Altered artery mechanics and structure in monocrotaline pulmonary hypertension

Pulmonary hypertension in rats, induced by an injection of monocrotaline, is associated with changes in the wall structure of the pulmonary arterial bed. We have studied the effects of this remodeling on mechanical properties of cylindrical pulmonary artery segments from rats 21 days after monocrotaline (MCT) injection. Resting and active (KCl induced) circumference-tension relationships were established for segments of extrapulmonary and intrapulmonary arteries isolated from the hilum and the fifth lateral branch from the axial pathway (all preacinar). The thicknesses of the vessel wall, the media, and adventitia were measured at several positions around the circumference of the artery by computerized analysis of histological cross sections of the segments fixed at a standard circumference. Resting and active stress were also calculated. The study shows that active circumferential tension and active stress are reduced in vessels from MCT-treated rats. Based on our findings, it is unlikely that altered contractile function of preacinar arteries contributes significantly to the increased vascular resistance seen in this model.     

Tactile neural mechanisms in monotremes

Monotremes, perhaps more than any other order of mammals, display an enormous behavioural reliance upon the tactile senses. In the platypus, Ornithorhynchus anatinus, this is manifest most strikingly in the special importance of the bill as a peripheral sensory organ, an importance confirmed by electrophysiological mapping that reveals a vast area of the cerebral cortex allocated to the processing of tactile inputs from the bill. Although behavioural evidence in the echidna, Tachyglossus aculeatus, suggests a similar prominence for tactile inputs from the snout, there is also a great reliance upon the distal limbs for digging and burrowing activity, pointing to the importance of tactile information from these regions for the echidna. In recent studies, we have investigated the peripheral tactile neural mechanisms in the forepaw of the echidna to establish the extent of correspondence or divergence that has emerged over the widely different evolutionary paths taken by monotreme and placental mammals. Electrophysiological recordings were made from single tactile sensory nerve fibres isolated in fine strands of the median or ulnar nerves of the forearm. Controlled tactile stimuli applied to the forepaw glabrous skin permitted an initial classification of tactile sensory fibres into two broad divisions, according to their responses to static skin displacement. One displayed slowly adapting (SA) response properties, while the other showed a selective sensitivity to the dynamic components of the skin displacement. These purely dynamically-sensitive tactile fibres could be subdivided according to vibrotactile sensitivity and receptive field characteristics into a rapidly adapting (RA) class, sensitive to low frequency (相似文献   

Forebrain mechanisms in neurogenic hypertension

In recent years a considerable amount of experimental evidence has suggested that forebrain structures are involved in the pathogenesis of high arterial pressure (AP). However, little is known about the location and function of these supramedullary structures in the hypertensive process. This report reviews a series of studies done to identify the location and to determine the contribution of some forebrain structures to both the development and maintenance of the elevated AP following selective aortic baroreceptor deafferentation (ABD). In the first series of studies, it was demonstrated that the elevated AP resulting from ABD was associated with increased metabolic activity in several forebrain structures: the paraventricular nucleus of the hypothalamus (PVH), supraoptic nucleus, nucleus circularis, median preoptic nucleus, subfornical organ (SFO), and central nucleus of the amygdala. In the second series, bilateral electrolytic lesions of the PVH were shown to prevent the development of and (or) reverse the elevated AP after ABD. Similarly, bilateral microinjections of the neurotoxin kainic acid into the PVH were shown to reverse the increased AP after ABD. In the final series, electrolytic lesions of the SFO were shown to attenuate the rise in AP after ABD and (or) to reduce the elevated AP to a level that remained above control values. Taken together, these data suggest that the PVH and SFO are components of a neuronal circuit involved in the hypertensive process following ABD, and that the SFO likely exerts its effect through the PVH.     

Vascular neuroeffector mechanisms in hypertension

Recent studies of the peripheral sympathetic nervous system indicate the presence of other vasoactive transmitters in addition to noradrenaline. There is now evidence suggesting ATP to be a co-transmitter of noradrenaline mediating the excitatory junction potential and the phentolamine-resistant component of the vasopressor response. In hypertension, changes in the neural regulation at both pre- and post-synaptic levels have been observed. In the spontaneously hypertensive rat (SHR), abnormal feedback regulation through presynaptic adrenoceptors and increases in release and uptake by the perivascular nerves are well characterized. Whether similar changes in the ATP release mechanism occur in the SHR and other forms of hypertension remain to be determined. A more important role for ATP in the neural regulation of the SHR tail artery has been proposed. In future studies, the possible contribution of co-transmitters to the responses should be taken into consideration.     

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

Nitric oxide (NO) and reactive oxygen species (ROS) play important roles in blood pressure regulation via the modulation of the autonomic nervous system, particularly in the central nervous system (CNS). In general, accumulating evidence suggests that NO inhibits, but ROS activates, the sympathetic nervous system. NO and ROS, however, interact with each other. Our consecutive studies and those of others strongly indicate that an imbalance between NO bioavailability and ROS generation in the CNS, including the brain stem, activates the sympathetic nervous system, and this mechanism is involved in the pathogenesis of neurogenic aspects of hypertension. In this review, we focus on the role of NO and ROS in the regulation of the sympathetic nervous system within the brain stem and subsequent cardiovascular control. Multiple mechanisms are proposed, including modulation of neurotransmitter release, inhibition of receptors, and alterations of intracellular signaling pathways. Together, the evidence indicates that an imbalance of NO and ROS in the CNS plays a pivotal role in the pathogenesis of hypertension.     

Salt-sensing mechanisms in blood pressure regulation and hypertension

High salt consumption contributes to the development of hypertension and is considered an independent risk factor for vascular remodeling, cardiac hypertrophy, and stroke incidence. In this review, we discuss the molecular origins of primary sensors involved in the phenomenon of salt sensitivity. Based on the analysis of literature data, we conclude that the kidneys and central nervous system (CNS) are two major sites for salt sensing via several distinct mechanisms: 1) [Cl(-)] sensing in renal tubular fluids, primarily by Na(+)-K(+)-Cl(-) cotransporter (NKCC) isoforms NKCC2B and NKCC2A, whose expression is mainly limited to macula densa cells; 2) [Na(+)] sensing in cerebrospinal fluid (CSF) by a novel isoform of Na(+) channels, Na(x), expressed in subfornical organs; 3) sensing of CSF osmolality by mechanosensitive, nonselective cation channels (transient receptor potential vanilloid type 1 channels), expressed in neuronal cells of supraoptic and paraventricular nuclei; and 4) osmolarity sensing by volume-regulated anion channels in glial cells of supraoptic and paraventricular nuclei. Such multiplicity of salt-sensing mechanisms likely explains the differential effects of Na(+) and Cl(-) loading on the long-term maintenance of elevated blood pressure that is documented in experimental models of salt-sensitive hypertension.     

Altered behavioural adaptation in mice with neural corticotrophin-releasing factor overexpression

Overproduction of corticotrophin-releasing factor (CRF), the major mediator of the stress response, has been linked to anxiety, depression and addiction. CRF excess results in increased arousal, anxiety and altered cognition in rodents. The ability to adapt to a potentially threatening stimulus is crucial for survival, and impaired adaptation may underlie stress-related psychiatric disorders. Therefore, we examined the effects of chronic transgenic neural CRF overproduction on behavioural adaptation to repeated exposure to a non-home cage environment. We report that CRF transgenic mice show impaired adaptation in locomotor response to the novel open field. In contrast to wild-type (WT) mice, anxiety-related behaviour of CRF transgenic mice does not change during repeated exposure to the same environment over the period of 7 days or at retest 1 week later. We found that locomotor response to novelty correlates significantly with total locomotor activity and activity in the centre at the last day of testing and at retest in WT but not in CRF transgenic mice. Mice were divided into low responders and high responders on the basis of their initial locomotor response to novelty. We found that differences in habituation and re-exposure response are related to individual differences in locomotor response to novelty. In summary, these results show that CRF transgenic mice are fundamentally different from WT in their ability to adapt to an environmental stressor. This may be related to individual differences in stress reactivity. These findings have implications for our understanding of the role of CRF overproduction in behavioural maladaptation and stress-related psychiatric disorders.     

Persistent neural activity: prevalence and mechanisms

Persistent neural activity refers to a sustained change in action potential discharge that long outlasts a stimulus. It is found in a diverse set of brain regions and organisms and several in vitro systems, suggesting that it can be considered a universal form of circuit dynamics that can be used as a mechanism for short-term storage and accumulation of sensory or motor information. Both single cell and network mechanisms are likely to co-operate in generating persistent activity in many brain areas.     

Sex steroids and vascular responses in hypertension and aging

Background: Sex hormones play a significant role in human physiology. Estrogen may have protective effects in the cardiovascular system, as evidenced by the decreased incidence of cardiovascular disease (CVD) in premenopausal compared with postmenopausal women.Objective: This review highlights the acute and long-term effects of sex hormones on the vascular endothelium and vascular smooth muscle (VSM) in adults. Changes in the sex hormone mix, their receptors, and their effects on vascular function in hypertension and aging are also discussed.Methods: Literature collected from the National Centers for Biotechnology Information as identified by a PubMed database search, as well as our experimental work, was used to highlight current knowledge regarding vascular responses to sex hormones in hypertension and in aging.Results: Experiments in adult female animals have shown that estrogen induces endothelium-dependent vascular relaxation via the nitric oxide (NO), prostacyclin, and hyperpolarization pathways. Also, surface membrane estrogen receptors (ERs) decrease intracellular free Ca²⁺ concentration and perhaps protein kinase C-dependent VSM contraction. However, clinical trials such as the Heart and Estrogen/progestin Replacement Study (HERS), HERS-II, and the Women's Health Initiative did not support the experimental findings and demonstrated adverse cardiovascular events of hormone therapy (HT) in aging women. The lack of vascular benefits of HT may be related to the hormone used, the ER, or the patient's cardiovascular condition or age. Experiments on vascular strips from aging (16-month-old) female spontaneously hypertensive rats have shown reduced ER-mediated NO production from endothelial cells and decreased inhibitory effects of estrogen on Ca²⁺ entry mechanisms of VSM contraction. The age-related decrease in ER-mediated vascular relaxation may explain the decreased effectiveness of HT on CVD in aging women.Conclusions: New HT strategies should further examine the benefits of natural estrogens and phytoestrogens. Transdermal estrogen may be more effective than the oral form, and specific ER modulators may maximize the vascular benefits and reduce the risk of invasive breast cancer. Variants of vascular ERs should be screened for genetic polymorphisms and postmenopausal decrease in the amount of downstream signaling mechanisms. HT may be more effective during the menopausal transition than in late menopause. Progesterone, testosterone, or their specific modulators may be combined with estrogen to provide alternative HT strategies. Thus, HT type, dose, route of administration, and timing should be customized, depending on the patient's cardiovascular condition and age, thereby enhancing the vascular benefits of HT in aging women.     

Maps in birds: representational mechanisms and neural bases

The often extraordinary navigational behavior of birds is based in part on their ability to learn map-like representations of the heterogeneous distribution of environmental stimuli in space. Whether navigating small-scale laboratory environments or large-scale field environments, birds appear to be reliant on a directional framework, for example that provided by the sun, to learn how stimuli are distributed in space and to represent them as a map. The avian hippocampus plays a critical role in some aspects of map learning. Recent results from electrophysiological studies hint at the possibility that different aspects of space may be represented in the activity of different neuronal types in the avian hippocampus.     

Neurohumoral mechanisms of sodium-dependent hypertension

The contribution of neurohumoral factors to arterial pressure has been studied in several models of sodium-dependent hypertension including the deoxycorticosterone-saline, Dahl salt-sensitive rats, and reduced renal mass-saline. Observations from these animals have largely pointed to the sympathetic nervous system and arginine vasopressin (AVP) as the critical factors responsible for mediating the increased arterial pressure. Our work has indicated that the one-kidney, figure-8 renal wrap model of experimental hypertension is also sodium dependent. In these rats, prior sodium depletion prevented the development of hypertension whereas high sodium intake exacerbated the increase in arterial pressure. An activation of the sympathetic nervous system and increased AVP activity appeared to be responsible for the hypertension in rats maintained on normal and high sodium intake. Stimulation of the AVP and sympathetic nervous systems in sodium-dependent hypertension may be associated with a suppression of cardiovascular gamma-aminobutyric acid (GABA)-ergic function in the central nervous system. The inhibitory neurotransmitter, GABA, and an inhibitor of GABA uptake, nipecotic acid, lowered arterial pressure in a sodium-stimulated model of hypertension.     

Central mechanisms of vascular headaches

The intracranial blood vessels supplying the dura and brain are innervated by sensory afferents from the trigeminal nerve. These fibers are believed to be responsible for conveying the pain associated with vascular head pain such as migraines. This paper reviews recently published data describing the existence of neurons within the cat trigeminal nucleus and thalamus that respond to electrical stimulation of the middle meningeal artery and superior sagittal sinus. Almost all of these neurons receive convergent input from the facial skin and most of the receptive fields include the periorbital region. On the basis of their cutaneous inputs, most of the neurons are classified as nociceptive. The characteristics of these cerebrovascular-activated neurons are consistent with their role in mediating vascular head pains and with the typical referral of such pains in man to the orbital region. This paper also presents preliminary results of recordings from rat trigeminal ganglion neurons activated by electrical stimulation of the middle meningeal artery and sagittal sinus. The latencies of activation of these neurons are indicative of conduction in slowly conducting myelinated axons and in unmyelinated axons. Some of the neurons could also be activated by mechanical stimuli applied to the vessels.     

Guidance of vascular and neural network formation

Blood vessels and nerves are structurally similar complex branched systems. Their guidance must be exquisitely regulated to ensure proper wiring of both networks. Recent results showed that specialized endothelial cells, resembling axonal growth cones, form the tips of growing capillaries. These endothelial tip cells guide outgrowing capillaries in response to gradients of extracellular matrix-bound vascular endothelial growth factor. Several axon guidance molecules, including Semaphorins, Netrins, Ephrins and Slits, have also been implicated in vessel pathfinding and network formation. In particular, Semaphorin3E and its receptor plexinD1 in addition to the Netrin receptor UNC5B have recently been shown to direct endothelial tip cell navigation.     

Central nervous system and mechanisms of hypertension

There are several mechanisms by which the central nervous system participates in the neural and humoral alterations associated with various forms of experimental hypertension. Structures in forebrain with multiple integrative roles in neuroendocrine control of the circulation are involved. Tissue surrounding the anteroventral region of the third cerebral ventricle (AV3V region) is involved physiologically in thirst, sodium homeostasis, osmoreception, secretion of vasopressin and natriuretic factor and sympathetic discharge to blood vessels. Destruction of this tissue prevents or reverses many forms of hypertension. In genetically based spontaneous hypertension, limbic structures such as the central nucleus of the amygdala rather than the AV3V region are the necessary neuroanatomic substrate. Recent evidence suggests that a circumventricular organ in brain stem, the area postrema, is also involved in the mediation of several forms of experimental hypertension. In renin- and nonrenin-dependent forms of renal hypertension, two major factors activate central mechanisms. First, direct central actions of angiotensin, acting through receptors in the subfornical organ and organum vasculosum of the lamina terminalis, increase sympathetic discharge and secretion of vasopressin through mechanisms integrated at the level of the AV3V region. Second, sensory systems originating in the kidney can activate increased sympathetic discharge through complex projection pathways involving forebrain systems. Mineralocorticoid hypertension appears to involve enhanced secretion of vasopressin and central vasopressinergic mechanisms also dependent on the AV3V region. Reciprocal connections between key central areas involved in control of arterial pressure provide the neuroanatomical basis for central nervous system participation in hypertension.