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

Abnormalities in cardiovascular Na,K-ATPase ion-transport function and regulation may play an important role in the pathogenesis of hypertension. However, it is not known whether these abnormalities are secondary to the effects of hypertension, such as increased pressure, or reflect an intrinsic abnormality in Na,K-ATPase gene expression and regulation. A genetic model of hypertension was used to address this issue. Na,K-ATPase alpha subunit gene expression in hearts was compared between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Pre-hypertensive, 4-week old SHR hearts exhibited an approximately 4 fold elevation in alpha 1 and 8 fold elevation in alpha 2 mRNA levels compared with age-matched WKY hearts. These SHR mRNA levels remained almost equivalent throughout the development of hypertension at 8 and 16 weeks of age. WKY alpha 1 and alpha 2 mRNA levels exhibited a progressive increase during the same time period. The neonatal alpha 3 mRNA isoform was detected only in pre-hypertensive (4-week) SHR hearts. We conclude that cardiac Na,K-ATPase alpha subunit gene expression is significantly altered in SHR even before the onset of hypertension. These findings suggest that an abnormality in cardiac Na,K-ATPase gene expression constitutes an early, if not primary, event in spontaneous hypertension.

The present paper summarizes our studies on the role of beta-2 adrenoceptor mediated vasodilatory mechanisms in the cardiovascular defense response of spontaneously hypertensive rats (SHR) and presents new data on the contribution of altered vascular responsiveness to vasodilators. SHR had similar blood pressure but exaggerated plasma norepinephrine (NE) and epinephrine (EPI) responses compared to their normotensive control strain, the Wistar-Kyoto (WKY), while the plasma catecholamine response of the first generation (F1) cross was intermediate. An examination of regional blood flow changes to footshock stress indicated that SHR compared to WKY had greater increases in mesenteric vascular resistance that appeared to be offset by more pronounced decreases in hindquarter vascular resistance. Blockade of beta-2 adrenoceptors, which are densely located in the skeletal muscle vasculature, led to greatly increased pressor responses to stress in SHR but was without effect in WKY. Results of our current work indicate that this response is due to increased stimulation of the beta-2 adrenoceptors during stress rather than to increased vascular reactivity. These results indicate that in SHR relative to WKY, the exaggerated sympatho-adrenal response to stress does not produce greater blood pressure responses because of the offsetting influences upon vasodilation and vasoconstriction.

Specific binding sites for [125I] porcine brain natriuretic peptide-26 ([125I]BNP-26) were investigated in the rat kidney by using receptor autoradiographic and membrane binding techniques. The binding sites were discretely localized in the glomeruli and inner medulla. There were no differences between the localization of [125I] BNP-26 and [125I] alpha-rat ANP binding sites. [125I]BNP-26 binding to solubilized membranes from isolated glomeruli of the rat kidney was saturable, and a single class of high-affinity sites. [125I]BNP-26 bound to two sites in solubilized inner medullary membranes. The rank order of potency to inhibit binding was BNP-26 = alpha-rat ANP (1-28) greater than atriopeptin III [ANP-(103-126)] much greater than atriopeptin I [ANP(103-123)] greater than des-Cys105, Cys121-ANP-(104-126). The possibility that BNP-26 regulates, as a circulating hormone, kidney functions by binding to ANP receptors would have to be considered.

It is recognized that endogenous dopamine (DA) plays an important role in regulation of sodium excretion under certain physiological and experimental conditions. However, the relative contribution of intrarenally produced DA to natriuresis accompanying various degrees of acute volume expansion (VE) still remains to be clarified. In the present study, acute iso-osmotic VEs were performed in pentobarbital-anesthetized rats over a 60 min period. The rats were divided into 3 groups, each received either modest (2.5% body weight), moderate (5% body weight), or large degree of VE (10% body weight), respectively. Acute VE in these three groups evoked pronounced increases in urine output (UV) and urinary sodium excretion (UNaV), which were associated with significant increase in urinary DA excretion (UDAV). Compared to the modest VE (2.5% body weight), moderate VE (5% body weight) produced larger increases in UV (43 +/- 4.7 vs 29.0 +/- 4.7 microliters/min, p less than 0.05) and UNaV (7.8 +/- 0.7 vs 4.7 +/- 1.0 microEq/min, p less than 0.05) with slight but significantly greater increase in UDAV (1.38 +/- 0.06 vs 1.23 +/- 0.02 ng/min, p less than 0.05). Compared to moderate VE (5% body weight), large VE (10% body weight) produced more pronounced increases in UV (91 +/- 14 vs 43 +/- 4.7 microliters/min, p less than 0.01) and UNaV (16 +/- 2.3 vs 7.8 +/- 0.7 microEq/min, p less than 0.01), however the increase in UDAV was similar to that seen during moderate VE. These results suggest that endogenous DA is involved in natriuretic response to various degrees of acute VE. Furthermore, it was discovered that the relative contribution of endogenous DA to overall VE-induced natriuresis is related to some extent to the degree of VE, inasmuch as DA appears to play a greater role in the overall natriuretic response seen during modest to moderate degree of VE.

89 patients were operated on for pheochromocytoma. 61 patients (37 women and 24 men) were available for extended follow-up. The final survey, performed 79.1 +/- 66.9 months postoperatively, provided data on survival, blood pressure tumor recurrence, malignant metastatic lesions, cardiovascular complications and coexisting diseases. There were 4 deaths during the follow-up period, including 2 instances of malignant pheochromocytoma. Permanent normalization of blood pressure was achieved in 38 patients (62.3%). This hypotensive effect was noted in 79.2% of patients with preoperative paroxysmal hypertension and in 40.8% of those with sustained hypertension. Permanent or re-developing postoperative hypertension was noted in 23 (37.7%) patients. This includes 4 cases of malignant pheochromocytoma, 4 cases of recurrent benign pheochromocytoma and 15 cases of essential hypertension. Cardiovascular complications during follow-up were rare and concerned the patients with essential hypertension diagnosed postoperatively.

Stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY) were maintained in isolation or in group to analyze the effect of isolation, one type of emotional stress, on the development of hypertension and its complications. SHRSP kept isolated during the whole or a half of the experimental period developed severer hypertension within a shorter period than those kept together with other animals throughout the experiment, and showed significantly higher incidences of cerebral stroke (40 or 33%) than the latter (8.3%). Histological and pathophysiological studies revealed pituitary-adrenal and cardiac hypertrophy accompanying more accelerated urinary epinephrine (E) excretion which indicated emotional stress caused by isolation might aggravate pathological lesions in hypertension. Neither WKY in isolation nor in groups developed hypertension, although isolated WKY had significantly heavier pituitary and adrenal glands accompanied with more accelerated urinary E and calcium excretions than WKY kept in groups.

Age-related changes in CGRP-containing vasodilator nerve activity in hypertension were studied in perfused mesenteric vascular beds isolated from SHR and normotensive rats (WKY). Perivascular nerve stimulation (PNS; 0.5-8 Hz) of both SHR and WKY preparations with active tone produced a frequency-dependent vasodilator response, which was abolished by 100 nM tetrodotoxin, 500 nM capsaicin or cold storage denervation. This response in SHR greatly decreased with age, whereas the response in WKY slightly decreased with age. The neurogenic vasodilation in 15- and 30-week-old SHR but not 8-week-old SHR was significantly smaller than that in age-matched WKY. Vasodilator responses to exogenous CGRP (0.1-30 nM) in SHR increased with age, whereas an age-related decrease in the vasodilation was found in WKY. Immunohistochemical studies showed an age-related decrease in CGRP-containing fibers in SHR. These results suggest that CGRP-containing vasodilator innervation is greatly decreased when SHR develop and maintain hypertension.

The present study was undertaken to elucidate the anti-tachycardic effect of a direct-acting vasodilator, budralazine, using an electrophysiological technique. Normotensive male Wistar rats were used. Rats were anesthetized intraperitoneally with urethane and alpha-chloralose. Intravenous administration of budralazine (0.5-5.0 mg/kg) produced a dose-dependent reduction of mean arterial pressure in anesthetized rats. At doses of 0.5 and 1.0 mg/kg, budralazine induced bradycardia accompanied with a decrease in cardiac sympathetic nerve activity (ICNA). Preganglionic adrenal sympathetic nerve activity (ASNA) was also reduced by budralazine (1.0 mg/kg). A 0.5 mg/kg of budralazine neither influenced carotid sinus nerve activity nor augmented aortic depressor nerve activity (ADNA). On the contrary, at dose of 5.0 mg/kg, budralazine produced a tachycardia accompanied with increases in both ICNA and ASNA. The ADNA was decreased by budralazine (5.0 mg/kg) significantly. These findings suggest that the central sympathoinhibitory action of budralazine may be responsible for the anti-tachycardic effect of budralazine and baroreceptor-mediated tachycardia occurred after high dose of budralazine.

The current study tested whether the spontaneously hypertensive rats (SHR) from Charles River Laboratories are resistant or not to NaCl-induced rises of blood pressure and deaths. These rats are fairly NaCl-resistant on a 2.1% high K diet, whereas they are quite susceptible to NaCl-induced hypertension and deaths on a 0.5% normal K diet. Thus, a high K diet strongly protects against a NaCl-induced rise of blood pressure as well as deaths in these SHR rats. Hence the level of dietary K determines the degree of NaCl sensitivity in these SHR rats.

A high salt diet produced increases in SBP, urinary protein excretion (UPE) and renal vascular lesions (RVL) across groups of male and female SHR rats which were allowed to develop moderate or excessive increases in SBP. A highly significant linear relationship between SBP and log-transformed UPE was found when the data from all groups were analyzed together. Males developed high blood-pressure more rapidly, and exhibited more severe RVL and greater UPE than females. Two results prevent the conclusion that the elevated UPE was simply due to the adverse effects of high BP on the kidney. First, the relationship between SBP and UPE across groups could not be demonstrated when regression analyses were performed within individual dietary sub-groups. Secondly, gender differences in UPE were highly significant by analysis of covariance adjusting for individual differences in SBP. The increases in SBP and UPE may be independent consequences of ingestion of a high salt diet.