Left ventricular failure is a condition that is characterized by chronic pulmonary venous congestion interspersed by episodes of acute pulmonary alveolar oedema. Previous investigations from this laboratory have demonstrated that the activity of rapidly adapting receptors (RARs) are influenced by fluid fluxes from microvasculature of the airways (Hargreaves et al. 1991). RARs have been shown to respond to acute pulmonary venous congestion with a sustained increase in activity. In those experiments, pulmonary venous congestion was caused by partial obstruction of the mitral valve to raise the left atrial pressure (LAP) by 5-10 mmHg. Since left ventricular failure usually presents as acute exacerbation of a chronic condition, it is of interest to determine whether the functions of the RARs are modified by persistent mild pulmonary venous congestion. The experiments reported in this paper were undertaken to test the hypothesis that the increase in RAR activity resulting from small acute increments of LAP (5 and 10 mmHg) was attenuated in animals maintained in a state of chronic pulmonary venous congestion. Chronic pulmonary venous congestion was produced surgically by partial destruction of the mitral valve. The experiments were undertaken in anaesthetized New Zealand White rabbits. The data from these animals were compared with intact control animals and sham-operated animals. METHODSExperiments were performed on forty-five male New Zealand White rabbits weighing 3·28 ± 0·05 kg (range 2·7-3·8 kg). The protocol was approved by the Animal Use and Care Committee of the University of California, Davis. Two groups of rabbits were studied: intact (control) rabbits and those with surgically induced mitral regurgitation. They were pre-medicated with ketamine HCl (50 mg kg¢, Mallinckrodt Veterinary Inc., Mundelein, IL, USA) and xylazine (5 mg kg¢, Bayer, Shawnee Mission, KA, USA) i.m., and then anaesthetized with pentobarbitone sodium (5 mg kg¢, Veterinary Laboratories Inc., Lenexa, KA, USA) given through an ear vein. Anaesthesia was maintained with pentobarbitone sodium (4 mg kg¢, Veterinary Laboratories Inc.) i.v. every half an hour. After induction of anaesthesia an uncuffed endotracheal tube (i.d. 3 mm and length 5 cm) was introduced through a tracheostomy and was tied in place. The rabbits were artificially ventilated (Model 55- 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 ± ...

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 agematched animals (control rabbits; n = 17). Percentage increases from weeks 0 to 12 in LV cross-sectional area (47 f 7 % vs. 2 f S%), LV volume (47 f 14% vs. 7 f 10%) and LV mass (27 f 4% vs. 3 f 6%), were greater (all P < 0.05) in LV hypertrophy vs. control rabbits, respectively. At 12 weeks, coronary resistance vessel (-130 pm, internal diameter) reactivity was evaluated using wire myography. Endothelium-dependent (i.e. acetylcholine, 10-8-10-5 M) and -independent (i.e. sodium nitroprusside, 10-9-104 M) relaxation, and receptor-mediated vasocontraction (i.e. endothelin-1, 10-"-10-7 M) were similar between groups. However, tension development in response to nitric oxide synthase inhibition (lo4 M NG-monomethyl-carginine) 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 hypertrzophy than control rabbits. Experimental Physiology (2001) 86.6,725-732. Left ventricular (LV) hypertrophy is an important risk factor for cardiac mortality and morbidity (Sheridan et al. 1993). Concentric LV hypertrophy develops to compensate for increased ventricular wall stress resulting from chronic pressure overload caused by, for example, aortic stenosis or systemic hypertension (pressure overload LV hypertrophy) while eccentric LV hypertrophy results from long-term volume overload caused by, for example, aortic or mitral regurgitation (volume overload LV hypertrophy) (Chilian, 1987).

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Pulmonary rapidly adapting receptors (RARs) in anaesthetized intact rabbits are activated by small changes in the extravascular fluid spaces of the major airways where they are located (Hargreaves et al. 1991). It has also been shown that stimulation of RARs in this manner causes reflex increases in respiratory rate (Kappagoda et al. 1989), tracheal tone (Kappagoda et al. 1988) and mucus production by the respiratory epithelium (Yu et al. 1989). All these reflex effects collectively form the syndrome of cardiac asthma which is characterized by wheezing, an increased respiratory rate and increased mucus production. Therefore, it was suggested that in chronic left ventricular dysfunction, intermittent, small acute elevations of left atrial pressure (LAP) cause these exacerbations in symptoms through activation of RARs (Hargreaves et al. 1991). However, in a recent study from our laboratory performed on rabbits maintained in a state of chronic pulmonary venous congestion (PVC) secondary to surgically induced mitral regurgitation (MR), acute small elevations (+10 mmHg) of LAP failed to activate RARs (Gunawardena et al. 1998). It was speculated that in these animals this lack of response of RARs could be due to a change either in the receptor per se, or in the extravascular space surrounding the receptor. These issues were addressed in the present study by testing the following hypotheses: (i) shrinking the extravascular space by an intravenous infusion of hypertonic albumin restores the sensitivity of previously insensitive RARs (to small, acute elevations of LAP) in rabbits with chronic PVC, (ii) the increase in extravascular fluid volume in major airways resulting from small elevations of LAP is less in animals with chronic PVC than in age-matched control animals, and (iii) enhancing the stimulus to RARs by increasing the LAP above 25 mmHg stimulates previously insensitive RARs in rabbits with chronic PVC. As in the 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¢, 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¢, 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...

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)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.