Hypotensive effect of aqueous extract of the leaves of Phyllanthus amarus Schum and Thonn (Euphorbiaceae)

The plant of Phyllanthus amarus is used as diuretic and to lower blood pressure in traditional medicine practice. The effect of the aqueous extract of the leaves of Phyllanthus amarus on blood pressure was evaluated in normotensive male rabbits. Intravenously administered aqueous doses (5 mg to 80 mg/kg) of the extract to anaesthesized normotensive male rabbits produced a significant fall in mean diastolic, systolic and mean arterial pressures in a graded dose response manner. The dose of 5 mg/kg produced the least hypotensive effect, causing a fall in mean diastolic, systolic, and mean arterial pressure of 13.3 +/- 3.1, 19.7 +/- 5.4, and 14.3 +/- 3.4 mmHg, respectively, while the dose of 80 mg/kg produced the greatest fall in mean diastolic, systolic, and mean arterial pressure of 49.7 +/- 7.9, 45.5 +/- 9.5, and 48.00 +/- 6.5 mmHg, respectively. The extract had a greater blood pressure depressant effect on the diastolic blood pressure than on the systolic blood pressure. The highest dose of 80 mg/kg caused 62.5% fall in diastolic blood pressure, compared to the 33.2% fall in systolic blood pressure caused by the same dose. Atropine at the dose of 1 mg/kg blocked the hypotensive effect of the aqueous extract in a competitive manner. Promethazine at the dose of 1 mg/kg did not block the hypotensive effect of the aqueous extract, but potentiated the effect of the extract. After the administration of promethazine, the maximum tolerable dose of the extract was 40 mg/kg as compared to the initial dose of 80 mg/kg. The extract was found to decrease both the force and rate of myocardial contraction in a concentration dependent manner. The extract also dose dependently inhibited the intrinsic myogenic contraction of isolated rat portal vein. The results obtained show that the extract has blood pressure lowering effect which may be by the combined effects of myocardial depression, muscarinic receptor mediated vascular smooth muscle relaxation and by the calcium channel ion blockade in vascular smooth muscle.     

Effects of benidipine, a long-lasting dihydropyridine-Ca2+ channel blocker, on cerebral blood flow autoregulation in spontaneously hypertensive rats

Chronic hypertension shifts cerebral blood flow (CBF) autoregulation towards higher blood pressure. We examined whether or not benidipine, a long-lasting dihydropyridine calcium channel blocker (CCB), improves the CBF autoregulation in spontaneously hypertensive rats (SHRs). CBF was analyzed by laser-Doppler flowmetry during stepwise hypotension by controlled bleeding. The lower limit of CBF autoregulation was calculated as the mean arterial blood pressure at which CBF decreased by 10% of the baseline. Mean arterial blood pressure and cerebral vascular resistance in SHRs were higher than those in normotensive Wistar rats. Oral administration of benidipine (3 mg/kg) for 8 d lowered the mean arterial blood pressure and cerebral vascular resistance, which were equivalent to the effects of amlodipine (3 mg/kg), another CCB, or candesartan (1 mg/kg), an Angiotensin II type-1 receptor blocker. The lower limit of CBF autoregulation in SHRs (142+/-4 mmHg) was significantly shifted to a higher-pressure level compared with Wistar rats (59+/-2 mmHg). The lower limit of CBF autoregulation was significantly lower in the benidipine-treated group (91+/-4 mmHg) than that in the control SHRs, and similar to that of the amlodipine group (97+/-6 mmHg). Benidipine reduced the lower limit of CBF autoregulation more effectively than candesartan (109+/-4 mmHg). In conclusion, benidipine shifted the limit of CBF autoregulation towards lower blood pressure in SHRs under hypotensive conditions by hemorrhage. These results suggest that benidipine may be useful for the treatment of hypertensive patients with the elderly or cerebrovascular disorders, in whom autoregulation of CBF is impaired.     

The Vascular Actions of Aqueous Extract of Lippia multiflora.

Intravenously administered aqueous leaf extract (6.3 to 12.5 mg/kg) in anaesthetised cats and (3.2 to 6.3 mg/kg) in anaesthetised rats, produced a significant fall (P < 0.05, n = 10) in the mean, systolic and diastolic blood pressure by as much as 75 +/- 5.0 mm Hg in cats and 35 +/- 10.00 mm Hg in rats. On the raised arterial perfusion pressure of the rabbit central ear artery preparation, the extract (12.5-50 microg) produced a transient rise in perfusion pressure, which was followed by a more significant and prolonged fall in the perfusion pressure. Phentolamine (1.0 microg/ml) antagonised the transient rise and propranolol (1.0 microg/ml abolished the fall in perfusion pressure. The results suggested: that vasodilatation, resulting from a combination of alpha-adrenoceptor blockade and beta-adrenoceptor stimulant action of the extract, aided by skeletal muscle relaxation might be responsible for the blood pressure lowering effect of the extract.     

Haemodynamic effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-blocker, in patients with cirrhosis and portal hypertension

BACKGROUND: Carvedilol is a non-selective vasodilating beta-blocker with weak alpha1 receptor antagonism. Recent studies have demonstrated its potential as a portal hypotensive agent. AIM: To assess the haemodynamic effects and patient tolerability of the acute and chronic administration of low-dose carvedilol. METHODS: Haemodynamic measurements were performed in ten cirrhotic patients before and 1 h after the administration of 12.5 mg oral carvedilol. The study was repeated 4 weeks after daily administration of 12.5 mg carvedilol. RESULTS: After acute administration of carvedilol, there was a 23% reduction in the hepatic venous pressure gradient from 16.37 +/- 2.14 to 12.56 +/- 3.91 mmHg (P < 0.05), with significant falls in the heart rate, mean arterial pressure and cardiac output. Chronic administration resulted in a further fall in the hepatic venous pressure gradient from a baseline of 16.37 +/- 0.71 to 9.27 +/- 1.40 mmHg (P < 0.001) with the mean arterial pressure being unaffected. The drug was well tolerated with only one patient experiencing asymptomatic hypotension. CONCLUSIONS: The results show that low-dose carvedilol is an extremely potent portal hypotensive pharmacological agent, and is worthy of further investigation in large randomized trials to assess its effect in preventing variceal haemorrhage.     

Cardiovascular and renal effects of milrinone in beta-adrenoreceptor blocked and non-blocked anaesthetized dogs.

The cardiovascular effects of the low Km cAMP phosphodiesterase inhibitor milrinone (0.01-0.3 mg/kg, i.v.) were characterized in anaesthetized dogs with or without beta-adrenoreceptor blockade (nadolol, 1 mg/kg, i.v.). Heart rate was increased by milrinone at greater than or equal to 0.1 mg/kg in non-blocked dogs (61 +/- 5 beats/min [mean +/- SEM, max. change] or 40.5 +/- 6.0%) and at greater than or equal to 0.03 mg/kg in beta-blocked dogs (33 +/- 5 beats/min or 26 +/- 4%). Mean arterial pressure was decreased at greater than or equal to 0.03 mg/kg in non-blocked dogs (-34 +/- 6mmHg or -27 +/- 5%) and at greater than or equal to 0.1 mg/kg in beta-blocked dogs (-17 +/- 4 mmHg or -15 +/- 3%). These changes were or tended to be greater in non-blocked than beta-blocked dogs. The maximum rate of rise in left ventricular pressure was increased at all doses in non-blocked (3747 +/- 388 mmHg/sec or 131 +/- 14%) and beta-blocked dogs (2517 +/- 445 mmHg/sec or 131 +/- 25%), with the absolute but not percent increase being greater in non-blocked than beta-blocked dogs. Left ventricular end diastolic pressure (LVEDP) was or tended to be reduced at greater than or equal to 0.03 mg/kg in beta-blocked dogs (-3 +/- 1 mmHg or -64 +/- 20%) and at 0.01-0.1 mg/kg in non-blocked dogs (-1.4 +/- 0.9 mmHg or -50 +/- 29%). The absolute, but not percent, decrease in LVEDP at 0.03 mg/kg was greater in beta-blocked than non-blocked dogs (-2.2 +/- 0.8 mmHg or 32 +/- 10% vs. 0.0 +/- 0.7 mmHg or 0 +/- 8%). Cardiac output (CO) was or tended to be similarly increased at 0.01-0.03 mg/kg in beta-blocked (0.2 +/- 0.1/min or 15 +/- 5%) and non-blocked dogs (1.2 +/- 0.7 1/min or 40 +/- 16%). In conclusion, beta-blockade attenuated the hypotensive and chronotropic effects, but did not eliminate the positive inotropism, the reduction in cardiac preload or the increase in CO induced by milrinone in anaesthetized dogs.     

Inhibition of the vascular actions of IgG aggregates by BN 52021, a highly specific antagonist of paf-acether

The effect of BN 52021, a selective antagonist of paf-acether (Braquet GB patent 8, 418, 424 July 19, 1984), was studied in normotensive rats challenged with different doses of paf-acether. Sudden death was observed in animals receiving an i.v. dose of 10 micrograms/kg of paf-acether and this was prevented by prior treatment with BN 52021 (5 mg/kg, i.v.). Animals receiving 2.5 micrograms/kg of paf-acether had a fall of mean arterial pressure of 92.5 +/- 4.7 mmHg which recovered to the prechallenge level 20.5 +/- 0.2 min thereafter. Previous treatment with BN 52021 (5 mg/kg, i.v.) reduced the mean arterial pressure fall to 47 +/- 0.9 mmHg and the time of recovery to 5.7 +/- 1.7 min. The extravasation of 125I-bovine serum albumin under the above conditions was reduced by BN 52021 from 36 +/- 3 to 18 +/- 3%. A lower dose of BN 52021 (1 mg/kg, i.v.) was also effective in reducing later extravasation, but was unable to prevent the extravasation which appears up to 10 min after the injection of paf-acether. To extend these findings to a model of endogenous production of paf-acether, other animals were challenged with soluble aggregates of human IgG (40 mg/kg, i.v.; I?arrea et al., Immunopharmacology 6:7, 1983).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal and systemic effects of chronic blockade of ET(A) or ET(B) receptors in normal rats and animals with experimental heart failure

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal hemodynamic changes and impaired excretory function in congestive heart failure. It has previously been demonstrated that acute administration of ABT-627 (endothelin-A blocker) abolished systemic and renal vasoconstriction in controls and rats with congestive heart failure induced by a surgically created aortocaval fistula (Abassi et al. Clin Sci (Lond) 2002;103:S245-S248). In contrast, acute endothelin-B blockade by A-192621 exaggerated the ET-1 induced systemic and renal vasoconstriction. The present study examined the renal and systemic effects of chronically administered ABT-627 (24 mg/kg per day) or A-192621 (72 mg/kg per day) for 7 days via osmotic minipumps inserted intraperitoneally on the day of operation of sham controls and rats with congestive heart failure. Tailcuff measurements revealed that ABT- 627 significantly decreased mean arterial pressure from 108 +/- 2 mmHg to 87 +/- 2 mmHg (P < 0.05), whereas A-192621 significantly increased mean arterial pressure from 110 +/- 3 mmHg to 122 +/- 3 mmHg (P < 0.05) in controls. Despite the hypotensive effect of ABT-627, daily sodium excretion dramatically increased, but to a lesser extent in A-192621-treated controls. Furthermore, chronic administration of ABT-627 to controls attenuated the systemic and renal vasoconstriction induced by ET-1 (1 nmol/kg intravenous), whereas A-192621 augmented these effects. Similarly, chronic treatment with ABT-627 totally abolished the systemic and renal vasoconstriction caused by injected ET-1 in rats with congestive heart failure, whereas A192621 potentiated these effects. Chronic treatment of animals with congestive heart failure with ABT-627 did not influence daily sodium excretion, whereas treatment with A192621 significantly improved daily sodium excretion. Interestingly, treatment with either ABT-627 or A192621 significantly decreased cardiac hypertrophy in rats with congestive heart failure. In conclusion, in sham controls endothelin-B receptor mediated vasodilation and natriuresis, probably as a result of tubular action, whereas in congestive heart failure the excretory contribution of endothelin-B receptor was attenuated, resulting in Na+ retention.     

FAILURE OF ASPIRIN TO MODIFY THE HYPOTENSIVE ACTION OF CAPTOPRIL IN SPONTANEOUSLY HYPERTENSIVE RATS

1. Oral administration of the angiotensin converting enzyme inhibitor, captopril (30 mg/kg per day) to spontaneously hypertensive rats of the Okamoto strain progressively reduced arterial blood pressure by 60 mmHg over 4–5 days. 2. Oral treatment of spontaneously hypertensive rats with aspirin (200 mg/kg per day) for one week did not alter blood pressure, but it greatly reduced the vasodepressor effects of intravenous injections of arachidonic acid (3 mg/kg). 3. The fall in blood pressure of spontaneously hypertensive rats treated concurrently with both aspirin (200 mg/kg per day) and captopril (30 mg/kg per day) was not different to the fall observed in rats treated with captopril alone. 4. The hypotensive action of captopril in spontaneously hypertensive rats does not appear to be due to stimulation of vasodilator prostanoid biosynthesis.     

Comparative haemodynamic responses to the first dose of short- and long-acting ACE inhibitors in patients with congestive heart failure

BACKGROUND: Angiotensin Converting Enzyme inhibitors (ACEi's) confer significant mortality and morbidity benefits in all functional grades of chronic heart failure (CHF). However, physicians' concerns regarding the possible occurrence of first-dose hypotension appear to be a contributing factor to their under-utilisation in both hospital and primary care settings. We investigated whether long-acting and short-acting ACEi's differ in their haemodynamic responses to the first-dose in patients with CHF. METHOD: This was a multicentre, randomised, open, two-parallel-group study of captopril 6.25 mg and perindopril 2 mg. 240 patients with CHF, age 68.9 +/- 8.9 years, of whom 66% were male, NYHA II-IV, with average blood pressure baseline values of 132.2 +/- 16.2/78.5 +/- 10.5 mmHg for systolic and diastolic blood pressure, and left ventricular ejection fraction (LVEF) of 31.3 +/- 7.4% received either captopril (n = 124) or perindopril (n = 116). Blood pressure was continuously monitored during the 8 h following drug intake. Minimum levels and maximum decreases in systolic, diastolic and mean arterial pressures were measured, along with the incidence of hypotensive episodes defined as mean blood pressure (MBP) fall > 20 mmHg, whether symptomatic or not. Subgroups of patients distributed according to age, baseline blood pressure (BP) and LVEF were subsequently analysed. RESULTS: Overall, a statistically significant treatment effect in favour of perindopril was observed. First-dose hypotension was observed more frequently following captopril than perindopril administration, with lower MAP minimal levels (78.0 +/- 8.9 vs. 84.5 +/- 10.1 mmHg, p < 0.0001), greater maximum falls (17.6 +/- 8.3 vs. 12.8 +/- 7.3 mmHg, p < 0.0001) and more frequent hypotensive episodes (42% vs. 15%, p < 0.0001). The incidence of at least one symptomatic episode was also significantly higher with captopril (10 patients vs. one patient, p = 0.029). Subgroup analyses according to age (< or = 70 years or > 70 years) or LVEF (< or = 30% or > 30%) reflected the main result. CONCLUSION: Initiation of treatment with ACE inhibitors is associated with different haemodynamic and clinical tolerances in CHF patients, regardless of their risk for hypotension, with possible clinical implications.     

Increased arterial distensibility induced by the angiotensin-converting enzyme inhibitor, lisinopril, in normotensive rats.

1. We investigated possible structural correlates of the beneficial effect of chronic angiotensin-converting enzyme inhibition (ACEI) with lisinopril on the aortic distensibility of normotensive rats. 2. Experiments were performed in young (4-month old), normotensive, Wistar rats which received lisinopril in their drinking water (0.9 or 9 mg kg-1 day-1) for 9 months. 3. Following ACEI treatment, rats were pithed and aortic pulse wave velocity was measured during the progressive rise in mean arterial blood pressure produced by i.v. infusion of the alpha 1-adrenoceptor agonist, phenylephrine. The slope of the regression line relating aortic pulse wave velocity to mean arterial blood pressure was taken as an index of aortic distensibility. Following this, the aorta was fixed in situ at a normotensive pressure level and histomorphometry was performed. We also measured the calcium content of the aortic wall by atomic absorption. 4. The lower dose of lisinopril failed to lower systolic arterial blood pressure (unanaesthetized rat) or mean arterial blood pressure (pithed rat). Chronic ACEI with the higher dose of lisinopril lowered both systolic arterial blood pressure (104 +/- 6 mmHg, controls 133 +/- 4 mmHg, unanaesthetized), and mean arterial blood pressure (27 +/- 1 mmHg, controls 34 +/- 2 mmHg, pithed). 5. Although the lower dose of lisinopril did not lower blood pressure, it did improve aortic distensibility as revealed by a fall in the slope relating aortic pulse wave velocity (Y) to mean arterial blood pressure (X). Values were 5.7 +/- 0.7, 3.8 +/- 0.6 and 2.7 +/- 0.3 in controls, and in low and high ACEI groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypoglycemic and hypotensive effects of Psidium guajava Linn. (Myrtaceae) leaf aqueous extract

The leaf of Psidium guajava Linn. (family, Myrtaceae) is used traditionally in African folk medicine to manage, control, and/or treat a plethora of human ailments, including diabetes mellitus and hypertension. In order to scientifically appraise some of the anecdotal, folkloric, ethnomedical uses of P. guajava Linn., the present study was undertaken to investigate the hypoglycemic and hypotensive effects of P. guajava leaf aqueous extract (PGE, 50-800 mg/kg) in rat experimental paradigms. The hypoglycemic effect of the plant's extract was examined in normal and diabetic rats, using streptozotocin (STZ)-induced diabetes mellitus model. Hypertensive Dahl salt-sensitive rats were used to investigate the hypotensive (antihypertensive) effect of the plant's extract. Chlorpropamide (CPP; 250 mg/kg, p.o.) was used as the reference hypoglycemic agent for comparison. Acute oral administrations of the plant's extract (PGE; 50-800 mg/kg, p.o.) caused dose-related, significant (p < 0.05-0.001) hypoglycemia in normal (normoglycemic) and STZ-treated, diabetic rats. Moreover, acute intravenous administrations of the plant's extract (PGE, 50-800 mg/kg i.v.) produced dose-dependent, significant reductions (p < 0.05-0.001) in systemic arterial blood pressures and heart rates of hypertensive, Dahl salt-sensitive rats. Although the exact mechanisms of action of the plant's extract still remain speculative at present, it is unlikely that the extract causes hypotension in the mammalian experimental animal model used via cholinergic mechanisms, since its cardiodepressant effects are resistant to atropine pretreatment. The numerous tannins, polyphenolic compounds, flavonoids, pentacyclic triterpenoids, guiajaverin, quercetin, and other chemical compounds present in the plant are speculated to account for the observed hypoglycemic and hypotensive effects of the plant's leaf extract. However, the results of this experimental animal study indicate that the leaf aqueous extract of P. guajava possesses hypoglycemic and hypotensive properties, and thus lend pharmacological credence to the suggested folkloric, ethnomedical uses of the plant in the management or control of adult-onset, type 2 diabetes mellitus and hypertension in some rural African communities.     

Involvement of gamma-aminobutyric acid (GABA) B receptors in the hypotensive effect of systemically administered GABA in spontaneously hypertensive rats

We investigated the effects of intraduodenally (i.d.) administered gamma-aminobutyric acid (GABA) on blood pressure (BP) in anesthetized spontaneously hypertensive rats (SHR) and the mechanism underlying this effect, especially the type of GABA receptor involved in the depressive effect of this amino acid. GABA (0.3 to 300 mg/kg, i.d.) caused a dose-related decrease in the BP of 9.20 +/- 3.96 to 35.0 +/- 5.34 mmHg (mean +/- S.E.M.) that lasted for 30 to 50 min. The minimum effective i.d. dose of GABA was 0.3 to 1.0 mg/kg. Results pertaining to the mechanism underlying the GABA-induced effects on BP were as follows: a) GABA did not alter the BP-related effects of exogenous noradrenaline and acetylcholine; b) pretreatment with hexamethonium decreased the GABA-induced fall in BP, and GABA tended to reduce the pressor response associated with injection of dimethyl phenylpiperazinium; and c) pretreatment with 2-hydroxysaclofen markedly reduced the GABA-induced drop in BP, whereas pretreatment with bicuculline did not. In conclusion, in SHR, low-dose (0.3 to 1.0 mg/kg, i.d.) GABA had a hypotensive effect, which may result from attenuation of sympathetic transmission through the activation of GABA(B) receptors at presynaptic or ganglionic sites.     

Mechanism of the hypotensive action of Rhazya stricta leaf extract in rats.

The hypotensive action of Rhazya stricta lyophilized leaf extract was found to be partly caused by the electrolyte content of the extract, and partly caused by a strongly basic alkaloidal fraction (AF). AF (0.05-1.6 mg animal(-1)) caused a dose-dependent reduction in mean arterial blood pressure (MAP) of urethane-anaesthetized rat preparations. In naiuml;ve pithed rats, AF administration (0.5-2.0 mg animal(-1)) significantly increased MAP. In pithed or spinalized rats made normotensive by noradrenaline infusion, AF (0.25 mg animal(-1)) did not cause any significant changes. Direct intracerebroventricular injection of AF (0.1-0.4 mg) markedly and significantly reduced MAP. It is suggested that the hypotensive action of AF to be mediated by a central mechanism.     

Chronic effects of angiotensin II and at1 receptor antagonists in subfornical organ-lesioned rats

1. Angiotensin (Ang) II is known to exert some of its effects centrally via circumventricular organs. These unique central nervous system areas lack the normal blood-brain barrier and, therefore, allow peptide hormones access to the brain. Of these, the subfornical organ (SFO) has been shown to be involved in many of the acute dipsogenic and pressor effects of AngII, but much less is known about the role of the SFO in the chronic effects of AngII. We hypothesized that the SFO is a central site involved in the chronic hypotensive effects of endogenous AT(1) receptor blockade, as well as the chronic hypertensive effects of exogenously administered AngII. 2. In order to test these hypotheses, SFO-lesioned (SFOx) or sham Sprague-Dawley rats were instrumented with venous catheters and radiotelemetric pressure transducers for intravenous administration of losartan or AngII and continuous measurement of blood pressure and heart rate. Rats were given 3 days of saline control infusion (7 mL/day of 0.9% NaCl) and were then infused with either losartan (10 mg/kg per day) or AngII (10 ng/kg per min) for 10 days. 3. By day 4 of losartan treatment, arterial pressure had decreased 24 +/- 2 and 18 +/- 2 mmHg in sham (n = 9) and SFOx (n = 10) rats, respectively. Furthermore, by day 5 of AngII infusion, arterial pressure had increased 12 +/- 3 mmHg in sham rats (n = 9), but only by 4 +/- 1 mmHg in SFOx rats (n = 9). In each treatment group, these attenuated pressure responses in SFOx rats continued through day 10 of treatment. 4. These results support the hypotheses that the SFO plays a role in both the hypotensive effects of chronic AT(1) receptor blockade and the chronic hypertensive phase of exogenously administered AngII.     

Inhalation of the endothelin-A receptor antagonist LU-135252 at various doses in experimental acute lung injury

We studied the effects of the inhaled endothelin-A receptor antagonist LU-135252 at different doses on hemodynamics and gas exchange in an animal model of acute lung injury. Thirtysix piglets (27 +/- 1 kg) were anesthetized, mechanically ventilated (FiO2 1.0), and surfactant-depleted by repeated lung lavage. The animals were randomly assigned to receive either nebulized LU- 135252 for 30 minutes at a dose of 0.3 mg/kg (n = 12), or at a dose of 3.0 mg/kg (n = 12); n = 12 animals received no further treatment (Controls). Induction of acute lung injury decreased PaO2 from 566 +/- 8 mmHg to 53 +/- 2 mmHg (mean +/- SEM) and increased intrapulmonary shunt (QS/QT) from 13 +/- 1% to 57 +/- 2%. Inhalation of LU-135252 at either dose induced a significant and sustained increase in PaO2 (0.3 mg/kg: 349 +/- 39 mmHg; 3.0 mg/kg: 219 +/- 40 mmHg), and a significant decrease in QS/QT (0.3 mg/kg: 19 +/- 2%; 3.0 mg/kg: 27 +/- 3%) when compared with Controls (PaO2: 50 +/- 3 mmHg, QS/QT: 50 +/- 5%) (P < 0.05; values at 4 hours). Mean pulmonary artery pressure in LU-135252-treated animals (0.3 mg/kg: 31 +/- 2 mmHg; 3.0 mg/kg: 30 +/- 1 mmHg) was significantly lower than in Controls (40 +/- 2 mmHg), while there were no differences in mean arterial pressure and cardiac output. We conclude that inhalation of LU-135252 at either dose improved gas exchange and hemodynamics comparably, indicating that the lower dose was already sufficient to block the majority of endothelin-A receptors in ventilated regions of the injured lung.     

Effects of intravenous ABT-870 (iron (III)-hydroxide oligosaccharide) on mean arterial pressure and heart rate in the anaesthetized beagle: comparison with other iron-containing haematinic agents

Iron-deficiency anaemia, a complication of end-stage renal disease (ESRD), is often treated with parenteral iron therapies that have been shown to produce dose-limiting hypotension in patients. ABT-870 (iron-(III)-hydroxide-oligosaccharide) is comprised of elemental iron complexed with oligosaccharide, a composition that we hypothesised would allow the hypotensive effects of parenteral iron therapy to be overcome, thus allowing a rapid rate of infusion to be well tolerated. Mean arterial pressure (MAP) and heart rate (HR) were monitored in anaesthetized dogs following the infusion of ABT-870 and iron sucrose administered at doses of 7.1 and 21.3 mg/kg using a rapid 30 s infusion. ABT-870 and iron sucrose were also monitored at doses of 7.1, 21.3 and 50 mg/kg administered over a 10 min period. Sodium ferric gluconate complex (SFGC) was administered in an identical fashion at doses of 12.5 and 31.2 mg/kg. A 30 s rapid infusion of ABT-870 at doses of 7.1 and 14.3 mg/kg or a 10 min infusion of ABT-870 at doses of 7.1 and 21.3 mg/kg produced little effect on MAP and HR. Infusion of the highest dose of ABT-870 (50 mg/kg) produced no consistent hypotension, but did produce an increase in HR (maximal increase 35 +/- 9 b.p.m.), an effect that lasted only 15 min. A 30 s rapid infusion of iron sucrose at 7.1 mg/kg produced modest increases in MAP and HR (5 +/- 1 mmHg and 5 +/- 2 b.p.m., respectively). However, rapid infusion of iron sucrose at 14.3 mg/kg produced hypotension (to -8 +/- 1 mmHg below baseline) and exerted variable, biphasic effects on HR ranging from -16 to +50 b.p.m. Although 10 min infusion of iron sucrose at 7.1 mg/kg exerted little effect on MAP and HR, at doses of 21.3 and 50 mg/kg iron sucrose elicited a profound dose-dependent decrease in MAP (-34 +/- 11 and -83 +/- 5 mmHg, respectively) and a pronounced increase in HR ranging from 32 to 49 b.p.m. above baseline. A 10 min infusion of SFGC at doses of 12.5 and 31.2 mg/kg produced a dose-dependent decrease in MAP (-28 +/- 18 and -67 +/- 12 mmHg below baseline) and a marked increase in HR (26 +/- 11 and 94 +/- 15 b.p.m. above baseline). In conclusion, unlike iron sucrose and SFGC, high doses of ABT-870 failed to exert consistent hypotensive effects. These data demonstrate that ABT-870 may have a substantial therapeutic window and considerable clinical potential for iron-replacement therapy.     

Comparisons of the depressor, inotropic and renal effects of milrinone and CI-930 to different pure vasodilators and diuretics in conscious instrumented dogs.

The cardiovascular and renal effects of graded i.v. dosages of two low Km cAMP cGMP-inhibitable (cGi) phosphodiesterase (PDE) inhibitors: CI-930 and milrinone (both 10-300 micrograms/kg), and three pure vasodilators: fenoldopam (0.1-3 micrograms/kg), Na nitroprusside (3-100 micrograms/kg) and hydralazine (0.1-3 mg/kg), were compared in conscious dogs. Mean arterial pressure was decreased by CI-930 at 0.3 mg/kg, milrinone at doses greater than or equal to 0.1 mg/kg (both by approximately -17 mmHg [max. change]), nitroprusside at doses greater than or equal to 0.01 mg/kg (-60 +/- 5 mmHg, [mean +/- SEM, max. change]), fenoldopam at doses greater than or equal to 0.001 mg/kg, and hydralazine at all doses (both by approximately -26 mmHg). Heart rate was increased by milrinone and CI-930 at dosages greater than or equal to 0.03 mg/kg (both by approximately 57 beats/min), nitroprusside and hydralazine at all dosages (54 +/- 18 and 91 +/- 18 beats/min, respectively) and fenoldopam at 3 micrograms/kg (21 +/- 2 beats/min). The cGi PDE inhibitors at 0.01-0.3 mg/kg and the pure vasodilators (except fenoldopam) at all dosages increased dP/dt (approximately 1500 and 900 mmHg/s, respectively). Milrinone (greater than or equal to 0.1 mg/kg), CI-930 (greater than or equal to 0.03 mg/kg), nitroprusside (greater than or equal to 0.01 mg/kg) and hydralazine (0.3-1 mg/kg) decreased left ventricular end diastolic pressure (all by approximately -4 mmHg). None of the agents adversely affected urinary volume, Na+ and K+ excretion rates. In conclusion, all agents (except fenoldopam) induced positive inotropic and chronotropic effects, and preload and afterload reduction. The cardiac effects of the pure vasodilators may be reflexly induced, whereas those of the cGi PDE inhibitors may be primarily due to inhibition of cardiac cGi PDE.     

Central noradrenergic neurones and the cardiovascular actions of clonidine in the rabbit

1. Clonidine (1 mug/kg), given by intracisternal injection to anaesthetized rabbits, lowered mean arterial blood pressure by 33 mmHg and heart rate by 32 beats/min.2. In animals pre-treated with 6-hydroxydopamine (6-OHD 500 mug/kg intracisternally) 7-10 days before, intracisternal clonidine (1 mug/kg) reduced mean arterial blood pressure by only 2.5 mmHg and heart rate by 4 beats/minute.3. The hypotensive action of intravenous clonidine was reduced to 49% of control by pre-treatment with intracisternal 6-OHD. In unanaesthetized normal animals intravenous clonidine (30 mug/kg) lowered mean arterial blood pressure by 19.3 mmHg, while after 6-OHD it fell only 9.4 mmHg.4. These studies suggest that the central hypotensive effect of clonidine is dependent on the integrity of central monoaminergic neurones.     

Effects Of L-Arginine And Furosemide On Blood Pressure And Renal Function In Volume-Expanded Rats

1. The aim of the present study was to investigate the effects of L-arginine (L-Arg) on blood pressure and water and electrolyte excretion in control and extracellular fluid volume-expanded rats (10% bodyweight with 0.9% NaCl) and to determine whether diuretic treatment with furosemide (FUR) can be optimized by the administration of L-Arg in this model. 2. Both groups of animals were anaesthetized, divided into groups and treated with either 7.5 mg/kg FUR, 250 mg/kg L-Arg, 1 mg/kg NG-nitro-L-arginine methyl ester (L-NAME), FUR + L-NAME or FUR + L-Arg. Mean arterial pressure (MAP), diuresis, natriuresis and kaliuresis were determined. 3. Extracellular fluid volume expansion induced no changes in MAP in control and volume-expanded rats (92+/-6 vs 100+/-8 mmHg, respectively). The hypotension induced by FUR in control and volume-expanded rats (69+/-7 and 76+/-5 mmHg, respectively) was significantly (P < 0.01) enhanced by the administration of L-Arg (54+/-3 and 64+/-3 mmHg, respectively). 4. Injection of L-NAME increased MAP and diminished diuresis, natriuresis and kaliuresis in both groups. 5. Furosemide-induced water and electrolyte excretion was blunted by the administration of L-NAME. 6. The combination of L-Arg + FUR increased diuresis induced by FUR alone (control rats: 29.33+/-1.68 vs 12.91+/- 0.41 microL/min per 100 g, respectively; volume-expanded rats: 248.5+/-25.4 vs 112,6+/-8.3 microL/min per 100 g, respectively; P < 0.01). 7. The administration of the combination of L-Arg + FUR promoted a decrease in the sodium/water excretion ratio compared with the administration of FUR alone (control rats: 0.230+/-0.018 vs 0.45+/-0.03, respectively, P < 0.001; volume-expanded rats: 0.091+/-0.010 vs 0.22+/-0.03, respectively, P < 0.01). 8. The potassium/water excretion rate induced by FUR alone and in the presence of L-Arg followed a pattern similar to that seen for natriuresis (control rats: 0.35+/-0.05 vs 0.20+/-0.05 microEq/min per 100 g, respectively; volume-expanded rats: 0.045+/-0.008 vs 0.014+/-0.003 microEq/min per 100 g, respectively; P < 0.01). 9. The decrease in the electrolyte/water excretion ratio observed with FUR + L-Arg in volume-expanded rats was greater than in control animals. 10. The results of the present study show that the administration of FUR with L-Arg contributes to enhanced hypotensive and diuretic effects of FUR, thus diminishing the relative electrolyte excretion in normal conditions and in extracellular fluid volume expansion.     

Effects of endothelin receptor antagonism with bosentan on peripheral nerve function in experimental diabetes.

1. The effects of the non-selective endothelin (ET) receptor (ETA/ETB) antagonist, bosentan, on sciatic nerve dysfunction in experimental diabetes were investigated. 2. Rats with 5-6 weeks untreated streptozotocin-diabetes exhibited characteristic slowed motor nerve conduction velocity (mean +/- s.d., 36.6 +/- 3.4 m s-1) and nerve laser Doppler flux (197 +/- 64 arbitrary units) compared to age-matched control animals (42.7 +/- 2.4 m s-1 and 398 +/- 77 arbitrary units, respectively). Preventative treatment of diabetic rats with bosentan at 100 mg kg-1 day-1 p.o. attenuated both these deficits (39.7 +/- 3.0 m s-1 and 305 +/- 56 arbitrary units, respectively) without affecting mean arterial pressure. 3. In control and untreated diabetic rats, ET-1, 1 nmol kg-1 i.v., caused an initial hypotension (duration, 30 +/- 13 and 26 +/- 9 s, respectively; change in mean arterial pressure, -27 +/- 13 and -25 +/- 7 mmHg, respectively) followed by prolonged hypertension (change in mean arterial pressure, 52 +/- 18 and 31 +/- 5 mmHg, respectively). Effectiveness of the chronic bosentan treatment was demonstrated by inhibition of the hypotensive response to ET-1 in treated diabetic rats (duration, 5 +/- 2 s; change in mean arterial pressure, -4 +/- 2 mmHg) although the hypertension was unaltered (change in mean arterial pressure, 32 +/- 9 mmHg). 4. Acute i.v. administration of 10 mg kg-1 bosentan caused variable and transient rises in nerve laser Doppler flux in control (78 +/- 63 arbitrary units) and untreated diabetic rats (93 +/- 77 arbitrary units).(ABSTRACT TRUNCATED AT 250 WORDS)