RESUMO
BACKGROUND AND PURPOSE: Diabetes causes sensory polyneuropathy with associated pain in the form of tactile allodynia and thermal hyperalgesia which are often intractable and resistant to current therapy. This study tested the beneficial effects of the non-peptide and orally active kinin B(1) receptor antagonist SSR240612 against tactile and cold allodynia in a rat model of insulin resistance. EXPERIMENTAL APPROACH: Rats were fed with 10% D-glucose for 12 weeks and effects of orally administered SSR240612 (0.3-30 mg kg(-1)) were determined on the development of tactile and cold allodynia. Possible interference of SSR240612 with vascular oxidative stress and pancreatic function was also addressed. KEY RESULTS: Glucose-fed rats exhibited tactile and cold allodynia, increases in systolic blood pressure and higher plasma levels of insulin and glucose, at 12 weeks. SSR240612 blocked tactile and cold allodynia at 3 h (ID(50)=5.5 and 7.1 mg kg(-1), respectively) in glucose-fed rats but had no effect in control rats. The antagonist (10 mg kg(-1)) had no effect on plasma glucose and insulin, insulin resistance (HOMA index) and aortic superoxide anion production in glucose-fed rats. CONCLUSIONS AND IMPLICATIONS: We provide the first evidence that the B(1) receptors are involved in allodynia in an experimental rat model of insulin resistance. Allodynia was alleviated by SSR240612 most likely through a direct inhibition of B(1) receptors affecting spinal cord and/or sensory nerve excitation. Thus, orally active non-peptide B(1) receptor antagonists should have clinical therapeutic potential in the treatment of sensory polyneuropathy.
Assuntos
Analgésicos não Narcóticos/uso terapêutico , Antagonistas de Receptor B1 da Bradicinina , Dioxóis/uso terapêutico , Hiperalgesia/tratamento farmacológico , Resistência à Insulina/fisiologia , Dor/tratamento farmacológico , Sulfonamidas/uso terapêutico , Animais , Aorta Torácica/metabolismo , Glicemia/análise , Temperatura Baixa , Modelos Animais de Doenças , Temperatura Alta , Insulina/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , Dor/metabolismo , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , TatoRESUMO
Nisoldipine, a calcium entry blocker, was given to 10 patients with congestive heart failure. During a 2 month follow-up period, 7 of the 10 patients were readmitted with pulmonary edema; daily furosemide doses were increased (128 +/- 87 to 192 +/- 135 mg/day, p less than 0.01), and plasma creatinine increased (1.5 +/- 0.5 to 1.8 +/- 0.6 mg/dl, p less than 0.05) (all values mean +/- SD). Despite this unfavorable clinical course, nisoldipine caused some beneficial chronic (1 month) hemodynamic effects. It decreased systemic vascular resistance (from 1,781 +/- 229 to 1,306 +/- 345 dynes X s X cm-5, p less than 0.01), decreased mean arterial pressure (from 88 +/- 0 to 74 +/- 4 mm Hg, p less than 0.001) and increased stroke volume index (from 27 +/- 6 to 33 +/- 9 ml/min per m2, p less than 0.02). Heart rate, pulmonary capillary wedge pressure and stroke work index did not change. However, nisoldipine's chronic renal and neurohumoral effects were not as favorable. These were assessed during a 5 hour water load (15 ml/kg body weight of 5% dextrose in water) and compared with the effects of a water load before therapy. Nisoldipine did not change creatinine clearance or sodium excretion, but decreased water excretion (from 58 +/- 35 to 46 +/- 40% of water load in 5 hours). Over this 5 hour study, mean plasma vasopressin was also higher with nisoldipine (1.9 +/- 2.3 versus 2.7 +/- 3.2 pg/ml, p less than 0.05), but mean plasma aldosterone was lower (67 +/- 31 to 47 +/- 27 mg/dl, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Rim/efeitos dos fármacos , Neurotransmissores/metabolismo , Nifedipino/análogos & derivados , Água Corporal/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Nifedipino/efeitos adversos , Nifedipino/uso terapêutico , Nisoldipino , Fatores de TempoRESUMO
OBJECTIVES: This study was conducted to evaluate the degree of neurohumoral activation around the time of hospital discharge after myocardial infarction. BACKGROUND: Because pharmacologic interventions that block the effects of neurohumoral activation improve the prognosis after infarction, we hypothesized that widespread neurohumoral activation persists in some patients until at least the time of hospital discharge and that the determinants of activation vary from one system to another. METHODS: Five hundred nineteen patients in the Survival and Ventricular Enlargement Study (SAVE) had plasma neurohormones measured before randomization at a mean of 12 days after infarction. All patients had left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt heart failure. RESULTS: Although all neurohormones except epinephrine were increased compared with values in age-matched control subjects, plasma norepinephrine (301 +/- 193 vs. 222 +/- 87 pg/ml, p < 0.001), renin activity (3.0 +/- 3.7 vs. 1.2 +/- 1.2 ng/ml per h, p < 0.001), arginine vasopressin (1.9 +/- 6.9 vs. 0.7 +/- 0.3 pg/ml, p < 0.001) and atrial natriuretic peptide (75 +/- 75 vs. 21 +/- 9 pg/ml, p < 0.001) values ranged from normal to very high, indicating a wide spectrum of neurohumoral activation. Activation of one system did not correlate with activation of another. The clinical and laboratory variables most closely associated with neurohumoral activation were Killip class, left ventricular ejection fraction, age and use of diuretic drugs. The association between neurohumoral activation and clinical and laboratory variables varied from one neurohormone to another. CONCLUSIONS: Neurohumoral activation occurs in a significant proportion of patients at the time of hospital discharge after infarction. Which neurohormone is activated and which clinical and laboratory variables determine this activation vary from one neurohormone to another.
Assuntos
Baixo Débito Cardíaco/fisiopatologia , Infarto do Miocárdio/sangue , Neurotransmissores/sangue , Função Ventricular Esquerda , Idoso , Aldosterona/sangue , Fator Natriurético Atrial/sangue , Baixo Débito Cardíaco/sangue , Dopamina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Neurotransmissores/metabolismo , Norepinefrina/sangue , Renina/sangue , Volume Sistólico , Vasopressinas/sangueRESUMO
OBJECTIVES: This study attempted to evaluate whether neurohumoral activation at the time of hospital discharge in postinfarction patients helps to predict long-term prognosis and whether long-term therapy with the angiotensin-converting enzyme inhibitor captopril modifies this relation. BACKGROUND: Neurohumoral activation persists at the time of hospital discharge in a large number of postinfarction patients. The Survival and Ventricular Enlargement (SAVE) study demonstrated that the angiotensin-converting enzyme inhibitor captopril improves survival and decreases the development of severe heart failure in patients with left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt postinfarction heart failure. METHODS: In 534 patients in the SAVE study, plasma neurohormone levels were measured a mean of 12 days after infarction. Patients were then randomized to receive captopril or placebo and were followed up for a mean (+/- SD) of 38 +/- 6 months (range 24 to 55). The association between activation of plasma neurohormones at baseline and subsequent cardiovascular mortality or the development of heart failure was assessed with and without adjustment for other important prognostic factors. RESULTS: By univariate analysis, activation of plasma renin activity and aldosterone, norepinephrine, atrial natriuretic peptide and arginine vasopressin levels were related to subsequent cardiovascular events, whereas epinephrine and dopamine levels were not. By multivariate analysis, only plasma renin activity (relative risk 1.6, 95% confidence interval [CI] 1.0 to 2.5) and atrial natriuretic peptide (relative risk 2.2, 95% CI 1.3 to 3.8) were independently predictive of cardiovascular mortality, whereas the other neurohormones were not. Only plasma renin activity and aldosterone, atrial natriuretic peptide and arginine vasopressin were independent predictors of the combined end points of cardiovascular mortality, development of severe heart failure or recurrent myocardial infarction. Except for 1-year cardiovascular mortality, the use of captopril did not significantly modify these relations. CONCLUSIONS: Neurohumoral activation at the time of hospital discharge in postinfarction patients is an independent sign of poor prognosis. This is particularly true for plasma renin activity and atrial natriuretic peptide. Except for 1-year cardiovascular mortality, captopril does not significantly modify these relations.
Assuntos
Captopril/uso terapêutico , Infarto do Miocárdio/sangue , Neurotransmissores/sangue , Idoso , Aldosterona/sangue , Análise de Variância , Arginina Vasopressina/sangue , Fator Natriurético Atrial/sangue , Canadá , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/mortalidade , Norepinefrina/sangue , Prognóstico , Modelos de Riscos Proporcionais , Renina/sangueRESUMO
STUDY OBJECTIVE: The aim was to study the occlusion time dependency of reperfusion induced increases in regional cardiac noradrenaline release from the ischaemic area in relation to the incidence of ventricular arrhythmias. DESIGN: The left anterior descending coronary artery was ligated for 15, 30 and 60 min in three separate groups of dogs (n = 10 per group). Each occlusion period was followed by a 30 min reperfusion period. The coronary sinus and the epicardial vein running in parallel with the left anterior descending coronary artery were cannulated for measurement of noradrenaline and lactate. EXPERIMENTAL MATERIAL: 30 adult mongrel dogs, 22.5(SEM 1.1) kg, were used for the study. The animals were anaesthetised with sodium pentobarbitone. MEASUREMENTS AND MAIN RESULTS: During occlusion, epicardial venous blood noradrenaline concentrations remained unchanged up to 30 min, but increased from 0.133(0.027) ng.ml-1 to 0.289(0.069) ng.ml-1 after 60 min of occlusion (p less than 0.05). However, epicardial venous blood lactate concentrations increased immediately upon occlusion, and remained elevated (p less than 0.05) during the whole period of occlusion in all groups. Neither noradrenaline nor lactate concentrations in coronary sinus blood increased during occlusion. During reperfusion, nine dogs showed early ventricular fibrillation. The highest incidence of fibrillation (n = 5/10) was found in the 15 min occlusion group, but the difference was not significant between groups. Epicardial venous blood noradrenaline concentrations increased to 0.371(0.076) ng.ml-1, 0.470(0.178) ng.ml-1, and 1.824(0.713) ng.ml-1 upon reperfusion following 15, 30 and 60 min occlusion, respectively (each p less than 0.05). Maximum increases in epicardial venous blood noradrenaline concentrations during reperfusion were correlated with duration of preceding occlusion (r = 0.60, n = 21, p less than 0.01). Maximum increases in mean arrhythmic ratios observed during the first 10 min of reperfusion were proportionally related to mean epicardial venous blood noradrenaline concentrations. The increases in epicardial venous blood noradrenaline concentrations and the incidence of ventricular arrhythmias in the 60 min occlusion group were greater (p less than 0.05) than in the other two groups. CONCLUSIONS: This study shows that noradrenaline is released progressively from the ischaemic area during occlusion for 60 min. The amount of noradrenaline washed out upon reperfusion and the incidence of reperfusion ventricular arrhythmias both appear to be dependent upon duration of preceding occlusion. The results suggest that cardiac noradrenaline released locally from the ischaemic region may contribute to the genesis of reperfusion ventricular arrhythmias, but not to that of reperfusion ventricular fibrillation.
Assuntos
Arritmias Cardíacas/sangue , Doença das Coronárias/sangue , Norepinefrina/sangue , Animais , Doença das Coronárias/etiologia , Vasos Coronários , Cães , Ventrículos do Coração , Lactatos/sangue , Ácido Láctico , Ligadura , Modelos Cardiovasculares , Reperfusão Miocárdica , Fatores de Tempo , Fibrilação Ventricular/sangueRESUMO
OBJECTIVE: In the present studies, we have investigated if aorta, like heart from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, (HR) also exhibit enhanced expression of G-protein levels and if these alterations occur before or after the development of blood pressure. METHODS: Sprague-Dawley rats treated with DOCA-salt or vehicle for 1, 2, 3 and 4 weeks were used for these studies. The levels of inhibitory guanine nucleotide regulatory proteins (Gi alpha-2, Gi alpha-3) and G beta proteins were determined by immunoblotting, whereas the levels of Gi alpha-2 and Gi alpha-3 and adenylyl cyclase type V enzyme mRNA were determined by Northern-blotting techniques. RESULTS: The blood pressure was significantly increased in DOCA-salt-treated rats as compared to sham-operated rats after 2 to 4 weeks of treatment; whereas no change in blood pressure was observed after 1 week of treatment (prehypertensive state). However, the levels of Gi alpha-2, Gi alpha-3 and G beta proteins and Gi alpha-2 and Gi alpha-3 mRNA were significantly enhanced in hearts and aorta from DOCA-salt treated rats after 1 week of treatment and remained elevated up to 4 weeks of treatment. In addition, the Gi-mediated inhibitions of adenylyl cyclase by Angiotensin II (Ang II) and C-ANF4-23 were also greater in DOCA-salt-treated rats as compared to sham-operated rats after 1 week and longer periods of treatments (2 to 4 weeks). On the other hand, the levels of Gs alpha were not altered up to 2 weeks of DOCA-salt treatment but significantly decreased in rats treated for 3 and 4 weeks. Furthermore, the stimulatory effects of guanine 5'-[gamma-thio]triphosphate (GTP gamma S), isoproterenol and forskolin on adenylyl cyclase were decreased in both hearts and aorta from DOCA-salt-treated rats after 1 to 4 weeks of treatment as compared to sham-operated rats. The mRNA levels of adenylyl cyclase, type V enzyme in hearts from DOCA-salt treated rats were significantly decreased after 3 and 4 weeks of DOCA-salt treatment but not in rats treated for 1 or 2 weeks. CONCLUSIONS: These results indicate that the enhanced expression of Gi alpha-2 and Gi alpha-3 precedes the development of blood pressure in DOCA-salt-induced hypertension. It can thus be suggested that the increased levels of Gi proteins and resulting decreased levels of cAMP may be one of the factors that contribute to the impaired cardiac contractility and increased vascular tone in DOCA-salt hypertension.
Assuntos
Adenilil Ciclases/metabolismo , Aorta/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Hipertensão/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Angiotensina II/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Fator Natriurético Atrial/farmacologia , Autorradiografia , Northern Blotting , Colforsina/farmacologia , Desoxicorticosterona , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Guanosina Trifosfato/farmacologia , Hipertensão/enzimologia , Immunoblotting , Isoproterenol/farmacologia , Fragmentos de Peptídeos/farmacologia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Sarcolema/efeitos dos fármacos , Sarcolema/enzimologia , Sarcolema/metabolismo , Cloreto de Sódio , Fatores de TempoRESUMO
STUDY OBJECTIVE: The aim was to assess myocardial, electrophysiological, and adrenergic changes caused by chronic administration of doxorubicin. DESIGN: Doxorubicin induced cardiotoxicity was produced in three groups of rabbits by injecting doxorubicin 0.75 mg.kg-1 three times a week for 7, 9 and 11 weeks. There were 36 controls. All studies were conducted within 16 to 36 h after the last injection. Histological, mechanical, and action potential changes produced by doxorubicin were examined in vitro. The effects of doxorubicin on beta adrenergic receptors and cyclic adenosine monophosphate (AMP) generation in myocardial membrane preparations were also evaluated. EXPERIMENTAL MATERIAL: 145 New Zealand white rabbits, 2.4-2.7 kg, were used. After excision of the heart, a papillary muscle was used for mechanical studies, a portion of the septum for intracellular action potential studies, and the rest of the heart for histological or biochemical studies. MEASUREMENTS AND RESULTS: Histological studies showed widespread myocardial damage that became more severe as the cumulative doses increased. Right ventricular papillary muscles of doxorubicin treated rabbits had lower total tension (1.5 v 3.3 g.mm-2 for controls, p less than 0.05) and dT/dt, shorter contraction duration, and lower velocity of shortening than the control muscles under all loading conditions. The changes progressed as the cumulative doxorubicin dose increased. Action potential duration was shorter in the doxorubicin treated groups (APD50 = 76 v 62 ms for controls, p less than 0.01), although resting action potential amplitude was normal. Tension-frequency response (6-36 stimuli.min-1) and response to increasing calcium concentrations (2.54-6.32 mM) were attenuated in the doxorubicin group. Percent change in tension and dT/dt in response to noradrenaline (50 microM), isoprenaline (20 microM), or dibutyryl cyclic AMP (40 mM), was increased in the doxorubicin group v controls (300-600% v 100-200% respectively), despite chronic increase in circulating catecholamines, depletion of myocardial catecholamines, and no change in beta adrenergic receptor number or affinity. The apparent increase in beta adrenergic responsiveness in the doxorubicin group may have been partly due to decreased basal cyclic AMP production (13 v 31 pMol.mg-1 protein.min-1, p less than 0.01), although maximum catecholamine stimulated cyclic AMP production was only mildly decreased (251 v 315 pMol.mg-1 protein.min-1, p less than 0.05). CONCLUSIONS - The subacute effects of chronic doxorubicin become progressively more marked as the cumulative dose increases, and there are significant differences in the myocardial characteristics between this chronic model and other models of heart failure. These differences may be related to the cytotoxic effects of doxorubicin on membranes and membrane bound enzymes.
Assuntos
Cardiomiopatias/induzido quimicamente , Doxorrubicina/toxicidade , Contração Miocárdica/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Feminino , Coração/efeitos dos fármacos , Masculino , Miocárdio/metabolismo , CoelhosRESUMO
OBJECTIVE: The aims were: (1) to study the acute effects of captopril on the action potential characteristics of ventricular fibres from the normal rat, (2) to compare the effects of captopril with those of perindoprilat, a non-thiol angiotensin I converting enzyme (ACE) inhibitor, (3) to determine the electrophysiological properties of the peptide substrates of converting enzyme, bradykinin and angiotensin I, and (4) to investigate whether the effects of captopril occurring in the healthy heart also occur in two models of ventricular hypertrophy. METHODS: Action potentials were recorded with the standard glass microelectrode technique in right ventricular preparations excised from rat hearts and superfused under baseline conditions and with drug containing or peptide containing Tyrode solution. Ventricular hypertrophy was induced in response to hypertension (unilaterally nephrectomised, DOCA-salt model) or 4 week old left ventricular infarction. RESULTS: In preparations from normal rat hearts, captopril increased action potential duration in a concentration dependent fashion [EC50 = 3.5 x 10(-8) M; maximum effect = 44(SEM 5.1)% prolongation at 10(-5) M for action potential duration at 90% repolarisation, APD90]. Perindoprilat similarly caused a dose dependent increase in action potential duration, but with 100 times greater potency [EC50 = 3.1 x 10(-10) M; maximum effect = 71(11)% prolongation at 10(-5) M for APD90]. SQ 14,534, a stereoisomer of captopril with one hundredth the ACE inhibitor potency, had no significant effect on action potential duration at 10(-5) M. Angiotensin I and bradykinin caused concentration dependent prolongation of action potential, but angiotensin II (10(-6) M) had no effect. Captopril (10(-5) M) had no significant effect in the hypertrophied right ventricle from DOCA-salt hypertensive rats, but significantly increased APD90 [39(4.9)%] in right ventricular preparations from rats with 4 week old anterior left ventricular infarction. CONCLUSIONS: In the rat, captopril prolongs action potential duration, an effect possibly due to local accumulation of bradykinin and angiotensin I.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Captopril/farmacologia , Cardiomegalia/fisiopatologia , Coração/fisiopatologia , Angiotensina I/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Bradicinina/farmacologia , Captopril/análogos & derivados , Relação Dose-Resposta a Droga , Hipertensão/fisiopatologia , Indóis/farmacologia , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
The purpose of the present study was to investigate alpha 1-adrenergic receptors in the heart as well as the activity and the sensitivity of the phosphoinositide pathway on tissue slices of atria, ventricles, and femoral artery of hypertensive rats treated for 4 weeks with deoxycorticosterone acetate (DOCA) and 1% saline. DOCA-salt hypertensive rats were characterized by an increased sympathoadrenal tone, as suggested by increased norepinephrine and epinephrine plasma levels. The basal activity of the phosphoinositide pathway, estimated by measuring the accumulation of inositol monophosphate in the presence of an excess of lithium, was found to be greater in atria than in ventricles and femoral artery in both normotensive and DOCA-salt hypertensive rats, but it was twofold greater in atria and ventricles of DOCA-salt hypertensive rats compared with normotensive rats. Following stimulation by norepinephrine, the production of inositol monophosphate was greater in atria and femoral artery than in ventricles in both groups. However, in DOCA-salt hypertensive rats, the production of inositol monophosphate was markedly enhanced, being about twofold greater in atria and femoral artery and about three times greater in ventricles than in tissues of normotensive rats. These differences between DOCA-salt hypertensive and normotensive animals do not appear to be associated with a difference in alpha 1-adrenergic receptor number or affinity since cardiac alpha 1-adrenergic receptor number was unchanged in hypertensive rats and the binding affinity to the receptor was significantly decreased in hypertensive rats compared with normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Desoxicorticosterona/farmacologia , Hipertensão/metabolismo , Fosfatos de Inositol/metabolismo , Músculo Liso Vascular/metabolismo , Miocárdio/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Cloreto de Sódio/farmacologia , Fosfatos Açúcares/metabolismo , Animais , Epinefrina/farmacologia , Hipertensão/etiologia , Masculino , Fosfatidilinositóis/metabolismo , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/efeitos dos fármacosRESUMO
The antihypertensive effects of atenolol and hydrochlorothiazide were compared with placebo in a randomized, double-blind crossover study, with the blood pressure responses related to sympathetic nervous system activity. Twelve patients with essential hypertension were given atenolol (100 mg), hydrochlorothiazide (50 mg), and placebo as single daily doses, each for 6 weeks. Mean supine, standing, and post-exercise blood pressures (mm Hg) on atenolol (155/94, 152/95, 177/93, respectively) and hydrochlorothiazide (154/99, 150/103, 172/96) were lower (p less than 0.01) than corresponding placebo values (172/109, 166/113, 204/111) at 6 weeks. The role of the sympathetic nervous system in the antihypertensive actions of atenolol and hydrochlorothiazide was examined. The supine plasma norepinephrine on placebo was used as an index of sympathetic activity to categorize each patient's "adrenergic status." The six "hyperadrenergic" patients with high resting norepinephrine values (mean, 302 pg/ml) exhibited a greater (p = 0.05) decrease in BP (-30/-20 mm Hg) on atenolol compared with the BP fall of -9/-11 mm Hg observed in the lower norepinephrine group (mean, 211 pg/ml). Resting plasma norepinephrine values did not predict the BP fall on hydrochlorothiazide. The "adrenergic status" of each patient as measured by the plasma norepinephrine concentration tended to be relatively constant regardless of therapy or the state of activity. In this study, atenolol was an effective antihypertensive agent comparable to hydrochlorothiazide in potency. Adrenergic status tended to predict the BP response to atenolol and was a relatively constant feature of the patients in all treatment phases.
Assuntos
Atenolol/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Epinefrina/sangue , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Norepinefrina/sangue , Propanolaminas/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Postura , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
Cardiovascular and hemodynamic reactivity was evaluated with M-mode echocardiography, phonocardiography, and carotidography in correlation with circulating catecholamine levels in 25 normotensive subjects, 15 borderline hypertensive patients, and 42 mildly hypertensive patients during isometric exercise at 30% of the maximum force for 3 minutes. At rest, norepinephrine and epinephrine levels were significantly higher, and the cardiac index was similarly increased in both groups of hypertensive patients, but the cardiac mass index was significantly increased only in the mildly hypertensive group. During isometric exercise, the sympathoadrenal reactivity as well as the pressor and chronotropic responses were similar in normotensive subjects and both groups of hypertensive patients. However, the variations in blood pressure were achieved through totally different hemodynamic mechanisms in normotensive subjects and hypertensive patients. In normotensive subjects, the increase in blood pressure could be linked mainly to an increase in cardiac contractility and performance, whereas in either group of hypertensive patients, the increase in blood pressure was mainly associated with an increase in peripheral resistance. These observations are consistent with the hypothesis of a blunted beta-adrenergic reactivity and a predominance of alpha-adrenergic vascular reactivity in borderline and mildly hypertensive patients. This phenomenon, which appears to be unrelated to age or severity of hypertension, could be an important mechanism underlying the development of hypertension in humans.
Assuntos
Hemodinâmica , Hipertensão/fisiopatologia , Epinefrina/sangue , Feminino , Humanos , Masculino , Norepinefrina/sangue , Esforço Físico , Receptores Adrenérgicos/fisiologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
As interactions between the renin-angiotensin and sympathetic nervous systems have been suggested in the pathogenesis of hypertension, we wanted to investigate the effect of chronic renin-angiotensin blockade with losartan and enalaprilat on the sympathetic reactivity to hypotension and on the cardiac beta-adrenergic-coupled adenylyl cyclase pathway in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Both treatments, exerting equipotent shifts of angiotensin-pressure responses, lowered blood pressure and attenuated cardiac hypertrophy similarly in SHR. The nitroprusside-induced hypotension was similar in both strains, but the associated increases in plasma catecholamines and heart rate were higher in SHR. In SHR treated with losartan and enalaprilat, the nitroprusside-induced hypotension was greater and associated with markedly attenuated increases in norepinephrine and heart rate. The binding affinity of cardiac beta-adrenoceptors was significantly lower, and beta2-adrenoceptor subtype was dominant in untreated SHR in contrast to WKY, in which beta1-adrenoceptor subtype was dominant. Enalaprilat treatment increased total beta-adrenoceptor density, whereas both treatments restored the binding affinity and beta1- and beta2-adrenoceptor proportions to normal in SHR. Isoproterenol-, guanylylimidodiphosphate [Gpp(NH)p]-, and forskolin-stimulated adenylyl cyclase reactivity was increased in SHR. Enalaprilat restored adenylyl cyclase reactivity to normal in SHR and reduced the sensitivity (EC50) of Gpp(NH)p-induced cAMP formation in both strains. The present study supports the possibility that functional alterations of the renin-angiotensin and sympathetic systems are involved in hypertension in SHR. The antihypertensive action of losartan and enalaprilat in SHR may be partly mediated through the normalization of sympathetic hyperreactivity and the restoration of beta-adrenergic signaling pathway sensitivity.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/farmacologia , Enalaprilato/farmacologia , Hipertensão/fisiopatologia , Imidazóis/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Tetrazóis/farmacologia , Adenilil Ciclases/metabolismo , Angiotensinas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/complicações , Hipertensão/metabolismo , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Losartan , Masculino , Miocárdio , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta/fisiologia , Reflexo/fisiologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
The effect of continuously slowing respiration (from 0.46 to 0.05 Hz, eg, from 30 to 3 breaths per minute) on cardiovascular variables was studied in 14 hypertensive patients and 16 normotensive subjects. Beat-to-beat time-frequency (Wigner) distributions were used for dynamic analysis of RR interval and systolic and diastolic pressures. Dominant breathing frequency at rest did not differ in hypertensive patients from the control group (0.21 versus 0.19 Hz). However, in the hypertensive group it was disturbed 34.4% of the time by slow breathing and apneas, which evoked transient blood pressure instability and increased spectral powers at low frequencies (range, 0.01 to 0.1 Hz). The nonrespiratory fluctuations (NONRFs) and respiratory fluctuations (RFs) in RR interval and NONRFs in systolic pressure were smaller in hypertensive patients (P < .001). In both groups, slowing of respiratory frequency from 0.46 to 0.05 Hz entrained RFs in the RR interval and systolic and diastolic pressures. RFs in the RR interval remained diminished in hypertensive patients (P < .001), but RFs in systolic pressure increased higher at maximum, corresponding to breathing frequencies from 0.07 to 0.09 Hz (P < .001). A dynamic cardiorespiratory index (ratio of RFs in RR interval and systolic pressure) was smaller (P < .01) in hypertensive patients than in normotensive subjects. Irregular breathing at rest was found in hypertensive patients. The transfer from respiration into RR interval was diminished, suggesting an impaired parasympathetic responsiveness in mild hypertension.
Assuntos
Eletrocardiografia , Hipertensão/fisiopatologia , Respiração , Adulto , Pressão Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
This study examined the contribution of phosphatidylinositol metabolism and the efficacy of protein kinase C-mediated desensitization in the exaggerated alpha 1b-adrenergic receptor-mediated inositol phosphate response in the aorta of the deoxycorticosterone acetate (DOCA)-salt rat model of hypertension. The basal accumulation of inositol phosphates and the basal incorporation of [3H]myo-inositol in the phosphatidylinositol lipid pool were significantly higher in the aorta of these hypertensive rats. A positive correlation (r = .88, P < .01) was demonstrated between basal inositol phosphate levels and the [3H]myo-inositol-labeled phosphatidylinositol lipid pool. In hypertensive rats, alpha 1b-adrenergic receptor-mediated inositol phosphate production in response to phenylephrine was significantly higher compared with normotensive rats. Despite the normalization of phenylephrine-mediated inositol phosphate production to the [3H]myo-inositol-labeled phosphatidylinositol lipid pool, the alpha 1b-adrenergic response remained significantly higher in the hypertensive rats. Phorbol ester activation of protein kinase C attenuated to a lesser extent phenylephrine-mediated inositol phosphate production (40%) in the aorta of hypertensive rats compared with the 80% attenuation observed in the aorta of normotensive rats. This desensitization was inhibited in both groups by the protein kinase C inhibitor staurosporine. The blunted desensitization of the alpha 1b-adrenergic receptor by protein kinase C activation was not associated with a decrease in protein kinase C activity in the hypertensive rats, because aortic strips from these animals were more responsive to phorbol ester activation than aortic strips from normotensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hipertensão/fisiopatologia , Fosfatidilinositóis/metabolismo , Proteína Quinase C/fisiologia , Receptores Adrenérgicos alfa/metabolismo , Alcaloides/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Desoxicorticosterona , Hipertensão/induzido quimicamente , Masculino , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Valores de Referência , Cloreto de Sódio , Estaurosporina , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
C-type natriuretic peptide (CNP) and brain natriuretic peptide (BNP) are members of the natriuretic peptide family, which have been shown to interact with ANP-C/ANF-R2 receptors in addition to ANP-B receptor subtypes. The present study was undertaken to investigate if the interaction of CNP and BNP with ANP-C receptors results in the inhibition of adenylyl cyclase activity. CNP and BNP inhibited adenylyl cyclase activity in heart and brain striatal membranes in a concentration dependent manner with an apparent Ki between 0.1 and 1.0 nM. Maximal inhibition observed in heart membranes were about 25% and 35% for BNP and CNP respectively, however the inhibitions in brain striatal membranes were smaller (approximately 20%). The inhibition was dependent on the presence of guanine nucleotides and was attenuated by pertussis toxin treatment. In addition, CNP inhibited the stimulatory effect of isoproterenol on adenylyl cyclase, whereas CNP as well as BNP showed an additive effect with the inhibitory response of angiotensin II on adenylyl cyclase activity. When the combined effect of C-ANF4-23/BNP, C-ANF4-23/CNP and BNP/CNP at optimal concentrations was studied together on adenylyl cyclase activity, the percent inhibition remained the same for C-ANF4-23 and BNP or C-ANF4-23 and CNP, however, an additive inhibitory effect was observed for BNP and CNP. These results suggest that CNP and BNP like C-ANF4-23 interact with ANP-C receptors and result in the inhibition of adenylyl cyclase activity. On the other hand, CNP and BNP interact with the ANP-C receptor, however, the interaction may be different sites or there may be two subpopulations of ANP-C receptors specific for each of the peptides. These results indicate that BNP and CNP, like ANP and C-ANF4-23, inhibit the adenylyl cyclase/cAMP signal transduction system through an inhibitory guanine nucleotide regulatory protein, by interacting with ANP-C receptor subtypes.
Assuntos
Inibidores de Adenilil Ciclases , Guanilato Ciclase/metabolismo , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Proteínas/farmacologia , Receptores do Fator Natriurético Atrial/metabolismo , Angiotensina II/farmacologia , Animais , Fator Natriurético Atrial/farmacologia , Membrana Celular/metabolismo , Nucleotídeos de Guanina/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Isoproterenol/farmacologia , Cinética , Peptídeo Natriurético Encefálico , Peptídeo Natriurético Tipo C , Proteínas do Tecido Nervoso/metabolismo , Proteínas/metabolismo , RatosRESUMO
Total plasma catecholamine levels, plasma norepinephrine levels, heart rate, and systolic and diastolic pressures were measured in 15 symptomatic patients with mitral valve prolapse and in 19 normal subjects in supine baseline conditions and in a standing position. In the 15 symptomatic patients, total plasma catecholamine levels and plasma norepinephrine levels were significantly elevated in both positions, and heart rate was lower than in normal subjects in the supine position but returned to normal in the upright position. Thus, symptomatic patients with mitral valve prolapse demonstrate increased resting sympathetic tone. In addition, the associated supine bradycardia suggested that increased vagal tone might also be present at rest. These observations support the hypothesis of a dual autonomic dysfunction in these patients and could account for some of the clinical manifestations of the mitral valve prolapse syndrome.
Assuntos
Catecolaminas/sangue , Prolapso da Valva Mitral/sangue , Agorafobia/complicações , Transtornos de Ansiedade/complicações , Pressão Sanguínea , Bradicardia/etiologia , Cardiomegalia/fisiopatologia , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Prolapso da Valva Mitral/psicologia , Norepinefrina/sangue , Norepinefrina/metabolismo , Pânico , Postura , Transtornos do Sono-Vigília/complicações , Sistema Nervoso Simpático/metabolismoRESUMO
Sympatho-adrenal tone and reactivity were evaluated in anaesthetized normotensive and DOCA-salt hypertensive rats, by measuring arterial plasma concentrations of norepinephrine and epinephrine under basal conditions and following bilateral carotid occlusion. Baseline norepinephrine levels were significantly higher in DOCA-salt hypertensive animals than in their respective normotensive controls, whether they were studied with intact vagi or following bilateral vagotomy. The possibility of a relationship between the increased basal sympathetic fibres and the maintenance of DOCA-salt hypertension is strongly suggested by the finding of a significant correlation between mean arterial pressure (MAP) and basal circulating norepinephrine values in those animals. Furthermore, the epinephrine increase following carotid occlusion was found to be markedly potentiated in hypertensive animals (intact or vagotomized), suggesting adrenal medullary hyperreactivity to baroreflex activation in this model of hypertension. In normotensive rats the epinephrine increase induced by the carotid occlusion was greatly potentiated by the administration of an alpha 2-antagonist (yohimbine), and completely abolished by administration of an alpha 2-agonist (clonidine). In contrast, the epinephrine response to carotid occlusion, which is already enhanced in hypertensive animals, was unaffected by the same treatments. These results therefore suggest that adrenal medullary hyperreactivity observed in DOCA-salt hypertensive rats may be due to a dysfunction of an alpha 2-adrenergic mechanism modulating adrenal medullary secretion.
Assuntos
Medula Suprarrenal/fisiopatologia , Desoxicorticosterona , Hipertensão/induzido quimicamente , Cloreto de Sódio , Sistema Nervoso Simpático/fisiopatologia , Animais , Artérias Carótidas/fisiopatologia , Clonidina/farmacologia , Epinefrina/sangue , Hipertensão/fisiopatologia , Masculino , Fibras Nervosas/fisiologia , Norepinefrina/sangue , Pressorreceptores/fisiopatologia , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos alfa/fisiopatologia , Vagotomia , Nervo Vago/fisiologia , Ioimbina/farmacologiaRESUMO
OBJECTIVE: To investigate inositol phosphate formation and its modulation by the cyclic AMP (cAMP) pathway in cultured aortic smooth muscle cells from spontaneously hypertensive rats (SHR). METHODS: Phenylephrine was used to stimulate inositol phosphate formation in cultured aortic smooth muscle cells from SHR and Wistar-Kyoto (WKY) rats. The smooth muscle cells from passages 6-14 were prelabelled with myo-[2-3H]-inositol (1.9 x 10(5) Bq/ml for 24 h) and inositol phosphate formation was measured after exposure to agonist for 45 min. (-)isoproterenol or forskolin-induced cAMP formation was also evaluated using a radioimmunoassay method. RESULTS: The basal level of inositol phosphate formation in smooth muscle cells from SHR was higher than that observed in smooth muscle cells from WKY rats. Phenylephrine increased the formation of inositol phosphates in a concentration-dependent manner (0.1-100 mumol/l). In the presence of 100 mumol/l phenylephrine, the increase in inositol phosphate formation was significantly greater in smooth muscle cells from SHR (214 +/- 6%) than that observed in smooth muscle cells from WKY rats (156 +/- 8%). When the cells were pretreated with 1 mmol/l 8-bromoadenosine 3':5'-cyclic monophosphate or with 10 mumol/l forskolin for 45 min, the basal production of inositol phosphates in smooth muscle cells both from SHR and from WKY rats was significantly and similarly decreased by about 20%. In the presence of 1 mmol/l 8-bromoadenosine 3':5'-cyclic monophosphate, 100 mumol/l phenylephrine-induced inositol phosphate formation was similarly decreased by 33 +/- 4 and 30 +/- 3% in smooth muscle cells from SHR and from WKY rats, respectively, whereas, in the presence of 10 mumol/l forskolin, inositol phosphate formation was reduced by 25 +/- 3 and 27 +/- 5%, respectively, in those cells. In contrast, isoproterenol induced less inhibition of phenylephrine-induced inositol phosphate formation in smooth muscle cells from SHR (14 +/- 2%) than it did in those from WKY rats (25 +/- 4.5%). Although there was no significant difference in basal or forskolin-induced cAMP accumulation between smooth muscle cells from SHR and those from WKY rats. (-)isoproterenol-induced cAMP accumulation was significantly lower in smooth muscle cells from SHR. CONCLUSION: A marked inhibitory effect of cAMP on the alpha 1-adrenoceptor-mediated inositol phosphate signal transduction pathway was demonstrated in smooth muscle cells of SHR and of WKY rats. Decreased cAMP formation with beta-adrenergic stimulation and increased inositol phosphate formation with alpha-adrenergic stimulation in SHR smooth muscle cells may both contribute to the dominant alpha 1-adrenergic activity observed in SHR.
Assuntos
AMP Cíclico/fisiologia , Hipertensão/metabolismo , Fosfatos de Inositol/biossíntese , Músculo Liso Vascular/metabolismo , Animais , Células Cultivadas , Isoproterenol/farmacologia , Masculino , Fenilefrina/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Adrenérgicos beta/fisiologiaRESUMO
The effect of haemorrhagic hypotension on plasma catecholamine levels was studied in anesthetized normotensive and DOCA-salt hypertensive rats. The basal levels of plasma norepinephrine (NE) were significantly higher in DOCA-salt hypertensive rats than in normotensive rats. Moreover, the elevations in plasma NE and epinephrine (E) levels induced by haemorrhagic hypotension were found to be markedly potentiated in DOCA-salt hypertensive rats. Pretreatment with the re-uptake blocker (desmethylimipramine) increased both basal and haemorrhage NE levels in DOCA-salt hypertensive as well as in normotensive rats. Consequently, basal and haemorrhage NE plasma levels remained significantly higher in the DOCA-salt hypertensive animals than in the normotensive rats even following neuronal re-uptake blockage. This suggests that the elevated NE concentrations found in the plasma of DOCA-salt hypertensive rats both under basal condition and during haemorrhagic hypotension do not reflect a defective re-uptake. Moreover, in contrast with what is observed in normotensive animals, bilateral adrenalectomy did not induce any increase in basal or haemorrhage NE levels in the DOCA-salt hypertensive rats. This constitutes yet more evidence supporting the existence of an impaired balance of the sympatho-adrenal axis in this hypertension model. The present study therefore suggests that the potentiated plasma catecholamine response to haemorrhage in DOCA-salt hypertensive rats is the consequence of an increased sympathoadrenal reactivity and not of an altered neuronal uptake. This hyperreactivity may result from an impaired regulation of the sympatho-adrenal axis in that hypertension model.
Assuntos
Medula Suprarrenal/fisiopatologia , Desoxicorticosterona , Hipertensão/fisiopatologia , Choque Hemorrágico/fisiopatologia , Sódio na Dieta/efeitos adversos , Sistema Nervoso Simpático/fisiopatologia , Animais , Epinefrina/sangue , Hipertensão/etiologia , Masculino , Norepinefrina/sangue , Ratos , Ratos EndogâmicosRESUMO
OBJECTIVE: To investigate the modification of plasma and tissue neuropeptide Y-like immunoreactivity (NPY-li) concentrations, in relation to blood pressure and plasma catecholamine levels, during the development of deoxycorticosterone acetate (DOCA)-salt hypertension. METHODS: Mean arterial pressure (MAP), heart rate, tissue and plasma NPY-li levels, and aortic norepinephrine and epinephrine plasma levels were measured in conscious DOCA-salt hypertensive rats treated for 1, 2 and 3 weeks, and in their respective normotensive controls. RESULTS: Both norepinephrine and NPY-li plasma levels increased significantly in parallel with blood pressure during DOCA-salt treatment, so that MAP was significantly correlated with plasma norepinephrine and NPY-li levels in hypertensive rats. Plasma NPY-li levels were also correlated with norepinephrine levels only in hypertensive rats, but were correlated with epinephrine levels only in normotensive animals. Tissue NPY-li content was lower in the mesenteric artery and heart ventricles after 1-3 weeks of DOCA-salt treatment, but the content in the adrenal gland was not significantly different from that in normotensive rats. CONCLUSIONS: In DOCA-salt hypertensive rats, increased plasma NPY-li levels originate primarily from the sympathetic nerves, since those levels were correlated exclusively with circulating norepinephrine levels and they were associated with a reduction in NPY-li content of the heart and mesenteric artery. It is thus possible that the enhanced release of NPY-li from sympathetic nerves could contribute to the rise in blood pressure and to the maintenance of hypertension in this experimental model.