A double-blind comparison of felodipine and hydrochlorothiazide added to metoprolol to control hypertension

Summary Seventy-six uncomplicated hypertensive patients treated in General Practice, whose seated diastolic blood pressure (Phase V) (dBP) remained 95 mmHg after a minimum of 4 weeks treatment with metoprolol 50 mg b.i.d. as antihypertensive monotherapy, were randomized to receive the selective calcium antagonist felodipine 5 mg b.i.d. or hydrochlorothiazide 12.5 mg b.i.d. in addition to metroprolol 50 mg b.i.d. The trial duration was 8 weeks, the dose of the felodipine or hydrochlorothiazide being doubled after 4 weeks if control of BP (dBP <90 mmHg) was not achieved on the initial doses.Over the trial period of 8 weeks, felodipine reduced dBP from 102 to 85 mmHg and hydrochlorothiazide from 101 to 91 mmHg; the dBP reduction in the felodipine group was greater than that in the hydrochlorothiazide group (17 vs 9 mmHg) and the attained dBP lower in the felodipine group. About half of the patients in each group required the higher dose.Both regimes were effective and well tolerated. In the dosages used, felodipine was a slightly more effective antihypertensive drug than hydrochlorothiazide when added to metoprolol. There was no apparent difference in the tolerability of the two regimes.     

Comparison of once daily felodipine 10 mg ER and hydrochlorothiazide 25 mg in the treatment of mild to moderate hypertension

Summary The efficacy of extended release felodipine 10 mg (ER) o.d., a new dihydropyridine calcium antagonist, and 25 mg hydrochlorothiazide (HCTZ) o.d. have been compared in a randomized, double-blind, crossover trial in 28 mildly to moderately hypertensive subjects (supine diastolic blood pressure, BP, 95 mm Hg and 110 mm Hg on three separate occasions).Both drugs significantly reduced systolic and diastolic BP in the sitting position felodipine from 157.1/93.8 mm Hg at baseline to 133/78.9 mm Hg 2.5 h after medication and to 138/82.7 mm Hg after 2 weeks of treatment, and HCTZ from 156/95.6 mm Hg to 147/88.4 mm Hg 2.5 h after medication and to 149/89.5 mm Hg also after 2 weeks.A decrease of the same magnitude in standing systolic and diastolic BP was observed after both treatment regimens with the exception of diastolic BP 2.5 h after dosing with HCTZ, which was not significantly lower. At all times (2.5 h and 2 weeks), the reduction in systolic and diastolic BP was greater after felodipine compared to HCTZ. Heart rate was significantly increased after felodipine in both the sitting and standing positions, and both 2.5 h following medication and after 2 weeks of treatment. The difference between the regimens was significant only 2.5 h after dosing. Overall, felodipine 10 mg ER o.d. was superior to 25 mg HCTZ o.d. in lowering BP.Presented in part at the Vth Scientific Meeting of the American Society of Hypertension, 17–20 May 1990, New York     

Enalapril versus atenolol in the treatment of hypertensive smokers

Summary A randomised crossover study has been done to compare the antihypertensive efficacy of enalapril and atenolol in 45 smoking, hypertensive men. Treatment was started with enalapril 20 mg/d or atenolol 50 mg/d and, if necessary, the doses were doubled after 4 weeks to achieve a sitting diastolic blood pressure 95 mm Hg, after which hydrochlorothiazide was added, if necessary.Both drugs lowered blood pressure significantly. However, enalapril was more efficient in lowering both systolic and diastolic blood pressure; the mean difference was significant after both 4 and 8 weeks in the sitting systolic (11.6 mm Hg and 7.9 mm Hg) and diastolic (3.3 mm Hg and 3.0 mm Hg) pressures and in the erect systolic pressures (8.2 mm Hg and 7.2 mm Hg), and after 8 weeks in the supine systolic pressure, too (8.9 mm Hg). The effect on enalapril was especially marked in moderate (<20 cigarettes/day) smokers. The need for diuretics was also significantly less in the enalapril group.It appears that angiotensin-converting enzyme inhibitors may be superior to -adrenoceptor blockers in the treatment of hypertensive smoking patients.     

Dose adjustment of nifedipine in hypertensive patients

Summary Ten patients with essential hypertension (WHO grade I–II) were treated in an open dose-adjustment study with the standard regimen of slow-release nifedipine 20 mg b. d. for 2 weeks and with an individualized dose for 6 weeks. The optimum dose, defined as that producing a pre-dose diastolic blood pressure (dBP) of 90 mm Hg at steady state, was determined from the individual concentration-effect relationship after a test-dose of 20 mg.On standard therapy, the reduction in pre-dose dBP was inadequate in 4 patients and it was excessive in 1 patient. After 2 weeks of individualized treatment, the required pre-dose antihypertensive effect was obtained in all patients. The individual doses required were 10 mg b. d., 10 mg t. d. s. 20 mg b. d., 20 mg t. d. s. and 20 mg q. d. s.One patient dropped out of the study because of side effects. Loss of the antihypertensive effect was observed in one patient after 6 weeks of treatment.On the optimized dose, the average value of the pre-and 2 h post-dose steady state nifedipine concentrations (27.6 g/l) compared well with model-derived optimum concentrations (28.6 l/l) (r=0.9210).The results show that the dose of nifedipine can be accurately predicted using the individual concentration-effect relationship after a single dose.     

Influence of Hydrodynamics and Particle Size on the Absorption of Felodipine in Labradors

Purpose. To study the influence of GI hydrodynamics and drug particle size on felodipine absorption in the dog. Methods. Labradors fistulated at midjejunum were used to selectively study the influence of hydrodynamics and particle size on the in vivodissolution and absorption of the poorly soluble, lipophilic drug felodipine. A combination of infusion and oral administration of either normal saline or a 5% glucose solution was used to maintain fasted and establish fed state motility patterns, respectively. The absorption characteristics of both a micronized (8 m) and a coarse fraction (125 m) of felodipine were subsequently studied under these two motility patterns. Results. A reduction in particle size led up to an approximate 22-fold increase in maximum plasma concentration and up to an approximate 14-fold increase in area under the curve, with a commensurate decrease in the time at which the maximum plasma concentration occurred. Although the absorption of felodipine from the solution and micronized suspension was not influenced by a change in the hydrodynamics, felodipine was absorbed from the coarse suspension almost twice as well in the fed state as under fasted conditions. Conclusions. Absorption from coarse suspensions of felodipine was sensitive to luminal hydrodynamics, whereas micronized suspensions were not. However, the particle size seems to have a much more important influence on the bioavailability of felodipine than the hydrodynamics per se.     

The role of α1- and α2-adrenoceptors in the coronary vasoconstrictor responses to neuronally released and exogenous noradrenaline in the dog

Summary 1. Coronary vasoconstriction was examined in response to the neuronal release of noradrenaline produced by bilateral carotid occlusion and the infusion of tyramine (5 – 50 Erg/kg/min i. v.) in anaesthetized dogs which had been vagotomized and treated with the -adrenoceptor antagonist propranolol (1.0 mg/kg i. v.). These responses were compared to those produced by the infusion of noradrenaline (0.1 – 0.5 g/kg/min i. v.). 2. Similar increases in late diastolic coronary resistance were produced by bilateral carotid occlusion (0.70 ± 0.25 mmHg min/ml), and intravenous infusions of tyramine, 20 g/kg/min (0.70 ± 0.12 mm Hg min/ml) and noradrenaline, 0.5 gg/kg/min (0.59 ± 0.11 mm Hg min/ml). 3. Selective antagonism at ₁-adrenoceptors with prazosin (0.5 mg/kg i. v.) attenuated the coronary constrictor response to bilateral carotid occlusion (0.36 ± 0.09 mm Hg min/ml), tyramine (0.12 ± 0.06 mm Hg min/ml) and noradrenaline (0.18 ± 0.07 mm Hg min/ml). Antagonism at ₂-adrenoceptors with idazoxan (1 mg/kg i. v.) attenuated the coronary vasoconstriction produced by bilateral carotid occlusion (0.30 ± 0.06 mmHg min/ml), tyramine (0.17 ± 0.08 mmHg min/ml) and noradrenaline (0.12 ± 0.03 mm Hg min/ml). Combined antagonism at both ₁- and ₂-adrenoceptors with prazosin and idazoxan abolished the responses to bilateral carotid occlusion, tyramine and noradrenaline. 4. These results show that coronary vasoconstriction produced by either neuronally released or exogenous noradrenaline is mediated by both ₁ and ₁-adrenoceptors. It appears that in the coronary resistance vessels of the dog postjunctional ₁- and ₂-adrenoceptors are both innervated by sympathetic nerves.     

Felodipine in combination with a β-adrenoceptor blocker as an effective substitute for triple therapy in severe hypertension

Summary We have studied the efficacy and tolerability of felodipine plus a -adrenoceptor blocker in 79 patients with essential hypertension previously treated with a combination of three or more anti-hypertensive agents, one of which was a -adrenoceptor blocker.After a 4-week run-in period on the same -blocker plus placebo (as a substitute for the other agents in the regimen), felodipine was added and its dose titrated to achieve a supine diastolic blood pressure or less than 90 mm Hg. This was followed by a 12-week maintenance phase in all patients, and 47 patients entered an optional long-term follow-up for an additional 9 months.The mean supine blood pressure was 149/88 mm Hg at entry and 174/108 mm Hg after the run-in phase. Felodipine significantly reduced the blood pressure to 142/85 mm Hg after dose titration and to 141/84 mm Hg after 12 weeks, 94% of patients achieving a supine diastolic blood pressure of 90 mm Hg or below. This reduction was maintained in the patients who were followed for 12 months.The adverse events recorded were usually mild, transient, and typical for an effective precapillary vasodilator. Nine of 74 patients (11%) were withdrawn in the first phase of the study because of adverse events and 5 of 47 patients were withdrawn during the long-term follow-up.These results show that the efficacy and tolerability of a combination of felodipine with a -blocker allow a simplified regimen for hypertensive patients who were previously taking three or more drugs for satisfactory blood pressure control.The Australian Felodipine Multicentre Study Group     

A comparison of fosinopril and hydrochlorothiazide with hydrochlorothiazide in non-insulin-dependent diabetes mellitus patients with mild to moderate hypertension

A multicentre, randomised, double-blind, parallel-group study of the tolerability and antihypertensive efficacy of once-daily fosinopril 20 mg/hydrochlorothiazide 12.5mg (FOS/HCTZ) compared with once-daily hydrochlorothiazide 25mg (HCTZ) was conducted in 142 patients with non-insulin-dependent diabetes mellitus (NIDDM) and mild to moderate essential hypertension. After 12 weeks of treatment, both groups had statistically significant mean changes from baseline in seated diastolic and systolic blood pressures (FOS/HCTZ, -15.0mm Hg; HCTZ, -11.9mm Hg for seated diastolic blood pressure). The difference between treatment groups was statistically significant (p < 0.001). In addition, normalisation of seated diastolic blood pressure was achieved in 85% of FOS/HCTZ patients compared with 71% of HCTZ patients. A statistically significant difference (p < 0.05) in favour of FOS/HCTZ was observed for the total number of favourable responses (normalisation or >/=10mm Hg reduction in seated diastolic blood pressure) at week 12 and for the end-point analysis. One FOS/HCTZ patient and 5 HCTZ patients discontinued treatment because of adverse events. No clinically significant changes in serum glucose, potassium or cholesterol were observed. A slight but statistically significant increase in fasting triglycerides occurred with FOS/HCTZ compared with HCTZ (+26.1 vs +13.5 mg/dl, respectively; p < 0.05). These results show that the combination of fosinopril and hydrochlorothiazide has considerable potential as an effective antihypertensive regimen that does not significantly alter glucose or lipid metabolism in patients with NIDDM.     

Influence of cardioselectivity and respiratory disease on pulmonary responsiveness to beta-blockade

Summary The effects on ventilation of the non-selective beta-blocker propranolol, and the relatively cardioselective beta-blocker, metoprolol, were compared in a randomized single-blind crossover study in 16 patients with asthma, bronchitis and emphysema (American Thoracic Society critieria). Group I had fixed airways disease with <20% improvement in FEV₁ following inhaled salbutamol 5 mg by nebuliser. Group II had reversible obstruction, >20% improvement. Bronchodilator therapy was withheld for 24h with the exception of aerosols which were permitted until 12h before study. After control observations on each of 2 study days, each patient received cumulative dosese of propranolol (maximum 170 mg) and metoprolol (maximum 187.5 mg). Ventilatory function (FEV₁, FVC, FEV₁%) was assessed at 0, 2, 4, 6 and 8h. In Group I, 2 patients were unable to complete the study. One patient became dizzy with propranolol 70 mg but tolerated metoprolol 187.5 mg. One patient developed wheeze with propranolol 15 mg but tolerated metoprolol 187.5 mg. Metoprolol was tolerated in all 8 patients with fixed disease, although FEV₁ was reduced by more than 30% in 1 patient. Three patients in Group II did not complete the study because of wheezing following propranolol 10 mg, metoprolol 37.5 mg; propranolol 17.5 mg, metoprolol 37.5 mg; propranolol 45 mg, tolerated metoprolol 187.5 mg respectively. Wheezing responded in all cases to inhaled isoprenaline. The response to either propranolol or metoprolol was unpredictable in patients with reversible disease. When wheezing occurred in this group, it developed following small, potentially subtherapeutic doses of each drug. Although metoprolol was better tolerated, the practical benefit of cardioselectivity in those patients with reversible airways disease was negligible.Presented in part at the Canadian Society for Clinical Investigation, Quebec City, Canada, September 1982     

The effect of nicotine on the swimming speed of pre-trained rats through a water alley

Summary In sessions of ten runs each, swimming time of rats through a 4 m long water alley was measured. Four doses of nicotine (0.05; 0.1; 0.2; 0.4 mg/kg given intraperitoneally 30 minutes before testing) were tested in sessions with a braking load on the tails of the animals either in all 10 runs of a session, or in every second run, or in none of the 10 runs. Regardless of the swimming condition, nicotine produced a considerable, and at doses of 0.1 mg/kg and over, significant decrease of performance in the first two runs. From the third to the 10th run, the changes caused by nicotine were smaller and differed depending on the swimming conditions.A dose of 0.1 mg nicotine/kg improved performance in the without-load-sessions and the without-load-runs of the alternating sessions, while both 0.1 and 0.2 mg/kg improved performance of the with-load-runs of the alternating sessions. Performance in the without-load-sessions and the without-load-runs was depressed by 0.4 mg/kg and that in the with-load-sessions by 0.2 and 0.4 mg/kg.     

Efficacy and Safety of Olmesartan Medoxomil and Hydrochlorothiazide Compared with Benazepril and Amlodipine Besylate

BACKGROUND: Most patients with stage 2 hypertension require two or more antihypertensive agents in order to achieve the BP goals recommended in current treatment guidelines. Accordingly, combinations of two drugs with different mechanisms of antihypertensive action are widely used. OBJECTIVE: The aim of this randomized, double-blind, multicenter 12-week study was to compare the efficacy, safety, and tolerability of a combination of olmesartan medoxomil/hydrochlorothiazide (HCTZ) with that of benazepril plus amlodipine besylate in patients with stage 2 hypertension. METHODS: Patients were eligible for randomization following a 3- to 4-week placebo run-in period if they had either (i) mean seated DBP>or=90 mm Hg but<115 mm Hg and mean seated SBP>or=160 mm Hg but <200 mm Hg, or (ii) mean seated DBP>or=100 mm Hg but<115 mm Hg. The difference in mean seated SBP measured on two separate visits during the run-in period was required to beor=95 mm Hg and<115 mm Hg or SBP>145 mm Hg and相似文献   

Role of Peripheral Adrenergic Responsiveness in the Development of DOCA/NaCl Hypertension in Rats

Alterations in - and -adrenergic responsiveness were investigated prior to and during the development of hypertension in rats treated with desoxycorticosterone acetate and NaCl (DOCA/ NaCl). The DOCA/NaCl rats became noticeably hypertensive (> 150 mm Hg) six weeks after the initiation of treatment. Prior to the development of hypertension, a reduced in vivo and in vitro - and an enhanced -adrenergic responsiveness of the DOCA/NaCl group resulted. At 2 and 12 weeks of the study, the dipsogenic response to isoproterenol was significantly attenuated in the DOCA/NaCl rats, whereas no difference in the dipsogenic response to 24 hour water deprivation was observed between control and DOCA/NaCl rats. Isoproterenol-induced relaxation of aortic smooth muscle from the DOCA/NaCl treated rats was significantly reduced at 4 weeks and further attenuated at 12 weeks of the study. However, aortic smooth muscle sensitivity to norepinephrine stimulation was significantly increased at 4 and 12 weeks of the study. These results suggest that alterations in both in vivo and in vitro - and -adrenergic responsiveness occur prior to establishment of hypertension of the DOCA/NaCl rats and that these alterations may have a role in the early stages of the development of this form of hypertension.     

Felodipine-ER once daily as monotherapy in hypertension.

One hundred and one hypertensive patients [diastolic pressure (dBP) 95-110 mm Hg after greater than or equal to 6 weeks with no antihypertensive therapy] were randomized to receive, double-blind, felodipine-ER 5 mg once daily (n = 49) or placebo (n = 52) for 2 weeks. Twenty-four hours post-dose, felodipine-ER 5 mg o.m. reduced dBP by a mean of 11 mm Hg; in contrast, dBP fell in the placebo group by 3 mm Hg (p less than 0.001). If the target dBP of less than or equal to 90 mm Hg was not attained at 2 weeks, the dose of felodipine-ER (or placebo) was doubled; if the target was not attained after a further 2 weeks, the doses were doubled again, to 20 mg felodipine-ER or placebo. If the target was achieved after 2 or 4 weeks, patients remained on that dose; the double-blind period for all patients was 6 weeks. After 6 weeks, the mean reduction in dBP in the felodipine-ER group was 14 mm Hg, significantly (p less than 0.001) greater than in the placebo group (8 mm Hg). Blood pressure "control" was defined prospectively as a seated dBP less than or equal to 90 mm Hg: after 6 weeks, 67% of patients receiving felodipine-ER compared with 27% on placebo had a controlled blood pressure (p less than 0.001). The figures after 2 weeks were 45% on 5 mg felodipine-ER and 21% on placebo (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of hydrochlorothiazide and atenolol as initial treatment in uncomplicated hypertension

Summary After screening a local population in the northern part of The Netherlands for hypertension, 119 patients with a diastolic pressure (DP) between 95 and 120 mmHg were randomised and treated either with 50 mg hydrochlorothiazide (n=59) or 100 mg atenolol (n=60). After 1 month of treatment 6 patients in the hydrochlorothiazide group and 24 patients in the atenolol group had reached a DP90 mmHg (p<0.001). 43 of the 50 non-responders to hydrochlorothiazide were switched to atenolol and 30 of the 35 non-responders to atenolol were changed to hydrochlorothiazide. One month after the switch 19 patients in the atenolol group and 2 patients in the hydrochlorothiazide group had reached a DP90 mmHg (p<0.001). After 6 months of treatment 32 of the 43 atenolol responders and 7 of the 8 hydrochlorothiazide responders were still receiving the same medication, as their DP was still90 mmHg. Non-responders to either medication were given the combination (n=46). 21 patients now became normotensive as did a further 10 after increasing the dose of atenolol to 200 mg. Thus, in all 70 patients had a blood pressure 90 mmHg after treatment for 4 months. Both drugs induced a significant reduction in the total of number of complaints after 1 month of treatment. They did not differ from each other. The reduction was seen both in responders and non-responders and persisted during treatment for 6 months. It is concluded that in terms of short-term efficacy the cardioselective, hydrophilic beta adrenoceptor-blocking drug atenolol is preferable to hydrochlorothiazide in the treatment of uncomplicated hypertension.     

Acute eosinophilic pneumonia associated with antidepressant agents

Acute eosinophilic pneumonia is a severe syndrome characterized by fever, lung infiltrates, blood eosinophilia and respiratory failure. We describe a case of acute eosinophilic pneumonia associated with clomipramine and sertraline. A 40yearold woman was admitted to the emergency department with 37.9 °C and respiratory rate of 35 respirations per minute. Blood analysis showed PaO² = 57.6 mm Hg and HCO³ = 21.7 mmol/l and 12.2 % eosinophils. Chest Xray showed infiltrates in both lower lobes. She was taking clomipramine 25 mg bid for the last 4 weeks and sertraline 50 mg/day for the last week. Other causes of acute eosinophilic pneumonia such as parasitic and fungal infections or collagen diseases were discarded. Both antidepressant were stopped and the patient became afebrile and asymptomatic. A week later the patient was discharged from hospital. Physicians should be aware of this adverse antidepresant reaction which may result in severe pulmonary symptoms.     

The haemodynamic effects of sotalol (MJ 1999) and propranolol in man

Summary In a dose of 40 mg, sotalol (MJ 1999) was more potent than 10 mg propranolol in blocking the cardiovascular effects of isoproterenol (5 healthy males, age 22–28 years). In a dose of 10 mg sotalol had weaker blocking properties. In a dose of 10 mg, propranolol under true basal conditions significantly decreased cardiac output (1.7 ± 0.34 1), stroke volume (31 ± 11 ml) and heart work (– 20 ± 7%), and increased the peripheral resistance (+35 ± 6%). Sotalol (10–40 mg i.v.) had no significant actions on cardiac output or any other cardiac function. There were statistically significant differences in the haemodynamic effects of sotalol and propranolol at doses producing a similar adrenergic -receptor blocking effect.This work was supported by grants from the Swedish State Medical Research Council (B69-14x-2546-01) and AB Bofors, Nobel-Pharma.For technical assistance we are indebted to Mrs. Anna-Greta Berggren and to Mrs. Anita Andersson.     

The cardiovascular effects of intraventricularly administered histamine in the anaesthetised rat

Summary In urethane-anaesthetised rats intraventricular (i.c.v.) injections of histamine (0.1–10.0 g) elicited dose-related rises in both the resting blood pressure and heart rate. These cardiovascular effects of histamine were antagonised in a dose-dependent manner by i.c.v. pretreatments with the histamine H₁-receptor antagonists mepyramine (10, 50 and 100 g) and diphenylpyraline (100 and 200 g). Pretreatment with the histamine H₂-receptor antagonist metiamide (100 and 200 g i.c.v.) failed to modify either of the responses. A dose-related antagonism of the hypertensive response to histamine i.c.v. was elicited by phentolamine (100 and 200 g i.c.v.) but the positive chronotropic effect was not modified by this pretreatment. The cardiovascular responses to histamine i.c.v. were abolished by mecamylamine (5.0 mg/kg i.v.) and greatly reduced by 6-hydroxydopamine (3×250 g i.c.v.), but only the tachycardia was significantly modified by atropine (100 g i.c.v.) and propranolol (1 mg/kg i.v.). Propranolol (100 g i.c.v.), bilateral vagotomy, or acute bilateral adrenal demedullation failed to modify the cardiovascular responses to histamine i.c.v. The results suggest that histamine is able to modify the resting blood pressure and heart rate by independent central modes of action, which involve central adrenergic and cholinergic mechanisms.Preliminary findings of this study were presented at the Autumn meeting of the British Pharmacological Society (Finch and Hicks, 1975).     

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.     

Effect of acute administration of propranolol and atenolol on baroreflex function in normal man

Summary The acute administration of the -adrenoceptor antagonists propranolol (80 mg) and atenolol (50 mg) on baroreflex function were investigated in healthy volunteers.Two h after administration both propranolol and atenolol significantly prolonged the supine R-R interval (1126, 1128 ms respectively) compared to placebo (1012 ms); systolic arterial pressure also fell (102.9, 102.0 mm Hg respectively) compared to placebo (112.6 mm Hg). Baroreflex function, assessed using glyceryl trinitrate to deactivate the baroreceptors was unchanged by these drugs compared to placebo. Baroreflex sensitivity (slope of the linear regression line relating R-R interval to systolic blood pressure) using phenylephrine to activate the baroreceptors, was also unchanged (17.2, 17.9 ms/mm Hg respectively) compared to placebo (19.9 ms/mm Hg). However both regression lines were shifted (p<0.05) to the left compared to placebo.     

Presynaptic dopamine DA2-receptors in rabbit jejunal arteries

Summary Excitatory junction potentials (e.j.ps) evoked by nerve stimulation with 15 pulses at 1 Hz were recorded from muscle cells of rabbit isolated jejunal arteries. LY 171555 1 mol/l, SKF 38393 10 mol/l, dopamine 10 ol/l and clonidine 0.1 mol/l depressed all e j.ps in the train. The percentage inhibition was inversely related to the number of pulses. S- and R-sulpiride, 10 mol/l, domperidone 1 mol/l, SCH 23390 1 mol/l and rauwolscine 1 mol/l did not change, or even depressed the first e j.ps. Of these compounds only S- and R-sulpiride, 10 mol/l and rauwolscine 1 mol/l facilitated the late e.j.ps. The percentage facilitation increased with the number of pulses until a maximum was reached; rauwolscine 1 ol/l had the largest effect. S- and R-sulpiride, 10 mol/l, as well as domperidone 1 ol/l antagonized the action of LY 171555 1 mol/l. S-Sulpiride was more potent than its R-isomer. SCH 23390 1 mol/l and rauwolscine 1 mol/l blunted the effect of SKF 38393 10 mol/l. Rauwolscine 1 mol/l slightly reduced the inhibition by dopamine 10 mol/l; S-sulpiride 10 mol/l was antagonistic only in the presence of rauwolscine 1 mol/l. When rauwolscine 1 mol/l, prazosin 0.1 mol/l, propranolol 1 mol/l and cocaine 10 mol/l was added to the medium, dopamine 10 mol/l continued to produce the same depression of e j.ps, as in the absence of these compounds. Under such conditions S-sulpiride 10 mol/l also counteracted dopamine 10 gmol/l. Rauwolscine 1 mol/l prevented the effect of clonidine 0.1 mol/l. The antagonists were not absolutely selective against only one type of agonist. We suggest that both presynaptic DA₂- and postsynaptic DA₁-receptors are present in rabbit jejunal arteries. The activation of either receptor-type may depress the e j.ps. Dopamine interferes with neuroeffector transmission due to ₂-adrenoceptor agonist properties; its DA₂-effect is unmasked only after ₂-adrenoceptor blockade. There was no evidence for a co-transmitter function of dopamine. Send offprint requests to P. Illes at the above address