Suppression of isoprenaline-induced increase in plasma renin concentration by vasoconstrictors in rats with nonfunctioning Macula densa

Summary The mechanism of the increase in plasma renin concentration caused by the -sympathomimetic agent isoprenaline has been further investigated.Rats were pretreated by occluding the left renal artery for 2 hrs, thus rendering the macula densa cells of this kidney nonfunctioning. After contralateral nephrectomy infusion of isoprenaline (1.5 g/kg min) still caused a strong increase in plasma renin concentration. This increase was significantly suppressed by simultaneous infusion of angiotensin II (1.0 g/kg min), the -sympathomimetic amine phenylephrine (60 g/kg min) or octapressin (10 mU/kg min). The results exclude any mediator-role of the macula densa receptors in the isoprenaline-induced release of renin.The possibility of a stimulation of renin release via the baroreceptors or a direct secretomotoric action of isoprenaline is discussed.Supported by Deutsche Forschungsgemeinschaft Me 541/1.     

The effect of angiotensin II blockade by saralasin (1-Sar-8-Sla-angiotensin II) in normal man

Summary The effects of the angiotensin II analogue saralasin were investigated in 6 normal individuals. Blood pressure, plasma renin (PRC), plasma aldosterone (PAC) and plasma saralasin were measured before and during infusion of saralasin (0.54–5.4 nmol/kg/min) with the subjects supine. Plasma angiotensin II concentration (PA II) was measured before the infusion. In the sodium replete state, PA II averaged 11 pmol/1 (range 5 to 17). Saralasin infusion produced an increase in mean arterial pressure (MAP) and PAC, and a slight fall in PRC, which is consistent with an angiotensin II-like effect or a so-called agonistic effect. After sodium depletion, induced by hydrochlorothiazide 50–100 mg/day for 5 days, PA II was high –91 pmol/l on average (range 41 to 217). Angiotensin II blockade produced a fall in MAP in the supine position. The agonistic effect of saralasin on adrenal receptors during sodium depletion was less pronounced or absent. PRC increased sharply during the infusion. Infusion of saralasin at the rate of 5.4 nmol/kg/min produced a plasma saralasin concentration of about 220 nmol/l, i. e. in molar terms the plasma concentration of the analogue was 2000 to 10000 times higher than that of the endogenous octapeptide. The relationship between changes in MAP and basal PA II prior to infusion showed that saralasin exhibited a shift from agonistic to antagonistic properties on vascular receptors when pre-infusion PA II changed from approximately 20 to 40 pmol/l. A shift from agonistic to antagonistic effect on aldosterone secretion was not consistently seen. It is concluded that angiotensin II does not have a decisive role in the maintenance of normal blood pressure during normal sodium balance. However, after sodium depletion the renin-angiotensin system contributes to blood pressure control, even in the supine position. In addition to its antagonistic properties, saralasin possesses a weak agonistic effect on vascular, as well as on renal and adrenal receptors. This has to be taken into consideration when saralasin infusion is used to define angiotensin II dependency in patients with hypertension.     

Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart

Summary Chronic -adrenoceptor stimulation leads to desensitization of the myocardial adenylyl cyclase signalling pathway which includes -adrenoceptor downregulation and upregulation of G_i-protein -subunits. However, these investigations have mainly been done in cellular preparations. In this study we report that isoprenaline infusion in vivo leads to an increase in myocardial G_ia and present evidence for functional consequences of this increase.Rats were treated by a 4-day subcutaneous infusion with isoprenaline (2.4 mg/kg·d), propranolol (9.9 mg/kg·d) and triiodothyronine (T₃, 0.5 mg/kg·d) for comparison. Isoprenaline treatment increased the pertussis toxin-sensitive amount of G_ia by 22±6% and decreased ₁- and ₂-adrenoceptor density from 35±4 to 23±6 fmol/mg protein and 24±4 to 8±6 fmol/mg protein, respectively. Contraction experiments on electrically driven papillary muscles revealed that the negative inotropic potency of the M-cholinoceptor agonist carbachol in the presence of isoprenaline was increased as compared to control (mean EC₅₀-values: 0.04 mol/l vs. 0.28 mol/l). All isoprenaline-induced effects were antagonized by simultaneously administered propranolol. T₃ treatment had no influence on the parameters investigated.The results suggest that chronic -adrenoceptor stimulation desensitizes myocardial adenylyl cyclase by at least two mechanisms: -adrenoceptor downregulation leading to diminished signal transduction in the stimulatory pathway and G_i upregulation leading to sensitization of the inhibitory pathway. Such adaptation might protect the heart from chronic exposure to catecholamines in heart diseases with elevated plasma catecholamine levels. Send offprint requests to U. Mende at the above addressParts of the results have been presented at the Wintertagung of the Deutsche Gesellschaft für Pharmakologie und Toxikologie in Hannover, 1990 (Mende et al., Naunyn-Schmiedebergs Arch Pharmacol 342 [Suppl]:R24). The work has been supported by the Deutsche Forschungsgemeinschaft     

Facilitatory presynaptic angiotensin receptors on the sympathetic nerves of the human saphenous vein and pulmonary artery. Potential involvement in β-adrenoceptor-mediated facilitation of noradrenaline release

Summary Spirally cut strips of human saphenous vein and pulmonary artery preincubated with ³H-noradrenaline were superfused in the presence of corticosterone and desipramine or cocaine. In the saphenous vein angiotensin I, angiotensin II and angiotensin III concentration-dependently increased the electrically (2 Hz) evoked tritium overflow (relative order of potency: angiotensin II > angiotensin I > angiotensin III). The angiotensin receptor antagonist saralasin displaced the concentration-response curve of angiotensin II to the right, and also blocked the facilitatory effect of angiotensin III. Captopril, an inhibitor of angiotensin converting enzyme, did not modify the concentration-response curve of angiotensin I and did not significantly diminish the release-increasing effect of the nonselective -adrenoceptor agonist isoprenaline, whereas saralasin attenuated the facilitatory effect of the ₂-adrenoceptor agonist procaterol. In the pulmonary artery the angiotensin receptor agonist Val⁵-angiotensin II-Asp¹--amide also increased the electrically evoked tritium overflow in a concentration-dependent manner. It is concluded that the sympathetic nerve fibres of the human saphenous vein (and probably of the human pulmonary artery as well) are endowed with facilitatory presynaptic angiotensin receptors. Angiotensin I exerted its facilitatory effect in the saphenous vein probably via direct stimulation of angiotensin receptors but not by conversion to angiotensin II. Furthermore, the ₂-adrenoceptor-induced facilitation of noradrenaline release may in part be mediated by local stimulation of angiotensin II synthesis, which may occur by increased formation or activation of renin and/or increased availability of angiotensinogen.This study was supported by a grant of the Deutsche Forschungsgemeinschaft Send offprint requests to M. Göthert at the above address     

Action of the competitive angiotensin II antagonist saralasin during the initial phase of glycerol-induced acute renal failure of the rat

Summary The effects of the competitive angiotensin II antagonist saralasin (1-sarcosine-8-alanine-5-isoleucine-angiotensin II) on renal function in healthy rats and in rats with myohemoglobinuric acute renal failure were studied. Acute renal failure was induced by an intramuscular injection of 50% glycerol (10 ml ·kg^–1). Functional impairment of the glycerol treated animals consisted in a decrease of renal blood flow (electromagnetic flowmeter) and GFR and in an increase of urine volume and arterial blood pressure.In healthy rats saralasin (6 g·kg^–1·min^–1 i.v.) had no renal effects by itself but antagonized the angiotensin II (200 ng·kg^–1·min i.v.) induced fall of renal blood flow and GFR and the increase of arterial blood pressure. Given to glycerol treated animals saralasin did not induce any change of arterial blood pressure, renal blood flow, GFR or the urinary excretion of fluid and sodium.Supported by Deutsche Forschungsgemeinschaft     

Different effects of noradrenaline,angiotensin II and BAY K 8644 on the abolition of autoregulation of renal blood flow by verapamil

Summary To examine the role of Ca channels in autoregulation of renal blood flow in response to changes of perfusion pressure, experiments were performed with perfused kidney in anesthetized dogs using a Ca channel activator, BAY K 8644, and vasoconstrictors such as noradrenaline and angiotensin II. Control observations usually showed excellent autoregulation of renal blood flow at pressures between 120 and 200 mm Hg, the autoregulatory index being less than 0.2. Verapamil (50 g/min, i.a. infusion) obviously inhibited the renal autoregulation. Simultaneous infusion of 5 g/min of BAY K 8644 with verapamil prevented both the increase of renal blood flow and the impairment of the autoregulation caused by verapamil. Whereas simultaneous infusion of noradrenaline (1 and 3 g/min) or angiotensin 11 (0.1 and 0.3 g/min) with verapamil dose-dependently reduced renal blood flow, these drugs could not antagonize the inhibitory effect of verapamil on autoregulation. The present experiments show that Ca channels play an important role in establishing renal autoregulation, and that a mere vasoconstriction by noradrenaline and angiotensin II is distinguished from autoregulatory performance.     

Antagonism by γ-aminobutyric acid of the stimulant effect of angiotensin II on cardiac sympathetic ganglia in spinal dogs

Summary The effects of angiotensin II and neuro-aminoacids administered through the right subclavian artery (i. a.) to the cardiac sympathetic ganglia were investigated in spinal dogs. Angiotensin II (1–8 g) elicited a dose-dependent positive chronotropic effect which was reduced after i. a. injection of saralasin (100g). The effect of angiotensin II was not reduced after combined treatment with either hexamethonium (10 mg/kg) plus atropine (0.1 mg/kg) or hemicholinium-3 (5 mg/kg) plus preganglionic stimulation. The dosedependent response to angiotensin II of heart rate was inhibited by GABA (50, 500g), GABOB (500g) and muscimol (50, 100g). The inhibition of the response to angiotensin II by a small dose of GABA (50g), but not by a high one (500g), was antagonized by i. a. injection of picrotoxin (2 mg). The positive chronotropism induced by bethanechol (25, 50g) and a small dose of acetylcholine (25g) were significantly inhibited by a high dose (500g) but not by a low dose (50g) of GABA. These results confirm that angiotensin II stimulates cardiac chronotropism by acting on the angiotensin II receptor located at the cardiac ganglia and show that this stimulant effect is antagonized by GABA.     

The role of cyclic AMP in the positive inotropic effect mediated by β1- and β2-adrenoceptors in isolated human right atrium

Summary The time course of the effects of isoprenaline (3 × 10^–7 mol/l) on contractile force and on the cyclic AMP level was studied in the electrically driven isolated muscle strip of the human right atrium. Isoprenaline produced a rise in cyclic AMP content (maximum increase after 60 s) preceding the increase in contractile force. The effects of isoprenaline on contractile force and on the intracellular level of cyclic AMP were enhanced in the presence of the phosphodiesterase inhibitor papaverine (10^–5 mol/l). On the other hand, the -adrenoceptor antagonist propranolol (10^–7 mol/l) suppressed isoprenaline-induced cyclic AMP increases, but reduced the increase in force of contraction by only 35%. In addition, both the ₁-selective antagonist bisoprolol (3 × 10^–9 × 10^–8 mol/l) and the ₂-selective antagonist ICI 118,551 (3 × 10^–9 × 10^–8 mol/l) inhibited the isoprenaline-induced cyclic AMP increase concentration-dependently; ICI 118,551 produced more pronounced inhibition than bisoprolol. It is concluded that cyclic AMP is involved in the positive inotropic action of isoprenaline evoked by ₁- and ₂-adrenoceptor stimulation in isolated human right atrium; however, an additional cyclic AMP independent mechanism cannot be ruled out. Send offprint requests to O.-E. Brodde at the above address     

Dopamine-induced diuresis in the cat without changes in renal hemodynamics

Summary The effects of intravenous (i.v.) and intraarterial (i.a.) injection and infusion of dopamine (DA) on renal hemodynamics, regional sympathetic activity and kidney function were investigated in anaesthetized cats. In response to the i.v. bolus injection of DA (25 g/kg), mean arterial blood pressure (MABP) was increased by 19.7%, renal blood flow (RBF) by 16.6%, and regional sympathetic discharges were inhibited. The principal effect of i.a. bolus injection of DA into the renal artery was vasoconstriction. Vasodilation was observed neither after lower doses of DA nor after pretreatment with phenoxybenzamine.During continuous i.v. infusion of 10 g DA kg^–1 min^–1 MABP, RBF, renal sympathetic discharges and glomerular filtration rate (GFR) did not change, whereas urine volume was increased by 120.5%, sodium excretion by 99.7%, chloride excretion by 143.2%, and potassium excretion by 31.9%. Urine osmolality was decreased and osmolal clearance increased. Raising the DA dose to 25 g kg^–1 min^–1 resulted in a fall of GFR, but the diuretic response was not significantly different from that of the low dose. Bulbocapnine (6 mg/kg i.v.) antagonized the DA-induced diuresis.In conclusion, the diuretic effect of DA in the cat is not dependent on a change in RBF, GFR or renal sympathetic activity. This suggests that a tubular site of action is primarily responsible for DA diuresis.     

Angiotensin II generation in the rat vena cava: Stimulation of local synthesis by β-adrenoceptor activation

Summary There is considerable evidence to suggest that isolated tissues have the capacity to generate angiotensin II and that angiotensin 11 thus generated may enhance noradrenergic neurotransmission. In the present study the possibility that there may be local formation of angiotensin II within the rat vena cava and its consequence to noradrenergic transmission has been investigated. The angiotensin II precursors, angiotensin I and a synthetic tetradecapeptide renin substrate, each enhanced the stimulation-induced efflux of radioactivity from tissues previously incubated with ³H-noradrenaline. The effects of angiotensin I were blocked by the converting enzyme inhibitor captopril and the receptor antagonist saralasin, indicating local conversion to angiotensin II. The effect of the tetradecapeptide was blocked by saralasin, but not by captopril, suggesting either a direct effect of this peptide or conversion to angiotensin II by a pathway not involving angiotensin converting enzyme. The -adrenoceptor agonist isoprenaline enhanced noradrenergic transmission in the rat vena cava, relaxed guinea-pig trachea precontracted with carbachol and increased heart rate in rat isolated atria. Captopril and saralasin blocked the effect of isoprenaline in the vena cava, but did not alter its effects in the atria or trachea. This suggests that in the rat vena cava the facilitation of noradrenergic transmission by isoprenaline may involve stimulation of local angiotensin II production. Send offprint requests to D. F. Story at the above address     

Effects of intravenous propranolol and metoprolol and their interaction with isoprenaline on pulmonary function,heart rate and blood pressure in asthmatics

Summary The effects of propranolol (0.06 mg/kg i.v.), the selective ₁-receptor antagonist metoprolol (0.12 mg/kg i.v.) and a placebo on pulmonary function, heart rate and blood pressure have been compared in asthmatics. The interaction of these drugs with increasing doses of isoprenaline on the same variables was also studied. The two-blockers reduced resting heart rate to the same extent, indicating the same degree of blockade of cardiac-receptors. Both-blockers reduced the basal forced expiratory volume in one second (FEV₁), and the effect tended to be more pronounced after propranolol. Isoprenaline caused a dose-dependent increase in FEV₁ and vital capacity (VC). These effects were almost completely blocked by propranolol, whereas after metoprolol the changes approached that of the placebo. The isoprenaline-induced increase in heart rate and fall in diastolic blood pressure was also inhibited to a considerably greater extent by propranolol than by metoprolol. The results show a selectivity of metoprolol for so-called ₁-receptors and indicate that metoprolol may be used in asthmatics provided that it is combined with ₂-receptor-stimulating drugs.     

Isoprenaline-induced increase in mRNA levels of inhibitory G-protein α-subunits in rat heart

Summary Long-term -adrenergic stimulation has been shown to desensitize the -adrenoceptor/adenylyl cyclase signalling pathway at both the receptor and the G-protein level. To further elucidate the cellular mechanism of G-protein regulation we investigated the influence of prolonged infusion of isoprenaline (2.4 mg/kg·d) on myocardial mRNA levels of different G-protein -subunits in rats. For comparison rats were treated with triiodothyronine (T₃; 0.5 mg/kg·d) which induces cardiac hypertrophy like isoprenaline but has different effects on the adenylyl cyclase system. Isoprenaline- and T₃-treated animals developed an increase in heart/body weight ratio of 41±3% and 27±4%, respectively (P<0.05). Isoprenaline increased myocardial total RNA concentration by 39±6% (P<0.05). Hybridization with ³²P-labeled rat cDNAs demonstrated an expression rank order of G_s-mRNA>G_i-2-mRNA>G_i–3-mRNA and no detectable expression of G_i–1-mRNA in rat myocardium. mRNA levels of G_s G_i–2 and G_i–3 were 36.9±1.28, 10.7±1.07 and 3.7±0.19 pg/g total RNA, respectively. Isoprenaline increased G_i–2 ^– and G_i–3-mRNA concentrations per g total RNA by 49±18% and 27±710, respectively (P<0.05). This effect was abolished by simultaneously administered propranolol (9.9 mg/kg·d), indicating a,-adrenoceptor-mediated mechanism. In contrast, T₃-induced cardiac hypertrophy was not accompanied by changes in G_i-mRNA expression. G_sa-mRNA levels were unaffected by either treatment.In conclusion, long-term stimulation with isoprenaline in vivo induces a -adrenoceptor-mediated increase in myocardial G_i–2 ^– and G_i–3-mRNA without affecting G_s-mRNA. These results suggest that similar increases in myocardial G_i–2-mRNA in end-stage human heart failure may be at least partly explained by increased -adrenergic stimulation due to increased sympathetic activity.Parts of this work were presented at the wintermeeting of the Deutsche Gesellschaft fur Pharmakologie und Toxikologie in Hannover, 1990 (Eschenhagen et al.), Naunyn-Schmiedebergs Arch Pharmacol 342 (Suppl):R8. The work was supported by the Deutsche Forschungsgemcinschaft Send offprint requests to: T. Eschenhagen at the above address     

α-Adrenoceptor-mediated inhibitory effect of the sympathetic nervous system on the isoprenaline-induced increase in plasma renin concentration

Summary The importance of the sympatho-adrenal system for the isoprenaline-induced increase in plasma renin concentration was investigated in conscious rats. Ganglionic blockade by trimethidinium (10 mg kg^–1) increased the dose-dependent elevation of plasma renin concentration induced by isoprenaline (0.03–0.48 g kg^–1 min^–1). Also treatment of the rats with guanethidine (6 mg kg^–1) or reserpine (2.5 mg kg^–1, given 16 and 7 h prior to the experiments) further increased the effect of isoprenaline (0.5 g kg^–1 min^–1) on plasma renin concentration. Unilateral renal denervation combined with contralateral nephrectomy doubled the effect of the -sympathomimetic amine on renin release. The -adrenoceptor antagonist phenoxybenzamine (3 mg kg^–1) also enhanced the effect of isoprenaline on this parameter.It is concluded that apart from a stimulation of renin release via -adrenoceptors the sympathetic nervous system may inhibit renin release via stimulation of -adrenoceptors.Supported by DFG Me 541/1Partial preliminary communication: Meyer et al. (1976)     

Serum glycoside concentrations after single or repeated intravenous doses ofβ-methyl-digoxin and digoxin

Summary The aim of the present investigation was to estimate the ratio of the intravenous doses of-methyl-digoxin and digoxin required to produce identical serum glycoside concentrations in man.20 patients on intravenous maintenance therapy were changed from-methyl-digoxin to the identical dose of digoxin or vice versa. Each drug was given for 7 days. Serum concentrations 13% higher were found during administration of-methyl-digoxin. Assuming a half life of 60 h after with drawal, the dose of digoxin producing the same minimum serum concentration was estimated to be 1.16 times higher than that of-methyl-digoxin.18 healthy volunteers received 0.4 mg -methyldigoxin, and 23 the same dose of digoxin, as an intravenous infusion over 2 h. The serum concentrations and urinary glycoside excretion were measured over a period of 32 hrs. During the first hour after the infusion the serum concentration of digoxin declined more rapidly than that of-methyl-digoxin. Thereafter, the ratio of the serum concentrations did not change appreciably up to the end of the investigation. The area under the serum concentration/time curve was about 13% greater for-methyl-digoxin than for digoxin; this difference was not significant.The average renal clearance was 96±9 ml for-methyl-digoxin, 151±13 ml for digoxin. Since the total body clearance of digoxin is only about 1.16 times higher than that of-methyl-digoxin, the lower renal clearance of-methyl-digoxin must partly be compensated by higher extrarenal clearance.From the ratios of the areas under the serum concentration/time curves after single doses of -methyldigoxin and digoxin, and the minimum serum concentrations during maintenance therapy, it was concluded that the dose of digoxin to produce the same average serum concentrations would be about 1.15 times higher than that of-methyl-digoxin. In comparison with the large variations in individual dosage of digoxin and-methyl-digoxin, this difference is too small to be of practical importance.     

The effect of urapidil on responses to phenylephrine,angiotensin and isoprenaline in man

Summary Intravenous urapidil, 40 mg bolus followed by an infusion of 18 mg·h^–1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 g·min^–1 before to 685 g·min^–1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has ₁-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.     

The influence of taurocholate and dehydrocholate choleresis on plasma disappearance and biliary excretion of indocyanine green in the rat

Summary The pharmacokinetics of indocyanine green (ICG; 3.9 moles/kg and 12.9 moles/kg) were investigated in rats given infusion of either saline, taurocholate (106 moles/h) or dehydrocholate (106 or 268 moles/h). During the infusion of saline and taurocholate the plasma concentration of ICG decreased in a mono-exponential manner. However, with dehydrocholate the clearance of ICG from plasma showed two phases with different half lives. The half life of the rapid component (2.2 min) was about the same as the one found in the control experiments.After injection of 12.9 moles/kg ICG the biliary excretion of the dye increased by 138% during taurocholate administration, while an equimolar dehydrocholate infusion resulted in a mean increament of 55%. Under these circumstances the bile flow was stimulated by 195% and 297% resp.With the lower dose of ICG (3.9 moles/kg) however, there was no stimulation of the biliary ICG excretion with taurocholate. At this dose level an infusion of dehydrocholate (106 mol/h) enchanced the biliary output of ICG by approximately 54%, while administration of 268 mol/h resulted in a slight but significant decrease of 31%.These observations can be explained by assuming interaction of the bile acids with the hepatic transport of ICG at different sites. The appearance of the second component of the plasma curve during dehydrocholate infusion is possibly related to a diminished hepatic storage capacity for ICG and is not due to an effect on the primary hepatic uptake or biliary output of the dye.     

Role of Ca channel in the renal autoregulatory vascular response analysed by the use of BAY K 8644

Summary The role of Ca channel and extracellular Ca²⁺ on autoregulation of renal blood flow was investigated in the perfused kidney of the anesthetized dog. The perfusion pressure was changed in the range between 60 and 200 mm Hg. Intra-arterial infusion of nifedipine (5 g/min) increased renal blood flow at a perfusion pressure above 100 mm Hg and inhibited autoregulation. Simultaneous infusion of 5 g/min of BAY K 8644 antagonized the effect of nifedipine. Renal blood flow was increased and autoregulatory relationship between flow and perfusion pressure was inhibited by EDTA (30 mg/min) infusion. The inhibitory effect of EDTA on renal autoregulation was counteracted by simultaneous infusion of CaCl₂ at 30 mg/min, but not counteracted by that of BAY K 8644 (5 g/min). BAY K 8644 also could not antagonize the inhibitory effect of a vasodilator, papaverine (5 mg/min) on renal blood flow autoregulation. These results provide the evidence that the renal autoregulation involves the process of Ca²⁺ influx into the vascular smooth muscle cell through the Ca channels. Send offprint requests to N. Ogawa at the above address     

A study of the adrenoceptor-mediated feedback mechanisms by using adrenaline as a false transmitter

Summary After incubation with 2.3 M ³H-(±)-adrenaline(³H-AD) or ³H-(-)-noradrenaline(³H-NA) for 60 min in the presence of hydrocortisone and U-0521, dog saphenous vein strips were perifused (the fluid containing cocaine+hydrocortisone+U-0521) and electrically stimulated. Tritium fractional release per shock was calculated for 1 and 5 Hz.Phentolamine (3 M) enhanced the overflow of tritium evoked by electrical stimulation at both frequencies but at 1 Hz the enhancement was higher for strips loaded with ³H-AD than for strips loaded with ³H-NA.Propranolol (1 M) reduced the overflow evoked by electrical stimulation at 1 Hz from the strips loaded with ³H-AD but not from those loaded with ³H-NA.Isoprenaline (0.04 M) increased the overflow of tritium evoked by electrical stimulation at 1 Hz from the strips loaded with ³H-NA but did not change that from strips loaded with ³H-AD.It is concluded that: a) the -adrenoceptor-mediated feedback mechanism is also present in the dog saphenous vein; b) this feedback mechanism also functions with the false transmitter AD; c) the use of ³H-AD as false transmitter revealed the existence of a -adrenoceptor-mediated positive feedback mechanism in this tissue.     

A comparison of the haemodynamic and hormonal effects of low and conventional dose cyclopenthiazide in normal volunteers

Summary In this study we compared low (125 g) and conventional (500 g) doses of cyclopenthiazide on the renin angiotensin system, plasma and extracellular fluid volumes and the pressor responsiveness to angiotensin II since we have previously shown that the two doses have the same antihypertensive effect but different effects on plasma renin activity.Following a two week placebo run-in period, 8 healthy male volunteers received 125 g or 500 g of cyclopenthiazide for 2 treatment periods of 4 weeks as part of a double blind, 2-part crossover study with treatment periods separated by a 4-week placebo washout phase. Measurements were made on two study days at the beginning and end of the active treatment periods. On the first day serum potassium, plasma renin activity and plasma angiotensin II levels were measured after a 1 h period of supine rest. Plasma and extracellular fluid volumes were also measured after appropriate equilibration times. The blood pressure responses to angiotensin II were assessed on day 2.The 500 g dose of cyclopenthiazide had a greater effect than the 125 g dose on plasma renin activity, serum potassium, angiotensin II levels and extracellular fluid volumes. Neither drug had any effect on plasma volume or the responsiveness to infused angiotensin II.Low dose cyclopenthiazide failed to increase angiotensin II levels, contract body fluid volumes or attenuate vascular reactivity in normotensive volunteers.     

Effect of epinine on tension of human renal arteries

Background: The present study aimed to characterize the effects of epinine, the active metabolite of ibopamine on tension development in human renal arteries.Methods and results: Experiments were performed on isolated human renal arteries rings obtained during surgery due to kidney tumors (n = 12). Epinine concentration-dependently relaxed isolated precontracted (PGF₂) human renal artery rings (P < 0.05) in the presence of phentolamine, as effectively (epinine – 30 +/– 4 mN, dopamine – 31 +/– 5 mN) and with the same potency as dopamine (epinine EC₅₀ 0.7 mol/l (0.4–1.2 mol/l), dopamine 0.5 mol/l (0.2–1.7 mol/l)). This effect was antagonized by the specific D₁-receptor-antagonist SCH 23390. Effective -adrenoceptor antagonistic concentrations of propranolol did not affect epinine-induced vasorelaxation. In the absence of -and -adrenoceptor-antagonists the potency of epinine to contract renal artery rings was significantly higher compared to dopamine indicating a higher affinity of epinine to -adrenoceptors.Conclusion: The present study provides evidence for direct vasodilatory effects of epinine via activation of D₁-receptors on human renal arteries.