Sensitization of cardiac vagal afferent reflexes at the sensory receptor level: an overview

The gain or sensitivity of reflexes originating in cardiac sensory receptors with vagal afferent pathways is highly dynamic. This modulation is usually attributed to central nervous system or efferent mechanisms. This paper briefly reviews evidence that modulation of reflexes originating in the heart can also occur at the sensory or afferent level. Five examples are cited: calcium antagonists, cardiac glycosides, arginine vasopressin, atrial natriuretic peptides, and changes in dietary sodium. These examples emphasize the role of ionic and humoral factors in regulation of cardiac vagal afferent function. This concept of sensory modulation of cardiac vagal afferents has implications for cardiovascular pharmacology and for pathophysiological states such as heart failure and hypertension.     

Mechanical stretch increases L-type calcium channel stability in cardiomyocytes through a polycystin-1/AKT-dependent mechanism

The L-type calcium channel (LTCC) is an important determinant of cardiac contractility. Therefore, changes in LTCC activity or protein levels could be expected to affect cardiac function. Several studies describing LTCC regulation are available, but only a few examine LTCC protein stability. Polycystin-1 (PC1) is a mechanosensor that regulates heart contractility and is involved in mechanical stretch-induced cardiac hypertrophy. PC1 was originally described as an unconventional Gi/o protein-coupled receptor in renal cells. We recently reported that PC1 regulates LTCC stability in cardiomyocytes under stress; however, the mechanism underlying this effect remains unknown. Here, we use cultured neonatal rat ventricular myocytes and hypo-osmotic stress (HS) to model mechanical stretch. The model shows that the Cavβ2 subunit is necessary for LTCC stabilization in cardiomyocytes during mechanical stretch, acting through an AKT-dependent mechanism. Our data also shows that AKT activation depends on the G protein-coupled receptor activity of PC1, specifically its G protein-binding domain, and the associated Gβγ subunit of a heterotrimeric Gi/o protein. In fact, over-expression of the human PC1 C-terminal mutant lacking the G protein-binding domain blunted the AKT activation-induced increase in Cav1.2 protein in cardiomyocytes. These findings provide novel evidence that PC1 is involved in the regulation of cardiac LTCCs through a Giβγ-AKT-Cavβ2 pathway, suggesting a new mechanism for regulation of cardiac function.     

Effect of vagotomy and thoracic sympathectomy on responses of the monkey to water immersion

Cardiopulmonary stretch receptors have been implicated as part of a reflex mechanism linking changes in blood volume to changes in renal excretion. Experiments were performed to determine whether total denervation of these receptors by combined cervical vagotomy and thoracic sympathectomy affects the renal responses of the monkey to head-out water immersion, a maneuver that translocates blood to the thorax and elicits an increase in renal salt and water excretion. Macaca fascicularis monkeys first underwent chronic bilateral thoracic sympathectomy or sham denervation performed in two stages a week apart. One to two weeks later, they were anesthetized with pentobarbital sodium, and the sympathectomized animals underwent bilateral cervical vagotomy. Control renal function did not differ between the two groups. Immersion of 90-min duration increased central venous and mean arterial pressures by similar amounts in both groups, but heart rate increased only in the sham-denervated animals. Denervation did not affect the magnitudes or delay the times of onset of the increases in urine flow, absolute and fractional sodium excretion, and osmolar and free water clearances occurring with immersion. These results demonstrate that in the anesthetized monkey cardiopulmonary receptors are not necessary for eliciting the renal responses to immersion.     

Cardiac natriuretic peptides: a physiological lineage of cardioprotective hormones?

Vertebrate hearts from fish to mammals secrete peptide hormones with profound natriuretic, diuretic, and vasodilatory activity; however, the specific role of these cardiac natriuretic peptides (NPs) in homeostasis is unclear. NPs have been suggested to be involved in salt excretion in saltwater teleosts, whereas they are proposed to be more important in volume regulation in mammals. In this review, we consider an alternative (or perhaps complementary) function of NPs to protect the heart. This hypothesis is based on a number of observations. First, evidence for NPs, or NP-like activity has been found in all vertebrate hearts thus far examined, from osmoconforming saltwater hagfish to euryhaline freshwater and saltwater teleosts to terrestrial mammals. Thus the presence of cardiac NPs appears to be independent of environmental conditions that may variously affect salt and water balance. Second, cardiac stretch is a universal, and one of the most powerful, NP secretagogues. Furthermore, stretch-induced NP release in euryhaline teleosts appears relatively independent of ambient salinity. Third, excessive cardiac stretch that increases end-diastolic volume (EDV) can compromise the mechanical ability of the heart by decreasing actin-myosin interaction (length-tension) or through Laplace effects whereby as EDV increases, the wall tension necessary to maintain a constant pressure must also increase. Excessive cardiac stretch can be produced by factors that decrease cardiac emptying (i.e., increased arterial pressure), or by factors that increase cardiac filling (i.e., increased blood volume, increased venous tone, or decreased venous compliance). Fourth, the major physiological actions of cardiac NPs enhance cardiac emptying and decrease cardiac filling. In fish, NPs promote cardiac emptying by decreasing gill vascular resistance, thereby lowering ventral aortic pressure. In mammals a similar effect is achieved through pulmonary vasodilation. NPs also decrease cardiac filling by decreasing blood volume and increasing venous compliance, the latter producing a rapid fall in central venous pressure. Fifth, the presence of NP clearance receptors in the gill and lung (between the heart and systemic circulation) suggest that these tissues may be exposed to considerably higher NP titers than are systemic tissues. Thus, a decrease in outflow resistance immediately downstream from the heart may be the first response to increased cardiac distension. Because the physiology of cardiac NPs is basically the same in fish and mammals, we propose that the cardioprotective effects of NPs have been well preserved throughout the course of vertebrate evolution. It is also likely that the cardioprotective role of NPs was one of the most primordial homeostatic activities of these peptides in the earliest vertebrates.     

Effect of β Adrenoreceptor Blocker Propranolol during Reflex Renal Dystrophy Induced by Sciatic Nerve Cutting

We present the data on the functional status of the mineralocorticoid receptor system in the rat kidney in the course of renal reflex dystrophy induced by sciatic nerve cutting against the background of both renal denervation and injections of propranolol, a -adrenoreceptor blocker. According to the state of renal mineralocorticoid receptors, the simultaneous block of both neural and humoral pathological stimuli coming to the kidney after the nerve injury prevented cytochemical changes in the organ more effectively than the block of neural transmission alone. We propose that both the central neural transmission and humoral mechanisms control the activity of the molecular structures responsible for aldosterone reception in the cells of renal tubules.     

Neural mechanisms in body fluid homeostasis

Under steady-state conditions, urinary sodium excretion matches dietary sodium intake. Because extracellular fluid osmolality is tightly regulated, the quantity of sodium in the extracellular fluid determines the volume of this compartment. The left atrial volume receptor mechanism is an example of a neural mechanism of volume regulation. The left atrial mechanoreceptor, which functions as a sensor in the low-pressure vascular system, is located in the left atrial wall, which has a well-defined compliance relating intravascular volume to filling pressure. The left atrial mechanoreceptor responds to changes in wall left atrial tension by discharging into afferent vagal fibers. These fibers have suitable central nervous system representation whose related efferent neurohumoral mechanisms regulate thirst, renal excretion of water and sodium, and redistribution of the extracellular fluid volume. Efferent renal sympathetic nerve activity undergoes appropriate changes to facilitate renal sodium excretion during sodium surfeit and to facilitate renal sodium conservation during sodium deficit. By interacting with other important determinants of renal sodium excretion (e.g., renal arterial pressure), changes in efferent renal sympathetic nerve activity can significantly modulate the final renal sodium excretion response with important consequences in pathophysiological states (e.g., hypertension, edema-forming states).     

The regulatory effects of opioid peptides--enkephalins--in controlling the activities of the cardiovascular system

In this review we analyse the experimental and clinical findings demonstrating important regulatory significance of met-enkephalin, leu-enkephalin and their derivatives in the control of cardiovascular system activity. Enkephalin-positive immunoreactivity is revealed in the heart of different species of animals, and their cardiovascular effects are established in numerous investigations. It is determined that cardiac effects of enkephalins are essentially associated with modulatory influence at the presynaptic and postsynaptic levels on the activity of extracardiac neural regulation. Cardiovascular effects of endogenous opioid system are extremely important in developing of myocardial ischemia, cardiac arrhythmias and congestive heart failure. The cellular mechanisms of opioid effects are associated with stimulation of mu- and delta-subtypes of opiate receptors which stimulation of mu- and delta-subtypes of opiate receptors which are coupled with conductivity of ion channels, adenylate cyclase activity, phosphoinositide turnover and calcium-calmodulin-dependent protein kynases.     

Novel aspects of angiotensin II action in the heart. Implications to myocardial ischemia and heart failure

The influence of angiotensin II (Ang II) on cardiac structural and electrophysiological remodeling was discussed including the novel concept that the renin angiotensin aldosterone is involved in the regulation heart cell volume. Particular attention was given to the role of Ang II AT1 receptors as mechanosensors which are activated by mechanic stretch independently of Ang II. These findings highly suggest that RAS inhibitors or AT1 receptor blockers have additional beneficial therapeutics effects by changing mechanical transduction. The influence of cell swelling on cell communication as well as the effect of Ang II on cell volume and the consequent activation of ionic channels and the generation of cardiac arrhythmias was reviewed. The discovery of ACE2 and its relevance to heart pathology was also discussed.     

Determinants of natriuretic peptide gene expression

The cardiac natriuretic peptides (NP) atrial natriuretic factor or peptide (ANF or ANP) and brain natriuretic peptide (BNP) are polypeptide hormones synthesized, stored and secreted mainly by cardiac muscle cells (cardiocytes) of the atria of the heart. Both ANF and BNP are co-stored in storage granules referred to as specific atrial granules. The biological properties of NP include modulation of intrinsic renal mechanisms, the sympathetic nervous system, the rennin-angiotensin-aldosterone system (RAAS) and other determinants, of fluid volume, vascular tone and renal function. Studies on the control of baseline and stimulated ANF synthesis and secretion indicate at least two types of regulated secretory processes in atrial cardiocytes: one is stretch-stimulated and pertussis toxin (PTX) sensitive and the other is Gq-mediated and is PTX insensitive. Baseline ANF secretion is also PTX insensitive. In vivo, it is conceivable that the first process mediates stimulated ANF secretion brought about by changes in central venous return and subsequent atrial muscle stretch as observed in acute extracellular fluid volume expansion. The second type of stimulation is brought about by sustained hemodynamic and neuroendocrine stimuli such as those observed in congestive heart failure.     

Arterial baroreflex function and cardiovascular variability: interactions and implications

The arterial baroreflex contributes importantly to the short-term regulation of blood pressure and cardiovascular variability. A number of factors (including reflex, humoral, behavioral, and environmental) may influence gain and effectiveness of the baroreflex, as well as cardiovascular variability. Many central neural structures are also involved in the regulation of the cardiovascular system and contribute to the integrity of the baroreflex. Consequently, brain injuries or ischemia may induce baroreflex impairment and deranged cardiovascular variability. Baroreflex dysfunction and deranged cardiovascular variability are also common findings in cardiovascular disease. A blunted baroreflex gain and impaired heart rate variability are predictive of poor outcome in patients with heart failure and myocardial infarction and may represent an early index of autonomic activation in left ventricular dysfunction. The mechanisms mediating these relationships are not well understood and may in part be the result of cardiac structural changes and/or altered central neural processing of baroreflex signals.     

Catecholamine-induced cardiac hypertrophy in a denervated,hemodynamically non-stressed heart transplant

Studies of stress-induced cardiac hypertrophy suggest that myocardial mass is regulated by the circulating level of epinephrine. The trophic effect is mediated by cardiac beta-adrenergic receptors, and in the murine, rat, and dog heart, specifically by beta₂-adrenergic receptors. The well-characterized functional effects of catecholamines on heart have obscured their role as myocardial trophic hormones. Therefore, we compared the effect of beta-adrenergic receptor stimulation on the myocardial mass of both a working innervated heart and an essentially nonworking denervated heterotopically transplanted heart in the same rat; in this model, the neural and stretch parameters are nonoperational in the transplanted heart. Ornithine decarboxylase (ODC), an enzyme elevated in a dose-dependent manner in heart by isoproterenol, was assayed in both hearts to determine the relationship between ODC activity and myocardial mass in response to isoproterenol administration in workin, innervated heart compared to denervated, nonworking heart. In both recipient and donor heart, the myocardial mass paralleled the ability of an isoproterenol bolus to stimulate ODC in the respective heart. However, beta-adrenergic receptor activity in the donor heart was decreased 5 days after transplantation as assessed by the differential ability of a single dose of isoproterenol to stimulate ODC activity. Beta-receptor coupling to ODC activity in the donor heart exceeded that of the recipient heart at 10 days posttransplantation suggesting a time-dependent elevation of beta-adrenergic receptor activity in donor heart. At all times, alterations in myocardial mass paralleled beta-adrenoceptor activity as assessed by the ability of isoproterenol administration to elevate ODC activity. The results support the concept that myocardial mass is regulated by the level of circulating hormones, particularly epinephrine.     

Pathophysiological roles of G-protein-coupled receptor kinases

G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptors (GPCRs) to effect receptor phosphorylation and to initiate profound impairment of receptor signalling, or desensitization. GPCRs form the largest family of cell surface receptors known and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations. This review focuses on the physiological role of GRKs revealed by genetically modified animals but also develops the involvement of GRKs in human diseases as, Oguchi disease, heart failure, hypertension or rhumatoid arthritis. Furthermore, the regulation of GRK levels in opiate addiction, cancers, psychiatric diseases, cystic fibrosis and cardiac diseases is discussed. Both transgenic mice and human pathologies have demonstrated the importance of GRKs in the signalling pathways of rhodopsin, beta-adrenergic and dopamine-1 receptors. The modulation of GRK activity in animal models of cardiac diseases can be effective to restore cardiac function in heart failure and opens a novel therapeutic strategy in diseases with GPCR dysregulation.     

Cardiovascular and renal effects of iso-rANP, a second natriuretic peptide from rat atria

Administration of a newly discovered second atrial peptide, iso-atrial natriuretic peptide (or iso-rANP(1-45) for the rat), caused hypotension, decreased heart rate, diuresis, and increased renal excretion of Na+, K+, and Cl- in the anesthetized rat. Bolus injections of chemically synthetic iso-rANP(1-45) had circulatory and diuretic activity equal to or greater than rANP(99-126) but, at low doses, a lesser effect on renal electrolyte excretion. The synthetic peptide fragment, iso-rANP(17-45), analogous in structure to rANP(99-126), had attenuated activity on the circulation, and at low doses, attenuated activity on the kidney. At higher doses, where renal responses to rANP(99-126) were less (downside of a biphasic response), both iso-rANP(1-45) and (17-45) had greater effects on water and electrolyte excretion than rANP(99-126). Injections of iso-rANP(1-45) and (17-45) increased hematocrit, whereas rANP(99-126) did not; furthermore, unlike rANP(99-126), iso-rANP did not affect arterial plasma Na+ concentration. The heart produces at least two genetically different atrial natriuretic peptides which affect the circulation and salt and water balance.     

Cardiac output distribution and intrarenal haemodynamics: role of thromboxanes.

The effects of imidazole, an inhibitor of thromboxane synthesis, were studied on the distribution of cardiac output and on the intrarenal haemodynamics in anaesthetized, furthermore on the salt and water excretion in conscious rats. Imidazole treatment (10 mg/100 g b.m., intraperitoneally, twice a day for two days) failed to influence the arterial blood pressure, the cardiac output and its distribution in organs investigated (heart, muscle, lung [bronchial fraction], skin, liver, spleen, small intestine, adrenal gland and kidneys). The medullary blood flow increased, while cortical blood flow remained unchanged, but the intrarenal percentile blood flow shifted towards the medulla. Imidazole elevated the water turnover in the animals, but no change in sodium and potassium excretion occurred. It is supposed that thromboxanes may affect the renal medullary vascular tone without altering the vascular smooth muscle activity in other organs.     

Phasic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation

The perfused in situ juvenile rat preparation produces patterns of phrenic discharge comparable to eupnea and gasping in vivo. These ventilatory patterns differ in multiple aspects, including most prominently the rate of rise of inspiratory activity. Although we have recently demonstrated that both eupnea and gasping are similarly modulated by a Hering-Breuer expiratory-promoting reflex to tonic pulmonary stretch, it has generally been assumed that gasping was unresponsive to afferent stimuli from pulmonary stretch receptors. In the present study, we recorded eupneic and gasplike efferent activity of the phrenic nerve in the in situ juvenile rat perfused brain stem preparation, with and without phrenic-triggered phasic pulmonary inflation. We tested the hypothesis that phasic pulmonary inflation produces reflex responses in situ akin to those in vivo and that both eupnea and gasping are similarly modulated by phasic pulmonary stretch. In eupnea, we found that phasic pulmonary inflation decreases inspiratory burst duration and the period of expiration, thus increasing burst frequency of the phrenic neurogram. Phasic pulmonary inflation also decreases the duration of expiration and increases the burst frequency during gasping. Bilateral vagotomy eliminated these changes. We conclude that the neural substrate mediating the Hering-Breuer reflex is retained in the in situ preparation and that the brain stem circuitry generating the respiratory patterns respond to phasic activation of pulmonary stretch receptors in both eupnea and gasping. These findings support the homology of eupneic phrenic discharge patterns in the reduced in situ preparation and eupnea in vivo and disprove the common supposition that gasping is insensitive to vagal afferent feedback from pulmonary stretch receptor mechanisms.     

Interaction between the natriuretic effects of renal perfusion pressure and the antinatriuretic effects of angiotensin and aldosterone in control of sodium excretion

Aldosterone has been recognized as an important sodium retaining hormone for many years. Recently we have demonstrated that angiotensin II has a much more powerful antinatriuretic effect than that of aldosterone. The importance of angiotensin II in regulation of sodium excretion has been observed in experiments in which angiotensin II has been infused intravenously or into the renal artery in acute and chronic situations, and in studies involving blockade of angiotensin II formation. In other experiments we have studied the effects of changes in renal perfusion pressure on sodium excretion. While earlier work by others indicated that an acute 10 mm Hg increase in perfusion pressure would increase sodium excretion 60%-70% we observed that a chronic 10 mm Hg change in perfusion pressure would result in a 300% change in sodium excretion. In view of evidence suggesting that changes in the ability of the kidney to excrete sodium normally at normal arterial pressure is an important element in hypertension we studied the effects of aldosterone and angiotensin II on arterial pressure regulation in normal dogs. High physiological levels of each hormone were infused intravenously for several weeks. Both produced sustained hypertension. Aldosterone hypertension was a typical volume loading type with sodium retention, increased blood volume and extracellular fluid volume and a slow rise in arterial pressure. Angiotensin hypertension was a typical vasoconstrictor type with high peripheral resistance, normal or decreased blood volume, decreased cardiac output, a rapid rise in arterial pressure and only initial sodium retention.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal dopamine receptors and hypertension

Dopamine has been recognized as an important modulator of central as well as peripheral physiologic functions in both humans and animals. Dopamine receptors have been identified in a number of organs and tissues, which include several regions within the central nervous system, sympathetic ganglia and postganglionic nerve terminals, various vascular beds, the heart, the gastrointestinal tract, and the kidney. The peripheral dopamine receptors influence cardiovascular and renal function by decreasing afterload and vascular resistance and promoting sodium excretion. Within the kidney, dopamine receptors are present along the nephron, with highest density on proximal tubule epithelial cells. It has been reported that there is a defective dopamine receptor, especially D(1) receptor function, in the proximal tubule of various animal models of hypertension as well as in humans with essential hypertension. Recent reports have revealed the site of and the molecular mechanisms responsible for the defect in D(1) receptors in hypertension. Moreover, recent studies have also demonstrated that the disruption of various dopamine receptor subtypes and their function produces hypertension in rodents. In this review, we present evidence that dopamine and dopamine receptors play an important role in regulating renal sodium excretion and that defective renal dopamine production and/or dopamine receptor function may contribute to the development of various forms of hypertension.     

Aldosterone and the heart: from basic research to clinical evidence

Recent views suggest that long-term exposure to elevated aldosterone concentrations might result in cardiac, vascular, renal, and metabolic sequelae that occur independent of the blood pressure level. Indirect evidence of the untoward effects of aldosterone on the heart has been clearly established in clinical studies that have tested the effects of mineralocorticoid receptor antagonists in the treatment of systolic heart failure. As it has become clear in recent years, the interaction between aldosterone and the heart has to deal with additional actions of the hormone on specific cell types, cellular mechanisms, and molecules that are involved in regulation of tissue responses, leading to hypertrophy, remodeling, and fibrosis. The majority of these effects are mediated by activation of the mineralocorticoid receptors that are expressed in cardiomyocytes and cardiac fibroblasts, and mediate the genomic effects of the hormone. Evidence of interactions between aldosterone and the heart that occur independent of the renal effects of aldosterone, however, is not limited to the context of systolic heart failure and observations obtained in other disease states have led, together with findings of animal studies, to a better understanding of the potential benefits of aldosterone antagonists. In this narrative overview, we highlight the most recent findings that have been obtained in experimental animal models and in clinical conditions that include, in addition to systolic heart failure, primary aldosteronism, essential hypertension, diastolic heart failure, and arrhythmia.