Search

The aerial part of Biebersteinia heterostemon Maxim. (Geraniaceae Biebersteiniaceae) known as ming jian na bao in Chinese, has been traditionally used in Tibetan folk medicine for treatment of diabetes and hypertension. The aim of the present study was to evaluate the effects of galegine obtained from an ethanol extract of the entire Biebersteinia heterostemon plant on the rat's cardiovascular system in order to characterize its contributions as an antihypertensive agent. The antihypertensive effect of galegine was investigated in pentobarbital-anesthetized hypertensive rats at three dose levels based on the LD 50 of galegine. Meanwhile a positive control group received dimaprit with the same procedure. Dimaprit infusion induced a significant hypotension which declined by an average margin of 20%. Simultaneously, single administration of galegine at the doses of 2.5, 5, and 10 mg/kg by intraperitoneal injection induced an immediate and dose-dependent decrease in mean arterial blood pressure (MABP) by an average margin of 40% with a rapid increase in heart rate (HR). We demonstrated that galegine is effective in reducing blood pressure in anesthetized hypertensive rats with rapid onset and a dose-related duration of the effects. The results indicate that galegine was the bioactive compound which can be used as a pharmacophore to design new hypertensive agents.

The effect of endothelin and nitric oxide (NO) inhibition on survival from septic shock was investigated in male Swiss albino mice (20-40 g), with particular emphasis on the timing of the administration of their blockers after Escherichia coli endotoxin (lipopolysaccharide, O55:B5, 60 mg kg(-1), i.p.) challenge. Mice were injected with the endothelin receptor antagonist bosentan (30 mg kg(-1), i.p., either 2 or 12 h after endotoxin) alone or in addition to the NO synthase blockers L-canavanine (100 mg kg(-1), i.p.), N(G)-nitro-L-arginine methyl ester (L-NAME, 3 mg kg(-1), i.p.) or aminoguanidine (15 mg kg(-1), i.p.), which were also given twice at 2 and 6 h after endotoxin. Control animals received saline, and survival rates in each group (n=10) were recorded over 24 h at 6-h intervals. At 24 h, the survival rate was 10% in controls, but 30% (n.s.) and 70% (P<0.05) in animals that received only bosentan at 2 and 12 h, respectively, indicating a relatively late involvement of endothelin in comparison to NO. In contrast, these figures were 70% (P<0.05) and 80% (P<0.05) at 12 h for L-NAME and L-canavanine, respectively, and 10% (n.s.) at 24 h, implying a relatively early involvement of NO compared to endothelin. Interestingly, survival in the aminoguanidine group (75% at 24 h, P<0.05 vs. controls) was markedly higher than that in the L-NAME and L-canavanine groups, an effect that was attributed to mechanisms other than NO inhibition. Survival was better (60%, P<0.05 vs. endotoxin alone) when bosentan was given at 2 h in combination with L-NAME, but the best outcome (90% survival, P<0.05) was observed in animals when bosentan was given at 12 h and L-NAME was injected twice at 2 and 6 h. However, the statistical analysis revealed no significant additional beneficial effect of L-NAME coadministered with bosentan. Therefore, we conclude that NO is involved during the earlier phases of septic shock in comparison to a relatively late involvement of endothelin peptides, and that bosentan alone appears to be beneficial when administered at least 12 h after the endotoxin challenge in our mice model of septic shock.

This study was designed to determine whether pyrazinoylguanidine (PZG) can attenuate cataract development in streptozotocin (STZ)-induced diabetic rats. After a single, intraperitoneal dose of STZ (45 mg/kg in 0.05 mol/l sodium citrate buffer), Sprague-Dawley rats (250-260 g) were divided into three groups. Beginning a week later, each group of diabetic rats received twice daily for 24 weeks by gavage one of the following: vehicle (saline 10 ml/kg), PZG (35 mg/kg), or captopril (15 mg/kg). PZG treatment prevented the development of diabetic cataracts (p = 0.0009 compared to vehicle). In contrast to PZG, 38% of vehicle-treated rats exhibited cataracts after 12 weeks, increasing to 89% after 16 weeks. At week 16, 22% of captopril-treated rats exhibited cataracts, a 75% reduction from vehicle-treated rats (p = 0.4289 compared to vehicle; p = 0.0571 compared to PZG). These results indicate that captopril can attenuate cataract formation in STZ-diabetic rats, whereas PZG completely suppresses it.

Potassium channels are ion channels in the cell membrane which are especially important for regulation of the membrane potential and the cell's excitability. Potassium channel openers are drugs that interfere with these channels, and several such substances have been developed. Existing substances show highest affinity to vascular smooth muscle. The clinical effect is relaxation of blood vessels resulting in lower blood pressure. However, current efforts are concentrated on finding substances which are selective for other cell types. Possible areas of application are treatment of hypertension, angina pectoris, arrhythmias, asthma and urinary bladder instability.

KATP openers are recognized as having a therapeutic potential for the treatment of various cardiovascular and noncardiovascular diseases. However, the first-generation agents open KATP in a variety of tissues that limit their potential clinical utility. This review describes our studies aimed at the identification of a common pharmacophore among structurally diverse KATP openers and the discovery of tissue-selective agents that may offer advantages over the first-generation agents for the treatment of cardiovascular diseases. Compounds (e.g., BMS-182264) combining the structural features of KATP openers cromakalim and pinacidil, show smooth-muscle relaxing and antihypertensive activities comparable to their predecessors, indicating cromakalim and pinacidil may express their biologic effects through similar structural requirements. The hypothesis about common features is further supported by radioligand-binding studies showing cromakalim, pinacidil, and the combination compound BMS-182264 bind to a similar receptor site in rat aortic smooth-muscle cells. Regardless of having a pharmacologic profile similar to cromakalim and pinacidil in vascular smooth muscle, BMS-182264 had no effect on action potential duration in guinea pig papillary muscle, indicating smooth-muscle selectivity for BMS-182264. We demonstrate that no correlation exists between anti-ischemic and smooth-muscle relaxing potencies for a variety of structurally different KATP openers. Efforts to find KATP openers selective for the ischemic myocardium led to the identification of BMS-180448 which, despite having similar anti-ischemic potency to cromakalim, was significantly less active as a smooth-muscle relaxant. This compound was shown to be efficacious as an anti-ischemic agent in vivo without affecting hemodynamic variables, a potential liability of first-generation compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

This study determined the effect of pinacidil on the concentration of plasma lipids and apolipoproteins in male patients previously equilibrated with 25 mg hydrochlorothiazide twice daily. Pinacidil therapy given to 52 hypertensives at 25 to 100 mg daily for 8 weeks resulted in a reduction of systolic and diastolic blood pressure concurrently to reductions in plasma cholesterol and triglycerides with no change in low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C). There was an associated decrease in apolipoproteins (Apo)B, C-III and E and elevation in ApoA-I. A parallel placebo group of 44 patients experienced reduction in diastolic blood pressure and an elevation in ApoA-I. These changes indicate that pinacidil will be a useful antihypertensive agent having properties on lipoprotein metabolism which would favor decreased risks of atherosclerosis.

In a controlled, double-blind, crossover study, the effects of guanadrel sulfate and propranolol on blood pressure (BP) and selected cardiopulmonary and metabolic variables were compared in 15 physically active and moderately hypertensive subjects. Guanadrel sulfate reduced systolic and diastolic BP at rest by -16 and -15 mm Hg, and at maximal exercise by -33 and -13 mm Hg, respectively (p less than 0.005), without affecting submaximal oxygen consumption (VO2), maximal VO2, ventilatory threshold, forced vital capacity, forced expiratory volume in 1 second, or fatigue, as assessed by perceived exertion. In contrast, propranolol significantly decreased diastolic BP at rest (-16 mm Hg) and systolic BP at maximal exercise (-44 mm Hg); however, it significantly decreased submaximal VO2 (-3.9 ml.kg-1.min-1), maximal VO2 (-3.9 ml.kg-1.min-1), ventilatory threshold (-0.3 liters.min-1), minute ventilation at submaximal exercise (-7.3 liters.min-1), forced expiratory volume in 1 second (-0.27 liters), and concomitantly increased the rating of perceived exertion at maximal exercise (1.9 U). Guanadrel sulfate was also associated with significant decreases in mean fasting plasma glucose and total serum cholesterol, whereas propranolol resulted in an increase in serum triglycerides (p less than 0.05). In contrast to propranolol, guanadrel sulfate appears to decrease BP without evoking negative metabolic consequences or impairing exercise tolerance.

Potassium channel activators (PCAs) open the membrane potassium channels, thus increasing the cell potassium efflux. This results in hyperpolarization of the cell membrane, the main result of which is a reduction of the penetration of calcium into cells. The resulting decrease of intracellular Ca++ produces relaxation of the smooth muscle fibres, notably in blood vessels. In animals, PCAs reduce total peripheral resistance and lower blood pressure. These vasodilator and hypotensive effects are accompanied by reflex tachycardia and stimulation of the renin-angiotensin system and they are antagonized by glibenclamide, an antagonist of ATP-dependent potassium channels. Very recent experimental data have shown that in the ischaemic myocardium PCAs tend to improve the balance between oxygen supply and demand and to exert a cardioprotective effect. Up to now, the only use of PCAs has been in arterial hypertension, and the only drugs used are pinacidil, minoxidil and diazoxide. Unfortunately, the PCAs that are available at present are rather poorly tolerated, which limits their development in this particular field. However, their combination with beta-blockers and/or diuretics reduces the incidence of their side-effects and improves their effectiveness. A synergistic effect between PCAs and angiotensin-converting enzyme inhibitors is probable.

Pinacidil is an orally administered antihypertensive drug that acts via direct relaxation of vascular smooth muscle to produce peripheral vasodilatation and a reduction in blood pressure without significant direct effects on cardiac electrophysiology. Pinacidil is unrelated to other antihypertensive drugs in clinical use, either in structure or mechanism of action. It belongs to a new class of agents called 'potassium channel openers' which act via potassium efflux to hyperpolarize cell membranes, indirectly causing a net reduction in intracellular calcium that leads to relaxation of vascular smooth muscle. Pinacidil is indicated in the management of essential hypertension. In clinical trials of up to 1 year duration, pinacidil administered twice daily in a controlled release capsule formulation has been shown to achieve adequate blood pressure control both in previously untreated patients and in those with blood pressure inadequately controlled by beta-adrenoceptor blocking drugs or thiazide diuretics. In long term (up to 1 year) comparative studies pinacidil was at least as effective as hydralazine, prazosin or nifedipine in maintaining blood pressure control. Pinacidil may also have a potential use in the treatment of patients with secondary renal hypertension. Clinical trials to date have usually allowed the addition of a thiazide diuretic and/or beta-adrenoceptor blocking drug to enhance the efficacy of pinacidil and/or to reduce the incidence of adverse effects. The main adverse effects of pinacidil treatment, which result from its peripheral vasodilator activity, are headache, oedema, palpitations and tachycardia. Although the overall incidence of adverse effects is quite high, they are usually mild, transient in nature and respond to a reduction in dose. Nevertheless, these effects may occasionally be severe, necessitating withdrawal from therapy. Thus, pinacidil is an effective antihypertensive drug for the treatment of mild to moderate essential hypertension. Despite its novel mechanism of action pinacidil causes adverse effects typical of peripheral vasodilators; during long term use with twice daily administration of the controlled release capsule formulation, the addition of a diuretic is often necessary to attenuate peripheral oedema and maintain adequate control of blood pressure. Further long term controlled trials are needed to determine the precise role of pinacidil relative to that of the angiotensin converting enzyme (ACE) inhibitors and calcium channel blocking drugs.

In a multicenter study with 54 patients with essential and renal hypertension (WHO I to III) the antihypertensive efficacy and safety of guanfacine were evaluated against clonidine in a double blind cross-over design. The treatment period for each drug lasted five weeks. There was a two week's wash-out period with placebo between the application of the respective preparations. During the first two weeks of treatment a daily dose of 3.3 mg guanfacine and 0.5 mg clonidine led to a significant fall in blood pressure from 187/103/138 mm Hg (s/d/m) to 152/86/113 mm Hg and from 186/101/136 mm Hg to 156/91/118 mm Hg respectively. During the following time blood pressure and dosage remained almost unchanged. In contrast to clonidine the guanfacine group showed a smaller fall in blood pressure in upright than in supine position. Both drugs showed a decrease of heart rate by approximately 4 beats per minute. Side effects such as dry mouth and tiredness were more pronounced under treatment with clonidine than with guanfacine (p less than or equal to 0,08). Guanfacine is well tolerated as a potential antihypertensive drug with relatively few side effects of mild nature.

The clinical pharmacology of a central antihypertensive drug, guanfacine, was studied in sustained essential hypertension. The study of the haemodynamics, performed in 7 patients demonstrated a significant decrease in blood pressure and a fall in heart rate (less than the one observed with clonidine): the peripheral resistances remained unchanged after 4 days treatment. A clinical trial was carried out in 20 patients with sustained essential hypertension. Guanfacine was given orally (2 to 4 mg/day) during 2 months; the results of this study confirmed the antihypertensive effect of the drug. The most frequent side effects were dryness of the mouth and sleepiness. Guanfacine kinetics were studied in patients after single and repeated oral doses. The plasma concentrations were fitted in a two compartments open model with first order absorption. Steady state plasma level during a long term treatment can be determined with the predicted values derived from simulation of the initial individual kinetic studies. For a 2 mg dosage the biological half-life was 22.8 +/- 3.6 h. Guanfacine kinetics were linear according to the dosage. In moderate permanent essential hypertension guanfacine can be easily prescribed in monotherapy at a posology of 2 to 4 mg/day.

Pinacidil (N''-cyano-N-4-pyridyls-N'-1,2,2-trimethyl-propyl guanidine, monohydrate), a recently developed direct-acting vasodilator, was given intravenously in a dosage of 0.1-0.2 mg/kg body weight to ten untreated hypertensive patients. Pinacidil caused a fall of blood pressure from 170/108 +/- 6/3 to 156/80 +/- 5/4 mm Hg (mean +/- SE). The proportional decrease of mean arterial pressure (MAP) was 13.7 +/- 1.6%. Together with the decrease of blood pressure an increase of heart rate by 29.7 +/- 6.2% occurred. The heart rate increased by 13.6 beats/min per 10 mm Hg decrease of MAP. Pinacidil also caused significant rise of plasma noradrenaline and plasma renin activity, whereas plasma adrenaline and aldosterone remained unchanged. The serum concentrations of pinacidil and its major metabolite pinacidil-N-oxide were within the expected limits. The authors conclude that intravenously administered pinacidil causes a rapid decrease of blood pressure, but at the cost of a considerable increase of heart rate, and thus does not offer advantages over other vasodilators.

The pharmacologic data obtained from animal experiments with guanfacine, a novel, centrally acting antihypertensive agent, are reviewed. When given orally, guanfacine lowers systemic blood pressure in conscious DOCA-NaCl-hypertensive rats, Grollman rats and spontaneously hypertensive rats in a dose-dependent manner. It is also effective in renal hypertensive cats. Guanfacine reduces blood pressure in cats, rabbits and rats after injection into the lateral cerebral ventricle and in dogs after infusion into the vertebral artery at intravenously ineffective doses. Vagally mediated reflex bradycardia in dogs is enhanced. The preganglionic splanchnic (sympathetic) nerve activity is reduced in cats. In rats, guanfacine reduces the noradrenaline turnover in the brain stem. All these findings indicate a central site of action. Peripheral alpha-adrenoceptor stimulant properties of guanfacine have been demonstrated in various studies. In addition to postsynaptic stimulant effects, presynaptic guanfacine-induced inhibition of sympathetic heart nerve stimulation is antagonized by rauwolscine but not by prazosin, indicating a highly preferential alpha 2-agonistic presynaptic action of the drug. In receptor binding studies using rat cortex membranes and human platelets, guanfacine exhibited a high selectivity for alpha 2 adrenoceptors. Guanfacine has the advantage over other centrally acting antihypertensives of being less sedative and causing no rebound hypertension after discontinuation of treatment. The latter is mainly due to its pharmaco-kinetic properties.

The administration of a new guanidine derivate, BS 100-141, to 20 patients resulted in a statistically highly significant reduction of blood pressure. A comparative clinical trial of BS 100-141 and alpha-methyl-DOPA showed BS 100-141 to be more efficient in lowering the arterial pressure than alpha-methyl-DOPA, especially when the drug was used in the second period of treatment. In the majority of the patients treated with BS 100-141 a slight increase in blood glucose concentration, not exceeding the upper limits of normal values, was found.

1. The haemodynamic mechanisms underlying the antihypertensive effect of guanfacine during chronic oral administration were studied. 2. Ten patients with essential hypertension were submitted to haemodynamic measurements at rest and during exercise, before and after 12 weeks' treatment with guanfacine alone at a daily dose of between 3 and 15 mg orally. 3. The relevant haemodynamic values were obtained by means of an arterial catheter in the aorta, a venous catheter in the right atrium, and the measurement of cardiac output using the thermodilution method. 4. The antihypertensive efficacy of guanfacine was confirmed. 5. In the seven patients with a high peripheral resistance the main effect of guanfacine was a marked decrease in total peripheral resistance. In three patients with hypertension characterized by high stroke volume and cardiac output, the main effect of guanfacine was to reduce these variables.

The antihypertensive effect of a new vasodilating drug, pinacidil, was compared with prazosin in a randomized, open study in general practice including 131 patients with a sitting diastolic blood pressure (DBP) between 100-115 mmHg. At inclusion 108 patients were untreated and the remaining patients were on treatment with thiazide diuretics and/or beta-blockers. The aim was to reduce the sitting DBP to less than or equal to 95 mmHg, which was achieved in 85% of the patients treated with pinacidil and in 77% of the patients treated with prazosin (NS). In the responding patients the reductions were (mean +/- SD) 16 +/- 7 mmHg (p less than 0.001) and 13 +/- 6 mmHg (p less than 0.001) in the pinacidil group (n = 60) and the prazosin group (n = 46), respectively (p less than 0.10). During 5 months of maintenance therapy no statistically significant differences in blood pressures between the two treatment groups were present. Side-effects were typical of vasodilator therapy, i.e. headache, dizziness, tachycardia and edema, leading to discontinuation of therapy in 10 patients in each treatment group. Heart rate (HR) was increased with pinacidil and unchanged with prazosin. Edema was frequently seen with pinacidil and dizziness with prazosin. Because of edema a thiazide diuretic was given to nine patients in the pinacidil group and two patients in the prazosin group. No clinically significant changes in ECG and biochemical variables were observed. In conclusion, the study has demonstrated that pinacidil is as effective an antihypertensive agent as prazosin. Pinacidil may be used as monotherapy. However, the study suggests that pinacidil should be used as add-on therapy to thiazide diuretics.

In the present study the effect of 1 year of antihypertensive treatment with guanfacine (g) has been evaluated in 18 hypertensive patients with adult-onset, non-insulin-dependent diabetes mellitus (WHO Type II). The treatment produced a marked improvement in the oral glucose tolerance test; guanfacine significantly decreased serum glucose levels, and affected only slightly the insulin secretion. It is suggested that the effect of g may be mediated via a reduction in catecholamine and/or growth hormone and ACTH secretion. The present results also suggest that treatment with guanfacine may improve individual coronary risk in hypertensive diabetic patients.

In this study the effect of DHE on postural hypotension induced by major antihypertensive drugs was evaluated in 40 patients. 30 patients were treated with methyldopa, five with guanoxan sulphate and five with bethanidine sulphate. To obtain a more accurate picture of the effectiveness of DHE and to test the reproducibility of its effect, each patient was observed during five separate, successive periods: in the first period the antihypertensive agent was given alone; in the second period it was given along with placebo; in the third period it was given with DHE; in the fourth period the antihypertensive agent was given alone again; and in the fifth period it was again given with DHE. In the third and in the fifth period, DHE was administered at the same time as the antihypertensive agent in a dose of 9-15 mg/24 h (3-5 mg three times daily). The first dose was given 1 h before rising, and the daily dosage was progressively increased. The beneficial effect of DHE on postural hypotension was evaluated by assessing the clinical symptoms in a semiquantitative manner and by measuring the arterial blood pressure and heart rate in a recumbent and standing position. The results were classified as follows: excellent, good, moderate and no response. In most cases, DHE was found to be an effective drug for the treatment of postural hypotension, an improvement in clinical symptoms being noted in 57.5% of patients tested (excellent and good results). In these patients the standing arterial blood pressure showed a significant response (p less than 0.01). DHE did not interfere with the therapeutic effect of the antihypertensive agents. Furthermore, DHE did not affect the heart rate, nor did it give rise to any adverse reactions.

The authors assessed the antihypertensive effect of guanfacine (Estulic Sandoz) in 28 stage II hypertensive patients with a pronounced pressure response to the isometric test. Over a period of 4.3 months on the average, they managed to normalise both resting and exercise blood pressure in 89% of subjects. In another study, the authors administered guanfacine to 30 I- and II- type diabetics with essential, primarily stage I, hypertension. Over an average of 6 months, blood pressure normalised in 81% and, when using a guanfacine-saluretic combination, in additional 11%, that is, in a total of 92% of patients. It has been demonstrated that guanfacine has no adverse metabolic action. By contrast, the level of compensation of diabetes mellitus improved allowing 50% of patients to decrease their doses of oral antidiabetic drugs and insulin as well. The authors believe that, in diabetics with hypertension, guanfacine can be rightly regarded as the drug of first choice since it is effective in single-drug therapy and can be used with advantage in patients with whatever complication of diabetes mellitus.

1. Thirty pregnant women aged 22-34 yr presenting with pre-eclampsia were treated with guanfacine for periods of 16-68 days. 2. Elevated blood pressure was lowered to a statistically and clinically significantly extent in the first week of treatment, falling almost to normal levels before parturition in 24 cases. Four days after delivery all the patients had normal blood pressures. 3. Oedema (localized or generalized) was not reduced to any extent by guanfacine and additional treatment was necessary in 17 cases. There was little effect on proteinuria. 4. Twenty-five patients reported side-effects attributable to the treatment (sedation in 25 cases, dryness of the mouth in 15, and feelings of dizziness in 6 cases). 5. No notable changes were observed in either foetal or maternal heart rate during the period of treatment. Of the 30 deliveries, 19 were spontaneous, 5 by vacuum extraction, and 6 were by Caesarean section because of suspected placental insufficiency. Six of the infants were 'small-for-date babies', but all developed normally later.

1. The antihypertensive effects and side-effects of guanfacine and clonidine were compared in a single-blind, cross-over study. 2. The study consisted of two active treatment periods of 6 weeks each, which were both preceded by a 2 weeks placebo period. Thirty ambulatory, hypertensive patients (blood pressure WHO severity grades I-II) were admitted to the study. The results are based on the 24 patients who completed the study. 3. The optimal daily dose of guanfacine was in over half of the patients 3-4 mg, and of clonidine correspondingly 0.3-0.45 mg. A similar and statistically significant decrease in blood pressure was achieved with both drugs. 4. The most common side-effects with both drugs were tiredness and dryness of the mouth.

Guanadrel sulfate, a new adrenergic neuron inhibitor similar to guanethidine sulfate, was tested on 199 outpatients by 11 investigators. The patients had mild, moderate, or severe hypertension as determined by diastolic blood pressures of 95 to 105, 106 to 114, and 115 to 120 mm Hg, respectively. Guanadrel was found to be an effective antihypertensive agent for all levels of hypertension. Since guanadrel has a short onset of action and a short offset of action, which prevents many of the side effects of guanathidine, the dosage could be adjusted rapidly and safely. At low doses side effects are infrequent. There was no organ toxicity and no CNS effect. Guanadrel should be an effective step II or step III drug for treatment of hypertension.

The centrally-acting antihypertensive drug guanfacine was studied in a group of 11 moderate hypertensives. In doses of 2 mg daily, an average reduction in diastolic blood pressure of 10.8 mmHg was achieved. Side-effects were few when doses were maintained below 3 mg daily. The blood pressure reduction was associated with a fall in plasma renin activity and an average weight gain of 1.8 kg. When guanfacine was tried in 6 very severe hypertensives who had proved resistant to other antihypertensive drugs, a similar reduction in diastolic pressure of 7 mmHg was achieved using a dose of 3 mg daily. It is considered that guanfacine is a useful new antihypertensive drug, effective in mild hypertension, and side-effects are few if doses are maintained below 3 mg daily. Above this dose, side-effects became prominent, and these included sedation, dry mouth and constipation.

Efficacy of guanfacine was studied in 20 hypertensive patients and 20 patients with diabetes mellitus and hypertension in a 12-month follow-up. Besides routine biochemical parameters, glycaemia, platelet aggregation and the parameters of serotonergic and adrenergic activity (5-hydroxyindoleacetic acid and vanilmandelic acid urinary excretion) were investigated. Blood pressure was well controlled and no changes in glucose levels occurred in either of the study groups. The decrease in the urinary excretion of vanilmandelic and 5-hydroxyindoleacetic acid was more marked in hypertensive patients with normal glucose tolerance. These data suggest that activity of both adrenergic and serotonergic systems may be more impaired in diabetes. Further, changes in the serotonergic system are not caused only by antiserotonergic drugs. Finally, guanfacine was shown to be an effective and suitable drug for the long-term treatment of hypertension, particularly in patients with diabetes mellitus II.

Forty-three patients with mild essential hypertension were randomized into two double-blind studies: pinacidil vs. placebo or pinacidil vs. hydralazine. Pinacidil (62 +/- 18 mg/day) decreased office systolic and diastolic blood pressures from 145 to 137 mm Hg and from 98 to 89 mm Hg, respectively, after 6 weeks of therapy. Similarly, hydralazine (128 +/- 28 mg/day) reduced supine systolic blood pressure from 140 to 134 mm Hg and supine diastolic blood pressure from 93 mm Hg to 84 mm Hg. Significant tachycardia was not noted with either drug. Ambulatory blood pressure was monitored for 24 h during the placebo-washout and efficacy phases with both pinacidil and hydralazine. Mean 24-h blood pressure was 128 systolic and 81 diastolic with pinacidil and 121 systolic and 76 diastolic with hydralazine. Reduction in awake hypertensive diastolic blood pressure was significant for both pinacidil and hydralazine. Normal sleep diastolic blood pressure was not reduced by pinacidil but was reduced by hydralazine. Side-effects with both drugs included edema, headache, and palpitations. These data demonstrate that pinacidil is as effective an antihypertensive agent as hydralazine.

The therapeutic efficacy and tolerance of guanfacine after 5-7 years' continuous treatment was investigated in 54 patients (30 females and 24 males) who were part of the 580 hypertensives originally participating in a 1-year clinical study reported previously. Only 41% of the patients were treated with guanfacine alone (mean daily dose, 2.2 mg), whereas 59% received combined drug therapy (mean daily dose of guanfacine, 5.7 mg). The results on efficacy and dosage after 5-7 years were identical with those obtained for the entire group after 1 year (n = 580) and 2 years (n = 162). The blood pressure of these patients was reduced from pretreatment values of 186/112 +/- 12/11 mmHg to 149/93 +/- 14/19 mmHg at the final examination. Thirty-four of the patients (63%) had normalized blood pressure. Six patients (11%), all of whom had been on combined therapy, complained of dryness of the mouth. Practically no other side effects and no drug interactions were observed, nor were there any signs of pharmacologic resistance.

Hypertrophy of the left ventricle in hypertension is associated with an increased risk of morbidity and mortality. Thus, the prevention of and regression of left ventricular hypertrophy should be essential goals of antihypertensive treatment. Some commonly used antihypertensive drugs do not have this ability, despite achieving adequate blood pressure control. In a double-blind randomised parallel group study, we evaluated the effects of adjunctive long term therapy with either pinacidil or nifedipine on blood pressure and left ventricular function and anatomy (echocardiography) in 22 patients with a diastolic blood pressure above 95mm Hg who were already receiving bendrofluazide 5mg daily. Pinacidil reduced left ventricular mass from 326.3 +/- 126.2g to 251.2 +/- 114.6g (p less than 0.001) compared with nifedipine, which reduced ventricular mass from 293.6 +/- 35.7g to 267.3 +/- 34.7 (p = 0.04). In this respect, pinacidil was more effective than nifedipine (p = 0.013). Pinacidil improved left ventricular diastolic function, measured by the isovolumetric relaxation time, whereas nifedipine did not affect this parameter. Global systolic function was little affected by either drug. However, the end systolic wall stress was significantly reduced by both therapeutic regimens. Pinacidil may, therefore, be a potentially valuable antihypertensive drug.

1. Sixteen patients with essential hypertension were treated with guanfacine and with clonidine for 5 weeks each in a double-blind, placebo-controlled, cross-over trial. Dosage ranged from 2 to 6 mg guanfacine and from 0.3 to 0.9 mg clonidine daily in two or three divided doses. 2. Both compounds caused a significant and comparable decrease in blood pressure. Patients whose blood pressure was not reduced to normal by 2 to 3 mg guanfacine daily did not respond better to an increase in the dose. 3. Dryness of the mouth and constipation occurred with about equal frequency with both agents, but sedation and orthostatic circulatory effects were considerably more frequent with clonidine. 4. A withdrawal syndrome was observed on discontinuation of clonidine in one patient as opposed to no rebound hypertension on stopping guanfacine treatment. 5. Guanfacine caused a significant decrease in plasma noradrenaline and adrenaline, suggesting a decrease in sympatho-adrenal activity.

The clinical pharmacology of potassium channel openers has been reviewed using pinacidil as a prototype drug. When administered acutely or chronically, the hemodynamic and neuroendocrine profile is that of a peripheral arterial vasodilator. The drug produces decreases in peripheral vascular resistance, and subsequent blood pressure decreases are associated with reflex increments in heart rate. When studied, plasma catecholamines increased about twofold during chronic therapy. Plasma renin activity, however, was not increased during chronic therapy with pinacidil monotherapy. When patients were treated with pinacidil doses ranging from 12.5 to 75 mg b.i.d., 66.9% of patients had a decrease in supine diastolic blood pressure to below 91 mm Hg and 10 mm Hg less than baseline, whereas only 23.9% of patients had similar falls during placebo treatment. During maintenance therapy with pinacidil, the average blood pressure during the daytime dosing interval was 137.8 +/- 1.2/83.4 +/- 0.7 mm Hg (mean +/- SEM). Titration of pinacidil as monotherapy resulted in a characteristic adverse event profile dominated by the presence of dose-related edema. Other characteristic events included tachycardia, palpitations and headache. When pinacidil was given to patients unresponsive to hydrochlorothiazide (25 mg b.i.d.), similar efficacy relative to placebo was noted with a change of post-dose supine diastolic blood pressure in the pinacidil group of 13.5 +/- 0.8 mm Hg and 7.3 +/- 0.9 mm Hg in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with essential hypertension were randomized to treatment with either prazosin or pinacidil, a new direct-acting vasodilator. Factors that might modulate the antihypertensive response and result in pseudotolerance to these drugs were measured before initiation of therapy and following 12 weeks of treatment. Despite significant reductions in blood pressure, pinacidil and prazosin did not produce an increase in plasma volume, did not activate the renin-angiotensin-aldosterone system, and did not interfere with the renal kallikrein-kinin system. The data fail to reveal evidence of physiologic compensatory changes that would lead to the development of pseudotolerance.

Prevention of complications of hypertension requires the lowering of blood pressure. The therapeutic goal is to achieve and maintain a diastolic pressure of less than 90 mm Hg with minimal adverse effects. The treatment of patients with established diastolic blood pressures between 90 and 104 mm Hg (determined from three separate readings) should be individualized; general measures such as weight loss and salt restriction should be tried first as an alternative to drug therapy. Patients with diastolic pressure in excess of 104 mm Hg should be treated with antihypertensive drugs; the first step should be the use of a thiazide diuretic in addition to general measures. Patients with diastolic pressures of 90 to 115 mm Hg may require the addition of a beta-adrenergic-receptor antagonist, methyldopa or clonidine if the therapeutic goal is not achieved; rarely they require the further addition of hydralazine or prazosin. Patients with diastolic pressures of 116 to 129 mm Hg usually require initially both a thiazide diuretic and a beta-blocker, methyldopa or clonidine; if the therapeutic goal is not achieved, hydralazine or prazosin is added, and if a further hypotensive effect is required guanethidine can be added. Patients with severe hypertension (diastolic pressures greater than 130 mm Hg) may require urgent treatment with combinations of drugs of all three levels. Emphasis should be placed on individualized therapy and patient compliance in the assessment of therapeutic failures. These "step-care" guidlines represent a framework for antihypertensive therapy devised from information available in 1977. It is not a rigid scheme and should be adjusted to the individual patient to ensure as normal a life as possible.

1. The effect of treatment with guanfacine for 12 weeks on blood pressure and plasma renin activity was investigated in 24 hypertensive patients (WHO I-III). 2. Systolic, diastolic and mean blood pressure values underwent significant reductions with a constant dose of guanfacine 3 mg daily for 1 week: from 197/115/149 (systolic/diastolic/mean) mmHg before therapy to 166/97/126 mmHg. After 4 weeks of treatment at varying doses, the blood pressure decreased to 157/91/118 mmHg, and after 12 weeks of treatment it levelled off at 147/83/109 mmHg. Heart rate remained essentially unchanged throughout the observation period. 3. During exercise, blood pressure and heart rate increased to the same extent during therapy as before treatment. Orthostatic hypotension was not seen in any of the patients. 4. Renin values decreased under therapy from 3.3 to 2.3 ng ml-1 h-1, but at no time during treatment did this decrease correlate with that of blood pressure. 5. Guanfacine treatment was accompanied by relatively few and mild side-effects.