Role of bradykinin in hypertension and the antihypertensive effect of angiotensin-converting enzyme inhibitors.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
I Gavras
Publications and source records attributed to I Gavras.
Renin-angiotensin and vasopressin in the development of salt-induced hypertension.
The purpose of this study was to assess the participation and interaction of the renin-angiotensin system and vasopressin in the early stages of the development of salt-induced hypertension. Subtotally nephrectomized rats, fed 1% saline, were treated over a 10-day period with either an antivasopressor V1 antagonist (by osmotic minipump) or an angiotensin converting enzyme inhibitor (either captopril or ramipril, given daily by oral gavage), or a combination of the two modes of treatment. Surprisingly, only ramipril (either alone or in combination with the V1 antagonist) could prevent the development of hypertension in these animals. Our data would not permit conclusion as to whether the different capacity of these agents to prevent salt-induced hypertension was due to a different degree of penetration into the central nervous system, or to some other property.
Angiotensin-Converting Enzyme Inhibitors↗
The role of vasopressin in blood pressure maintenance in diabetic orthostatic hypotension.
The purpose of these studies was to assess the role of vasopressin in maintaining supine and upright blood pressures in hypertensive diabetic subjects. Patients with (n = 6) or without (n = 10) evidence of autonomic insufficiency had blood pressure and heart rate monitored before and after receiving an intravenous injection of 0.5 mg of a V1 vasopressin inhibitor. None of the patients had supine changes in blood pressure or heart rate. However, upon assuming the erect position, the six patients with preexisting orthostatic hypotension had an average blood pressure fall of 44 mm Hg after vasopressin inhibition (as opposed to 20 mm Hg before), accompanied by a modest rise in heart rate of 20 beats/min. Those without autonomic dysfunction were separated into two subgroups. Four developed an average fall in orthostatic blood pressure of 18 mm Hg after vasopressin inhibition, whereas the remaining six had no change. There were no distinguishing hormonal characteristics (vasopressin, renin, and catecholamine levels) between the groups, but in the patients with autonomic dysfunction, the renin level failed to rise when upright. We conclude that vasopressin plays an important role in preventing or minimizing orthostatic hypotension in diabetic patients. Its pressor contribution is crucial in those with autonomic insufficiency and impaired renin and sympathetic responses, in whom the pressor effectiveness of vasopressin is greatly enhanced.
Arginine Vasopressin↗
Angiotensin converting enzyme inhibitors. Properties and side effects.
The purpose of this brief review is to separate the characteristic properties and side effects attributable to the pharmacology of the whole class of angiotensin converting enzyme (ACE) inhibitors from those attributable to the chemical structure and kinetics of each particular ACE inhibitor. The former would be predictable and probably similar for all agents and, therefore, would be expected to recur with each agent, whereas the latter are likely to be characteristic of individual compounds and may be avoidable by changing to another compound with similar pharmacology but different molecular structure.
Angiotensin-Converting Enzyme Inhibitors↗
Vascular and sympathoadrenal responses to bradykinin and a bradykinin analogue.
These experiments were designed to assess the interaction of bradykinin and its antagonist (Arg-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg-trifluoroacetic acid) with the sympathoadrenal system. Three groups of male Wistar rats received 5-minute intra-arterial infusions of either dextrose (Group 1, n = 6), bradykinin, 250 micrograms/min (Group 2, n = 5), or bradykinin, 25 micrograms/min (Group 3, n = 4). Six other groups received a similar infusion of the bradykinin antagonist at 250 micrograms/min. They were either intact rats (Group 4, n = 10) or rats previously submitted to chemical sympathectomy (Group 5, n = 17), to adrenal enucleation (Group 6, n = 8), to combined alpha-adrenergic and beta-adrenergic blockade (Group 7, n = 7), to alpha 1-adrenergic receptor blockade (Group 8, n = 8), or to alpha 2-adrenergic receptor blockade (Group 9, n = 8). Bradykinin infusion produced a sustained fall in mean arterial pressure (MAP) in Groups 2 and 3 (by -48 +/- 3 and -36 +/- 7 mm Hg, respectively) associated with similar increases in plasma epinephrine levels (100-fold), and norepinephrine (sevenfold) as compared with Group 1. The bradykinin antagonist infusion in intact rats produced a 23 +/- 4 mm Hg rise in MAP associated with a sixfold increase in epinephrine and a twofold increase in norepinephrine. Group 5 rats with lower baseline catecholamine levels had an even larger MAP rise (30 +/- 6 mm Hg) accompanied by a rise in epinephrine and norepinephrine proportionally similar to that of intact animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Antagonists↗
Anti-hormones and blood pressure: bradykinin antagonists in blood pressure regulation.
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Animals↗
Antihypertensive effectiveness of the nifedipine gastrointestinal therapeutic system.
The results of a multicenter trial conducted in order to determine the therapeutic efficacy of the gastrointestinal therapeutic system (GITS) formulation of nifedipine in comparison with hydrochlorothiazide and placebo in the management of mild to moderate essential hypertension are presented. During a one-week wash-out phase, antihypertensive therapy was discontinued in all patients. After a three-week single-blind placebo period, eligible patients were randomly assigned in a double-blind fashion to one of three treatment groups for a one-week titration period and a nine-week efficacy period. Patients received either nifedipine GITS, 30 or 60 mg daily; hydrochlorothiazide, 25 or 50 mg daily; or placebo. Sitting and standing blood pressures decreased by an average 11.6/10.4 and 10.8/10.8 mm Hg, respectively, with nifedipine GITS therapy, and 14.8/10.8 and 14.3/8.2 mm Hg, respectively, with hydrochlorothiazide therapy. Compared with placebo, these changes were highly significant for both sitting (p less than or equal to 0.005) and standing (p less than or equal to 0.02) measurements. Heart rate remained essentially unchanged in all three groups. It was therefore concluded that monotherapy with nifedipine GITS, at doses of 30 or 60 mg given once daily, effectively reduces blood pressure in patients with hypertension to a degree comparable with that seen in hydrochlorothiazide therapy.
Adult↗
Stimulation of vasopressin by calcium microinjections in the area of the paraventricular nucleus of the hypothalamus.
The present experiments were designed to investigate the effect of local calcium application on the paraventricular nucleus (PVN) on arginine-vasopressin (AVP) release and blood pressure. A microinjection of 2 microliter of calcium gluconate 10% in the PVN elevated AVP levels to 71.6 +/- 8.7 pg/ml compared to 3.3 +/- 0.6 pg/ml in control rats receiving iso-osmolar solution of dextrose 11% (P less than 0.001), whereas peripheral plasma epinephrine and norepinephrine were normal. Despite the increase of plasma AVP levels, blood pressure and heart rate remained unchanged indicating that other unknown mechanisms counteract AVP's pressor effect. These data suggest that locally applied Ca2+ in the vasopressinergic neurons of the hypothalamus strongly stimulates the release of AVP.
Animals↗
Central catecholamines and alpha-adrenoceptors in acute hypertension induced by intracerebroventricular hypertonic saline.
We measured the tissue content of catecholamines and the numbers and affinities of alpha 1- and alpha 2-adrenergic receptors in specific areas of the hypothalamus and medulla oblongata of rats treated with intracerebroventricular microinjection of hypertonic saline, in comparison to controls treated with an equal volume of iso-osmolar dextrose solution. Rats given 20 microliter of 4% NaCl into the lateral ventricle showed an average rise in blood pressure of 14 +/- 2 mmHg and a decrease in heart rate of 63 +/- 11 beats/min (P less than 0.001 for both), associated with dopamine suppression in the anteroventral area of the third ventricle (AV3V) and increased concentrations of dopamine in the C2 region of the medulla and of epinephrine in the area postrema. Affinities of medullary alpha 2-adrenoceptors were decreased in the saline-treated rats, whereas the number of receptors tended to be higher. It is suggested that sodium may produce its pressor effect by diminishing the affinity of central alpha 2-adrenoceptors for neurotransmitters, resulting in disinhibition of certain sympathoinhibitory neurons and increased sympathetic outflow.
Animals↗
Contribution of bradykinin to maintenance of normal blood pressure.
The purpose of these experiments was to investigate whether the vasodilator tissue hormone bradykinin contributes to the maintenance of normal blood pressure. A newly synthesized peptide competitive antagonist of bradykinin, the compound Arg-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg-trifluoracetic acid (B3852), capable of inhibiting the depressor effect of exogenous bradykinin by over 50%, was infused into 10 normotensive rats at a rate of 500 micrograms/0.1 ml/min. Blood pressure rose immediately, from a baseline of 104 +/- 5 to 131 +/- 7 mm Hg at the end of a 5-minute infusion, and returned to baseline within 2 to 3 minutes after discontinuation of the infusion. When similar doses were administered by continuous infusion to previously nephrectomized rats (n = 5) or as an acute bolus to adrenalectomized rats (n = 5), blood pressure rose from 111 +/- 3 to 125 +/- 5 mm Hg and from 112 +/- 4 to 128 +/- 5 mm Hg, respectively. The data suggest that a vasodepressor action of endogenous bradykinin contributes to maintenance of normal peripheral vascular tone, and that this action is not mediated through adrenal catecholamines or renomedullary prostaglandins.
Animals↗
Vasopressin in end-stage renal disease: relationship to salt, catecholamines and renin activity.
The blood pressure changes and behavior of vasoactive hormones after various stimuli were studied in eighteen patients with end-stage renal disease maintained on chronic hemodialysis. Group A patients (n = 9) were not subject to intra- or post-dialysis hypotensive episodes, and Group B (n = 9) frequently had such episodes. A 500 ml hypertonic saline infusion produced no change in blood pressure in either group, despite significant rise of vasopressin levels in both. Plasma renin activity levels were similar and became appropriately suppressed by the infusion in both groups, whereas norepinephrine rose significantly only in Group A, but not Group B where it was already higher at baseline. The regular dialysis session produced, as expected, a significantly more profound hypotensive effect in Group B, but was accompanied in both groups by decrease in vasopressin and increase in plasma renin activity. Norepinephrine change differed in the two groups: it decreased in Group A as expected from its capacity to be dialyzed, but rose in several hypotensive patients in Group B, indicating appropriate response to baroreceptor stimulation and leading to an unchanged average. These findings suggest that dialysis-induced hypotensive episodes are not necessarily associated with autonomic neuropathy or with abnormal patterns of vasopressor hormone response to stimuli. They also shed new light on the factors regulating vasopressin secretion under these circumstances, since they indicate that the osmoreceptor and/or sodium-sensitive receptor may be a more dominant mechanism in the regulation of vasopressin release than the volumetric mechanism responding to fluid volume changes.
Adult↗
The antihypertensive contribution of bradykinin as assessed by a specific bradykinin antagonist.
A new specific antagonist of bradykinin was used to examine the contribution of bradykinin to the depressor effect of different antihypertensive drugs in two-kidney renovascular rats. First we tested the inhibitory capacity of this peptide for exogenously injected bradykinin (75-200 ng). An inhibition of the vasodepressor action of bradykinin by over 50% was found when the bradykinin inhibitor was infused at a rate of 40 micrograms/min, with little difference at higher rates of infusion. We then infused this inhibitor in four groups of renovascular hypertensive rats. In three groups the blood pressure had been decreased by pretreatment either with the converting enzyme inhibitor MK 421, saralasin or sodium nitroprusside, respectively. The fourth group received no pretreatment. Infusion of the inhibitor produced an immediate increase in blood pressure by 30% only in the MK 421 group, but no change in the three other groups. These results indicate that bradykinin is involved in the decrease of blood pressure produced by converting enzyme inhibition in experimental renovascular hypertension.
Animals↗
Efficacy and tolerability of enalapril monotherapy in mild-to-moderate hypertension in older patients compared to younger patients.
In an eight-week, multicenter open-label study of enalapril monotherapy for mild-to-moderate essential hypertension, data for 115 of the 276 participants between the ages of 55 and 75 years (whites, n = 90; blacks, n = 25) were analyzed. These data were compared with similar data for the study subset of 92 younger patients between the ages of 21 and 45 years (whites, n = 58; blacks, n = 34). The most striking finding was the overall lack of significant differences in response between older and younger patients. There were, however, significant differences in response to therapy between the two racial groups studied. In the older group, normotension was achieved in 66% of white patients and 60% of black patients with a single daily dose of enalapril ranging from 5 to 40 mg; the group means, 13 +/- 1 mg in whites vs 22 +/- 2 mg in blacks, differed significantly (P less than 0.05). Thirty-one percent of older white patients attained normotension with a daily dosage of 5 mg, whereas only 4% of black patients in this age group did so. Only 4% of the older white patients but 24% of the older black patients reached the highest recommended daily dosage of 40 mg of enalapril. Adverse reactions occurred in 11% of the older white patients and 16% of the older black patients (a nonsignificant difference), consisting mostly of gastrointestinal discomfort, malaise, dizziness, and pruritus. There were no significant biochemical abnormalities, the only consistent change being a slight increase in mean plasma potassium from 4.34 to 4.45 mEq/L in older whites (P less than 0.05). Enalapril appeared to be generally effective and well tolerated in the management of mild-to-moderate hypertension in the older subset of patients in this study. Efficacy and tolerability data for older and younger patients were comparable.
Adult↗
Double-blind, placebo-controlled trial of twice-daily nifedipine as a step-2 agent in mild essential hypertension.
Nifedipine is a calcium-channel blocker that produces vasodilatation and decreased peripheral resistance in humans. Several clinical reports document blood-pressure-lowering effects of nifedipine with either acute or chronic administration. Little data are available to evaluate sustained-release nifedipine as a step-2 agent. We performed a multicenter double-blind, placebo-controlled trial of twice-daily nifedipine in the treatment of mild essential hypertension not controlled by diuretic alone. Seventy-one subjects completed 8 weeks of treatment with nifedipine or placebo in combination with a stable dose of diuretic. Treatment groups were comparable with respect to age, sex, race, duration of hypertension, and pretreatment weight. Baseline supine blood pressure was no different in the two treatment groups (144 +/- 15/98 +/- 6 mmHg in the nifedipine/diuretic-treated group and 145 +/- 16/98 +/- 6 mmHg in the placebo/diuretic-treated group). After 8 weeks of treatment, supine blood pressure was 132 +/- 11/88 +/- 6 mmHg in the nifedipine/diuretic-treated group and 140 +/- 16/92 +/- 8 mmHg in the placebo/diuretic-treated subjects (p less than 0.01 for both systolic and diastolic blood pressure when compared to placebo/diuretic). Nifedipine with diuretic had similar effects on standing blood pressure. Nifedipine/diuretic decreased blood pressure from baseline values within 1 week of treatment, and the effect persisted for 8 weeks. Heart rate increased in nifedipine/diuretic-treated subjects during the first 2 weeks of treatment but returned to baseline by 4 weeks. No laboratory abnormalities could be attributed to nifedipine/diuretic treatment. Side effects were mild and infrequent. In summary, nifedipine/diuretic is effective and well tolerated in the treatment of uncomplicated essential hypertension inadequately controlled with diuretic therapy alone.
Adult↗
[Clinical management of hypertension in the elderly].
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Aged↗
Clinical management of hypertension in the elderly.
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Aged↗
Clinical utility of angiotensin converting enzyme inhibitors in hypertension.
Oral angiotensin converting enzyme inhibition was introduced eight years ago and is becoming increasingly popular for the treatment of hypertension and congestive heart failure. This treatment causes blood pressure lowering associated with suppression of angiotensin and aldosterone, lack of orthostatic hypotension or metabolic disturbances, redistribution of regional blood flows in favor of vital organs and, in the long term, decreased sympathetic drive and regression of left ventricular hypertrophy. It is effective as monotherapy in more than 50 percent of unselected patients; addition of a diuretic increases the percentage of responders to more than 80 percent. It is the treatment of choice for patients with concurrent diabetes, asthma, gout, depression, or very active life-style. Side effects, observed originally in patients with severe hypertension and renal failure treated with very high doses of captopril, are rare in otherwise healthy hypertensive patients receiving smaller doses of this drug and virtually absent with second-generation angiotensin converting enzyme inhibitors like enalapril.
Administration, Oral↗
Norepinephrine applied in the paraventricular hypothalamic nucleus stimulates vasopressin release.
The present experiments were designed to investigate the effect of norepinephrine (NE) applied directly in the area of the paraventricular nucleus (PVN) of the hypothalamus on arginine-vasopressin (AVP) release and blood pressure. A microinjection of 0.4 micrograms NE in the PNV produced a plasma AVP level of 26.3 +/- 5.3 pg/ml compared to 5.3 +/- 0.6 pg/ml in controls receiving dextrose (P less than 0.001). This rise was associated with blood pressure elevations varying between 10 and 13 mm Hg, lasting for about 5 min. Systemic injection of an antivasopressor AVP antagonist reversed or prevented the blood pressure rise induced by NE microinjection. The data suggest that locally applied NE in vasopressinergic neurons of the hypothalamus stimulates the release of AVP and induces an AVP-dependent rise in blood pressure.
Animals↗