Systolic and diastolic learning: an analogy to the cardiac cycle.
It has been observed that the active-passive classification of adult learning can be viewed in terms of a systolic-diastolic model. This model represents an analogy to the cardiac cycle and the work done by the heart during these two phases of the cycle. The determinants of systolic and diastolic learning can be compared to the determinants of cardiac function: preload, afterload and contractility. Similarly, dysfunction in these two phases of learning can be compared to cardiac dysfunction from a pathophysiologic perspective. (+info)
Targeted disruption of the beta2 adrenergic receptor gene.
beta-Adrenergic receptors (beta-ARs) are members of the superfamily of G-protein-coupled receptors that mediate the effects of catecholamines in the sympathetic nervous system. Three distinct beta-AR subtypes have been identified (beta1-AR, beta2-AR, and beta3-AR). In order to define further the role of the different beta-AR subtypes, we have used gene targeting to inactivate selectively the beta2-AR gene in mice. Based on intercrosses of heterozygous knockout (beta2-AR +/-) mice, there is no prenatal lethality associated with this mutation. Adult knockout mice (beta2-AR -/-) appear grossly normal and are fertile. Their resting heart rate and blood pressure are normal, and they have a normal chronotropic response to the beta-AR agonist isoproterenol. The hypotensive response to isoproterenol, however, is significantly blunted compared with wild type mice. Despite this defect in vasodilation, beta2-AR -/- mice can still exercise normally and actually have a greater total exercise capacity than wild type mice. At comparable workloads, beta2-AR -/- mice had a lower respiratory exchange ratio than wild type mice suggesting a difference in energy metabolism. beta2-AR -/- mice become hypertensive during exercise and exhibit a greater hypertensive response to epinephrine compared with wild type mice. In summary, the primary physiologic consequences of the beta2-AR gene disruption are observed only during the stress of exercise and are the result of alterations in both vascular tone and energy metabolism. (+info)
Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors.
The activation state of beta-adrenergic receptors (beta-ARs) in vivo is an important determinant of hemodynamic status, cardiac performance, and metabolic rate. In order to achieve homeostasis in vivo, the cellular signals generated by beta-AR activation are integrated with signals from a number of other distinct receptors and signaling pathways. We have utilized genetic knockout models to test directly the role of beta1- and/or beta2-AR expression on these homeostatic control mechanisms. Despite total absence of beta1- and beta2-ARs, the predominant cardiovascular beta-adrenergic subtypes, basal heart rate, blood pressure, and metabolic rate do not differ from wild type controls. However, stimulation of beta-AR function by beta-AR agonists or exercise reveals significant impairments in chronotropic range, vascular reactivity, and metabolic rate. Surprisingly, the blunted chronotropic and metabolic response to exercise seen in beta1/beta2-AR double knockouts fails to impact maximal exercise capacity. Integrating the results from single beta1- and beta2-AR knockouts as well as the beta1-/beta2-AR double knock-out suggest that in the mouse, beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR). Compensatory alterations in cardiac muscarinic receptor density and vascular beta3-AR responsiveness are also observed in beta1-/beta2-AR double knockouts. In addition to its ability to define beta-AR subtype-specific functions, this genetic approach is also useful in identifying adaptive alterations that serve to maintain critical physiological setpoints such as heart rate, blood pressure, and metabolic rate when cellular signaling mechanisms are perturbed. (+info)
Activation of GABAA but not GABAB receptors in the NTSblocked bradycardia of chemoreflex in awake rats.
In the present study we analyzed effects of bilateral microinjections of muscimol (a GABAA agonist) and baclofen (a GABAB agonist) into the nucleus tractus solitarius (NTS) on bradycardic and pressor responses to chemoreflex activation (potassium cyanide, 40 micrograms/rat iv) in awake rats. Bilateral microinjections of muscimol (25 and 50 pmol/50 nl) into the NTS increased baseline mean arterial pressure (MAP): 119 +/- 8 vs. 107 +/- 2 mmHg (n = 6) and 121 +/- 8 vs. 103 +/- 3 mmHg (n = 6), respectively. Muscimol at 25 pmol/50 nl reduced the bradycardic response to chemoreflex activation 5 min after microinjection; with 50 pmol/50 nl the bradycardic response to chemoreflex activation was reduced 5, 15, 30, and 60 min after microinjection. Neither muscimol dose produced an effect on the pressor response of the chemoreflex. Effects of muscimol (50 pmol/50 nl) on basal MAP and on the bradycardic response of the chemoreflex were prevented by prior microinjection of bicuculline (a GABAA antagonist, 40 pmol/50 nl) into the NTS. Bilateral microinjections of baclofen (12.5 and 25 pmol/50 nl) into the NTS produced an increase in baseline MAP [137 +/- 9 vs. 108 +/- 4 (n = 7) and 145 +/- 5 vs. 105 +/- 2 mmHg (n = 7), respectively], no changes in basal heart rate, and no effects on the bradycardic response; 25 pmol/50 nl only attenuated the pressor response to chemoreflex activation. The data show that activation of GABAA receptors in the NTS produces a significant reduction in the bradycardic response, whereas activation of GABAB receptors produces a significant reduction in the pressor response of the chemoreflex. We conclude that 1) GABAA but not GABAB plays an inhibitory role in neurons of the lateral commissural NTS involved in the parasympathetic component of the chemoreflex and 2) attenuation of the pressor response of the chemoreflex by activation of GABAB receptors may be due to inhibition of sympathoexcitatory neurons in the NTS or may be secondary to the large increase in baseline MAP produced by baclofen. (+info)
Cardiovascular phenotype and temperature control in mice lacking thyroid hormone receptor-beta or both alpha1 and beta.
We have used a telemetry system to record heart rate, body temperature, electrocardiogram (ECG), and locomotor activity in awake, freely moving mice lacking thyroid hormone receptor (TR)-beta or TR-alpha1 and -beta (TR-alpha1/beta). The TR-alpha1/beta-deficient mice had a reduced heart rate compared with wild-type controls. The TR-beta-deficient mice showed an elevated heart rate, which, however, was unresponsive to thyroid hormone treatment regardless of hormonal serum levels. ECG revealed that the TR-beta-deficient mice had a shortened Q-Tend time in contrast to the TR-alpha1/beta-deficient mice, which exhibited prolonged P-Q and Q-Tend times. Mental or pharmacological stimulation of the sympathetic nervous system resulted in a parallel increase in heart rate in all animals. A single injection of a nonselective beta-adrenergic-receptor blocker resulted in a parallel decrease in all mice. The TR-alpha1/beta-deficient mice also had a 0.4 degrees C lower body temperature than controls, whereas no difference was observed in locomotor activity between the different strains of mice. Our present and previous results support the hypothesis that TR-alpha1 has a major role in determining heart rate under baseline conditions and body temperature and that TR-beta mediates a hormone-induced increase in heart rate. (+info)
Dietary salt intake alters cardiovascular responses evoked from the rostral ventrolateral medulla.
The present experiments examined whether in rats consuming diets with either high NaCl content (8%) or low Na+ content (0.01%) for 2 wk excitatory inputs to the rostral ventrolateral medulla (RVLM) would be altered. In chloralose-anesthetized rats, injection of glutamate into the RVLM elicited a pressor response that, compared with rats fed a control diet, was 50% larger in rats fed a diet containing 8% NaCl and was 25% smaller in rats fed a diet containing 0.01% Na+. Pressor responses produced by electrical stimulation of sciatic nerve afferents, as well as by microinjections into the RVLM of L-dihydroxyphenylalanine or carbachol, were all potentiated by high dietary salt intake and reduced by low dietary salt intake. Dietary salt intake had no effect on pressor responses produced by intravenous injection of phenylephrine, indicating that salt-related alterations in cardiovascular responses produced by central activation could not be accounted for by changes in peripheral vascular reactivity. The decrease in arterial pressure produced by injection of glutamate into the nucleus of the solitary tract was also potentiated by the high salt diet, suggesting that the sensitivity of central baroreceptor reflex pathways may be altered by dietary NaCl. These results indicate that the amount of NaCl consumed in the diet can change the sensitivity of RVLM sympathoexcitatory neurons, and this change in sensitivity is not restricted to any particular class of cell surface receptors. (+info)
Cardiovascular changes associated with dehydration and drinking in unrestrained, lactating goats.
The aim of this study was to investigate if the alertness connected with seeing water increased arterial blood pressure and heart rate to the same extent as the act of drinking, and if ingestion of warm water caused a different effect compared with ingestion of cool water on these cardiovascular variables. Seven goats of the Swedish domestic breed (Capra hircus) were used in a cross-over design. The animals were dehydrated for 24 h. They were allowed to watch water being prepared for 11-16 min, after which they were given access to warm (35 degrees C) or cool (15 degrees C) water. The goats drank 6.86 +/- 0.36 l of the warm water and 4.54 +/- 0.35 l of the cool water (P < 0.05) within the first hour. The arterial blood pressure, heart rate and activity of the animals were registered by an implanted telemetric device. Dehydration did not affect the cardiovascular variables, except before feeding in the morning, when the heart rate accelerated faster in dehydrated goats. Heart rate increased abruptly when dehydrated goats saw water being prepared, remained at the increased level during drinking and then slowly declined. It increased again during the afternoon feeding, to a level similar to that on control days, but between 18.00 and 06.00 h the heart rate was higher than during control nights. Blood pressure did not change when the goats saw water, but increased when they drank. On the morning following rehydration, the rise in heart rate in response to feeding was delayed compared with that during control and dehydration periods. It is concluded that seeing water caused arousal in the goats, resulting in an accelerated heart rate. The additional rise in blood pressure during the act of drinking appears to be a combination of excitement and sensory inputs from the pharyngeal region, causing a temporary activation of the sympathetic nervous system. (+info)
Role of nitric oxide in the regulation of cardiovascular autonomic control.
Alteration in function of the cardiac autonomic nervous system has proved to be a powerful predictor of cardiac death or serious arrhythmia in patients with cardiac disease, yet little is known about the mechanisms by which this system is regulated. Recent evidence suggests that the gaseous molecule nitric oxide (NO) may act as an important mediator in this pathway. Histochemical staining techniques have identified neuronal populations that contain NO synthase within medullary cardio-regulatory sites and their peripheral autonomic pathways. Drugs that modulate the NO pathway (administered both systemically and into the central nervous system) cause changes in pre- and post-ganglionic sympathetic nerve activity that imply that NO serves to inhibit central sympathetic outflow. There is also evidence that NO may attenuate cardiovascular end-organ responses to sympathetic stimulation. Studies suggest that NO modulates cardiac vagal control, increasing the activity of central vagal motoneurons and, more contentiously, contributing to the bradycardic effects of vagal stimulation. NO also modulates so-called 'indirect' vagal inhibition of sympathetic cardiac responses. Additionally, central attenuation of baroreflex-mediated vagal control has been described. There is relatively little information available on the importance of NO in the regulation of human cardiovascular autonomic control. Further well-controlled studies are required. (+info)