ATP and markedly enhanced prazosin-resistant pressor responses. These pressor responses were abolished by the P2-purinoceptor antagonist suramin (300 mumol/L). The results demonstrate an increased alpha 2-adrenoceptor-mediated automodulation of norepinephrine release in SHR kidneys caused by increased intrasynaptic norepinephrine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1995

Beta-adrenergic, angiotensin II, and bradykinin receptors enhance neurotransmission in human kidney.

The aim of this study was to investigate angiotensin II (Ang II) receptor-, bradykinin receptor-, and beta-adrenergic receptor-mediated modulation of norepinephrine release from human renal sympathetic nerves and to characterize the respective receptor subtypes involved. Human cortical kidney slices were incubated with [3H]norepinephrine, placed in superfusion chambers between two platinum electrodes, and superfused with Krebs-Henseleit solution. The sympathetic nerves were stimulated electrically at 2.5 Hz for 1 minute, and the stimulation-induced outflow of radioactivity was taken as an index of endogenous norepinephrine release. Ang II and its precursor Ang I (both 0.01 to 1 mumol/L) enhanced stimulation-induced outflow of radioactivity in a concentration-dependent manner, with EC50 values of 0.03 and 0.05 mumol/L, respectively. The enhancement by Ang I but not that by Ang II was inhibited by the angiotensin-converting enzyme inhibitor captopril (3 mumol/L). The concentration-response curves of Ang I and Ang II were shifted to the right by EXP 3174 (0.01 mumol), the in vitro active form of the Ang II type 1 receptor antagonist losartan, with affinity estimates of 8.72 and 9.30, respectively. A higher concentration of EXP 3174 (0.1 mumol/L) abolished the facilitatory effects of Ang I and Ang II. The Ang II type 2 receptor antagonist PD 123319 (10 mumol/L) did not alter the facilitation by Ang II. In the absence of other drugs, bradykinin (0.01 to 1 mumol/L) failed to modulate stimulation-induced outflow of radioactivity but in the presence of captopril (3 mumol/L) enhanced it in a concentration-dependent manner, with an EC50 of 0.1 mumol/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Low concentrations of angiotensin II unmask vasoconstrictory alpha 2-adrenoceptors in isolated perfused kidneys of spontaneously hypertensive rats.

OBJECTIVES: The aim of the present study was to evaluate the role of vascular alpha 1- and alpha 2-adrenoceptors in kidneys of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). METHODS: SHR and WKY kidneys (12-14 weeks) were isolated and perfused with Krebs-Henseleit solution. Concentration-response curves for the alpha 1-adrenoceptor agonist methoxamine and the alpha 2-adrenoceptor agonist UK 14304 were constructed alone and in the presence of the alpha 1-adrenoceptor antagonist prazosin, the alpha 2-adrenoceptor antagonist idazoxan and exogenous angiotensin II. RESULTS: Methoxamine induced a maximal pressor response of 247 +/- 9 mmHg with an EC50 of 1.3 +/- 0.1 microM in SHR and of 193 +/- 4 mmHg with an EC50 of 1.1 +/- 0.1 microM in WKY. The concentration-response curve for methoxamine was shifted to the right by prazosin with a pA2 value of 9.29 (SHR) and 9.26 (WKY) and by idazoxan with a pA2 value of 6.45 (SHR) and 6.33 (WKY). UK 14304 induced a maximal pressor response of 41 +/- 12 mmHg in SHR and of 37 +/- 8 mmHg in WKY. Angiotensin II (0.1 nM) did not significantly alter pressor responses to methoxamine but caused a marked shift to the left of the concentration-response curve for UK 14304. UK 14304 then induced a maximal pressor response of 92 +/- 13 mmHg with an EC50 of 0.07 +/- 0.01 microM in SHR and of 78 +/- 14 mmHg with an EC50 of 0.14 +/- 0.01 microM in WKY. In the presence of angiotensin II (0.1 nM) the concentration-response curve for UK 14304 was shifted to the right by prazosin with a pKB of 6.36 (SHR) and 6.33 (WKY) and by idazoxan with a pKB of 7.68 (SHR) and 7.65 (WKY). CONCLUSIONS: The results demonstrate a predominant role of vasoconstrictory alpha 1-adrenoceptors over alpha 2-adrenoceptors in SHR and WKY isolated kidneys. Low physiological concentrations of angiotensin II unmask functional vascular alpha 2-adrenoceptors which are slightly more sensitive in SHR than in WKY kidneys.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1994

Alpha 2D-adrenoceptors modulate renal noradrenaline release in normotensive and spontaneously hypertensive rats.

The aim of the present study was to investigate alpha-adrenoceptor modulation of neurotransmission in kidneys of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) and to classify the prejunctional alpha 2-adrenoceptor subtype involved. Kidneys of SHR (12-14 weeks) and age-matched WKY were isolated and the sympathetic nerves were stimulated electrically. The renal nerve stimulation-induced outflow of endogenous noradrenaline was measured by high-pressure liquid chromatography with electrochemical detection (HPLC-ECD). In the presence of uptake blockade by cocaine and corticosterone, the renal nerve stimulation-induced outflow of endogenous noradrenaline was significantly greater in SHR than in WKY at 1 Hz (688 +/- 42 pg/g vs. 525 +/- 46 pg/g) and 4 Hz (5265 +/- 495 pg/g vs. 3544 +/- 245 pg/g). At a stimulation frequency of 1 Hz the alpha 2-adrenoceptor agonist UK 14304 (0.01-1 microM) potently inhibited the renal nerve stimulation-induced outflow of noradrenaline with a pEC50 of 7.49 (7.32-7.68) and a maximum of 91% in SHR and with a pEC50 of 7.46 (7.30-7.74) and a maximum of 92% in WKY. alpha-Adrenoceptor antagonist affinity estimates (pKB values) against UK 14304 at the prejunctional alpha 2-autoreceptors were determined. The rank order of affinities (phentolamine > rauwolscine > 2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane HCl (WB 4101) > prazosin) was identical in SHR and WKY, and comparison with data from radioligand binding, molecular cloning and functional studies in other tissues and cell lines indicates that prejunctional alpha 2-autoreceptors of SHR and WKY kidneys are of the alpha 2D subtype.

Animals↗
PubMed1994

Effects of imidazolines on noradrenaline release in rat isolated kidney.

The aim of the present study was to investigate whether or not activation of imidazoline receptors modulates noradrenaline release in the rat isolated kidney. Kidneys were pre-exposed to 3H-noradrenaline and the renal nerves were stimulated with 6 pulses at 100 Hz. The stimulation induced (S-I) outflow of radioactivity was taken as an index of endogenous noradrenaline release. The imidazoline derivatives clonidine (1-1000 nmol/l) and moxonidine (10-1000 nmol/l) inhibited S-I outflow of radioactivity with an EC50 of 6.8 nmol/l and 62.5 nmol/l and a maximum of 88% and 97%, respectively. The concentration response curves for clonidine and moxonidine were shifted to the right by the selective alpha 2-adrenoceptor antagonist rauwolscine (0.1 mumol/l) in a parallel manner with identical pKB's of 8.52 and 8.46, respectively. Furthermore, the alpha-adrenoceptor agonist (-)-alpha-methylnoradrenaline (0.1-30 nmol/l), which has no affinity for imidazoline binding sites, inhibited S-I outflow of radioactivity with and EC50 of 2.4 nmol/l and a maximum of 94%. Rauwolscine (0.1 mumol/l) again shifted the concentration response curve for this alpha-adrenoceptor agonist to the right with a pKB of 8.40. Moreover, the selective alpha 2-adrenoceptor antagonist 2-[2-(2-methoxy-1,4- benzo-dioxanyl)]imidazoline HCl (RX821002, 0.01 mumol/l) shifted the concentration response curves for clonidine and moxonidine to the right with pKB's of 9.46 and 9.18, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-2 Receptor Antagonists↗