RESUMEN
To assess the function of the final step of the pathway for aldosterone biosynthesis, the responsiveness of plasma 18-hydroxycorticosterone and aldosterone concentrations to angiotensin II infusion was studied in 14 patients with nonazotemic diabetes mellitus as compared with 14 normal controls approximately matched for sex and age. In addition, the responses of both steroids to corticotropin injection were investigated in the diabetic patients. Under basal conditions, plasma aldosterone levels were slightly lower in the patients than in normal controls, while plasma 18-hydroxycorticosterone concentrations were similar in the two study groups. Angiotensin II induced marked and comparable increases in plasma 18-hydroxycorticosterone and aldosterone levels in normal and diabetic subjects. Plasma 18-hydroxycorticosterone and aldosterone levels before and after angiotensin II infusion were significantly interrelated; this correlation was similar in normal subjects (r = 0.61; P less than 0.001) and diabetic patients (r = 0.51; P less than 0.005). Plasma 18-hydroxycorticosterone and aldosterone were significantly increased by corticotropin in the patients. These findings indicate that the terminal step of aldosterone biosynthesis, which involves the production of 18-hydroxycorticosterone and aldosterone, is largely unaltered in patients with nonazotemic diabetes mellitus.
Asunto(s)
18-Hidroxicorticosterona/sangre , Hormona Adrenocorticotrópica/farmacología , Aldosterona/biosíntesis , Angiotensina II/farmacología , Corticosterona/análogos & derivados , Diabetes Mellitus/sangre , Adulto , Anciano , Aldosterona/sangre , Femenino , Humanos , Infusiones Parenterales , Masculino , Persona de Mediana Edad , UremiaRESUMEN
OBJECTIVE: To assess the efficacy and tolerance of a diuretic-free antihypertensive therapy with a Ca2+ antagonist and an angiotensin-converting enzyme (ACE) inhibitor in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: After a 2-wk washout and a 4-wk placebo phase, 47 hypertensive patients with NIDDM randomly received verapamil or enalapril alone and, if blood pressure remained elevated, both agents combined over 30 wk. RESULTS: Verapamil or enalapril alone normalized blood pressure to less than 90 mmHg diastolic in 30 patients; verapamil decreased mean +/- SE blood pressure from 159/98 +/- 3/1 to 146/87 +/- 3/2 mmHg (n = 18, P less than 0.001) and enalapril from 166/99 +/- 5/2 to 146/86 +/- 3/1 mmHg (n = 12, P less than 0.001). In 17 patients who were still hypertensive after 10 wk of monotherapy, combination of both drugs decreased blood pressure from 170/104 +/- 4/2 to 152/90 +/- 4/2 mmHg (P less than 0.001). Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total lipids, high-density and low-density lipoprotein cholesterol, apolipoproteins A-I and B, creatinine, and urinary albumin-creatinine ratio were not significantly modified. CONCLUSIONS: In hypertensive patients with NIDDM, a diuretic-free therapy based on the Ca2+ antagonist verapamil and/or the ACE inhibitor enalapril can effectively decrease blood pressure without adversely affecting carbohydrate and lipid metabolism.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Enalapril/uso terapéutico , Hipertensión/tratamiento farmacológico , Verapamilo/uso terapéutico , Glucemia/análisis , Presión Sanguínea/efectos de los fármacos , Quimioterapia Combinada , Enalapril/administración & dosificación , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Proteinuria/metabolismo , Verapamilo/administración & dosificaciónRESUMEN
Hypertension accompanying diabetes mellitus may involve abnormalities in at least two major blood pressure-regulating systems: the body sodium-fluid volume state and cardiovascular reactivity. In metabolically stable nonazotemic diabetes, exchangeable sodium is increased by 10% on average, regardless of age, insulin dependence or nondependence, or the presence or absence of diabetic retinopathy or clinical nephropathy (proteinuria greater than or equal to 0.3 g/24 hr). Possible contributing mechanisms include renal sodium retention and an extravascular shift of fluid and sodium; intracellular accumulation is not excluded. Circulatory volume is normal or low and the total exchangeable sodium/blood volume ratio increased. In hypertensive diabetes, the latter abnormality is particularly pronounced; systolic pressure tended to correlate with exchangeable sodium (r = 0.47, p less than 0.001) and diastolic pressure with the plasma sodium/potassium ratio (r = 0.25, p less than 0.05). Plasma aldosterone, renin, epinephrine, and norepinephrine levels are generally normal or sometimes low in metabolically stable nonazotemic diabetic patients with normal or high blood pressure; the plasma clearance of norepinephrine also appears to be unaltered. The cardiovascular pressor responsiveness to norepinephrine is often exaggerated relative to concomitant plasma concentrations, regardless of age, type of antidiabetic treatment, or presence or absence of diabetic retinopathy, peripheral neuropathy, or high blood pressure. Pressor responsiveness to angiotensin II also may sometimes be increased relative to plasma renin levels. Sodium retention and diabetic vasculopathy of resistance vessels could be important complementary mechanisms of hyperreactivity. In diabetes with mild hypertension, diuretic treatment restored exchangeable sodium, norepinephrine pressor responsiveness, and blood pressure toward normal. Thus sodium retention and cardiovascular hyperreactivity tend to occur even at the normotensive, nonazotemic stage of diabetes and may concomitantly predispose for the frequent development of hypertension in the diabetic population.
Asunto(s)
Diabetes Mellitus/fisiopatología , Hipertensión/fisiopatología , Presorreceptores/fisiopatología , Adulto , Anciano , Aldosterona/sangre , Angiotensina II/sangre , Presión Sanguínea , Epinefrina/metabolismo , Femenino , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Norepinefrina/metabolismo , Volumen Plasmático , Potasio/metabolismo , Renina/sangre , Sodio/metabolismo , Equilibrio HidroelectrolíticoRESUMEN
The effects of selective alpha 1-adrenergic blockade with terazosin on blood pressure and cardiovascular pressor responsiveness were assessed in 17 subjects with mild to moderate essential hypertension (mean age, 48 +/- 2 [SEM] years). As compared with a 2-week placebo period, 8 weeks of terazosin treatment (mean dose, 10.5 +/- 1.7 mg/day) caused a fall of supine (from 153/103 +/- 3/2 to 143/96 +/- 4/2 mm Hg; p less than 0.025) and upright (from 145/106 +/- 4/2 to 131/94 +/- 5/3 mm Hg; p less than 0.01) arterial pressure; a marked blunting of cardiovascular pressor responsiveness to norepinephrine, as judged from the pressor dose (from 73 +/- 9 to 2156 +/- 496 ng/kg/min; p less than 0.02) and from the rightward shift (p less than 0.01) of the plasma concentration-blood pressure response curve; and a slight increase in plasma norepinephrine concentration (from 37.7 +/- 3.3 to 52.2 +/- 7.8 ng/dl; p less than 0.01). Heart rate, body weight, exchangeable sodium, blood volume, and norepinephrine plasma clearance; plasma epinephrine, renin, angiotensin II, and aldosterone levels; the relationships between angiotensin II-induced increases in arterial pressure or plasma aldosterone and the concomitant increments of plasma angiotensin II; and heart rate responsiveness to isoproterenol did not change significantly after terazosin treatment. These findings suggest that the fall of arterial pressure induced by selective alpha 1-adrenergic blockade in subjects with essential hypertension is associated with, and probably explained by, inhibition of alpha 1-mediated, noradrenergic-dependent vasoconstriction. alpha 1-Adrenergic receptor antagonism did not modify body sodium concentration, the adrenomedullary component of the sympathetic nervous system, angiotensin II levels, or beta-adrenergic dependent mechanisms.
Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Sistema Cardiovascular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Piperazinas/uso terapéutico , Prazosina/análogos & derivados , Adulto , Presión Sanguínea/efectos de los fármacos , Interacciones Farmacológicas , Electrólitos/sangre , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Isoproterenol/farmacología , Masculino , Persona de Mediana Edad , Norepinefrina/metabolismo , Norepinefrina/farmacología , Cooperación del Paciente , PosturaRESUMEN
Hypertension in diabetic patients is more common than in controls, contributes substantially to their increased cardiovascular morbidity and mortality, and should be treated as accurately as diabetes mellitus itself. After appropriate exclusion of secondary forms, the first therapeutic step consists of reduction of overweight, salt intake, and smoking; the omission of interfering drugs; and adequate instruction. Step 2 has usually been the prescription of a diuretic drug, in spite of its known side effects on carbohydrate and lipid metabolism. A new possible alternative may be a calcium antagonist. Results in 10 hypertensive diabetic persons suggest that at a dose that normalizes blood pressure, neither carbohydrate nor lipid metabolism is altered, uric acid decreases, the exaggerated cardiovascular reactivity toward norepinephrine becomes normal, and the pressor dose for angiotensin II tends to rise. Body weight, blood volume, exchangeable sodium, as well as plasma and urinary sodium, potassium, and creatinine levels were unchanged. The third therapeutic step is the addition of a cardioselective beta blocker in a moderate dose. This avoids the disadvantages of beta 2-adrenergic blockade such as decreased insulin output, prolonged hypoglycemia, diminished glucagon secretion, and increased vasospasticity during hypoglycemic states, as well as aggravation of peripheral vascular disease. Alternatives are other sympatholytics with their known tendency to cause or increase orthostatic and sexual problems or, again, a calcium antagonist. In step 4, a hydralazine-type drug or prazosine is added. The fifth step, which adds minoxidil or captopril to the previous drugs, should only be taken after a specialist reevaluates the overall situation.
Asunto(s)
Antihipertensivos/uso terapéutico , Complicaciones de la Diabetes , Hipertensión/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Diuréticos/uso terapéutico , Humanos , Hipertensión/etiología , Simpaticolíticos/uso terapéuticoRESUMEN
Several blood-pressure-regulating factors including exchangeable sodium, blood volume, plasma renin, aldosterone, norepinephrine (NE), and epinephrine (E) levels, urinary catecholamine excretion rates, and cardiovascular responsiveness to infused NE and angiotensin II (AII) were compared among age-matched subgroups of normal subjects (15 with normal weight, 15 with overweight) and patients with essential hypertension (15 with either normal weight, overweight, or obesity). Exchangeable sodium, blood volume, plasma and urinary sodium and potassium, plasma renin, aldosterone and epinephrine levels, and NE or E excretion rates did not differ significantly among the five subgroups. Minimal differences included a slightly higher heart rate in overweight patients than in overweight normal subjects (p less than 0.01) and a tendency for a higher plasma NE in overweight than in normal weight patients. Plasma NE obtained immediately before NE infusion as well as the plasma clearance of NE did not differ among the five subgroups except, however, for a somewhat low NE clearance in obese patients. The NE pressor dose tended to be lower in normal-weight hypertensive than in normal-weight normotensive subjects. No alteration was apparent in overweight or obese hypertensive patients. Pressor responses to AII were similar in the different subgroups. These findings suggest that overweight does not confer a unique aberration in the body sodium-volume state, circulating renin, aldosterone or catecholamines, or cardiovascular responses to NE or AII which result in hypertension.
Asunto(s)
Sistema Cardiovascular/fisiopatología , Hipertensión/fisiopatología , Obesidad/fisiopatología , Presorreceptores/fisiopatología , Adulto , Aldosterona/sangre , Angiotensina II , Volumen Sanguíneo , Peso Corporal , Epinefrina/sangre , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Potasio/metabolismo , Renina/sangre , Sodio/metabolismoRESUMEN
The acute responsiveness of plasma catecholamine, renin (PRA), and aldosterone levels to exogenous norepinephrine was studied under placebo conditions and following renin (PRA), and aldosterone levels to exogenous norepinephrine was studied under placebo conditions and following renin-angiotensin activation by diuretic pretreatment in 25 normal subjects and 34 patients with borderline-to-moderate essential hypertension. Norepinephrine infusion caused increases in plasma norepinephrine (PNE) that correlated with the infused norepinephrine dose (p < 0.001); this relationship was similar in normal and hypertensive subjects and unaltered by diuretic therapy. Plasma epinephrine and dopamine levels were unchanged during norepinephrine infusion. Norepinephrine infusion at pressor doses stimulated PRA (p < 0.01). The PRA responses correlated with the dose of infused norepinephrine (p < 0.0025), and norepinephrine-stimulated PRA correlated with basal PRA (p < 0.001). These norepinephrine-PRA relationships were unaltered by diuretic treatment and similar in normal and hypertensive subjects. In both groups, norepinephrine also caused a similar increase in plasma aldosterone (p < 0.05) under placebo conditions, but not following diuretic therapy. These findings demonstrate that an acute increase in the blood levels of the adrenergic neurotransmittor, norepinephrine, causes mild but distinct stimulation of plasma renin and aldosterone levels. Renin release in response to exogenous norepinephrine is not enhanced following renin-angiotensin activation by diuretic pretreatment. The responsiveness of the renin-angiotensin-aldosterone system to an acute norepinephrine input seems to be intact in essential hypertension.
Asunto(s)
Aldosterona/sangre , Catecolaminas/sangre , Norepinefrina/administración & dosificación , Renina/sangre , Adolescente , Adulto , Anciano , Clortalidona/administración & dosificación , Femenino , Humanos , Hipertensión/fisiopatología , Indapamida/administración & dosificación , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Placebos , Potasio/sangre , Sodio/sangre , Factores de TiempoRESUMEN
The responsiveness of plasma aldosterone to the infusion of angiotensin II at dose rates of 2, 4, and 10 ng/kg X min was assessed in 11 normal subjects and 13 patients with mild essential hypertension before and after 4 weeks of treatment with the sympatholytic agent debrisoquine. Debrisoquine treatment caused a significant (P less than 0.01) decrease in circulating norepinephrine (-45%), but did not modify plasma levels of angiotensin II, renin, aldosterone, or epinephrine or the metabolism of sodium or potassium. In normal subjects, debrisoquine caused a significant shift to the left (P less than 0.05) of the correlation relating plasma aldosterone to plasma angiotensin II levels. In patients with essential hypertension, the aldosterone-angiotensin II interrelationship was not modified. These findings suggest that the sympathetic nervous system exerts an inhibitory influence on aldosterone responsiveness to angiotensin II in normal man, and that this physiological interaction is impaired in patients with essential hypertension.
Asunto(s)
Aldosterona/sangre , Angiotensina II/farmacología , Hipertensión/sangre , Norepinefrina/antagonistas & inhibidores , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Debrisoquina/farmacología , Femenino , Humanos , Infusiones Parenterales , Masculino , Persona de Mediana EdadRESUMEN
The influence of agents that inhibit sympathetic nerve activity on cardiovascular responsiveness as related to major pressor factors has been unclear. Therefore, these components were evaluated in 11 normal subjects and 13 patients with mild essential hypertension before and after 4 weeks of sympathetic neuron blockade with the agent debrisoquine. In these normal and mildly hypertensive subjects, sympathetic neuron blockade caused approximately similar decreases in urinary and supine or upright plasma norepinephrine (NE) levels (average changes in the two groups, -41% and -45%, respectively; p less than 0.05 to less than 0.005), the chronotropic dose of isoproterenol (-45% and -38%), and the NE pressor dose (-47% and -51%, p less than 0.01), while the relationship between NE-induced changes in blood pressure and concomitant plasma NE concentrations was displaced to the left (p less than 0.01). Supine heart rate was also lowered (-10% and -8%, p less than 0.05). Compared to the orthostatic variations during placebo conditions, mild postural decreases in blood pressure were apparent in both the normal and hypertensive groups (-8% and -7.5%). However, supine blood pressure was unchanged following debrisoquine treatment. Other parameters were also not consistently changed, such as total blood volume, exchangeable body sodium, urinary electrolytes, plasma epinephrine, renin, and angiotensin II (AII) levels, the pressor dose of infused AII, and the relationship between AII-induced changes in blood pressure and plasma AII measured before and during AII infusion. These findings demonstrate that the reduction in sympathetic outflow during sympathetic neuron blockade may elicit a hyperresponsiveness of alpha- and beta-adrenergic receptors that is equal in normal subjects and patients with mild essential hypertension.
Asunto(s)
Debrisoquina/uso terapéutico , Hipertensión/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Receptores Adrenérgicos/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Adulto , Anciano , Angiotensina II/metabolismo , Presión Sanguínea/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/metabolismo , Receptores Adrenérgicos/fisiología , Renina/sangreRESUMEN
To elucidate the mechanisms involved in calcium-mediated blood pressure (BP) control, plasma norepinephrine (NE), epinephrine, renin activity, and angiotensin II (AII) levels and the cardiovascular pressor responsiveness to NE and AII were assessed before and during acute mild hypercalcemia or short-term calcium (Ca) inhibition with nifedipine in 20 normal and five borderline hypertensive subjects. In normal subjects, systolic BP and plasma NE and epinephrine concentrations were increased significantly (p less than 0.05) during an acute rise in serum Ca of 3.1 mg/dl (intermediate rate Ca infusion, 0.05 mg/kg/min for 3 hours), but not following an increase of 1 mg/dl (low rate Ca infusion, 0.034 mg/kg/min for 2 hours). In the borderline hypertensive group, low-rate Ca infusion elevating serum Ca by 1 mg/dl was associated with a slight increase in systolic BP (p less than 0.05) and plasma catecholamines. In both groups, the pressor responses to infused NE and AII, and plasma renin and AII levels, were unchanged during mild to moderate hypercalcemia. Nifedipine given for 2 weeks (average dose, 48 mg/d) reduced BP significantly (p less than 0.05) in the borderline hypertensive subjects only and NE pressor responses in both groups (p less than 0.025), but had no significant effect on plasma catecholamines, renin, or AII levels. These findings suggest that the adrenergic BP control mechanism may be more dependent on clinical variations in calcium metabolism than the angiotensin BP regulatory mechanism. Acute hypercalcemia may increase BP at least in part by causing an increase in adrenergic activity without an equivalent decrease in cardiovascular reactivity. Calcium inhibition with nifedipine may modify noradrenergic BP control by lowering the NE pressor reactivity without causing an equivalent increase in adrenergic activity.
Asunto(s)
Presión Sanguínea , Calcio/fisiología , Hipertensión/fisiopatología , Adulto , Aldosterona/sangre , Angiotensina II/sangre , Angiotensina II/farmacología , Epinefrina/sangre , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Nifedipino/farmacología , Norepinefrina/sangre , Norepinefrina/farmacología , Renina/sangreRESUMEN
Dose-response curves relating plasma angiotensin II (AII) concentration during AII infusion to blood pressure (BP), to plasma aldosterone, and to plasma 18-hydroxycorticosterone were compared in normal subjects and in patients with essential hypertension, Conn's syndrome, and nontumorous hyperaldosteronism. The BP response was steeper than normal in patients with Conn's syndrome and essential hypertension. Before infusion, mean plasma aldosterone concentration was approximately four-fold higher in Conn's syndrome than in the normal group, while that of 18-hydroxycorticosterone was ninefold higher. Neither increased significantly during AII infusion. In essential hypertension, both corticosteroids were within the normal range, but their responses to AII infusion were greater than normal. In the three subjects with non-tumorous hyperaldosteronism, plasma aldosterone and 18-hydroxycorticosterone concentrations were raised, and their responses to AII infusion resembled those found in essential hypertension and were different from those found in Conn's syndrome. This suggests that nontumorous hyperaldosteronism is not a variant of Conn's syndrome. In the response to AII and in other ways, it is indistinguishable from essential hypertension.
Asunto(s)
18-Hidroxicorticosterona/sangre , Aldosterona/sangre , Angiotensina II/farmacología , Corticosterona/análogos & derivados , Hiperaldosteronismo/fisiopatología , Hipertensión/fisiopatología , Neoplasias de las Glándulas Suprarrenales/fisiopatología , Adulto , Angiotensina II/sangre , Presión Sanguínea , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana EdadRESUMEN
The effect of the selective alpha 1-antagonist terazosin on serum lipoproteins and certain blood pressure-regulating factors was assessed in 15 patients with essential hypertension. Terazosin given during 8 weeks reduced arterial pressure (from 153/103 +/- 3/2 (SE) to 143/96 +/- 5/2 mm Hg; P less than 0.02) but did not modify body weight, heart rate, blood volume, plasma renin activity, aldosterone and catecholamine levels, or serum cholesterol, triglycerides, and their lipoprotein fractions. In nine of the patients, blood pressure control was not achieved with terazosin monotherapy and the diuretic methyclothiazide, 2.5 mg, was added. After 8 weeks of combined treatment, blood pressure decreased further (P less than 0.05); serum lipids and lipoprotein fractions did not change as compared with placebo or terazosin conditions. These findings indicate that terazosin in monotherapy does not unfavorably influence lipid metabolism.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Hipertensión/tratamiento farmacológico , Lipoproteínas/metabolismo , Prazosina/análogos & derivados , Antagonistas Adrenérgicos alfa/uso terapéutico , Adulto , Presión Sanguínea/efectos de los fármacos , Ensayos Clínicos como Asunto , Quimioterapia Combinada , Femenino , Humanos , Masculino , Meticlotiazida/farmacología , Meticlotiazida/uso terapéutico , Persona de Mediana Edad , Prazosina/farmacología , Prazosina/uso terapéuticoRESUMEN
Calcium antagonists may affect the regulation of body sodium and adrenergic-dependent mechanisms. Exchangeable sodium, blood volume, plasma norepinephrine, renin, aldosterone, pressor responsiveness to norepinephrine, heart rate responses to isoproterenol, and lipid metabolism were studied in 15 patients with essential hypertension after 8 weeks of treatment with verapamil (348 +/- 68 (SD) mg/day). Supine blood pressure decreased from 153/103 +/- 19/12 mm Hg to 140/95 +/- 14/12 mm Hg (P less than 0.01). Exchangeable sodium, blood volume, plasma norepinephrine, renin and aldosterone, serum total cholesterol, the lipoprotein fractions, and apoprotein levels were unchanged. The norepinephrine pressor and the isoproterenol chronotropic doses tended to increase, whereas the dose-response curve of blood pressure related to plasma norepinephrine was significantly displaced to the right (F = 5.34; P less than 0.05). The antihypertensive effect of verapamil is associated with a decreased cardiovascular pressor responsiveness to norepinephrine without changes in endogenous noradrenergic activity. Moreover, verapamil does not modify the sodium/fluid volume state, the activity of the renin-angiotensin aldosterone axis, or lipid metabolism.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Verapamilo/uso terapéutico , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Sistema Cardiovascular/fisiopatología , Ensayos Clínicos como Asunto , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Isoproterenol/farmacología , Masculino , Persona de Mediana Edad , Norepinefrina/farmacología , Potasio/metabolismo , Renina/sangre , Sodio/metabolismo , Verapamilo/efectos adversosRESUMEN
Calcium entry blockade may affect the pressor reactivity to vasoconstrictors. The pressor response to norepinephrine and angiotensin II, as well as several other blood pressure modulating factors, were studied in normal subjects (n = 9) and patients with essential hypertension (n = 10) before and after 8 weeks of treatment with the long-acting dihydropyridine amlodipine. In control subjects, calcium entry blockade did not modify blood pressure, the pressor and aldosterone response to angiotensin II, the activity of the renin-angiotensin and sympathetic nervous systems, or urinary dinoprostone (prostaglandin E2) excretion; however, the pressor response to norepinephrine was significantly decreased (p less than 0.01). In patients with hypertension, amlodipine decreased blood pressure (p less than 0.01) and the pressor response to both norepinephrine and angiotensin II (p less than 0.01), without changes in body weight, plasma renin, angiotensin II and catecholamine levels, dinoprostone excretion, or aldosterone responsiveness to angiotensin II. These findings suggest that calcium entry blockade modifies sympathetic-dependent vasoconstriction in both normal subjects and in patients with hypertension. Angiotensin II pressor response may be selectively decreased in essential hypertension.
Asunto(s)
Angiotensina II/farmacología , Antihipertensivos/farmacología , Nifedipino/análogos & derivados , Norepinefrina/farmacología , Adulto , Amlodipino , Presión Sanguínea , Peso Corporal , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Electrólitos/sangre , Electrólitos/orina , Femenino , Frecuencia Cardíaca , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Nifedipino/farmacología , Nifedipino/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
Pressor responses to norepinephrine (NE) or angiotensin II (AII) were studied in 27 diabetic patients without heart or renal failure and in 27 normal subjects. Mean plasma or 24-hour urinary sodium, blood volume and preinfusion plasma NE levels were similar in diabetic and normal subjects; exchangeable sodium was higher (p less than 0.02) and preinfusion plasma renin activity (PRA) was slightly lower in diabetic patients. The NE pressor and threshold doses were lower in diabetic patients than in normal subjects (76 versus 141 and 16 versus 41 ng/kg/min, respectively; p less than 0.05). The AII pressor dose also tended to be lower in diabetic patients (7.2 versus 11.9 ng/kg/min; p less than 0.05), but the AII threshold dose did not differ between the two groups (1.1 versus 1.6 ng/kg/min). These findings were similar in the diabetic subgroup without or with retinopathy (N = 13 and 14, respectively) and in those with normal or high blood pressure (N = 17 and 10, respectively). These observations suggest that in nonazotemic diabetes mellitus increases in AII pressor responsiveness are associated with a concomitant reduction in PRA. However, cardiovascular pressor responsiveness to NE tends to be exaggerated despite normal plasma NE levels and this alteration may occur already in the normotensive stage of diabetes mellitus. Cardiovascular hyperresponsiveness in diabetic subjects may be related to excess body sodium or structural alterations in the vasculature, or both.
Asunto(s)
Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus/fisiopatología , Norepinefrina/farmacología , Adulto , Angiopatías Diabéticas/etiología , Femenino , Humanos , Hipertensión/etiología , Masculino , Persona de Mediana Edad , Presorreceptores/efectos de los fármacosRESUMEN
Interrelations among blood pressure, exchangeable sodium, blood volume and plasma renin activity were studied in 40 normal subjects and in 40 patients with early stage kidney disease (mean plasma creatinine, 2 mg/100 ml). Findings in eight normotensive patients did not differ significantly from those in normal subjects. However, 32 hypertensive patients showed increases (p less than 0.05) in mean exchangeable sodium and in the products of the logarithm of plasma renin activity and exchangeable sodium or blood volume. In normal subjects, blood pressure did not correlate with any of the parameters measured. In the patients, it correlated significantly (p less than 0.05) with duration of hypertension (r = 0.70), exchangeable sodium (r = 0.34) and with sodium-renin (r = 0.38) or volume-renin (r = 0.30) products, but not with blood volume or circulating renin individually. Multiple regression analysis with blood pressure as a dependent variable, and duration of hypertension and the sodium-renin or volume-renin products as independent variables, revealed correlation coefficients of 0.77 and 0.76, respectively. These findings suggest that hypertension accompanying early stage kidney disease may depend at least partly on subtle abnormalities in the sodium volume-renin feedback mechanism as well as on a factor related to the duration of preexisting hypertension.
Asunto(s)
Volumen Sanguíneo , Hipertensión/complicaciones , Enfermedades Renales/complicaciones , Renina/sangre , Adulto , Anciano , Presión Sanguínea , Femenino , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Enfermedades Renales/metabolismo , Enfermedades Renales/fisiopatología , Masculino , Persona de Mediana Edad , Sodio/análisis , Factores de Tiempo , Desequilibrio Hidroelectrolítico/fisiopatologíaRESUMEN
Interrelations among blood pressure, circulatory volume, plasma renin activity (PRA) and urinary catecholamine excretion rates were studied in normal subjects and in patients with benign essential hypertension. Mean plasma or blood volumes related to lean body mass, products of blood volume and the logarithm of PRA, and catecholamine excretion rates did not differ significantly between normal and hypertensive subjects. In both normal subjects and hypertensive patients, blood pressure levels correlated positively with the noradrenaline excretion rate (r = 0.40 and 0.36, respectively; p less than 0.025) but not with adrenaline excretion, circulatory volume or the volume-renin product. The logarithm of PRA correlated inversely with mean blood pressure in normal subjects (r = 0.40; p less than 0.001) but not in hypertensive patients; however, there was no convincing evidence for an inappropriate blood pressure-PRA relationship as a prominent feature in the hypertensive patients. PRA did not correlate with blood volume. Patients with low PRA relative to sodium excretion (21 per cent of hypertensive population) were consistently normovolemic, but they tended to be older and excreted less (p less than 0.025) adrenaline than patients with normal or high PRA. The patient subgroup with high PRA relative to sodium excretion (11 per cent of population) was hypovolemic (p less than 0.02); despite this, urinary sodium output was high (172 +/- 64 meq/24 hours). These data reveal no evidence for major roles of PRA, circulatory volume and free peripheral catecholamines in the maintenance of benign essential hypertension. Essential hypertension with low PRA is usually not a hypervolemic state, but it may reflect diminished adrenergic activity, factors associated with aging and effects of a high systemic pressure. High PRA in benign essential hypertension may be at least partly a consequence of hypovolemia resulting from high blood pressure-induced sodium diuresis.
Asunto(s)
Presión Sanguínea , Volumen Sanguíneo , Catecolaminas/orina , Hipertensión/metabolismo , Renina/sangre , Adulto , Composición Corporal , Estatura , Creatinina/orina , Epinefrina/metabolismo , Humanos , Persona de Mediana Edad , Sodio/orinaRESUMEN
Ketanserin is a selective serotonin-S2 receptor antagonist with alpha 1-adrenoceptor inhibiting activity. The relative contribution of the latter mechanism to antihypertensive efficacy was studied in a group comprising eight normal subjects, 10 patients with essential hypertension and eight diabetics with arterial hypertension. Ketanserin treatment administered over a period of 8 weeks, decreased arterial pressure in patients with essential hypertension and, to a lesser extent, in diabetics, but not in normal subjects. In all three groups, exchangeable sodium, blood volume, the activity of the adrenergic and renin-angiotensin-aldosterone systems and the pressor responsiveness to norepinephrine (NE) or angiotensin II (Ang II) were unaltered, while the pressor reactivity to phenylephrine showed a significant decrease in normal subjects only. This suggests that the antihypertensive mechanism of ketanserin does not involve a modification of the physiological relationship between endogenous noradrenergic and pressor reactivity to NE. Moreover, ketanserin does not interfere with Ang II-dependent mechanisms.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Angiopatías Diabéticas/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Ketanserina/uso terapéutico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/fisiología , Sistema Renina-Angiotensina , Factores de TiempoRESUMEN
Renal clearance of lithium and sodium, glomerular filtration rate, renal plasma flow and certain other parameters of proximal tubular function were determined in 10 normotensive men without, and 13 normotensive men with a family history of essential hypertension after a low- and high-sodium diet. Under low-sodium conditions, the two groups did not differ in mean body weight, exchangeable sodium, plasma renin activity, clearances of inulin, para-aminohippurate (PAH), lithium, sodium, potassium, uric acid or inorganic phosphate, although blood pressure tended to be slightly, but not significantly, higher in those with a family history of hypertension. After changing to the high sodium diet, body weight, exchangeable sodium, and sodium clearance increased and renin decreased significantly (P less than 0.05) and to a similar extent in the two groups; systolic blood pressure increased only in subjects with a family history of hypertension. In both groups renal clearances of inulin, PAH, lithium, potassium, uric acid and inorganic phosphate remained unchanged. These findings do not support the concept that familial predisposition to hypertension is associated with an enhanced proximal reabsorption of sodium. Moreover, the pressor response to a high sodium intake in predisposed subjects is not mediated by an abnormal adaptation of renal sodium metabolism.
Asunto(s)
Hipertensión/genética , Túbulos Renales Proximales/metabolismo , Sodio en la Dieta/metabolismo , Adulto , Presión Sanguínea/efectos de los fármacos , Electrólitos/metabolismo , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Circulación Renal/efectos de los fármacos , Sodio en la Dieta/farmacologíaRESUMEN
The responsiveness of plasma aldosterone to an angiotensin (Ang) II infusion was assessed in normotensive young men, nine without and 13 with a family history of essential hypertension, after 7 days of low (mean urinary sodium 12 +/- 10 mmol/24 h) and 7 days of high (269 +/- 92 mmol/day) sodium intake. Under both conditions, the two study groups did not differ in body weight, arterial pressure, heart rate, plasma or urinary sodium and potassium or plasma renin, aldosterone or Ang II levels. However, after both dietary periods, the relationship between plasma aldosterone and plasma Ang II concentrations had shifted significantly (P less than 0.01) to the right in predisposed compared to non-predisposed subjects. The sodium-related changes in adrenocortical sensitivity to Ang II were similar in the two groups. The pressor response to Ang II did not differ between the two groups of subjects. These findings suggest that, in addition to the known cardiovascular abnormalities of sympathetic, renal and ion transport mechanisms, a fourth area of disturbance involving the response of plasma aldosterone to Ang II may be present in normotensive subjects with familial predisposition to essential hypertension.