VASOACTIVITY GENERATED FROM PLATELETS BY IMMUNE COMPLEXES IN PRE-ECLAMPSIA

Circulating immune complexes in excess of the equivalent of 20 micrograms/ml heat-aggregated IgG were found in fourteen out of twenty patients diagnosed as having preeclampsia. Only six of the nineteen controls tested had similar levels of immune complexes. Recent studies have established that concentrations of heat aggregated IgG in excess of 20 micrograms/ml activate human platelets to release sufficient concentrations of vasoactive agents to constrict a human blood vessel in vitro. It is therefore suggested that in vivo platelet activation by circulating immune complexes may release sufficient concentrations of vasoactive agents to contribute to the hypertension in pre-eclampsia.     

ROLE OF UTERINE FACTORS IN THE DEVELOPMENT OF HYPERTENSION IN SHR

1. To examine whether the uterine environment plays a role in the development of hypertension in the spontaneously hypertensive rats (SHR), we have compared fetal weight, placental weight, and amniotic fluid composition of SHR and Wistar-Kyoto (WKY) rats after 20 days of gestation. 2. Pregnant SHR and WKY were anaesthetized at 20 days of gestation and the uterus and embryonic sacs removed. Fetal and placental weights were recorded and amniotic fluid collected for measurement of volume, osmolality and electrolyte composition. 3. No significant difference was found in litter size and placental weight between SHR and WKY. Total embryonic sac weight and fetal weight of SHR were significantly lower than WKY. Amniotic fluid volume, sodium concentration and osmolality of SHR were significantly higher than WKY, while amniotic fluid potassium concentration of SHR was significantly lower than WKY. 4. Thus, the SHR foetus was significantly underweight compared to the WKY and was bathed in amniotic fluid with a significantly higher osmolality and sodium concentration. As the mature foetus is known to drink amniotic fluid, it is hypothesized that the elevated Na/K ratio in SHR amniotic fluid may instigate or accelerate the hypertensive process.     

DEVELOPMENT OF ANGIOTENSIN CONVERTING ENZYME IN FETAL LUNG AND PLACENTA OF THE RAT AND HUMAN

Angiotensin converting enzyme (ACE) activity in fetal lung and placenta was determined by the method of Cushman and Cheung (1971) during the second trimester of human pregnancy and throughout the rat gestation. The enzyme activity in the neonatal rat lung was also determined during the first 19 days of life. The enzyme activity in both tissues of both species increased with gestation. The activity in human fetal lung at the end of the second trimester was already 70% of that present in the adult human lung while rat fetal lung enzyme activity at term was only 15% of the adult value. The activity in the term placenta of the human and rat was respectively 13% and 5% that of the adult lung value. Developmental increases in enzyme activity continued in the neonatal rat lung till adult value at about 19 days postpartum. The pattern of fetal lung enzyme development in the rat resembled that of the rabbit fetal lung as determined by other investigators using different techniques but was different from that of the human. The findings support the suggestion that ACE in the lung and placenta play important roles in the maintenance of circulatory homeostasis during the latter part of gestation, at birth and early postpartum, albeit at a different extent in different species.     

AUTACOIDS AND CONTROL OF HUMAN PLACENTAL BLOOD FLOW

1. Humans have a haemochorial, villous placenta. Uterine blood passes through maternal sinuses, bathing placental villi through which fetal blood circulates. Blood flow through each circulation is high and vascular resistance low. This haemodynamic situation is essential for efficient placental function. 2. The low placental vascular resistance is due to a lack of nervous influences together with pregnancy-induced changes promoting vasodilatation. Increases occur in output of the vasodilators prostacyclin and nitric oxide and also in membrane sodium pump activity. 3. Many autacoids are present in umbilical blood. Fetal vessels of the placenta develop intense vasoconstriction in the presence of some autacoids, such as thromboxane A₂ and prostaglandins F_2α and E₂, and respond weakly to others, such as angiotensin II and 5-hydroxytryptamine. Nevertheless, vasodilator influences predominate. 4. The diseases of pre-eclampsia and fetal growth retardation are associated with reduced output of nitric oxide and prostacyclin and with increased production of thromboxane A₂ and endothelin-1. These changes promote vasoconstriction, increased vascular sensitivity to vasoconstrictor stimuli, platelet aggregation and intravascular coagulation, retarding blood flow and feto-placental growth. 5. Aspirin and glyceryl trinitrate have been investigated for possible therapeutic use in pre-eclampsia and fetal growth retardation. Improved drug therapy is likely as knowledge increases of the importance of autacoids in normal placental function and in the changes that occur during disease.     

GOOD VIBRATIONS? RESPIRATORY RHYTHMS IN THE CENTRAL CONTROL OF BLOOD PRESSURE

1. Arterial blood pressure is maintained, and reflexly controlled, by the activity of neurons in the medulla and spinal cord. 2. Rhythmic, automatic, respiratory activity is generated by neurons in the ventral medulla and transmitted to pre-motoneurons and motoneurons in the medulla and spinal cord. 3. Sympathetic nerve activity often has a respiratory rhythmicity. 4. One site at which the interaction between respiratory and sympathetic neurons occurs is the ventrolateral medulla. 5. Different types of sympathetic neurons, such as muscle vasoconstrictor, sudomotor and pilo-erector, have different patterns of respiratory rhythmicity. 6. Inputs from medullary respiratory neurons to medullary sympathetic premotor neurons may be the mechanism that co-ordinates the activity of these two vital systems.     

ACCURATE DETERMINATION OF THE SIZE OF THE FIRST INTRON DELETION IN THE RENIN GENE OF SHR FROM AN AUSTRALIAN COLONY

1. It has been reported that the first intron of the renin gene of the spontaneously hypertensive rat (SHR) is shorter than that of the Wistar-Kyoto (WKY) rat, suggesting a role for this difference in the development of hypertension. 2. The genealogy of some Australian SHR colonies has raised doubts about its similarity to the Japanese, American and European colonies. 3. The polymerase chain reaction (PCR) technique has been used with primers identical to the flanking region of the first intron of the renin gene to determine its length in SHR, WKY and Sprague-Dawley (SD) from an Australian colony. 4. The size of the first intron of the renin gene in SHR, WKY and SD was found to be approximately 3870, 4550 and 5000 base pairs, respectively, results which agree with those previously published. 5. It was concluded that the first intron deletion, and its size, has been conserved in an Australian SHR colony.     

AUTACOID INTERACTIONS IN THE REGULATION OF BLOOD FLOW IN THE HUMAN PLACENTA

1. Interactions between autacoids may play important roles in the regulation of blood flow in the foetal placenta. In order to investigate this aspect of placental haemodynamics, human normal-term placentae were perfused in vitro and the responses of the foetal vessels to various combinations of vasoactive agents were determined. 2. Vasoconstriction responses to 5-hydroxytryptamine (5-HT) were potentiated in the presence of endothelin-1 (ET-1), the thromboxane A₂-mimetic U46619 and a nitric oxide synthase inhibitor, N-nitro-l -arginine (NOLA), but not in the presence of angiotensin II. 3. N-Nitro-l -arginine caused vasoconstriction of the perfused placenta and indomethacin attenuated this effect and blocked the potentiation of the 5-HT response by NOLA. 4. Indomethacin did not affect ET-1-induced pressure increases and infusion of U46619 had no effect on release of ET-Iike immunoreactivity into the foetal placental circulation. 5. The present study provides evidence of interactions between several autacoids in human perfused placentae in vitro. These interactions may play important roles in foetal placental haemodynamics in normal or pathological situations.     

MODULATION OF VASOCONSTRICTION BY ENDOTHELIUM-DERIVED NITRIC OXIDE: THE INFLUENCE OF VASCULAR DISEASE

1. The endothelium makes a significant contribution to the regulation of vascular tone through the release of potent vasodilator agents such as nitric oxide (NO) and prostacyclin (PGI₂) as well as vasoconstrictor compounds such as endothelin. Recognition of this function of the endothelium has created a new focus for the investigation of vasoconstrictor activity under physiological and pathological conditions. 2. It has been well established that removal of the endothelium enhances responses to a variety of contractile agents in conductance arteries and that such modulation is predominantly due to the release of NO. The use of selective inhibitors of NO synthesis has confirmed that the endothelium-derived nitric oxide also modulates constriction in resistance vessels. 3. In a number of cardiovascular disease states there is impairment of endothelial function. Thus one of the consequences of atherosclerosis, hypertension and ischaemia is a reduction in endothelium-dependent vasodilatation, both at a basal level and in response to endogenous and exogenous stimuli. In addition, enhanced responses to vasoconstrictors have been reported in those disease states. Such observations have led to the attractive hypothesis that enhanced constriction in vascular disease results from attenuate NO-induced dilatation. However, whilst there is some evidence that pathological impairment of endothelial function is accompanied by increased constrictor activity, particularly where serotonergic mechanisms are involved, it is inappropriate to make the general assumption that where disease impairs NO activity there will also be increased sensitivity to all constrictor stimuli.     

STRUCTURAL INFLUENCES ON RESISTANCE IN THE HINDLIMB VASCULAR BED OF THE RENAL HYPERTENSIVE RABBIT

1. The contribution of arteriolar structural change to hindlimb vascular resistance was examined in the renal wrap hypertensive rabbit. 2. Haemodynamic variables were recorded at rest and after maximal vascular dilation using sodium nitroprusside and peripheral autonomic effector blockade. In the same animals at the end of experiments, morphometric measurements of hindlimb muscle arterioles were made. 3. Mean arterial pressure (MAP) and hindlimb vascular resistance were elevated in hypertensive animals compared with normotensive animals at rest and after maximal dilation. 4. Lumen area and lumen diameter were reduced whereas wall area and wall area to lumen area ratio were increased in hypertensive animals compared with normotensive animals. 5. In the renal wrap model of hypertension, the reduction in lumen area of arterioles, < 200 pm in diameter, is sufficient to explain the increase in haemodynamic resistance.     

MATERNOFETAL TRANSFER OF PHENYTOIN, p-HYDROXY-PHENYTOIN AND p-HYDROXY-PHENYTOIN-GLUCURONIDE IN THE PERFUSED HUMAN PLACENTA

1. Transplacental transfer of the anti-epileptic agent phenytoin (PHT), its phase I metabolite, p-hydroxy-phenytoin (p-OH-PHT), and its phase II conjugate p-OH-PHT-glucuronide, was studied in term placental lobules perfused single pass in both maternal and fetal circuits. 2. Ratios of clearance of PHT, p-OH-PHT and p-OH-PHT-glucuronide to clearance of antipyrine were 1.08 +/- 0.03, 0.52 +/- 0.02 and 0.12 +/- 0.01 (mean and s.e.m.), respectively. 3. Transfer was positively correlated with lipophilicity as measured by the apparent partition coefficient determined between octanol and pH 7.4 buffer.     

THE EFFECT OF PRAZOSIN THERAPY ON PLATELET ACTIVATION IN ESSENTIAL HYPERTENSION

1. Plasma levels of beta-thromboglobulin, initial and total platelet aggregation (induced by adrenaline or adenosine diphosphate [ADP]) were determined in 26 normotensive subjects and 26 patients with untreated essential hypertension. Groups of 18 essential hypertensive patients and 18 age- and sex-matched normotensives were compared. 2. After 7 days of treatment with prazosin in a dose of 2-8 mg daily the above measures were repeated in 18 essential hypertensive patients. A significant increase in plasma levels of beta-thromboglobulin, initial and total adrenaline-induced as well as ADP-induced platelet aggregation was found in hypertensives. Prazosin restored the mean arterial blood pressure in hypertensives to normal, but it had no significant influence either on increased beta-thromboglobulin levels or on initial and total aggregability. 3. The results confirm increased platelet aggregation and in vivo platelet activation in patients with essential hypertension; however there is a discrepancy with previous reports about those results obtained after prazosin therapy. The results suggest that increased platelet aggregation and in vivo activation need not be restored to normal after effective antihypertensive therapy alone. They give reason for the combination of antihypertensive together with anti-aggregatory therapy in essential hypertension.     

VASCULAR SMOOTH MUSCLE POLYPLOIDY IN THE DEVELOPMENT AND REGRESSION OF HYPERTENSION

1. Two groups of spontaneously hypertensive rats (SHR) were treated with enalapril (25-30 mg/kg per day): Group I received treatment from 4 to 14 weeks of age to inhibit development of hypertension and Group R received the drug from 14 to 20 weeks of age to reverse established hypertension. 2. Systolic blood pressure, ploidy of aortic smooth muscle cells (flow cytometric DNA analysis) and aortic hypertrophy (medial cross-sectional area) were determined at times both during and after enalapril treatment (up to 30 weeks). 3. Enalapril treatment normalized blood pressure to that of age-matched Wistar-Kyoto rats in both groups. Blood pressure rose again following cessation of treatment. 4. In untreated SHR the incidence of polyploid cells increased concomitantly with increasing pressure throughout the time studied, whereas in Group I the incidence remained low. In Group R, the incidence of polyploidy directly paralleled both the decrease (normalization) and the rise in blood pressure following cessation of treatment. 5. Hence, the incidence of vascular smooth muscle cell polyploidy is not simply a result of growth of the vessel with increasing age of the SHR, but parallels inhibition, reversal, and redevelopment of hypertension.     

ROLE OF NITRIC OXIDE IN THE CONTROL OF THE RENAL MEDULLARY CIRCULATION

1. Nitric oxide (NO) has been implicated as an important controller in the short- and long-term regulation of arterial pressure. Studies performed in our laboratory have demonstrated that chronic intravenous administration of the NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME) selectively decreases renal medullary blood flow, causes sodium and water retention and leads to hypertension. 2. To determine the importance of the renal medullary effects in this model of hypertension, further studies were conducted to examine the influence of selective stimulation or inhibition of renal medullary NO on whole kidney function and cardiovascular homeostasis. With the use of a unique catheter to directly infuse into the renal medullary interstitial space, stimulation (bradykinin or acetylcholine) or inhibition (L-NAME) of renal medullary NO selectively increased or decreased renal medullary blood flow. 3. The changes in medullary flow in these experiments were associated with parallel changes in sodium and water excretion independent of alterations in renal cortical blood flow or glomerular filtration rate. 4. Studies were then undertaken to examine the long-term effects of selective NO inhibition in the renal medulla on cardiovascular homeostasis. Chronic infusion of L-NAME directly into the renal medullary interstitial space of uninephrectomized Sprague-Dawley rats led to a selective decrease in renal medullary blood flow that was sustained throughout the 5 day L-NAME infusion period. The decrease in medullary blood flow was associated with retention of sodium and the development of hypertension and the effects were reversible. 5. The data reviewed indicate that NO in the renal medulla has a powerful influence on fluid and electrolyte homeostasis and the control of blood pressure.     

ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN HYPERTENSION PRODUCED BY UNILATERAL RENAL ARTERY CONSTRICTION IN THE RAT

1. Conscious rats which had undergone unilateral renal artery constriction were infused for 1 h with a specific antagonist of angiotensin II, 1-Sar-8-Ala-angiotensin II (P-113). 2. There was a highly significant correlation between the change in blood pressure induced by P-113 and the pre-infusion plasma renin concentration (PRC), regardless of initial blood pressure or the duration of stenosis. However, the blood pressure fall was not significantly greater in nineteen hypertensive rats than in eleven which remained normotensive. P-113 did not abolish the hypertension. 3. The extent to which angiotensin II supports blood pressure in rats with renal artery constriction is directly related to the PRC.     

香蕉采后生理研究

香蕉(Musa acuminata Vwarf Cavendish AAA组)采收后在20～30℃室温下后熟,一般经两周后出现呼吸跃交,呼吸速率从刚采收的20～30mgCO_2·kg~(-1)·h~(-1)(27℃测定)急剧上升至120～150mgCO_2·kg~(-1)·h~(-1),以后下降。末成熟(熟度70～30％)的香蕉含淀粉较高,约10～14％,可溶性糖在1％以下;随着成熟度的增加,淀粉逐渐水解,至完熟时,下降至1％以下,可溶性糖则增至15～18％。淀粉转化与呼吸跃变的高峰期基本同时出现。呼吸高峰过后,含糖量下降。果皮叶绿素含量随果实成熟而下降,从10mg·100g~(-1)下降至3～7mg·100g~(-1)。完熟后期果皮渐变为黄褐色。果肉含水量随果实成熟从76.27％增至81.14％;果肉与果皮的比率则从1.14增至1.81。经保鲜剂处理的香蕉果实,其呼吸跃变的出现以及淀粉的分解和可溶性糖的积累均延迟约7天,呼吸高峰值亦略降低,但对淀粉和糖的最终含量无显著影响。生产上可根据香蕉采后生理特性,使用综合保鲜技术,延缓生理进程,防止病害侵染,以延长果实的寿命。     

ON THE ROLE OF SEROTONIN IN THE PATHOGENESIS OF PULMONARY HYPERTENSION INDUCED BY ANORECTIC DRUGS; AN EXPERIMENTAL STUDY IN THE ISOLATED PERFUSED RAT LUNG II. FENFLURAMINE, MAZINDOL, MEFENOREX, PHENTERMINE AND R 800

1. The influence of the anorectic drugs fenfluramine, mazindol, mefenorex, phentermine and R 800, an experimental compound, on pulmonary vascular resistance has been studied in the isolated, perfused rat lung. 2. R 800 caused a strong vasoconstriction, which was not antagonized by methysergide or phentolamine; the other drugs listed did not alter vascular resistance. 3. Mazindol and phentermine significantly prolonged the vasoconstrictive effect of serotonin due to inhibition of its metabolic breakdown. 4. Although fenfluramine inhibited serotonin metabolism it also prevented the vasoconstrictive effect of serotonin, due to its ability to act as a serotonin antagonist. 5. Mefenorex did not affect pulmonary vascular resistance, either directly or indirectly via a serotoninergic mechanism.     

EFFECTS OF AUTONOMIC BLOCKADE ON THE HYPERTENSIVE RESPONSE OF THE FETUS TO HYPEROSMOLALITY

1. Infusions of hyperosmotic mannitol to the ewe caused a rise in fetal arterial pressure in 17 chronically catheterized fetal sheep aged 120-140 days. The fetal heart slowed in 13 out of 17 of these fetuses. The rise in pressure occurred before there was any rise in fetal urinary osmolality. 2. In seven fetal sheep combined alpha- and beta-adrenoceptor and muscarinic blockade delayed the onset of the rise in blood pressure and no bradycardia was observed. It is concluded that the hypertension was due in part to increased activity of the sympatho-adrenal system, and that any reflex bradycardia that occurred was mediated by the vagus. 3. In three other fetal sheep aged 125-131 days, the cardiovascular responses elicited by infusion of hyperosmotic mannitol to the ewe were not blocked by a specific vasopressin antagonist. Thus vasopressin could not be responsible for either the initial rise in pressure nor the delayed hypertensive response that was not blocked by alpha- and beta-adrenoceptor blockade. 4. Fetal blood volume was maintained even though the changes in plasma osmolality and electrolytes were indicative of a fall in blood volume. Thus changes that threaten maintenance of fetal blood volume seem to induce increased solute and water transport across the placenta or from the extracorporeal fluid compartments.     

ADVANTAGES OF PERMUTATION (RANDOMIZATION) TESTS IN CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY

1. The statistical procedures that are used most commonly in clinical and experimental pharmacology and physiology are designed to test for differences between two means. 2. The classical procedures for detecting such differences are those in which, under the population model of inference, the test statistic is referred to the t- or F-distributions. The validity of statistical inferences from these tests depends on a number of assumptions. Foremost among these is that the experimental groups have been constructed by taking random samples from defined populations. The statistical inferences then apply to the sampled populations. 3. In biomedical research this sampling process is seldom followed. Instead, samples are usually acquired by non-random selection, and are then divided by randomization into experimental groups. This being the case, it is theoretically invalid to use the classical t- or F-tests to analyse the experimental results. 4. The validity of inferences from the classical tests also depends on other assumptions, such as that the sampled populations are normal in form and of equal variance. It is difficult to be certain that these assumptions are fulfilled when group sizes are small, as they usually are in pharmacology and physiology. Breach of them, especially if the groups are unequal in size, can lead to serious statistical errors. 5. Exact permutation tests are designed to make statistical inferences under the randomization model. These conclusions apply only to the results of experiments actually performed. By permuting the statistic of interest, such as the difference between arithmetic means, geometric means, medians, mid-ranges or mean-ranks of randomized groups of observations, the probability is calculated that the observed difference or a more extreme one could have occurred by chance. This inferential process is consistent with the way most biomedical experiments are designed and conducted. 6. Exact permutation tests, or sampled permutation tests based on Monte Carlo random sampling of all possible permutations, can now be performed on personal computers. They are commended to biomedical investigators as being superior to the classical tests for analysing their experimental results when the central tendencies of two independent groups, or of two sets of measurements on the same group, are compared. 7. When there is doubt that the assumptions for t-tests are satisfied, investigators sometimes use non-parametric rank-order procedures such as the Wilcoxon-Mann-Whitney rank-sum test for independent groups or the Wilcoxon signed rank-sum test for paired observations. These procedures are permutation tests for differences between mean-ranks and are invalid tests for differences between medians or means. 8. When experiments are complex and based on randomization rather than random sampling, as in randomized block, Latin square, factorial or split-unit designs, analysis of these by permutation tests is to be preferred on theoretical grounds, though the necessary computer software is not readily available.     

PRESSOR SENSITIVITY TO ANGIOTENSIN I AND ANGIOTENSIN II DURING THE DEVELOPMENT OF EXPERIMENTAL RENAL HYPERTENSION IN THE RAT

Treatment with the potent angiotensin converting enzyme inhibitor perindopril completely prevented any rise in blood pressure in the 2-kidney, 1-clip (2K1C) model of renal hypertension in rats. Withdrawal of this inhibitor was followed by a slow rise in blood pressure. In 2K1C rats treated with perindopril, pressor responses to angiotensin I fell during the treatment period, but returned to normal after the inhibitor was stopped. Pressor responses to angiotensin II (AII) increased during treatment with perindopril; this was presumably due to increased receptor sensitivity consequent on the falls in endogenous AII levels. Responses to AII fell to control levels after the inhibitor was stopped. It is concluded that an increased pressor sensitivity to AII is not the cause of the slowly developing hypertension in the 2K1C model of hypertension, and that the slow pressor response to AII must be due to other factors.     

GIRAFFES,RATS AND MAN – WHAT IS THE IMPORTANCE OF THE ‘STRUCTURAL FACTOR’ IN NORMO- AND HYPERTENSIVE STATES?

1. The normal structural adaptation of heart and vessels to regional changes in load or/and tissue demands is surveyed with respect to its importance for cardiovascular function in normotension as well as in physiological (giraffes) and pathophysiological (e.g. human and rat primary hypertension) variants of high pressure states. 2. At the local level it implies an entirely appropriate adjustment of cardiovascular geometric design according to principles inherent in the LaPlace and Poiseuille laws. However, when generalized to all systemic circuits, as in primary hypertension, it invites to a potentially dangerous positive feedback interaction with even ordinary functional pressor influences. 3. It is further emphasized how resistance vessels, besides the obvious influence of changes in: (i) vascular smooth muscle activity, are greatly affected also by changes of their (ii) geometric design, (iii) wall distensibility, and (iv) transmural pressure, how each of these four parameters can be independently altered and how they interact. Genetic reinforcements and various trophic influences may facilitate the extent and rate of 'structural upward resetting' in primary hypertension, and this resetting also encompasses the barostat mechanisms. 4. Against such a background it is, in fact, from a physiological point of view, more difficult to explain how 85-90% of the population manage to maintain lifelong normotension than to explain why hypertension gradually afflicts the remaining 10-15%. It points to the presence of potentially powerful and durable, negative feedback that are still poorly understood (e.g. Muirhead's renomedullary depressor system).(ABSTRACT TRUNCATED AT 250 WORDS)