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The splenorenal reflex induces changes in mean arterial pressure (MAP) and renal function. We hypothesized that, in addition to spinal pathways previously identified, these effects are also mediated through central pathways. We investigated the effect of elevated splenic venous pressure on central neural activation in intact, renal-denervated, and renal + splenic-denervated rats. Fos-labeled neurons were quantified in the nucleus of the tractus solitarius (NTS), paraventricular nucleus (PVN), supraoptic nucleus (SON), and subfornical organ (SFO) after 1-h partial splenic vein occlusion (SVO) in conscious rats bearing balloon occluders around the splenic vein, telemetric pressure transducers in the gastric vein (splenic venous pressure), and abdominal aorta catheters (MAP). SVO stimulated Fos expression in the PVN and SON, but not NTS or SFO of intact rats. Renal denervation abolished this response in the parvocellular PVN, while renal + splenic denervation abolished activation in the magnocellular PVN and the SON. In renal-denervated animals, SVO depressed Fos expression in the NTS and increased expression in the SFO, responses that were abolished by renal + splenic denervation. In intact rats, SVO also induced a fall in right atrial pressure, an increase in renal afferent nerve activity, and an increase in MAP. We conclude that elevated splenic venous pressure does induce hypothalamic activation and that this is mediated through both splenic and renal afferent nerves. However, in the absence of renal afferent input, SVO depressed NTS activation, probably as a result of the accompanying fall in cardiac preload and reduced afferent signaling from the cardiopulmonary receptors.

Stenosis of either the portal or splenic vein increases splenic afferent nerve activity (SANA), which, through the splenorenal reflex, reduces renal blood flow. Because these maneuvers not only raise splenic venous pressure but also reduce splenic venous outflow, the question remained as to whether it is increased intrasplenic postcapillary pressure and/or reduced intrasplenic blood flow, which stimulates SANA. In anesthetized rats, we measured the changes in SANA in response to partial occlusion of either the splenic artery or vein. Splenic venous and arterial pressures and flows were simultaneously monitored. Splenic vein occlusion increased splenic venous pressure (9.5 +/- 0.5 to 22.9 +/- 0.8 mmHg, n = 6), reduced splenic arterial blood flow (1.7 +/- 0.1 to 0.9 +/- 0.1 ml/min, n = 6) and splenic venous blood flow (1.3 +/- 0.1 to 0.6 +/- 0.1 ml/min, n = 6), and increased SANA (1.7 +/- 0.4 to 2.2 +/- 0.5 spikes/s, n = 6). During splenic artery occlusion, we matched the reduction in either splenic arterial blood flow (1.7 +/- 0.1 to 0.7 +/- 0.05, n = 6) or splenic venous blood flow (1.2 +/- 0.1 to 0.5 +/- 0.04, n = 5) with that seen during splenic vein occlusion. In neither case was there any change in either splenic venous pressure (-0.4 +/- 0.9 mmHg, n = 6 and +0.1 +/- 0.3 mmHg, n = 5) or SANA (-0.11 +/- 0.15 spikes/s, n = 6 and -0.05 +/- 0.08 spikes/s, n = 5), respectively. Furthermore, there was a linear relationship between SANA and splenic venous pressure (r = 0.619, P = 0.008, n = 17). There was no such relationship with splenic venous (r = 0.371, P = 0.236, n = 12) or arterial (r = 0.275, P = 0.413, n = 11) blood flow. We conclude that it is splenic venous pressure, not flow, which stimulates splenic afferent nerve activity and activates the splenorenal reflex in portal and splenic venous hypertension.

The atrial volume reflex is attenuated in pregnancy. This may be mimicked by chronic administration of 5α-pregnan-3α-ol-20-one (pregnan). We investigated whether afferent output from sensory receptors may be suppressed at this time. Vagal afferent nerve activity was measured during discrete localized stimulation of the atrial volume receptors by inflation of a balloon at the superior vena caval-right atrial junction. The receptors were classified as high- (HF) or low- (LF) frequency subtypes on the basis of their response to graded atrial distension. Although both HF (regression coefficient = 0.50 ± 0.11 Hz/μl, r2 = 0.47, P < 0.001) and LF (regression coefficient = 0.03 ± 0.05 Hz/μl, r2 = 0.009, P = 0.613) subtypes could be identified in virgin rats, only LF (regression coefficient = 0.09 ± 0.05 Hz/μl, r2 = 0.044, P = 0.099) receptors were found in late-pregnant animals. Similarly, in virgin rats treated chronically with pregnan (500 μg/24 h for 2 days), only LF receptors were identified (regression coefficient = −0.004 ± 0.078 Hz/μl, r2 = 0.000, P = 0.962), whereas both subtypes were present in the vehicle-treated animals (HF regression coefficient = 0.626 ± 0.255 Hz/μl, r2 = 0.317, P = 0.029; LF regression coefficient = −0.012 ± 0.071 Hz/μl, r2 = 0.002, P = 0.866). By contrast, acute intracardiac pregnan (2.6 μg/kg) did not alter vagal afferent nerve activity. In conclusion, stretch-induced discharge of high-frequency atrial receptors is suppressed during pregnancy, whereas that of low-frequency receptors is preserved. This effect may be mimicked by chronic, but not acute, pregnan. We propose that, during pregnancy, pregnan alters the transducer properties of the atrial volume receptors, thus allowing blood volume to increase.

We have previously shown that ANP causes differential constriction of the splenic vasculature of the rat (veins greater than arteries), which may be inhibited by blocking the production of cGMP with A7195. In this paper, we report experiments done on vessels derived from guanylyl cyclase (GC)-A knockout mice. Small splenic arteries (∼150-μm diameter) and veins (∼250-μm diameter) were dissected from male GC-A-deficient 129sv mice or age-matched wild-type controls and mounted in a wire myograph. In the wild-type mice, ANP exhibited higher potency in the veins than in the arteries (EC50 values wild-type mice: artery, 8 ± 3 × 10−9 M, n = 5 vs. vein, 6 ± 4 × 10−10 M, n = 5; P < 0.05). The concentration-response curve for ANP-induced vasoconstriction was also shifted leftward in denuded compared with intact arteries (EC50 values: denuded artery: 5 ± 3 × 10−10 M, n = 5 vs. intact artery, 8 ± 3 × 10−9 M, n = 5; P < 0.05), i.e., the denuded vessels were more reactive. By contrast, ANP caused no significant change in tension from baseline in intact splenic arteries, intact splenic veins, or denuded splenic arteries derived from the GC-A-deficient mice, although these vessels did show normal concentration-dependent increases in tension to phenylephrine. We conclude that ANP causes vasoconstriction in the splenic vasculature by an endothelium-independent mechanism, mediated via guanylyl cyclase.

Atrial distension increases c- fosexpression 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 μg/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- fosexpression. 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.

Nitric oxide (NO) biosynthesis increases during pregnancy and has been shown to suppress baroreceptor activity. The renal response to a simulated increase in circulating blood volume (atrial distension) is also attenuated at this time. We hypothesized that blocking NO biosynthesis during pregnancy would restore the renal response. Female rats were implanted with indwelling intracardiac balloons and central venous cannulas. After recovery, they were mated, and on day 14 of pregnancy, osmotic minipumps containing the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) or its inactive enantiomer N G-nitro-d-arginine methyl ester (d-NAME) (120 mg/2 ml at 10 μg/min) were implanted. In response to atrial distension (1 h), urine output increased in the d- and l-NAME-treated virgin rats. During pregnancy ( day 20), this response was attenuated in the d-NAME-treated, but not thel-NAME-treated, animals, i.e., after a simulated increase in circulating blood volume, inhibition of NO biosynthesis restored the renal response of pregnant rats to that seen in virgin animals. We conclude that, during normal pregnancy, increased NO biosynthesis blunts the reflex renal response to atrial distension.

During lipopolysaccharide (LPS)-induced endotoxemia, increased intrasplenic fluid efflux contributes to a reduction in plasma volume. We hypothesized that splenic sympathetic nerve activity (SSNA), which increases during endotoxemia, limits intrasplenic fluid efflux. We reasoned that splenic denervation would exaggerate LPS-induced intrasplenic fluid efflux and worsen the hypotension, hemoconcentration, and hypovolemia. A nonlethal dose of LPS (150 μg · kg−1 · h−1 for 18 h) was infused into conscious male rats bearing transit time flow probes on the splenic artery and vein. Fluid efflux was estimated from the difference in splenic arterial inflow and venous outflow (A-V). LPS significantly increased the (A-V) flow differential (fluid efflux) in intact rats (saline −0.01 ± 0.02 ml/min, n = 8 vs. LPS +0.21 ± 0.06 ml/min, n = 8); this was exaggerated in splenic denervated rats (saline −0.03 ± 0.01 ml/min, n = 7 vs. LPS +0.41 ± 0.08 ml/min, n = 8). Splenic denervation also exacerbated the LPS-induced hypotension, hemoconcentration, and hypovolemia (peak fall in mean arterial pressure: denervated 19 ± 3 mmHg, n = 10 vs. intact 12 ± 1 mmHg, n= 8; peak rise in hematocrit: denervated 6.7 ± 0.3%, n = 8 vs. intact 5.0 ± 0.3%, n = 8; decrease in plasma volume at 90-min post-LPS infusion: denervated 1.08 ± 0.15 ml/100 g body wt, n = 7 vs. intact 0.54 ± 0.08 ml/100 g body wt, n = 8). The exaggerated LPS-induced hypovolemia associated with splenic denervation was mirrored in the rise in plasma renin activity (90 min post-LPS: denervated 11.5 ± 0.8 ng · ml−1 · h−1, n = 9 vs. intact 6.6 ± 0.7 ng · ml−1 · h−1, n = 8). These results are consistent with our proposal that SSNA normally limits LPS-induced intrasplenic fluid efflux.

We recently demonstrated that fluid is filtered out of the splenic circulation and into the lymphatic system. The current experiments were designed to investigate the importance of this route of fluid extravasation in endotoxemia. Lipopolysaccharide (LPS) was infused into conscious intact and splenectomized rats (150 μg ⋅ kg−1⋅ h−1iv for 18 h). In the intact rats, mean arterial pressure (MAP) fell from 101 ± 2.4 to 88 ± 3.9 mmHg ( n = 7) and then stabilized at about 90 mmHg. Hematocrit rose from 41 ± 0.9 to 45 ± 0.4% at 40 min, at which time plasma volume had fallen from 4.7 ± 0.12 to 4.0 ± 0.05 ml/100 g body wt. In the splenectomized rats MAP did not fall and hematocrit did not rise. There also was no change in plasma volume, i.e., splenectomy prevented the hypotension and hemoconcentration customarily induced by LPS. In a second series of experiments, splenic arterial and venous blood flows were simultaneously measured in anesthetized rats infused with LPS (150 μg ⋅ kg−1⋅ h−1). LPS increased splenic fluid efflux. We conclude that during endotoxemia the initial fall in circulating blood volume may be attributed to fluid extravasation from the splenic vasculature.