Cardiovascular regulation during administration of co-dergocrine to normal subjects

Summary Whether and to what extent activation of peripheral presynaptic dopamine₂-receptors may modulate the release of norepinephrine (NE) and so affect blood pressure (BP) in normal or hypertensive man is not clear. The hydrogenated ergotoxine derivative, co-dergocrine, given in effective antihypertensive rather than excessive experimental doses, has recently been shown to act predominantly as a peripheral dopamine₂-receptor agonist in several species. Accordingly, BP regulation assessed has been in 8 normal men on placebo and after 3 weeks on co-dergocrine 4 mg/day. Co-dergocrine significantly reduced urinary NE excretion from 43 to 33 µg/24 h, supine and upright plasma NE 21 to 16 and 49 to 36 ng/dl, respectively, heart rate (–8 and –5%, respectively) and upright systolic BP, 115 to 102 mm Hg; upright diastolic BP also tended to be lower. A standard pressor dose of infused NE was lowered from 131 to 102 ng/kg/min, and the relationship between NE-induced changes in BP and concomitant NE infusion rate or plasma NE concentration was displaced to the left. Exchangeable sodium and plasma volume tended to be slightly decreased. Plasma and urinary electrolytes and epinephrine, plasma renin activity and aldosterone levels, pressor responsiveness to angiotensin II, the chronotropic responses to isoproterenol, and the NE-induced rise in BP, plasma clearance of NE, glomerular filtration rate and effective renal plasma flow were not consistently modified. The findings are consistent with effective peripheral dopamine₂-receptor agonism by co-dergocrine in humans. Peripheral presynaptic dopaminergic activation may modulate sympathetic activity and BP in normal man.     

Comparison of enalapril and propranolol in essential hypertension

Summary In 40 patients with essential hypertension, enalapril was compared with propranolol as an antihypertensive agent in a double-blind study. The patients were randomly given either enalapril 5–10–20 mg bid or propranolol 40–80–120 mg bid in a treatment consisting of step-by-step increases in dosage. When the diastolic blood pressure remained >90 mm Hg on the highest dosage, hydrochlorothiazide was added. Both enalapril and propranolol reduced blood pressure, although the patients tended to achieve lower blood pressures while on enalapril. More patients on propranolol required additional diuretic therapy than patients on enalapril.Propranolol reduced heart rate; with enalapril there were no changes in heart rate. Both drugs increased serum potassium and urea. Plasma renin substrate was reduced by enalapril, but raised by propranolol. Enalapril increased plasma renin activity and angiotensin I, while propranolol reduced both. Converting enzyme activity was lowered with enalapril but was unchanged with propranolol. Both drugs reduced angiotensin II. Plasma aldosterone concentration was more suppressed with propranolol than with enalapril.     

Haemodynamic effects of indenolol at rest and after a submaximal workload in essential hypertension

Summary The effect of indenolol on heart rate and blood pressure at rest and after submaximal workload has been studied in 19 patients with established essential hypertension. A stepwise increase from moderate to submaximal exercise was chosen to mimic challenges normally occurring in daily life. After 4 weeks of once a day indenolol therapy a significant, gradual reduction in the following cardiovascular parameters was observed: heart rate at rest fell by 20%, 30% after exercise and 31% after recovery; systolic blood pressure showed a fall of 15% at rest, 19% after workload and 14% after recovery; the reduction in diastolic blood pressure was 15% at rest, 11% after exercise and 12% after recovery. The rate-pressure product was decreased by 32% at rest, 43% after exercise and 42% after recovery. It is concluded that the most important pharmacological effect of indenolol is the significant decrease in myocardial oxygen demand. In patients with essential hypertension indenolol not only produces a definite antihypertensive effect, but it also increases workload tolerance and decreases subjective symptoms during physical activity. Compliance was good and no severe side effects were observed.     

Effects of bisoprolol on blood pressure,serum lipids and HDL-cholesterol in essential hypertension

Summary Fifty patients with essential hypertension WHO Grades I–II have been treated for 3 months with bisoprolol, a new selective betablocker, in doses up to 40 mg once daily. Forty-three patients reached the preset target diastolic blood pressure of 90 mmHg on a mean daily dose of 16.8 mg bisoprolol. There was no effect on serum lipids and HDL-cholesterol during the study. The side-effects were mild and were those usually associated with beta-blocking therapy.     

Serum lipoprotein changes during atenolol treatment of essential hypertension

Summary Serum lipoproteins were determined in 15 patients before and during antihypertensive treatment with atenolol 0.1–0.2 g/day for a mean of 8 months. The mean blood pressure fell from 171/103 to 154/93 mm Hg (p<0.05). Significant lipoprotein changes were an increase in very low density triglycerides (VLDL-TG) from 1.21±0.95 (SD) to 1.62±1.24 mmol/l (p<0.01) and in low density (LDL) TG from 0.46±0.12 to 0.51±0.12 mmol/l (p<0.05). Together, these TG increases resulted in development of hypertriglyceridaemia in 7/15 patients during atenolol treatment. No effect on whole serum cholesterol or on the high density lipoprotein cholesterol concentrations were found. Thus, some patients on long term treatment with atenolol seem to receive the benefit of normotension at the cost of hypertriglyceridaemia. This may have practical implications, since hypertriglyceridaemia constitutes an important risk factor for atherosclerosis.     

Antihypertensive effects of bisoprolol during once daily administration in patients with essential hypertension

Summary Biosprolol is a new beta₁-selective beta-blocking agent with a plasma half-time of 10–12 h and without partial agonist properties.Forty-eight patients with essential hypertension were randomly treated with 5, 10, or 20 mg bisoprolol given once daily for 8 weeks. All measurements were made 24 hours after the last dose.Bisoprolol had antihypertensive and beta-blocking properties both at rest and during exercise. The 20 mg dosage regimen was more effective than that of 5 mg and 10 mg.The drug was well tolerated and all the 48 patients completed the trial.     

Inhibition of the aldosterone response to sodium depletion in man by stimulation of dopamine DA2 receptors

Summary In this study we have investigated the effect of co-dergocrine, a selective DA₂-agonist, on plasma aldosterone concentrations (PAC) in twelve patients with essential hypertension both in basal conditions and during sodium depletion.Sodium depletion resulted in an increase of PAC from 38 (13) pg/ml to 297 (21) pg/ml. The PAC response to sodium depletion was reduced to 155 (29) pg/ml by co-dergocrine.No significant PAC changes were found in patients maintained on a normal sodium intake. In addition the drug did not significantly modify plasma renin activity (PRA) in either experimental group.These results suggest that the dopaminergic inhibition of aldosterone secretion in man is mediated by DA₂-receptors in the adrenal cortex.     

Long-term haemodynamic effects of sustained-release trimazosin at rest and during exercise in essential hypertension

Summary The long-term haemodynamic effect of sustained-release trimazosin (mean daily dose 418 mg) at rest and during exercise has been examined in 14 male patients (age 30–61 y) with previously untreated mild or moderate essential hypertension. Cardiac output (dye dilution), heart rate and intra-arterial blood pressure were measured supine and sitting at rest, and during bicycle exercise.After 11 months of trimazosin treatment the mean casual blood pressure was reduced from 165/106 mm Hg to 147/92 mm Hg. The intra-arterial systolic and diastolic pressure was reduced by 3–7% at rest and during 50, 100 and 150 W exercise. Total peripheral resistance was reduced by 8–14% and cardiac output was slightly higher (2–8%) in all situations.Stroke volume and heart rate remained unchanged, as did body fluid volumes (isotope dilution) and body weight.Side effects were minor and transient.Thus, the haemodynamic responses to trimazosin are similar to but weaker than those of other alpha₁-adrenoceptor blockers. The efficacy of the sustained-release formulation of trimazosin was low and daily doses above 600 mg are likely to be needed by many patients.     

Acute and long-term haemodynamic effects of propranolol and indenolol in hypertension

Summary The haemodynamic effect of indenolol, a -adrenoceptor blocker with intrinsic sympathomimetic activity (ISA) in animals, has been evaluated in a double-blind cross-over randomized trial after acute (3 days) and long-term treatment (28 days), in 12 hypertensive patients in comparison with that of propranolol. Patients were evaluated at rest and during isometric exercise (hand grip). The overall acute effect of both -adrenoceptor blocking drugs was to decrease mean blood pressure, heart rate and cardiac output, while total peripheral resistance increased. In the long-term studies the haemodynamic effect of propranolol was still characterized by cardiodepression and unchanged peripheral resistance. Patients on the long-term treatment with indenolol showed normal cardiac output and reduced total peripheral resistance.The data are compatible with a relatively strong ISA of indenolol, which would be responsible for the haemodynamic pattern observed during chronic treatment.     

Effects of acute and long-term beta-adrenoceptor blockade with propranolol on haemodynamics,plasma catecholamines and renin in essential hypertension

Summary The effect of an acute intravenous and repeated oral doses of propranolol on haemodynamics, plasma and urinary catecholamines and plasma renin activity was studied in patients with essential hypertension. Intravenous injection of propranolol 5 mg produced a fall in cardiac output but had no consistent effect on blood pressure. Treatment with oral propranolol for 24 weeks lowered cardiac output and blood pressure; total peripheral resistance did not differ from the pretreatment values. Neither acute intravenous nor chronic oral administration of the beta-blocker affected the resting plasma levels of noradrenaline and adrenaline. Long-term treatment with propranolol reduced urinary excretion of vanilmandelic acid without affecting urinary catecholamine excretion. Acute intravenous injection of propranolol decreased plasma renin activity less than did chronic oral treatment with the drug. The observed time course of plasma renin activity was compatible with the view that suppression of this enzyme contributed to the antihypertensive effect of propranolol.     

Dose-titration study of alfuzosin,a new alpha1-adrenoceptor blocker,in essential hypertension

Summary An open, dose-titration study of alfuzosin, a new selective post-synaptic alpha₁-adrenoceptor antagonist with additional direct vasodilator properties has been performed. After a 3-week runin placebo period, 12 patients with essential hypertension received alfuzosin 5 mg oral b.d., and then the dose was doubled every week, up to a maximum of 20 mg q.i.d. if the supine diastolic blood pressure was >90 mm Hg. The study lasted for 4 weeks.Supine blood pressure (SBP) decreased from 160/102 (Day 0) to 148/89 mm Hg and upright blood pressure (UBP) from 151/102 (Day 0) to 137/84 mm Hg. Alfuzosin did not cause any significant change in supine or upright heart rate.In addition, after the first dose of alfuzosin, supine and upright blood pressure and heart rate (SHR and UHR) were measured every 30 min for 5 h. The fall in blood pressure was significant after 90 min and it lasted up to the 5th hour; the maximum effect was observed after 3 h: SBP decreased from 159/103 (time 0) to 137/84 mm Hg and UBP from 150/102 (time 0) to 123/79 mm Hg.SHR was increased from 72 (time 0) to 81 beats/min at the 5th hour and UHR from 87 to 101 beats/min at the 4th hour.A weak but significant correlation was observed between the hypothensive effect 12 h after drug intake and the plasma concentration of the drug at that time. A 10% decrease in supine diastolic blood pressure was found at a drug plasma concentration higher than 7 ng/ml.Nine of the 11 patients reached the end-point (supine diastolic BP90 mm Hg) at the end of 28 days: 1 at the dose of 5 mg b.d., 6 at 10 mg b.d. and 2 at 20 mg q.i.d. At the high dose they both complained of palpitations. Two other patients complained of mild and transient palpitations at lower doses.     

Presynaptic regulation of electrically evoked dopamine overflow in nucleus accumbens: a pharmacological study using fast cyclic voltammetry in vitro

Summary Fast cyclic voltammetry has been used to measure electrically evoked dopamine overflow from slices of rat nucleus accumbens in vitro. The substance detected was shown voltammetrically and biochemically to be dopamine of neuronal origin. Enough dopamine was released by a single electrical pulse to be easily detectable, and under these conditions there was no auto-inhibition by the endogenous transmitter (as demonstrated by the failure of dopamine antagonists to increase the amount released). There was no significant inhibition, or enhancement, of release by agonists at the following receptor types: dopamine D₁, 5-hydroxytryptamine, cholinoceptors, ₁-, ₂-, -adrenoceptors, cholecystokinin or neurotensin receptors. However, the dopamine D₂ receptor agonist, quinpirole, was capable of totally inhibiting the release; this effect was concentration-dependently antagonized by the D₂ antagonists haloperidol, sulpiride, metoclopramide and clozapine, with potencies which corresponded to their affinities for D₂ receptors in striatal tissue. The results show that the presynaptic receptors on dopaminergic nerve terminals are of the D₂ type and apparently identical to those in the corpus striatum.     

Effects of treatment with nifedipine and metoprolol in essential hypertension

Summary In a double-blind trial 26 patients with essential hypertension were treated with nifedipine or placebo for 8 weeks, following a 4-week run-in place-bo period in all patients. The daily dosage of nifedipine during this phase was 10mg 3 times daily. Metoprolol was then added to the therapeutic regimen of both groups for a further 12 weeks. Both nifedipine and metoprolol used as mono-therapy caused statistically significant reductions of arterial pressure. The addition of metoprolol to nifedipine tended to reduce blood pressure further, but blood pressures were not significantly lower than during nifedipine mono-therapy. Side-effects were few and only two patients had to be withdrawn during active therapy, one for headaches during nifedipine therapy, and another for asthma during metoprolol treatment. Combined therapy with a beta-adrenoceptor blocking agent, such as metoprolol, and a calcium antagonist with vasodilating properties, such as nifedipine, offers a theoretically interesting approach in the treatment of hypertension, even though the practical outcome in the present study probably suffered from an inadequate dose of nifedipine during the period of combined therapy.     

Influence of hydrochlorothiazide on the plasma levels of triglycerides,total cholesterol and HDL-cholesterol in patients with essential hypertension

Summary

The influence of hydrochlorothiazide (HCT) treatment on the plasma levels of triglycerides, total cholesterol and high density lipoprotein cholesterol (HDL-cholesterol) was studied in lo patients with essential hypertension. After a placebo period of 4 weeks, 50?mg HCT twice daily was given for a period of 9 months, followed by a second placebo period of 4 weeks. Triglycerides, total cholesterol and HDL-cholesterol were determined at the end of both placebo periods and after 1, 3, 6 and 9 months of HCT. For the whole group, there were no significant changes in triglycerides or HDL-cholesterol, whereas total cholesterol significantly increased during HCT. In 6 patients, plasma triglycerides were higher during HCT as compared to both placebo periods. In only 4 patients did HDL-cholesterol increase during HCT. Changes in triglycerides, total cholesterol and HDL-cholesterol were not related and no correlation was found with changes in blood pressure, body weight or serum potassium. In conclusion, this study confirms a possible adverse effect of diuretic treatment on plasma lipids, which should be considered when determining therapeutic regimens for hypertension.     

Preliminary clinical pharmacological studies of S3341, a new hypotensive agent,and comparison with clonidine in normal males

Summary S3341, a new hypotensive agent which binds to alpha₂-receptors in animal brain preparations, was studied in normal healthy male volunteers. A dose ranging study with 15 and 25 µg/kg of S3341 was performed in a double blind, placebo controlled randomised and balanced manner with 3 subjects. A decrease or BP without noticeable sedation (assessed by visual analogue scales) was seen. One, 2 mg of S3341, 0.1 and 0.2 mg of clonidine were then compared in a double blind, placebo controlled, randomised and balanced manner in 10 subjects. BP, heart rate, systolic time intervals (STI), critical flicker frequency, choice reaction time, pursuit rotor, stimulated salivary volume, and dryness of mouth and sedation with visual analogue scales, were measured at 0, 1.5, 3.0, 4.5 and 6.0 h after drug administration. The relationship between decreases in BP and sedation was assessed by linear regression analysis, with the former as the independent (predictor) response and the latter as the dependent (response) variate. Both drugs produced a similar decrease of BP which was significantly different from placebo. Changes in psychomotor function tests were not significant. Both drugs produced dryness of mouth and sedation which were significantly different from placebo but changes were less with S3341. Clonidine showed a significantly steeper slope than S3341 in the relationship between decreases in BP and sedation. This must be interpreted with caution as there was wide variation in the correlation between decreases in BP and sedation, but it may be possible to achieve lesser sedation with S3341.     

特拉唑嗪对原发性高血压病人的血压、血脂及糖代谢的影响

目的：观察特拉唑嗪对３８例（男性２２例，女性１６例；年龄５６±ｓ８ａ）原发性高血压Ｉ期病人血压、血脂及糖代谢的影响。方法：特拉唑嗪首剂于晚上睡前服１ｍｇ，以后根据血压情况逐渐增量，最大剂量为１０ｍｇ／ｄ，８ｗｋ为一个疗程。结果：特拉唑嗪治疗后，血压下降（Ｐ＜０．０１），糖负荷曲线略降低，胰岛素水平（Ｉｎｓ）及胰岛素抵抗（ＩＳＲ）降低（Ｐ＜０．０１），心率及血脂无改变（Ｐ＞０．０５）。结论：特拉唑嗪对原发性高血压Ｉ期者，在改善血压的同时，不影响脂代谢，对糖代谢、胰岛素及ＩＳＲ有益。     

Acute haemodynamic and neurohumoral effects of intravenous nisoldipine in patients with severe congestive heart failure

Summary Twenty patients (5 females, 15 males) with severe heart failure (NYHA IV), due to coronary artery disease in 14, and congestive cardiomyopathy in 6, received an intravenous bolus of the calcium blocker nisoldipine 0.2 mg followed by a continous infusion of 0.2 g · kg^–1 · min^–1. Haemodynamic measurements were performed at baseline and after 30 min.The mean arterial pressure fell from 91 to 73 mm Hg, pulmonary capillary wedge pressure from 31 to 26 mm Hg and systemic vascular resistance from 1695 to 1040 dyn · s · cm^–5.The cardiac index (2.2 to 2.71 · min^–1 · m^–2, and stroke volume index (25 to 33 ml · m^–2) were markedly increased. There was no reflex tachycardia as the heart rate dropped from 92 to 85 beats · min^–1. Plasma renin activity and norepinephrine concentration did not change significantly.The findings indicate that nisoldipine acts as a strong vasodilator and that it has a beneficial acute haemodynamic effect in patients with severe left heart failure irrespective of its aetiology.     

Histamine H1- and H2-receptors in the gastrointestinal circulation

Summary Evidence for the presence of specific histamine H₁- and H₂-receptors in the gastrointestinal circulation was obtained using histamine, 2-methylhistamine (a specific H₁-agonist), 4-methylhistamine (a specific H₂-agonist), and selective H₁- and H₂-receptor antagonists in the anesthetized dog. Histamine and 2-methylhistamine increased conductance in the vascular beds of the superior mesenteric artery, the left gastric artery and the common hepatic artery, whereas 4-methylhistamine mainly enhanced conductance in the vascular beds of the left gastric artery and the common hepatic artery. All three agents depressed systemic arterial blood pressure. The vasodilatory effect of histamine and 2-methylhistamine on the superior mesenteric artery bed occurred earlier and was of shorter duration than their effect on the two other vessels. The H₁-receptor antagonists mepyramine and clemastine blocked the response of the superior mesenteric artery bed to histamine, but had a lesser inhibitory effect on the histamine response of the common hepatic artery and the left gastric artery. The addition of the H₂-receptor antagonist cimetidine to mepyramine blockade augmented the inhibiting effect of mepyramine on the common hepatic artery. Cimetidine bolus injections prevented enhancement of vascular conductance by 4-methylhistamine, but did not influence conductance enhancement by histamine or 2-methylhistamine. These data demonstrate there are separable histamine H₁- and H₂-receptors in the gastrointestinal circulation which are distinguished by anatomic location, temporal relationships of receptor response, and response to specific histamine H₁- and H₂-agonists and antagonists.     

Aliskiren,the first in a new class of direct renin inhibitors for hypertension: present and future perspectives

Aliskiren, the direct renin inhibitor, is the first new class of drug available in 13 years for the treatment of hypertension. Renin has long been recognized as a preferred site for blockade of the renin-angiotensin-aldosterone system because it prevents conversion of angiotensinogen to angiotensin I. Aliskiren binds to the active site of the renin molecule, blocking angiotensinogen cleavage, thus, preventing the formation of angiotensin I. Clinical studies have demonstrated at least equivalent or superior blood pressure lowering efficacy compared with existing drugs with a favorable side effect profile. Aliskiren possesses possible synergistic potential when combined with a thiazide diuretic, ACE inhibitor, angiotensin receptor blocker and calcium channel blocker both in terms of efficacy and tolerability. This review aims to define the role of aliskiren in the therapeutic management of hypertension.     

Effect of pinacidil on blood pressure,plasma catecholamines and plasma renin activity in essential hypertension

Summary Pinacidil, a new cyanoguanidine derivative, is an antihypertensive agent with arteriolar vasodilating properties, which acts on precapillary resistance vessels. A trial was carried out in 30 patients with essential hypertension WHO I-II. The treatment period was divided into three phases. Hydrochlorothiazide (HCTZ) and amiloride were administered for 4 weeks in Phase 1 and supine and standing blood pressure decreased significantly. During Phase 2 pinacidil was added to HCTZ/amiloride for the following 3 months. A further significant reduction in blood pressure was obtained. In the next period of treatment (Phase 3) patients were divided into two groups. For 1 month Group A (15 patients) received pinacidil alone and Group B (15 patients) received HCTZ/amiloride. Conventional laboratory blood tests in all patients remained unchanged during treatment. Reported side effects during Phase 2 were headache (2 patients), dizziness (3 patients), palpitations (2 patients) and ankle oedema (2 patients). Plasma renin activity was slightly increased at the end both of Phases 1 and 2. Plasma catecholamines were increased but not significantly at the end of Phase 2 as compared to Phase 1. The results indicate that pinacidil is effective in lowering blood pressure in mild to moderate essential hypertension.