Clinical and experimental hypertension. Part A, Theory and practice最新文献

The effects of lifetime captopril treatment on vasopressin (VP) were assessed in spontaneously hypertensive rats (SHR). Pregnant and nursing dams were treated with oral Captopril (100 mg/kg/day). After weaning, the pups were maintained on Captopril (50/kg/day) for 19-20 wks. Blood pressures of Captopril-treated SHR were in the normotensive range and significantly lower (p less than .001) than SHR control rats. Control and Captopril-treated SHR were perfused and brains were sectioned for immunohistochemical staining with a polyclonal antibody directed against vasopressin (VP). Compared to control SHR, Captopril-treated rats displayed decreased VP-like immunoreactivity in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. Captopril treatment also selectively decreased the number of brightly labeled cell bodies in the SON and PVN and reduced VP-like labeling in the axons of the neurons in these nuclei. Concurrent with a decrease in VP-like immunoreactivity, Captopril treatment reduced plasma VP levels (RIA) (p less than 0.01, Captopril, 5.6 +/- 0.5 pg/ml; control, 11.8 +/- 2.2 pg/ml). Scatchard analysis of 3H-VP binding indicated that Captopril treatment increased the number but not the affinity of VP receptors in the hypothalamus and brain stem of SHR. These results suggest that in SHR oral Captopril treatment attenuates the synthesis and release of VP, an effect that may contribute to the blood pressure lowering effect of converting enzyme inhibitors.

Additive combination studies of an angiotensin converting enzyme (ACE) inhibitor, captopril, and a renin inhibitor, ditekiren (U-71038), were carried out in conscious sodium-depleted and sodium replete cynomolgus monkeys. The agents elicited dose-additive hypotensive responses regardless of the order of drug administration in sodium-depleted monkeys. A dose-additive blood pressure response was also observed when the administration of captopril was preceded by ditekiren in conscious sodium replete monkeys. None of the animals in these groups exhibited significant alterations of heart rate. An apparent over-additive hypotensive response, accompanied by tachycardia, occurred in sodium replete monkeys when ditekiren was administered after captopril. It was proposed that the captopril-induced hyperreninemia may have allowed the blood pressure to become partially renin-dependent and therefore susceptible to the inhibitory action of ditekiren. The results of these studies suggested that both ditekiren and captopril elicited cardiovascular effects in conscious cynomolgus monkeys via a decreased formation of angiotensin II.

The concentrations of total ([T-Mg]), ultrafilterable ([UF-Mg]), and protein-bound or nonfilterable ([NF-Mg]) magnesium were measured in the plasma and in the intracellular compartment of blood from 8 essential hypertensive patients and 9 normotensive subjects. In the former, [T-Mg] was unchanged in the plasma but decreased in whole blood due to decreases of both [UF-Mg] and [NF-MG]; [UF-Mg] was increased in plasma but decreased intracellularly while [NF-Mg] was decreased in plasma and unchanged intracellularly. These concentrations correlated significantly with the average blood pressures. Decreased Mg binding to the erythrocyte membrane was also observed in 13 additional essential hypertensive patients. This decreased binding may well be responsible for the decreased intracellular [UF-Mg] in the blood of such patients. The cause of the decreased Mg binding to the erythrocyte membrane is unknown, but the binding is returned to normal by incubating erythrocytes from essential hypertensive patients with blood plasma from normotensive subjects. Decreased Mg binding to cell membranes must also occur in frankly Mg-deficient patients, some of whom, as a consequence of the primary deficiency of this mineral, are hypertensive. Normal Mg binding to erythrocyte membranes was observed in two patients with hypertension indicating that hypertension per se does not cause decreased Mg binding to cell membranes. These observations suggest that decreased Mg binding to cell membranes may be an important contributing factor in some cases of essential hypertension.

A linear discriminant analysis was applied to blood pressure data of 162 first generation colony-born offspring of normotensive (C), hypertensive (H), or borderline hypertensive (B) African green monkeys who were being selectively bred in an attempt to establish a strain of spontaneously hypertensive monkeys. The offspring were classified according to their parents' blood pressures as CC, HH, or Mixed (e.g. HC). Blood pressures were measured by indirect methods from unanesthetized offspring aged 0.5-6 years of age. The discriminant score was used to classify each of the 533 blood pressure measurements of the CC, Mixed, and HH offspring into one of three predicted groups: normotensive, borderline hypertensive, or hypertensive. The group means of the three predicted groups compared without regard to offspring type were significantly different (p less than .001). In addition, the percentage of blood pressure measurements predicted to be normal or elevated differed among the three offspring groups (p less than .001). 82% of the blood pressure measurements from CC offspring were classified as normotensive, compared with 58% and 40% of the blood pressure measurements from the Mixed and HH groups, respectively. In contrast, 25% of the blood pressure measurements from the HH groups were classified as hypertensive, compared with 10% and 4% from the Mixed and CC groups, respectively. Blood pressures of the normotensive, borderline hypertensive, and hypertensive subgroups derived from the CC group were consistently and significantly lower (p less than .001) than their respective counterparts in the Mixed and HH groups. The results of the discriminant analysis indicate a trimodal distribution of blood pressures in the first generation offspring and a significant separation of blood pressures among the offspring after a single generation.

We examined the role of pontine sites in the tonic control of vasomotor tone under normal and reduced tidal volumes. Lidocaine was microinjected in pons at the level of the Kölliker-Fuse nucleus (KFN). Injections were made bilaterally 6, 7, 8, and 9 mm below dura, and 0.9 and 2.5 mm lateral to midline. Lidocaine in KFN produced a fall (-14 mmHg) in mean arterial pressure (MAP) at normal and reduced tidal volumes. These effects were mediated primarily by a reduction in hindquarter vascular resistance. Lidocaine into a ventromedial site (8.0 mm beneath dura, 0.9 mm lateral to midline) increased MAP by increasing renal, mesenteric, and hindquarter vascular resistance. After sino-aortic deafferentation (SAD), reduced tidal volume augmented the pressor and blunted the tachycardic responses to lidocaine injected into the ventromedial pons (9.0 mm beneath dura, 0.9 mm lateral to midline). SAD also enhanced the pressor response to lidocaine injected into ventromedial pons. This work demonstrates a role for supra-medullary sites in the tonic control of vasomotor tone.

The protein kinase inhibitor, staurosporine, was examined for hemodynamic actions in conscious rats and for its effects on isolated vascular smooth muscle. In conscious normotensive rats, staurosporine, 0.1 to 1.0 mg/kg intravenous, produced a dose-related decrease in blood pressure. Doses of 0.1 and 0.5 mg/kg produced reflex tachycardia, while heart rate decreased following 1.0 mg/kg. Higher doses of staurosporine (5 and 10 mg/kg), although not significantly altering heart rate, caused a precipitous drop in blood pressure and all rats died within 48 hours of treatment. Spontaneously hypertensive rats were significantly more sensitive than normotensive rats to the blood pressure lowering effects of staurosporine. The depressor activity of staurosporine was also observed in cord-stimulated pithed rats indicating that hypotension is a peripherally- rather than centrally-mediated effect of staurosporine. In ring preparations of rat thoracic aorta, staurosporine (3 nM to 0.1 mM) produced a concentration-dependent inhibition of serotonin-induced contraction, consistent with its ability to lower blood pressure by an effect at a peripheral vascular site. These results provide the first documentation of the potent cardiovascular activity of staurosporine in the conscious rat and support the contention that protein kinases, in particular protein kinase C, may be important in the regulation of vascular tone.

We conducted a randomized, double-blind, cross-over comparison of six weeks' treatment with 5 mg clopamide or with 25 mg hydrochlorothiazide in 17 hypertensive patients (average age 62 years). No significant differences were found between the two treatments in blood pressure control, plasma biochemical values, body weight or response to a comprehensive "quality of life" questionnaire. Despite the apparently identical performance of both drugs, significantly (x2 = 4.76; P less than 0.05) more patients expressed a preference for clopamide (12) than for hydrochlorothiazide (3). Two had no preference. Current quality of life assessments are relatively insensitive and patient preference remains a valid discriminator between otherwise comparable medications.

The precise mechanism of the diuretic and natriuretic effects of Atrial Natriuretic Factor (ANF) is still unclear. The present study was undertaken with the aim of elucidating the mechanism of interaction between ANF, dopamine (DA) and DA receptors in the renal effects of ANF in rats. In pentobarbital anesthetized rats, ANF infusion (10 micrograms/kg/hour) produced marked diuresis and natriuresis which was accompanied by significant hypotension, bradycardia and also a modest increase in glomerular filtration rate. However, there was no accompanying increase in urinary DA excretion during ANF infusion. Pretreatment with SCH 23390, a selective DA-1 receptor antagonist caused significant attenuation of the diuretic and natriuretic effects of ANF whereas the hemodynamic changes produced by ANF were still evident in SCH 23390 treated animals. Plasma ANF levels were elevated to the same magnitude in both the control and SCH 23390 treated groups. Pretreatment with carbidopa, a dopa decarboxylase inhibitor also significantly blunted the diuretic and natriuretic effects of ANF. The antagonism of the ANF-induced diuresis and natriuresis by SCH 23390 and carbidopa was comparable in magnitude. These results suggest that endogenous DA, via activation of DA-1 receptors plays a permissive role in the renal effects of ANF, perhaps by enhancing tubular responsiveness to ANF. However, there does not appear to be a stimulatory effect of ANF on renal DA production or release.