ROLE OF THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS IN CARDIOVASCULAR REGULATION

1. The paraventricular hypothalamic nucleus (PVH) is a complex structure with both neuroendocrine and autonomic functions. It is a major source of vasopressin and the primary source of corticotropin-releasing factor. In addition, parvicellular PVH neurons have reciprocal connections with brain-stem autonomic centres and directly innervate sympathetic preganglionic neurons. Evidence is reviewed which indicates that in conscious rats PVH activation increases blood pressure, heart rate, renal nerve activity and plasma renin activity. 2. In conscious rats, a non-hypotensive haemorrhage (13 mL/kg blood loss over 24 min) results in increased numbers of Fos-immunoreactive cell nuclei within both magnocellular and parvicellular PVH neurons, including the ventral medial parvicellular regions known to contain neuronal projections to brainstem autonomic centres and spinal cord sympathetic preganglionic neurons. 3. Cell-selective ibotenate lesions of the parvicellular PVH significantly blunt the corticosterone response but do not alter blood pressure, heart rate or plasma renin concentration response to non-hypotensive or hypotensive haemorrhage. This and earlier studies indicate that, while the PVH is necessary for the corticosterone response and contributes to increased vasopressin release during blood loss, it does not play an important role in the sympathetic nervous system and renin-angiotensin responses to hypovolaemia and hypotension. 4. There is evidence to indicate that the parvicellular PVH serves as a necessary relay for cardiovascular and renin responses to certain behavioural stressors. We propose that cardiovascular information relayed to parvicellular PVH autonomic regions may be used to modulate behavioural, rather than homeostatic, effects on haemodynamics and renin release.     

INTEGRATIVE ROLE OF THE LAMINA TERMINALIS IN THE REGULATION OF CARDIOVASCULAR AND BODY FLUID HOMEOSTASIS

1. Cardiovascular and body fluid homeostasis depends upon the activation and co-ordination of reflexes and behavioural responses. In order to accomplish this, the brain receives and processes both neural and chemical input. Once in the brain, information from sources signalling the status of the cardiovascular system and body fluid balance travels, and is integrated, throughout a widely distributed neural network. Recent studies using neuroanatomical and functional techniques have identified several key areas within this neural network. One major processing node is comprised of structures located along the lamina terminalis. 2. Structures associated with the lamina terminalis include the median preoptic nucleus (MePO) and two sensory circumventricular organs (SCVO), the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT). Current evidence indicates that blood-borne signals, such as angiotensin II (AngII), reach SCVO (e.g. SFO) where they are transduced. This information is then carried via neural pathways to brain nuclei (e.g. MePO) where it is integrated with other inputs, such as those derived from systemic arterial blood pressure and volume receptors. 3. Because of their receptive and integrative functions, lamina terminalis structures are essential for the normal control of hormone release (e.g. vasopressin), sympathetic activation and behaviours (thirst and salt appetite), which collectively contribute to maintenance of cardiovascular and body fluid homeostasis.     

REFLEX REGULATION OF HORMONAL RESPONSES DURING PREGNANCY

1. During pregnancy in most species, the resting levels of plasma angiotensin II, plasma ACTH (corticotropin) are increased. The concentration of vasopressin is also increased relatively to the osmolality in rats and in humans. 2. In the pregnant state mean arterial pressure is decreased, despite an increase in blood volume. Vasopressin and ACTH responses to hypotension are altered in pregnant ewes; the relationship between mean arterial pressure and vasopressin or ACTH response is shifted to the left, consistent with a change in set-point for regulation of mean arterial pressure. The vasopressin and cortisol responses to hypotensive haemorrhage are also altered in the pregnant dog; in this case the slope of the relation between mean arterial pressure and hormone response is decreased. 3. The decrease in hormone responses to hypotension is stimulus-specific; ACTH responses to hypoglycaemia are increased in the pregnant ewe and AVP responses to hyperosmolality are not altered in the pregnant ewe. 4. The heart rate responses to hypotension are also decreased in pregnant ewes, consistent with the observation that baro-reflex responses are decreased in the pregnant rat. 5. The data suggest that a change in regulation of arterial pressure alters the hormonal responses to hypotension in the pregnant state.     

REGULATION AND ROLE OF UROKINASE PLASMINOGEN ACTIVATOR IN VASCULAR REMODELLING

1. Urokinase plasminogen activator (uPA) is produced and secreted by multiple vascular cell types, thus influencing the processes and the extent to which the vasculature is remodelled during the development of the intima or a neointima and during hypertrophy and angiogenesis. 2. Urokinase plasminogen activator mRNA expression is up- and down-regulated by growth factors, cytokines and steroids. Urokinase plasminogen activator is secreted as a single chain inactive form that may be proteolytically converted to active or inactive forms. Targeting of proteolytic activity may occur via focalized expression of uPA and its cell surface receptors (uPAR). Proteolytic activity is also controlled through the often co-ordinated expression of specific inhibitors. 3. A proteolytic cascade involving uPA provides its major role in tissue remodelling through the primary degradation of extracellular matrix and secondarily through the activation of transforming growth factor-β or release from the matrix of basic fibroblast growth factor. In addition, uPA secreted by growth factor-stimulated vascular cells may contribute to the chemotactic and mitogenic responses ascribed to the growth factor and recent evidence strongly suggests that uPA has direct biological actions on vascular cells. 4. The cell surface binding of uPA via its growth factor-like domain to uPAR localizes and activates the protease, but may also initiate transmembrane signalling of biological responses, including migration/invasion and proliferation. As the uPAR lacks intracellular signalling domains, the signals may be transduced via interactions between uPA/uPAR and more classical signalling receptors. The mechanism by which uPA may be involved in cell signalling is yet to be elucidated.     

EVALUATION OF DRUG-INDUCED RENO-RENAL VASOMOTOR REFLEX IN THE DOG

1. Renal arterial infusions of endogenous vasoactive compounds were administered, and elctromagnetic flow probes were used to measure simultaneous ipsilateral and contralateral renal blood flow. 2. The expected ipsilateral renal blood flow changes resulting from infusions of acetylcholine, noradrenaline, angiotension II, bradykinin and PGE2 were observed. There were no transient, phasic or sustained contralateral renal blood flow changes. 3. These results suggest that a previously hypothesized reno-renal vasomotor reflex communication does not exist. The discrepancies between these present studies and previous ones proposing such a reflex may be due to the methods chosen for measurement of renal blood flow.     

PARTICIPATION OF PROSTANOIDS IN CHEMICAL ACTIVATION OF THE PERICARDIAL PRESSOR REFLEX IN DOGS

1. Experiments were performed on anaesthetized, open-chest dogs to determine the reflex effects on systemic blood pressure and heart rate produced by stimulation of the parietal pericardium with bradykinin, prostacyclin, prostaglandin E₂ (PGE₂), prostaglandin D₂ (PGD₂) and arachidonic acid. 2. Pericardial application of bradykinin (1 μg) consistently elicited reflex increases in blood pressure and heart rate, whereas application of prostanoids or arachidonic acid in doses up to 10 μg failed to produce any cardiovascular responses. 3. Indomethacin, applied either directly to the parietal pericardium (1 μg/ml) or given intravenously (5 mg/kg) caused a long lasting reduction of the reflex responses to bradykinin. The reflex effects of bradykinin could be temporarily restored by treatment of the pericardium with either prostacyclin (0.1 μg/min) or PGE₂ (0.1 μg/min). PGD₂ (0.1-1 μg/min) did not influence the bradykinin induced pericardial reflex. 4. Superfusion of arachidonic acid (3 μg/min) over the pericardium amplified the reflex effects of bradykinin when given before, but not when given after indomethacin treatment. 5. The results indicate that locally formed prostanoids, specifically prostacyclin and PGE₂, can facilitate activation of the pericardial pressor reflex by bradykinin. The findings may be relevant to the changes in cardiovascular activity occurring during pericardial inflammation.     

ALTERED LEVELS OF NEUROPEPTIDES IN THE MEDULLA AND SPINAL CORD OF SPONTANEOUSLY HYPERTENSIVE RATS

1. Spontaneously hypertensive rats (SHR) are useful for investigating the possible pathophysiological and neurochemical basis of human essential hypertension. 2. The accepted pathogenic mechanism of hypertension in SHR is an increased central sympathetic drive which results in an increased peripheral resistance. 3. The neurochemical basis of the increased sympathetic drive is unknown. The observation that there are reduced levels of neuropeptides (vasoactive intestinal peptide, neuropeptide Y, cholecystokinin octapeptide, neurotensin and calcitonin gene related peptide) in the spinal cord in SHR rats compared with age and gender matched Wistar-Kyoto normotensive rats could provide a basis for understanding the mechanism of hypertension in SHR.     

THE BARORECEPTOR-HEART RATE REFLEX IN RENAL HYPERTENSION IN THE RABBIT

SUMMARY 1. The 'steady-state' properties of the baroreceptor-heart rate reflex were studied in twenty-one renal hypertensive and twenty-eight normotensive unanaesthetized rabbits. In each animal, intravascular pressures were varied by inflating balloons previously placed around the aorta and inferior vena cava. An average curve relating mean arterial pressure (MAP) to heart period (HP; pulse interval) was constructed for each group.
2. The average resting MAP was 134 mmHg (s. e. m. = 5.7) in hypertensive and 91 mmHg (s. e. m. = 4.0) in normotensive rabbits. The mean values for resting HP in the two groups were 254 ms (s. e. m. = 13.4) and 258 ms (s. e. m. = 3.2), respectively. The baroreflex-dependent heart period range (HPR) between the lower and upper plateau levels of the MAP-HP curve of hypertensive rabbits was about 80% of the normotensive value. The average gain (change in HP per unit change in MAP) in hypertensives was about 50% of the normotensive value. The threshold pressure for evoking an increase in HP during a rise in MAP, and the median blood pressure (i. e. MAP corresponding to half HPR), were both about 40 mmHg higher in the hypertensive group than in normotensive rabbits.
3. The parameter changes in the MAP-HP curve in renal hypertension are closely similar to those previously observed in patients with essential hypertension of the same severity. The baroreflex changes in essential hypertension are thus probably non-specific accompaniments of chronic blood pressure elevation.     

THE ROLE OF THE MACULA DENSA IN RENIN SYNTHESIS

1. The role of the macula densa in renin synthesis was studied using mice with one hydronephrotic kidney. 2. Renin synthesis was assessed by measurement of renal renin, renal mRNA for renin and plasma renin. 3. Sodium depletion stimulated mRNA and renal renin to a similar extent in the hydronephrotic and contralateral kidney. 4. Enalapril stimulated mRNA concentration in both kidneys but renal renin did not rise in the hydronephrotic kidney. 5. Propranolol did not alter the response to sodium depletion in either kidney. 6. The macula densa is not crucial for the stimulation of renin synthesis following sodium depletion. However, it may regulate renin production after mRNA synthesis, possibly by controlling the conversion of prorenin to renin.     

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.     

胰岛素对淋巴细胞免疫活性的调节作用

以四氧嘧啶糖尿病小鼠为模型,观测模型鼠免疫细胞活性及胰岛素对其脾淋巴细胞DNA合成及白细胞介素2(IL-2)产生的影响。实验结果表明,病鼠在高血糖低胰岛素状态下淋巴细胞DNA合成及IL—2的产生均明显降低(均P<0.01)。将病鼠脾淋巴细胞悬浮于含胰岛素的培液内,其淋巴细胞DNA合成及IL-2产生均显著升高。     

THE ROLE OF THE RENAL NERVES IN RENIN SYNTHESIS

1. Renin synthesis and secretion were studied in Balb/c mice with a denervated left kidney. 2. Denervation inhibited renin secretion. 3. Denervation reduced the renal renin content. 4. Denervation reduced renal renin mRNA. 5. Renal denervation inhibits renin secretion by blocking the synthetic system prior to mRNA formation.     

CD23在银屑病发病中的作用

为了解ｓＣＤ２３及ＣＤ２３在银屑病发病中的意义，采用双抗体夹心ＥＬＩＳＡ法及免疫组化法对３４例银屑病患者血清ｓＣＤ２３水平及皮损ＣＤ２３表达进行了测定，结果显示银屑病患者血清ｓＣＤ２３水平与对照组比较未见明显变化，表明ｓＣＤ２３及ＣＤ２３在银屑病发病中意义不大。     

THE PHARMACOLOGICAL ROLE OF P-GLYCOPROTEIN IN THE INTESTINAL EPITHELIUM

P-glycoprotein, a membrane-associated transport protein, has recently been recognised as an important element of the intestinal epithelium. This paper summarises thein vivodata on the pharmacological role of intestinal P-glycoprotein. These data show that P-glycoprotein contributes to the elimination of many drugs by mediating their direct secretion from the blood into the intestinal lumen. In addition, there is also evidence that this protein can limit oral drug absorption. Hence, inhibition of intestinal P-glycoprotein, e.g. by a reversal agent like cyclosporin A, may be a promising strategy for improving the oral bioavailability of P-glycoprotein substrate drugs. Indeed, several preclinical and clinical studies have shown that coadministration of drugs with a reversal agent can substantially increase oral drug absorption.     

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.