Effects of mitral regurgitation on the reflex diuresis to pulmonary lymphatic obstruction in rabbits.

Increasing the extravascular fluid of the airways acutely by obstructing pulmonary lymph drainage causes a reflex diuresis mediated by neuronal nitric oxide synthase in the renal medulla. The authors examined this reflex in rabbits with a chronic increase in extravascular fluid of the airways resulting from surgically induced mitral regurgitation. Intact rabbits served as controls. Renal neuronal (nNOS) and endothelial (eNOS) nitric oxide synthase expressions were also examined. The reflex was absent in rabbits with mitral regurgitation. There were significant increases in medullary and cortical nNOS mRNA compared to controls. The observed changes in mRNA levels correlated with nNOS protein levels. eNOS mRNA was unaffected.

Role of adrenergic receptors in the reflex diuresis in rabbits during pulmonary lymphatic obstruction.

The role of adrenergic receptors in the reflex diuresis in response to pulmonary lymphatic drainage was examined in anaesthetized, artificially ventilated New Zealand White rabbits. Pulmonary lymphatic drainage was obstructed by raising the pressure in a pouch created from the right external jugular vein. This pulmonary lymphatic obstruction results in a reflex increase in urine flow and sodium excretion. This reflex is abolished by renal denervation and by administration of L-NAME, a non-selective inhibitor of nitric oxide synthase. Also, infusion of the relatively selective neuronal nitric oxide synthase blocker, 7-nitroindazole sodium salt, into the renal medulla abolished the reflex diuresis. In this study the effects of adrenergic receptor antagonists on the reflex increase in urine were observed. Both ureters were cannulated in order to determine urine flow from both kidneys separately. Prazosin, an alpha1 adrenergic receptor antagonist, was infused into the renal medulla of the right kidney, while the left kidney acted as control. Administration of prazosin in this manner did not block the reflex diuresis in response to pulmonary lymphatic obstruction in either kidney. However, rauwolscine, an alpha2 adrenergic receptor antagonist, abolished the reflex increase in urine and sodium excretion in the ipsilateral kidney while preserving it in the contralateral kidney. These findings suggest that the increase in urine flow in rabbits caused by pulmonary lymphatic obstruction is dependent upon activation of alpha2 adrenergic receptors within the renal medulla.

Effects of gadolinium chloride on slowly adapting and rapidly adapting receptors of the rabbit lung.

Effects of gadolinium chloride, an inhibitor of stretch-activated channels, on the responses of slowly adapting receptors (SARs) and rapidly adapting receptors (RARs) to hyperinflation were investigated. The increase in activity of RARs resulting from sustained elevations of left atrial pressure (LAP) was also assessed with gadolinium chloride application. Action potentials (AP) of SARs and RARs during hyperinflation were recorded from the vagus nerve of anesthetized New Zealand White rabbits before and after application of gadolinium chloride (20mM) directly on the receptor area of the nerve endings. There was a significant reduction of activity in SARs (n = 9) and RARs (n = 7) after application of gadolinium chloride. Activity of RARs (n = 6) increased when the LAP was elevated by 5 and 10 mmHg. This effect was abolished after gadolinium chloride was applied to receptor endings and the activity was restored when gadolinium chloride was removed. This suggests that stretch-activated channels play a role in SARs and RARs activity.

Role of nitric oxide in the reflex diuresis in rabbits during pulmonary lymphatic obstruction.

The role of nitric oxide in the reflex diuresis in response to pulmonary lymphatic drainage was examined in anaesthetized, artificially ventilated New Zealand White rabbits. Pulmonary lymphatic drainage was obstructed by raising the pressure in a pouch created from the right external jugular vein. Pulmonary lymphatic obstruction resulted in a significant increase in urine flow from an initial control value of 8.9 +/- 0.5 ml (10 min)(-1) to 12.1 +/- 0.6 ml (10 min)(-1) during lymphatic obstruction (mean +/-s.e.m.; n= 17, P < 0.001). This increase in urine flow was accompanied by a significant increase in the excretion of sodium. Additionally, renal blood flow remained unchanged during the increase in urine flow caused by lymphatic obstruction. Intravenous infusion of L-NAME, a non-selective inhibitor of nitric oxide synthase (NOS), abolished the reflex diuresis. Furthermore, intraperitoneal administration of the relatively selective neuronal NOS blocker, 7-nitroindazole also abolished the response. It was observed that infusion of a more soluble neuronal NOS blocker, 7-nitroindazole sodium salt (7-NINA), into the renal medulla also abolished the reflex diuresis. These findings suggest that the increase in urine flow in rabbits caused by pulmonary lymphatic obstruction is dependent upon the integrity of neuronal NOS activity within the renal medulla.

Responses of C fiber afferents of the rabbit airways and lungs to changes in extra-vascular fluid volume.

Effects of changes in extra-vascular fluid volume produced by pulmonary lymphatic obstruction and plasmapheresis on the activities of bronchial and pulmonary C fiber receptors and rapidly adapting receptors (RARs) were investigated in New Zealand White rabbits. In intact rabbits, pulmonary lymphatic obstruction either alone or in combination with plasmapheresis did not stimulate pulmonary C fiber receptors. Only the combined stimulus activated the bronchial C fiber receptors. Bronchial C fiber receptors were also stimulated by graded increases in left atrial pressure (+5 and +10 mmHg). In contrast, RARs were activated by lymphatic obstruction either alone or in combination with plasmapheresis. These procedures increase the extra-vascular fluid volume in the carina and bronchi but not in the lungs (alveoli). In rabbits with chronic pulmonary venous congestion secondary to mitral valve damage, bronchial C fiber receptors were not stimulated by these increments in left atrial pressure which were insufficient to increase the extra vascular fluid content of the airways. However, both pulmonary and bronchial C fiber receptors were stimulated when the left atrial pressure was raised to 25 mmHg in these animals to cause pulmonary edema.

Airway rapidly adapting receptors--sensors of pulmonary extra-vascular fluid volume.

The factors regulating transfer of fluid into the pulmonary extra-vascular space and the role of sensory receptors of the airways in detecting such fluid fluxes are reviewed and discussed. It is concluded that the rapidly adapting receptors (RARs) located in apposition to bronchial venules are highly sensitive to changes in the pulmonary extra-vascular space produced by mild elevations of left atrial pressure, plasmapheresis and pulmonary lymphatic obstruction and their activation causes respiratory stimulation, an increase in tracheal tone and cough. There is a reflex diuresis also following the stimulation of these receptors by pulmonary lymphatic obstruction. It is proposed that the RARs function as a sensory component of the pulmonary defence mechanisms which preserve the 'milieu interior'.

Volume overload left ventricular hypertrophy: effects on coronary microvascular reactivity in rabbits.

The mechanisms controlling the coronary vascular responses of vessels perfusing the left ventricular (LV) myocardium that is hypertrophied from chronic volume overload are unclear. We hypothesised that endothelial function is compromised, and receptor-mediated contraction is exacerbated, in coronary resistance vessels from rabbits with LV hypertrophy compared to controls. The mitral valve of 10 rabbits was damaged surgically to cause mitral regurgitation and chronic volume overload, resulting in LV hypertrophy (LV hypertrophy rabbits). Echocardiographic assessment at 12 weeks verified that mitral regurgitation was present in LV hypertrophy but not sham-operated, weight- and age-matched animals (control rabbits; n = 17). Percentage increases from weeks 0 to 12 in LV cross-sectional area (47 +/- 7 % vs. 2 +/- 8 %), LV volume (47 +/- 14 % vs. 7 +/- 10 %) and LV mass (27 +/- 4 % vs. 3 +/- 6 %), were greater (all P < 0.05) in LV hypertrophy vs. control rabbits, respectively. At 12 weeks, coronary resistance vessel (approximately 130 microm, internal diameter) reactivity was evaluated using wire myography. Endothelium-dependent (i.e. acetylcholine, 10(-8)-10(-5) M) and -independent (i.e. sodium nitroprusside, 10(-9)-10(-4) M) relaxation, and receptor-mediated vasocontraction (i.e. endothelin-1, 10(-11)-10(-7) M) were similar between groups. However, tension development in response to nitric oxide synthase inhibition (10(-6) M N (G)-monomethyl-L-arginine) was greater (P < 0.05) in LV hypertrophy compared to control rabbits. These results indicate that while coronary resistance vessel function is similar between groups, our estimate of basal nitric oxide production is greater in vessels from LV hypertrophy than control rabbits.

Predictors of plasma triglyceride elevation in patients participating in a coronary atherosclerosis treatment program.

PURPOSE: Low-fat, high-carbohydrate diets have been used successfully to prevent and treat coronary heart disease, although these diets have been shown to cause elevations in fasting plasma triglyceride concentrations. The present study investigated metabolic factors (glucose, insulin, body weight) associated with changes in plasma triglyceride concentrations in patients participating in a comprehensive, multidisciplinary program, which included the use of a very low-fat diet designed to regress atherosclerotic cardiovascular disease. METHODS: Thirty-six patients were entered into the study and placed on a 10% fat diet. Body mass index and fasting plasma insulin, glucose, lipids, and apolipoproteins were assessed at entrance into and after 3 months of participation in the program. Statistical analysis (discriminant function analysis) was used to identify factors that predicted elevations in plasma triglyceride that occurred during therapy. RESULTS: For the entire group, significant reductions in body weight (-2.4%), fasting glucose (-6%), total cholesterol (-8%), and low-density lipoprotein cholesterol (-11%) were observed, while insulin and triglycerides showed no significant changes. Twenty-one of the patients experienced an increase in fasting triglyceride concentration of 10% or greater. CONCLUSIONS: Three variables (baseline body mass index and fasting triglyceride and insulin concentrations) accurately classified 90% of those who would experience a > or = 10% elevation in triglycerides (P = 0.0002) and 67% of those who experienced no change. The present analysis provides a practical algorithm for clinicians to predict which patients will experience significant elevations in plasma triglyceride concentration when undergoing risk factor reduction that includes the consumption of a very low-fat, high-carbohydrate diet.

Effects of cocoa extracts on endothelium-dependent relaxation.

The aim of this study was to examine the effects of procyanidins derived from cocoa on vascular smooth muscle. Two hypotheses were tested: 1) extracts of cocoa, which are rich in procyanidins, cause endothelium-dependent relaxation (EDR), and 2) extracts of cocoa activate endothelial nitric oxide synthase (NOS). The experiments were carried out on aortic rings obtained from New Zealand White rabbits. The polymeric procyanidins (tetramer through decamer of catechin) caused an EDR. In addition, the Ca(2+)-dependent NOS activity, measured by the L-arginine to L-citrulline conversion assay, was significantly increased in aortic endothelial cells exposed to polymeric procyanidins, whereas monomeric compounds had no such effect. These findings demonstrate that polymeric procyanidins cause an EDR that is mediated by activation of NOS.

Rapidly adapting receptors in a rabbit model of mitral regurgitation.

1. Unlike in normal rabbits, pulmonary rapidly adapting receptors (RARs) in rabbits with chronic mitral regurgitation (MR) do not respond to small changes in extravascular fluid (EVF) volume in major airways. The present study examined the effect of shrinking the EVF volume in rabbits with chronic MR by infusing hypertonic albumin, to see whether this response of RARs is restored. The effect of raising the left atrial pressure (LAP) acutely above 25 mmHg (to cause pulmonary oedema) on RARs was also investigated. 2. Mean RAR activities in rabbits with MR (n = 6) at initial control, LAP +5 mmHg, LAP +10 mmHg and final control periods were 20.9 +/- 9. 5, 18.8 +/- 11.3, 27.0 +/- 11.2 and 17.2 +/- 9.8 action potentials min-1, respectively (P > 0.05, ANOVA). After infusion of 35 % bovine serum albumin i.v. these values were 9.4 +/- 3.2, 30.6 +/- 14.6, 48. 9 +/- 10.1 and 18.4 +/- 7.3 action potentials min-1, respectively (P < 0.01, ANOVA). In rabbits with chronic MR (n = 7) raising the LAP above 25 mmHg stimulated RARs. 3. EVF content of the airways and lungs was measured in rabbits with MR and in control rabbits, at baseline and after elevation of the LAP by 10 or 25 mmHg for 20 min. In control rabbits the EVF contents in the lower trachea, carina and bronchi at baseline and at LAP +10 mmHg were 52.1 +/- 1.2 and 57.8 +/- 1.7 %, respectively (P < 0.05, Student's t test). In rabbits with MR these values were 58.3 +/- 1.5 and 56.9 +/- 1.9 %, respectively. When the LAP was elevated by 25 mmHg the EVF content increased to 62.4 +/- 1.1 % (P < 0.05, t test compared with baseline and LAP +10 mmHg). 4. We concluded that in rabbits with chronic MR, RARs are unable to respond to acute, small elevations of LAP because there is no concomitant increase in EVF content in the vicinity of these receptors. Furthermore, these receptors can be activated in these animals by elevating the LAP above 25 mmHg or can be made sensitive to acute small elevations of LAP by shrinking the chronically expanded EVF compartment.

Lifestyle modification program in management of patients with coronary artery disease: the clinical experience in a tertiary care hospital.

OBJECTIVES: The authors examined clinical outcomes in 71 male and female patients with coronary atherosclerosis who enrolled in a 2-year, independent-living, lifestyle modification program. The findings in 43 patients who completed the program were compared with those in 28 patients who dropped out of the program. BACKGROUND: Clinical studies suggest that lifestyle modification of risk factors for coronary atherosclerosis reduces subsequent cardiac events but there are very few reports of the effect of these programs in patients living independently. METHODS: Patients with diagnosed coronary atherosclerosis were managed for a 2-year period in a structured multidisciplinary program by a team that included two cardiologists, a nurse, a dietitian, an exercise physiologist, and a clinical psychologist. The overall aim of the program was to normalize or control all major reversible cardiovascular risk factors. Patients were required to participate in several weekly sessions for exercise, meditation/stress reduction training, dietary education and counseling, and participatory dinners. There was a strong emphasis on patient's self care, inclusion of support members, and regular monitoring of and feedback to patients. RESULTS: Data comparing baseline and 2-year outcomes showed a significant reduction in body weight, dietary intake of total/saturated fat and cholesterol, serum low- and high-density lipoprotein concentration, and an increase in exercise capacity. In the compliant group, the incidence of cardiac events was 2.3% over 2 years. CONCLUSION: Multidisciplinary lifestyle modification programs addressing cardiovascular risk factors are known to have a significant impact upon cardiac risk factors in patients with coronary atherosclerosis. Data show that these changes can be accomplished in independent-living patients in a program offered through a routine cardiology service. However, compliance is an important issue in these self-regulated programs.

Reduced oxidative susceptibility of LDL from patients participating in an intensive atherosclerosis treatment program.

The goal of this investigation was to determine whether participation in an atherosclerosis treatment program would reduce the oxidative susceptibility of LDL from patients with coronary artery disease. The treatment program included intensive exercise therapy, stress management, and consumption of a diet containing 10% fat. The size and antioxidant and lipid contents of LDL particles from 25 patients were analyzed at baseline and after 3 mo of therapy. The susceptibility of LDL to copper-mediated oxidation was measured by a conjugated diene assay and headspace gas chromatography (HSGC). Atherosclerosis treatment significantly reduced plasma total cholesterol and apolipoprotein B concentrations and the molar ratio of LDL cholesterol ester to apolipoprotein B (P < 0.01). The LDL content of alpha-tocopherol and beta-carotene was increased (27% and 17%, respectively, P < 0.04) and the molar ratio of LDL cholesterol ester the sum of LDL alpha-tocopherol and LDL beta-carotene decreased from 159 at baseline to 122 at 3 mo (P < 0.01). The lag phase of LDL conjugated diene formation increased 24%, whereas the maximum rate of oxidation slowed 29% (P < 0.01). As assessed by HSGC, copper-catalyzed formation of volatile lipid oxidation products was reduced 15% (P < 0.007); the reduction in volatiles was correlated with an increase in the alpha-tocopherol content of LDL (r=-0.48, P < 0.01). The principal determinants of reduced LDL oxidative susceptibility were the particle contents of alpha-tocopherol and beta-carotene. To our knowledge, this is the first report to document a reduction in LDL oxidation in coronary artery disease patients undergoing atherosclerosis-reversal therapy.

Effect of chronic mitral valve damage on activity of pulmonary rapidly adapting receptors in the rabbit.

1. The effects of acute pulmonary venous congestion on the activity of rapidly adapting receptors (RARs) were determined in intact (control and sham-operated) rabbits and in rabbits 6 and 12 weeks after surgical destruction of the mitral valve. 2. Destruction of the mitral valve increased the mean left atrial pressure (LAP) by approximately 2.6 and 3.8 mmHg, 6 and 12 weeks after surgery, respectively. These changes were accompanied by significant increases in left ventricular weight. The effect of acute increments in LAP on RAR activity was examined against this background of chronic pulmonary venous congestion. 3. In intact control and sham-operated animals RAR activity increased from 48.8 +/- 0.9 to 83. 5 +/- 3.6 and 121.1 +/- 4.7 action potentials min-1 when the LAP was raised by 5 and 10 mmHg, respectively, above control values. Six weeks after surgery only 40 % of RARs were activated in this way. 4. In animals maintained for 12 weeks after surgery, RAR activity at LAPs of 6.6 +/- 1.2 (control), 11.6 +/- 1.2 and 16.6 +/- 1.2 (mmHg) were 35.5 +/- 2.3, 33.8 +/- 14.4 and 34.0 +/- 3.4 action potentials min-1, respectively. These changes were statistically not significant. 5. Slowly adapting receptors (SARs) in the lung showed a small but statistically significant increase in activity when the left atrial pressure was acutely elevated in both intact and mitral valve damaged animals . 6. It is concluded that chronic pulmonary venous congestion resulting from destruction of the mitral valve attenuates the ability of RARs to respond to acute moderate elevations of LAP.

Sensory axonopathy in mild to moderate peripheral arterial disease.

The effect of mild to moderate arterial occlusive disease on peripheral nervous system conduction was prospectively investigated in 18 subjects and 18 control subjects, aged 40 to 85 years. Experimental and control subjects underwent a thorough history and physical followed by vascular and electrophysiologic studies. The primary outcome measure was the sensory nerve action potential. Although 33% of the subjects with peripheral arterial disease had experienced paresthesias, the clinical evaluation of sensation was relatively unaffected. Sensory conduction studies revealed 30% absent sural responses and 56% absent superficial peroneal nerve responses in subjects with peripheral arterial disease compared with 3 and 14% absent responses in control subjects, respectively (P = 0.044; 0.025). There were no differences in distal latency or sensory amplitude, although the superficial peroneal amplitude did approach significance (P = 0.06). No significant differences were found in motor distal latency, amplitude, or conduction velocity. Age, leg length, temperature, disease severity, presence of paresthesias, cholesterol levels, and past alcohol or tobacco ingestion did not account for the difference in sensory responses. These results support the presence of a mild sensory axonopathy in subjects with peripheral arterial disease. Electromyographers should be cognizant of absent distal responses from peripheral arterial disease so as not to ascribe the findings to an alternative pathology and should not attribute abnormal motor conduction results to the presence of this degree of peripheral arterial disease.

A high cholesterol diet blocks the effect of calcium channel blockers on the uptake of sugars in rabbit intestine.

Two classes of calcium channel blockers, nisoldipine (NIS) and verapamil (VER), alter the intestinal uptake of sugars, and varying the lipid composition of the diet also modifies intestinal transport function. This study was undertaken in adult male New Zealand rabbits to assess the effect of 3 weeks of dosing with NIS (1 mg.kg-1.day-1) or VER (4 mg.kg-1.day-1) on the in vitro jejunal uptake of D-galactose and L- or D-glucose. The value of the maximal transport rate of D-galactose (Vmax) increased with NIS and VER, compared with control vehicle. The value of the apparent Michaelis constant (K(m)) rose with NIS and fell with VER, and the value of the passive permeability coefficient (Pd) estimated from the uptake of L-glucose fell with NIS and rose with VER. These effects of NIS and VER on Vmax, K(m), and Pd were prevented by feeding a high cholesterol (2.8%) supplemented chow diet (HCD), as compared with chow alone. These effects were not due to any change in the animal's weight gain or intestinal mucosal surface area. The acute exposure of the jejunal tissue in vitro to varying concentrations of NIS but not VER reduced the uptake of D-glucose but had no effect on basal short circuit current (Isc) in either chow or HCD. Isc stimulated with glucose or theophylline was less in chow-fed rabbits compared with HCD-fed rabbits given NIS or VER. Thus, the active transport of sugars by the sodium-dependent transporter in the brush-border membrane, SGLT1, and the passive uptake by the paracellular route are variably influenced by these two classes of calcium channel blockers, and this effect is modified by the cholesterol content of the diet.