Aspects of cardiovascular reflexes in pathologic states

Cardiovascular reflexes that are mediated by receptors in the heart and blood vessels control a variety of important hemodynamic and humoral functions. The action of these receptors can be shown to be abnormal in several pathologic states. Left atrial receptors exhibit a depressed discharge sensitivity in dogs with chronic congestive heart failure caused by an aortocaval fistula. The reflex effects of atrial receptor stimulation are also depressed in heart failure. Left ventricular receptor stimulation has been implicated in the abnormal vascular responses to exercise in patients with aortic stenosis. The arterial baroreflex control of heart rate is abnormal in animals and humans with various forms of hypertension. Arterial baroreceptors from hypertensive animals show a resetting of their pressure-discharge curve to higher pressures. The arterial baroreflex is also depressed in chronic heart failure. This effect may result from an abnormality of the efferent limb of the reflex arc or from changes in the interaction between baroreceptors and cardiac receptors centrally. A final possibility may be abnormal arterial baroreceptor discharge characteristics in heart failure.     

Release of atrial natriuretic peptide by atrial distension

A heterologous radioimmunoassay was used to measure the concentration of immunoreactive atrial natriuretic peptide (iANP) in plasma from the femoral artery of eight chloralose anaesthetized dogs. Mitral obstruction which increased left atrial pressure by 11 cmH2O increased plasma iANP from 97 +/- 10.3 (mean +/- SE) to 135 +/- 14.3 pg/mL. Pulmonary vein distension increased heart rate but did not increase plasma iANP. Bilateral cervical vagotomy and administration of atenolol (2 mg/kg) did not prevent the increase in iANP with mitral obstruction. Samples of blood from the coronary sinus had plasma iANP significantly higher than simultaneous samples from the femoral artery confirming the cardiac origin of the iANP. Release of iANP depends on direct stretch of the atrium rather than on a reflex involving left atrial receptors.     

Atrial reflexes during high frequency oscillatory ventilation

High frequency oscillatory ventilation (HFOV) is a new method of artificial ventilation which has been advocated for use in critically ill individuals. It alters the discharge in pulmonary stretch receptors (SAR) from a phasic to a continuous pattern. Since some cardiovascular neurones in the medulla are influenced by the discharge from SAR, experiments were undertaken to determine whether the reflexes from the left atrial (volume) receptors (LAR) were influenced by HFOV. The reflex increases in heart rate and urine flow which result from activation of the (LAR) were examined during both intermittent positive pressure ventilation (IPPV) and HFOV. In five dogs, the increase in heart rate was 23.9 +/- 4.3 and 24.5 +/- 5.4 beats/min during IPPV and HFOV, respectively. In six dogs the response of an increase in urine flow was examined and this response also was not altered by HFOV. It is concluded that the integrity of these reflexes was unaffected by HFOV in the anesthetized dog model.     

Time course of release of atrial natriuretic peptide in the anaesthetized dog

In 12 chloralose anaesthetized dogs plasma concentration of immunoreactive atrial natriuretic peptide (IR-ANP) was measured using a radioimmunoassay. Plasma IR-ANP was 74 +/- 4.8 pg/mL (mean +/- SE) and increased by 39 +/- 4.1 pg/mL when left atrial pressure was increased by 10 cm H2O during partial mitral obstruction. Observation of the time course of the changes in IR-ANP during atrial distension showed that IR-ANP was increased within 2 min of atrial distension and declined after atrial distension, with a half-time of 4.5 min. The time course of the changes in IR-ANP was unaffected by vagotomy or administration of atenolol. Maximum electrical stimulation of the right ansa subclavia failed to produce any change in IR-ANP. IR-ANP was higher in coronary sinus plasma than in femoral arterial plasma confirming that the heart was the source of the IR-ANP. The results support the hypothesis that IR-ANP is released from the heart by a direct effect of stretch of the atrial wall rather than by a neural or humoral mechanism involving a reflex from atrial receptors.     

Substance P in the nucleus of the solitary tract augments bronchopulmonary C fiber reflex output

Bronchopulmonary C fibers defend the lungs against injury from inhaled agents by a central nervous system reflex consisting of apnea, cough, bronchoconstriction, hypotension, and bradycardia. Glutamate is the putative neurotransmitter at the first central synapses in the nucleus of the solitary tract (NTS), but substance P, also released in the NTS, may modulate the transmission. To test the hypothesis that substance P in the NTS augments bronchopulmonary C fiber input and hence reflex output, we stimulated the C fibers with left atrial capsaicin (LA CAP) injections and compared the changes in phrenic nerve discharge, tracheal pressure (TP), arterial blood pressure (ABP), and heart rate (HR) in guinea pigs before and after substance P injections (200 microM, 25 nl) in the NTS. Substance P significantly augmented LA CAP-evoked increases in expiratory time by 10-fold and increases in TP and decreases in ABP and HR by threefold, effects prevented by neurokinin-1 (NK1) receptor antagonism. Thus substance P acting at NTS NK1 receptors can exaggerate bronchopulmonary C fiber reflex output. Because substance P synthesis in vagal airway C fibers may be enhanced in pathological conditions such as allergic asthma, the findings may help explain some of the associated respiratory symptoms including cough and bronchoconstriction.     

Effect of increased left atrial pressure on breathing frequency in anesthetized dog

Distension or loading of the isolated canine left heart caused reflex tachypnea in prior studies. The object of the present effort was to explore the possibility that this depended primarily on atrial distension. Cardiopulmonary bypass perfusion and ligation of pulmonary veins were used to isolate the left-heart chambers of anesthetized dogs. Simultaneous distension of the beating left atrium and fibrillating ventricle stimulated breathing frequency (f), whereas isolated ventricular distension did not. At other times, intervals of atrial fibrillation were imposed under two different conditions: 1) while the right heart and lungs were bypassed and systemic perfusion was provided by the left ventricle using blood returned to the left atrium by pump and 2) while the ventricles fibrillated and systemic perfusion was supplied directly by the pump. Atrial fibrillation increased left atrial pressure and stimulated f in condition 1. In condition 2, f increased only if fibrillation was associated with a rise in left atrial pressure. Vagal cooling blocked the effect of fibrillation. I conclude that left atrial distension may initiate reflex tachypnea.     

Effect of NOS inhibition on central response to atrial distension during pregnancy

Atrial distension increases c-fos expression in the paraventricular nucleus of virgin, but not pregnant, rats. We proposed that nitric oxide (NO), biosynthesis of which increases during pregnancy, blunts this reflex and that blocking NO biosynthesis would restore the response. Female rats were implanted with indwelling intracardiac balloons. On day 14 of pregnancy, osmotic minipumps containing either D- or N(G)-nitro-L-arginine methyl ester (L-NAME) (120 mg/2 ml at 10 microg/min) were implanted. On day 20, the rats were infused with saline (3 ml/h) with or without atrial balloon inflation (1 h). The brains were then processed for quantitation of c-fos expression. In the virgin rats, and in the pregnant rats treated with L-NAME, atrial distension significantly increased hypothalamic c-fos expression. In the pregnant animals treated with D-NAME, the response was greatly attenuated. NO had no effect on the increase in atrial receptor afferent discharge (single-fiber recordings) elicited by atrial distension. We conclude that, during pregnancy, NO attenuates central processing of the reflex response to atrial distension but does not alter the transducer properties of the volume receptors.     

Mechanism of the pressor response to intraperitoneal injection of bradykinin in guinea pigs.

Single intraperitoneal (IP) injection of bradykinin (BK) in anesthetized guinea pigs caused concentration-related pressor effects and slight, not significant tachycardia. Intravenous injections of BK in the same animal model evoked hypotension and a marked tachycardia. IP injection of des-Arg9-BK, a selective B1 receptor agonist, caused no changes of blood pressure or heart rate. The pressor response to IP BK was reduced by concomitant IP injection of lidocaine or of D-Arg[Hyp3,D-Phe7,Leu8]BK, a B2 receptor antagonist. It was also inhibited by acute animal pretreatment with sympatholytic drugs, by chronic animal exposure to capsaicin, or acute spinalization, but it was not affected by atropine, propranolol, indomethacin, [Leu8]des-Arg9-BK, a B1 receptor antagonist, or by acute cervical vagotomy. These results suggest that pressor responses to IP BK in anesthetized guinea pigs are reflex in nature, involving abdominal, capsaicin-sensitive, nonvagal visceral afferents, efferent components of the sympathetic nervous system and possibly supraspinal centers, and likely to be mediated by B2 receptors of kinins presumably located on abdominal visceral afferents.     

Respiratory arrhythmias and airway CO2, lung receptors, and central inspiratory activity

The purpose of this study was to determine whether hypocapnia affects heart rate secondary to an effect on pulmonary receptors. Dogs were anesthetized and placed on cardiopulmonary bypass. Interrelationships among airway CO2, central inspiratory activity, and lung receptor effects on respiratory-related heart rate changes (respiratory arrhythmias) were studied after vagal efferent activity was increased secondary to baroreceptor stimulation. Hypocapnia, isolated to the lungs, produced an increase in the magnitude of the respiratory arrhythmias observed. Two mechanisms may produce these results. Hypocapnia affects pulmonary receptors, which 1) reflexly alter heart rate and 2) modulate breathing frequency, thus altering the dynamics of the respiratory arrhythmias that were produced. The results also suggested that the reflex increase in heart rate in response to lung inflation and the Hering-Breuer expiratory-facilitatory reflex are either produced by different pulmonary receptors or by the same pulmonary receptors but may be mediated by different central mechanisms.     

Distension of the pulmonary vein - atrial junctions and plasma vasopressin in the chloralose-anaesthetized dog

The effects of localized distension of the pulmonary vein - left atrial junctions on plasma arginine vasopressin (AVP) have been examined in chloralose anaesthetized dogs. Pulmonary vein distension caused an increase in heart rate and a decrease in plasma AVP concentration. Cooling the vagosympathetic nerves to 10 degrees C caused an increase in arterial pressure and plasma AVP concentration and prevented the changes in heart rate and plasma AVP concentration caused by pulmonary vein distension. Cooling the vagus nerves to 16 degrees C did not change heart rate, arterial pressure, or plasma AVP concentration but significantly reduced the changes in heart rate and plasma AVP concentration caused by pulmonary vein distension. Propranolol (0.5 mg/kg) decreased heart rate and prevented the increase in heart rate associated with pulmonary vein distension but did not abolish the decrease in plasma AVP concentration. It is concluded that distension of the pulmonary vein - left atrial junctions causes a decrease in plasma AVP concentration by stimulating atrial receptors with myelinated afferent fibres. The decrease in plasma AVP concentration is not secondary to the reflex changes in heart rate caused by pulmonary vein distension.     

Femoral artery occlusion augments TRPV1-mediated sympathetic responsiveness

Muscle metabolic by-products stimulate thin fiber muscle afferent nerves and evoke reflex increases in blood pressure and sympathetic nerve activity. Previous studies reported that chemically sensitive transient receptor potential vanilloid type 1 (TRPV1) channels present on sensory muscle afferent neurons have an important impact on sympathetically mediated cardiovascular responses. The reflex-mediated reduction in blood flow to skeletal muscle leads to limited exercise capacity in patients with peripheral arterial occlusive disease. Thus, in this study, we tested the hypothesis that the expression of enhanced TRPV1 receptor and its responsiveness in primary afferent neurons innervating muscles initiate exaggerated reflex sympathetic responses after vascular insufficiency to the muscle. Muscle vascular insufficiency was induced by the femoral artery ligation in rats for 24 h. Our data show that 1) the ligation surgery leads to the upregulation of TRPV1 expression in the dorsal root ganglion; 2) the magnitude of the dorsal root ganglion neuron TRPV1 response induced by capsaicin is greater in vascular insufficiency (4.0 +/- 0.31 nA, P < 0.05 vs. sham-operated control) than that in sham-operated control (2.9 +/- 0.23 nA); and 3) renal sympathetic nerve activity and mean arterial pressure responses to capsaicin (0.5 microg/kg body wt) are also enhanced by vascular insufficiency (54 +/- 11%, 9 +/- 2 mmHg in sham-operated controls vs. 98 +/- 13%, 33 +/- 5 mmHg after vascular insufficiency, P < 0.05). In conclusion, sympathetic nerve responses to the activation of metabolite-sensitive TRPV1 receptors are augmented in rats with the femoral artery occlusion compared with sham-operated control animals, due to alterations in the expression of TRPV1 receptor and its responsiveness in sensory neurons.     

Differential regional expression of three natriuretic peptide receptor genes within primate tissues.

The natriuretic peptide receptors are three homologous cell surface proteins, each with a single transmembrane domain. The atrial natriuretic peptide receptor type A (ANPRA) and the homologous receptor type B (ANPRB) are both membrane guanylyl cyclases that synthesize cyclic GMP as an intracellular second messenger. The third receptor in this family, the atrial natriuretic peptide receptor type C (ANPRC), is not coupled to cyclic GMP production. We report on the distribution of the ANPRA, ANPRB, and ANPRC mRNAs in rhesus monkey tissues assayed by in situ hybridization. ANPRA mRNA is most abundantly expressed in the kidney glomerulus, adrenal zona glomerulosa, pituitary, cerebellum, and endocardial endothelial cells of the right and left atrium and right ventricle. In contrast, abundant ANPRB expression appears to be confined to the adrenal medulla, pituitary, and cerebellum. ANPRC mRNA appeared to be expressed very differently than ANPRA and ANPRB. In the heart, ANPRC mRNA is expressed most prominently in endocardial endothelial cells of all four chambers but is also found throughout the myocardium only in the right atrium. These data identify major sites of natriuretic peptide receptor mRNA expression and suggest that there may be prominent cell type-specific differential distribution of these receptors in central and peripheral targets for the natriuretic peptides.     

Cardiovascular responses to emotional stress during activation of the brain imidazoline receptors

In alert normotensive and hypertensive (SHR) rats, effects of imidazoline receptor activating compounds of the central nervous system on the level of blood pressure, heart rate and value of arterial baroreceptor reflex at rest and in emotional tension, were investigated. It was shown, that the activation of the cerebral imidazoline receptors leads to an increase in the baroreceptor reflex value (both in resting and in emotional tension) and a decrease in the pressor reaction evoked by emotional affect. No data showing the role of imidazoline receptors in functioning of systems regulating of the initial level of blood pressure were obtained.     

Decreased atrial natriuretic factor receptors and impaired cGMP generation in glomeruli from the cardiomyopathic hamster

To determine a possible basis for the decreased action of atrial natriuretic factors (ANF) in congestive heart failure, we compared the cardiomyopathic hamster (CMH) in frank congestive failure, and the age-matched, normal, F1B strain of Golden Syrian Hamsters. Scatchard analysis of competitive binding studies revealed two classes of glomerular receptors. The CMH exhibited decreased binding overall and a markedly decreased number of high affinity receptors but comparable receptor affinity compared to the F1B. In contrast, the low affinity receptor population in the CMH had a much greater affinity compared to the F1B while receptor number was similar. Plasma ANF levels were substantially elevated in the CMH compared to the F1B and in-vitro generation of cGMP was significantly lower in the CMH. Such abnormalities could contribute to the resistance to ANF in this disease.     

Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure

Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in utero placement of an aortopulmonary shunt. Immediately after spontaneous birth, shunt lambs were treated lifelong with either an endothelin A receptor antagonist (PD-156707) or placebo. At 4 wk of age, PD-156707-treated shunt lambs (n = 6) had lower pulmonary vascular resistance and right atrial pressure than placebo-treated shunt lambs (n = 8, P < 0.05). Smooth muscle thickness or arterial number per unit area was not different between the two groups. However, the number of alveolar profiles per unit area was increased in the PD-156707-treated shunt lambs (190.7 +/- 5.6 vs. 132.9 +/- 10.0, P < 0.05). Plasma endothelin-1 and cGMP levels and lung NOS activity, cGMP, eNOS, preproendothelin-1, endothelin-converting enzyme-1, endothelin A, and endothelin B receptor protein levels were similar in both groups. We conclude that chronic endothelin A receptor blockade attenuates the progression of pulmonary hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.     

Regulation of insulin-like growth factor-1 by the renin-angiotensin system during regression of cardiac eccentric hypertrophy through angiotensin-converting enzyme inhibitor and AT1 antagonist

Angiotensin II (Ang II) mediates its effects through its non-tyrosine-kinase G protein coupled Ang-II type 1 receptor (AT1). Growing evidence indicates that a functional insulin-like growth factor-1 (IGF-1) tyrosine kinase receptor is required for Ang-II-induced mitogenesis. Along with Ang II, we have previously shown that changes in IGF-1 receptor binding at myofibers are causative agents for cardiac eccentric hypertrophy. This study investigated the interaction of the renin-angiotensin system with the IGF-1 receptor during the development and regression of cardiac hypertrophy. Alterations in IGF-1 binding were evaluated in the CHAPS-pretreated perfused heart. Four weeks of aortocaval shunt increased relative heart mass by 76% without a major change in body mass or systolic blood pressure. Binding studies showed that IGF-1 has a higher affinity for the cardiac myofibers of shunt than sham rats. Two weeks of treatment with the angiotensin-converting enzyme (ACE) inhibitor captopril (0.5 g/L in drinking water) or the AT1-antagonist losartan (10 mg/(kg x day)) reduced cardiac hypertrophy by 54 and 42%, respectively. However, while both ACE inhibition and AT1-antagonist treatments produced equivalent regression in ventricular hypertrophy, captopril was more efficacious than losartan in the regression of atrial hypertrophy. Regression of cardiac hypertrophy in the shunt by either captopril or losartan was accompanied with a reduction or normalization of the elevated IGF-1 affinity. Thus, the induction and regression of cardiac eccentric hypertrophy seems to be largely dependent on cross talk between the renin-angiotensin system and the IGF-1 axis at the receptor level.     

Vagal modulation of intestinal afferent sensitivity to systemic LPS in the rat

The central nervous system modulates inflammation in the gastrointestinal tract via efferent vagal pathways. We hypothesized that these vagal efferents receive synaptic input from vagal afferents, representing an autonomic feedback mechanism. The consequence of this vagovagal reflex for afferent signal generation in response to LPS was examined in the present study. Different modifications of the vagal innervation or sham procedures were performed in anesthetized rats. Extracellular mesenteric afferent nerve discharge and systemic blood pressure were recorded in vivo before and after systemic administration of LPS (6 mg/kg iv). Mesenteric afferent nerve discharge increased dramatically following LPS, which was unchanged when vagal efferent traffic was eliminated by acute vagotomy. In chronically vagotomized animals, to eliminate both vagal afferent and efferent traffic, the increase in afferent firing 3.5 min after LPS was reduced to 3.2 +/- 2.5 impulses/s above baseline compared with 42.2 +/- 2.0 impulses/s in controls (P < 0.001). A similar effect was observed following perivagal capsaicin, which was used to eliminate vagal afferent traffic only. LPS also caused a transient hypotension (<10 min), a partial recovery, and then persistent hypertension that was exacerbated by all three procedures. Mechanosensitivity was increased 15 min following LPS but had recovered at 30 min in all subgroups except for the chronic vagotomy group. In conclusion, discharge in capsaicin-sensitive mesenteric vagal afferents is augmented following systemic LPS. This activity, through a vagovagal pathway, helps to attenuate the effects of septic shock. The persistent hypersensitivity to mechanical stimulation after chronic vagal denervation suggests that the vagus exerts a regulatory influence on spinal afferent sensitization following LPS.     

Regulation of atrial contraction by PKA and PKC during development and regression of eccentric cardiac hypertrophy

ANG II plays a major role in development of cardiac hypertrophy through its AT1 receptor subtype, whereas angiotensin-converting enzyme (ACE) inhibitors are effective in reversing effects of ANG II on the heart. The objective of this study was to investigate the role of PKA and PKC in the contractile response of atrial tissue during development and ACE inhibitor-induced regression of eccentric hypertrophy induced by aortocaval shunt. At 1 wk after surgery, sham and shunt rats were divided into captopril-treated and untreated groups for 2 wk. Then isometric contraction was assessed by electrical stimulation of isolated rat left atrial preparations superfused with Tyrode solution in the presence or absence of specific inhibitors KT-5720 (for PKA) and Ro-32-0432 (for PKC) and high Ca2+. Peak tension developed was greater in shunt than in sham hearts. However, when expressed relative to tissue mass, hypertrophied muscle showed weaker contraction than muscle from sham rats. In sham rats, peak tension developed was more affected by PKC than by PKA inhibition, whereas this differential effect was reduced in the hypertrophied heart. Treatment of shunt rats with captopril regressed left atrial hypertrophy by 67% and restored PKC-PKA differential responsiveness toward sham levels. In the hypertrophied left atria, there was an increase in the velocity of contraction and relaxation that was not evident when expressed in specific relative terms. Treatment with ACE inhibitor increased the specific velocity of contraction, as well as its PKC sensitivity, in shunt rats. We conclude that ACE inhibition during eccentric cardiac hypertrophy produces a negative trophic and a positive inotropic effect, mainly through a PKC-dependent mechanism.     

Role of serotonin in thromboxane A2-induced coronary chemoreflex

We reported previously that the thromboxane A(2) (TxA(2)) mimetic U-46619 stimulates cardiac vagal afferent nerves, eliciting a reflex decrease in heart rate (HR) and arterial blood pressure (ABP). The present experiments were designed to test the hypothesis that TxA(2) evokes these changes via the release of serotonin [5-hydroxytryptamine (5-HT)] and activation of the 5-HT(3) receptor. Injections of the 5-HT(3) antagonist tropisetron (1 mg of 3-tropanyl-indole-3-carboxylate or ICS-205-930) attenuated the decreases in HR and ABP induced by left atrial injections of U-46619 (20 microg). Tropisetron administration also eliminated the U-46619-induced increase in impulse frequency in a majority of cardiac, vagal afferent units tested. Measurement of serum 5-HT levels revealed an elevation in serum 5-HT levels after U-46619 injection in those rabbits that displayed a significant HR change following injection of U-46619. These results indicate that although other factors may also contribute to these reflex responses, the release of 5-HT and stimulation of the 5-HT(3) receptor plays a significant role in coronary reflexes induced by TxA(2).