Effect of ovariectomy and estrogen replacement on cardiovascular disease in heart failure-prone SHHF/Mcc- fa cp rats.

The importance of endogenous and exogenous estrogen levels to the development of cardiovascular disease in women in controversial. The purpose of our study was to examine the effect of estrogen on the development of hypertension, cardiac hypertrophy, ventricular function, and gene expression for atrial natriuretic peptide (ANP) and components of the renin angiotensin system in spontaneously hypertensive heart failure rats (SHHF/Mcc- facp). Development of hypertension was prevented in 3-month-old ovariectomized rats receiving subcutaneous 17 beta -estradiol implants (EST) compared to ovariectomized (OVX) and controls (CON). EST had the least left ventricular hypertrophy, CON were intermediate, and OVX had the most (P<0.05), correlating well with systolic blood pressure. OVX had significantly lower percentage V(1)myosin isoform compared to EST and CON, indicating reversion to a more immature phenotype associated with hypertrophy. Similarly, OVX had decreased percentage left ventricular shortening fraction by echocardiography compared to EST and CON. These changes were not accompanied by alterations in plasma ANP, or in expression of mRNA for left ventricular ANP, renal renin, or hepatic angiotensinogen. Serum angiotensin converting enzyme activity was lower in EST compared to CON or OVX. When 17 beta -estradiol was given to 17-month-old rats that had naturally ceased estrous cycling, there was no effect on hypertension, progression of cardiac functional decline, or survival. In conclusion, estradiol treatment given prior to the development of hypertension in SHHF prevented left ventricular hypertrophy and hypertension. Development of congestive heart failure was not delayed if 17 beta -estradiol was begun in the post-menopausal period. Effectiveness of estrogen therapy may depend on age or whether hypertension is already established at the time treatment is begun.     

雌激素及其受体对心血管系统保护作用实验研究进展

雌激素对心血管系统具有重要的保护作用。雌激素及其受体主要通过调节血管舒张功能、抑制血管平滑肌细胞增殖和迁移以及影响肾素 -血管紧张素等介导这一保护作用。但临床上雌激素替代治疗尚未得到肯定 ,需进一步研究     

甲状腺激素对心血管系统的影响

甲状腺激素在体内有广泛的生理作用,对心血管系统的功能状态有一定的调节和促进作用,体内甲状腺激素代谢紊乱可导致心血管系统疾病.甲状腺激素可以通过核内、核外等机制直接对心肌细胞产生影响,增加心脏收缩力和心肌耗氧量;另一方面,甲状腺激素也可以引起血液动力学变化,并通过对交感神经系统的影响增强儿茶酚胺对心肌的作用.     

Dissociation of the responses of the renin-angiotensin system and sympathetic nervous system to a vasodilator stimulus in congestive heart failure

The ability of neurohumoral reflex control mechanisms to respond to a vasodilator mediated alteration in hemodynamic status was studied. A sodium nitroprusside infusion was administered to 5 normal subjects and 47 patients with severe congestive heart failure resulting in significant decreases in mean arterial pressure and in systemic vascular resistance. As expected in normals the vasodilator stimulus caused a reflex activation in both the renin-angiotensin system and sympathetic nervous system as measured by increased plasma renin activity and plasma norepinephrine, respectively. In the patients with heart failure, plasma renin activity rose similarly in response to nitroprusside (+63% in heart failure, 100% in normals, P = NS) while plasma norepinephrine remained essentially unchanged (+11% in heart failure, 98% in normals, P less than 0.01). These data demonstrate that the neurohumoral dysfunction seen in patients with heart failure is not uniform. In patients with severe congestive heart failure the renin-angiotensin system apparently is activated by mechanisms other than sympathetic nervous stimulation. This intact reflex humoral response may still function in opposition to the beneficial hemodynamic effects produced by direct vasodilators such as nitroprusside.     

Opiate receptor antagonism in right-sided congestive heart failure. Naloxone exerts salutary hemodynamic effects through its action on the central nervous system

Opiate receptor inhibition causes adrenergic receptor-mediated increases in aortic pressure, cardiac output, and left ventricular contractile function in right heart failure. To study whether the effects of opiate receptor inhibition are mediated by means of an action on the central opiate system, we administered equimolar doses of naloxone hydrochloride and naloxone methobromide (MeBr) and normal saline to heart failure dogs. Chronic stable right heart failure was produced by progressive pulmonary artery constriction and tricuspid valve avulsion. Naloxone hydrochloride caused an increase in mean aortic pressure, cardiac output, left ventricular dP/dt and dP/dt/P, plasma catecholamines, and regional blood flows to the myocardium, quadriceps muscle, kidneys, and splanchnic beds. Plasma beta-endorphin and adrenocorticotropin also increased. In contrast, neither normal saline nor naloxone MeBr (which does not cross the blood-brain barrier) affected the systemic or regional hemodynamics or neurohormones. Naloxone hydrochloride was also administered to anesthetized heart failure dogs. Pentobarbital anesthesia removed cortical perception of nociceptive stimulation, reduced the increase in plasma epinephrine, and abolished vasodilation in skeletal muscle that occurred in conscious dogs after naloxone hydrochloride administration but had no major effects on responses of plasma norepinephrine, systemic hemodynamics, or other regional blood flows to opiate receptor inhibition. Naloxone hydrochloride had no effect in sham-operated dogs. The results indicate that the hemodynamic effects of naloxone are mediated by an action within the central nervous system. Furthermore, since pentobarbital anesthesia did not markedly alter the hemodynamic responses to naloxone hydrochloride, the acute salutary effects of opiate receptor inhibition probably are not caused by removal of the antinociceptive effect of endogenous opioids in heart failure.     

Prolactin's mitogenic action on the pigeon crop-sac mucosal epithelium involves direct and indirect mechanisms

It has long been known that prolactin (PRL) induces proliferation of the mucosal epithelial lining of the pigeon crop-sac. This system was used to study possible interactions of other hormones with PRL's mitogenic effect directly on the crop-sac cells. Injection of a sheep pituitary powder into the loose skin between the leg and abdomen of pigeons increased the responsiveness of the crop-sac to direct, local application of PRL. Similar systemic injections of anterior pituitary hormones, ACTH and TSH (alone or together), or a combination of LH and FSH, were without effect on the local response to PRL. However, systemically injected PRL and GH resulted in a dramatic augmentation of the response of the organ to local injection of PRL. PRL was more potent than GH in this regard. These results suggest that PRL has at least two modes of action as a mitogen on this epithelium—its well-known direct action on the cells and an indirect action as well that is possibly mediated by the secretion of another factor into the blood stream. Because it was previously found that somatomedin-like molecules, including proinsulin, act synergistically with PRL to promote proliferation of these cells when coinjected locally with PRL (T. R. Anderson, J. Rodriguez, D. S. Pitts, E. M. Spencer, and C. S. Nicoll, 1983, In “Insulin-like Growth Factors/Somatomedins,” de Gruyter, Berlin), the effects of systemic injections of proinsulin were also tested. Proinsulin had a potentiating effect similar to that of the pituitary powder and of GH or PRL. These results are consistent with the following interpretations: When PRL promotes crop-sac proliferation to produce crop-milk in pigeons and doves, the hormone acts through at least two mechanisms. One of these is a direct effect on the crop-sac, which sensitizes the mucosal epithelium to the mitogenic action of a somatomedin-like growth factor. The second effect is an increase in the production and/or secretion of the factor, which then acts synergistically with PRL to promote proliferation of the crop-sac mucosal cells. More direct evidence for this proposal was provided by the finding that serum from saline- or PRL-treated pigeons did not stimulate crop-sac mucosal growth when it was injected locally. However, the serum from PRL-treated birds had a much higher level of an activity that augmented the effects of PRL when the sera were locally injected in combination with PRL. This synergist has been tentatively named “synlactin.” The possibility that the PRL-induced cell proliferation in other target organs may also involve a synlactin-like mechanism was discussed.     

Differentiation of drugs acting centrally upon the cardiovascular system by means of sympathetic and vagal responses.

The response pattern of the autonomic nervous system was investigated after central administration (intra-cisternal, vertebral artery) of amphetamine, morphine, fentanyl, dextromoramide and the substance R 28935, chemically related to the neuroleptic agent pimozide. Effects on the sympathetic system were measured by recording electrical discharges of fibres of the (preganglionic) major splanchnic nerve in anaesthetized cats; those on the vagal system by recording the heart rate in anaesthetized dogs under beta-adrenoceptor blockade; the baroreceptor reflex was elicited by the blood pressure increase of i.v. injected angiotensin. All substances decreased the spontaneous discharge rate of the splanchnic nerve. Amphetamine facilitated the vagally mediated reflex bradycardia and this was antagonized by the alpha-adrenoceptor blocking agent piperoxan. Amphetamine did not affect the resting heart rate, as has already been shown for clonidine and related substances. The narcotic analgesics lowered the resting heart rate but did not facilitate the baroreceptor reflex response. R 28935 neither influenced resting heart rate nor the baroreceptor reflex response in beta-blocked dogs. On the basis of the vagal response pattern it was therefore possible to distinguish between 3 groups of central hypotensive drugs.     

Menstrual cycle effects on the neurohumoral and autonomic nervous systems regulating the cardiovascular system

Gonadal hormones may affect homeostatic mechanisms regulating the cardiovascular system. We investigated this relationship at five different crucial hormonal time points along the menstrual cycle. Eight eumenorrheic healthy subjects underwent a battery of autonomic tests, hemodynamics, and volume-regulatory hormone measurements. Fluid-regulatory hormones, plasma renin activity, and aldosterone increased along the luteal phase (P = 0.003 and 0.02, respectively), whereas rest supine-corrected hematocrit declined in the course of the menstrual cycle (P = 0.001). Plasma norepinephrine decreased from 1.4 +/- 0.2 to 0.95 +/- 0.1 nmol/liter (P < 0.02) [early follicular (EF) to late follicular]. Thereafter, concentrations gradually returned to EF levels. Lf to Hf domain ratio (spectral analysis of electrocardiogram) showed a difference from that of norepinephrine. The cardiovagal baroreflex sensitivity increased significantly along the luteal phase (P = 0.04). The dose of isoproterenol required to increase heart rate (HR) 15 beats per minute was 0.19 +/- 0.04 microg during the EF time point, and it increased to 0.39 +/- 0.06 microg during the late luteal time point (P = 0.05). However, blood pressure, HR, and their responses to orthostatic stress remained unchanged. Fluctuations in the ovarian hormones along the menstrual cycle are associated with unchanged blood pressure and HR, despite the significant variations in the different homeostatic mechanisms regulating the cardiovascular system.     

Enhanced baroreceptor control of the cardiovascular system by polyunsaturated Fatty acids in heart failure patients.

OBJECTIVES: The intention of this study was to test the hypothesis that, in heart failure patients, dietary supplementation of polyunsaturated fatty acids (PUFA) enhances arterial baroreceptor control of the cardiovascular system. BACKGROUND: Administration of PUFA reduces the risk of life-threatening arrhythmias in patients surviving myocardial infarction. This might result from potentiation of arterial baroreflexes, but whether or not PUFA enhance baroreflex function has never been studied in humans. METHODS: Patients with post-myocardial infarction left ventricular dysfunction underwent beat-to-beat blood pressure (BP) (Finapres, Ohmeda Inc., Englewood, Colorado) and R-R interval (electrocardiogram) recording; baroreceptor reflexes were assessed from the bradycardic and depressor responses to graded neck suction (NS) as well as by computation of the alpha "spontaneous" baroreflex sensitivity index. Assessments were repeated after prolonged treatment with PUFA (2 g/die, n = 15) or placebo (n = 10). RESULTS: Baseline BP and R-R interval were unaffected by PUFA. Both reflex depressor and bradycardic responses to NS increased after PUFA (respectively from -0.09 +/- 0.01 to -0.16 +/- 0.01 mm Hg x mm Hg(-1), p < 0.01, and from 1.25 +/- 0.9 to 1.76 +/- 1.1 ms x mm Hg(-1), p < 0.04) but not after placebo. The spontaneous baroreflex sensitivity increased in the PUFA (from 8.99 +/- 1.4 to 12.2 +/- 1.2 ms x mm Hg(-1), p < 0.02) but not in the placebo group. Polyunsaturated fatty acids (but not placebo) treatment also significantly increased R-R interval total variance and low-frequency and high-frequency spectral powers. CONCLUSIONS: Dietary PUFA supplementation markedly potentiates baroreflex function and enhances heart rate variability in patients with stable congestive heart failure.     

A critical period for estrogen action on neurons of the song control system in the zebra finch.

The song nuclei of the male zebra finch (Poephila guttata) contain larger neurons than those of the female. This gender difference arises after hatching as a result of cell atrophy in the female and cell growth in the male. Implantation of estrogen in female chicks induces masculine differentiation of neurons in their song nuclei. The effects of estrogen on neuron size decline steeply after posthatching day 35 when neuronal atrophy begins. Estrogen loses its masculinizing effects completely after day 45 when the adult level of neuronal atrophy is reached. Thus, the end and the intensity of hormone action appear to be correlated with the timing of neuronal atrophy.     

On the mechanism of prolactin and estrogen action in 7,12 dimethylbenz(A)anthracene-induced mammary carcinoma in the rat. II. In vivo tumor responses and estrogen receptor.

In order to test the in vivo effect of prolactin on estrogen receptor (ER) binding capacity in tumors induced by 7,12 dimethylbenz(a)anthrancene (DMBA-tumor), growth of the tumors from changes in prolactin and estrogen levels was compared retrospectively with cytoplasmic ER levels. It was demonstrated that some tumors required prolactin, some needed prolactin-estrogen during their growth period anda small number were not influenced by hormonal milieu. ER was present in hormonally dependent tumors but was low or absent in hormonaly-independent tumors. Deletion of hormones by endocrine ablation in the host rat resulted in tumor regression loss of ER. Replenishment of ER and subsequent tumor growth were accomplished by injection of prolactin or prolactin-estrogen in endocrine ablated rats but were not achieved in rats bearing tumors exposed to prolactin-nafoxidine. Our results demonstrate that both estrogen and prolactin were essential for growth of hormonally dependent DMBA-tumors. Tumor growth was also prevented when cytoplasmic ER was not replenished , indicating that ER may be an indispensable prerequisite for growth. Prolactin, independently of or cooperatively with estrogen, stimulated ER binding capacity. These results support the hypothesis that there may exist a prolactin regulatory mechanism of estrogen action at the tumor site. The interactions of estrogen and prolactin in situ in modulating hormonal receptor binding capacities may contribute to the overall stimulatory effect of these two hormones on DMBA-tumors.     

Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system.

In addition to the major population of infiltrating leukocytes recovered from inflamed rat central nervous system (CNS), all of which expressed high levels of leukocyte common antigen CD45, many cells were coisolated that were MRC OX42+ (complement receptor 3/CD11b) but expressed low-to-moderate levels of CD45 and major histocompatibility complex (MHC) class I molecules. Most cells from normal CNS, in contrast, lay within this latter, CD45low population. From previous in situ immunohistochemical studies, the fortuitously isolated CD45low cells were probably resident (ramified) microglia. Using irradiation chimeras, we show that resident microglia respond to inflammation by upregulating CD45, CD4, and MHC class I molecules with a minority of these cells increasing their expression of MHC class II molecules. A 3- to 4-fold increase in the number of microglia isolated from inflamed CNS provided indirect evidence that the cells had proliferated. In normal CNS, a very small population of blood-derived CD45high-expressing cells are present; most MHC class II expression is associated with these few cells and not with the resident microglia.     

Lysophosphatidylcholine increases cytosolic calcium in ventricular myocytes by direct action on the sarcolemma.

Lysophosphatidylcholine (LPC) accumulates in myocardial tissues during ischemia, and has toxic effects which may contribute to the arrhythmias and relaxation abnormalities that occur during acute ischemia. These effects of LPC may be mediated in part by calcium overload. To test this hypothesis, spontaneously contracting cultured embryonic chick ventricular myocytes were superfused with various concentrations of LPC (10, 50 and 100 microM) while effects on contractile motion (video motion detector) and changes in free intracellular calcium ion concentration ([Ca2+]i indo-1 fluorescence) were determined. At concentrations greater than or equal to 10 microM, a dose-related, time-dependent effect occurred after exposure to LPC, consisting of the development of contracture and marked elevation of [Ca2+]i. LPC also produced a dose-related, time-dependent inhibition of K+ uptake, indicating there was inhibition of the Na(+)-K+ ATPase Na+ pump. However, the LPC-induced increase in [Ca2+]i was not due to Na+ overload caused by inhibition of the Na(+)-K+ ATPase Na+ pump because superfusion with a zero-Na+ solution did not prevent an increase in [Ca2+]i after LPC exposure; and the increase in [Ca2+]i after exposure to LPC occurred too rapidly to be accounted for by Na+ pump inhibition. Removal of extracellular Ca2+ prevented the rise in [Ca2+]i, after exposure to LPC but treatment with verapamil failed to inhibit the increase in [Ca2+]i induced by LPC. We conclude that LPC produces contracture due to an increase [Ca2+]i. These effects are seen at concentrations of 10 microM and greater, are not due to altered Na(+)-K+ ATPase Na+ pump or calcium channel function, and are probably related to the detergent properties of this amphiphile. There effects may account in part for myocardial dysfunction during ischemia in intact tissue.