The incretin effect is reduced in NIDDM, although a corresponding attenuation of incretin hormone secretion does not occur. We characterized the direct interaction of GLP-I, an important incretin hormone, and leptin on insulin secretion and signal transduction in B-cells. Leptin inhibited GLP-I stimulated insulin release from the isolated perfused rat pancreas. Both phases of the biphasic insulin secretory response were inhibited. GLP-I receptor binding and GLP-I induced cAMP generation remained unchanged. Leptin reduced the GLP-I mediated increase of cytosolic Ca2+ concentration. It had similar effects on calcium elevations induced by forskolin. The effect was more pronounced during the plateau phase than during the initial peak. These effects could help to explain leptin's inhibitory effects on insulin secretion. The inhibition of GLP-I's insulinotropic effects by leptin may be an interesting aspect in the pathophysiology of NIDDM. The existence of an "adipo-insular axis" is suggested, in which leptin represents a negative feed-back signal from the adipose tissue to the endocrine pancreas.
Previous data suggest that renal afferent nerve activity is increased in hypertension exerting sympathoexcitatory effects. Hence, we wanted to test the hypothesis that in renovascular hypertension, the activity of dorsal root ganglion (DRG) neurons with afferent projections from the kidneys is augmented depending on the degree of intrarenal inflammation. For comparison, a nonhypertensive model of mesangioproliferative nephritis was investigated. Renovascular hypertension (2-kidney, 1-clip [2K1C]) was induced by unilateral clipping of the left renal artery and mesangioproliferative glomerulonephritis (anti-Thy1.1) by IV injection of a 1.75-mg/kg BW OX-7 antibody. Neuronal labeling (dicarbocyanine dye [DiI]) in all rats allowed identification of renal afferent dorsal root ganglion (DRG) neurons. A current clamp was used to characterize neurons as tonic (sustained action potential [AP] firing) or phasic (1–4 AP) upon stimulation by current injection. All kidneys were investigated using standard morphological techniques. DRG neurons exhibited less often tonic response if in vivo axonal input from clipped kidneys was received (30.4% vs. 61.2% control, p < 0.05). However, if the nerves to the left clipped kidneys were cut 7 days prior to investigation, the number of tonic renal neurons completely recovered to well above control levels. Interestingly, electrophysiological properties of neurons that had in vivo axons from the right non-clipped kidneys were not distinguishable from controls. Renal DRG neurons from nephritic rats also showed less often tonic activity upon current injection (43.4% vs. 64.8% control, p < 0.05). Putative sympathoexcitatory and impaired sympathoinhibitory renal afferent nerve fibers probably contribute to increased sympathetic activity in 2K1C hypertension.
INTRODUCTION AND AIMS: Renal denervation may be beneficial in hypertension with inflammatory renal disease: in hypertension renal afferent control of sympathetic nerve activity could be impaired. Recently, we found that afferent renal neurons showed a characteristic excitability, exhibiting predominantly a sustained firing upon current injection. So far, excitability of these neurons under pathological conditions such as renal inflammation in hypertension is unclear. Hence, in an in vitro model we wanted to test the hypothesis that a proinflammatory mediator like CXCL1 could alter the firing pattern of neurons with renal afferents and thus decrease their excitability. METHODS: Dorsal root ganglion (DRG) neurons (Th11-L2) were incubated with the chemokine CXCL1 (1,5nmol/ml) for 12 hours before patch clamp recordings. Labelling (DiI) allowed the identification of renal afferent neurons. Current clamp was used to characterize neurons as “tonic”, i.e. sustained action potential (AP) firing or “phasic”, i.e. <5 APs according to their firing response to current injections. AP properties were determined in renal and non-renal neurons incubated with CXCL1 and compared to controls. Results: Renal afferent DRG neurons exhibited in 57% (23 of 41) a tonic firing pattern vs.11,7% (3 of 27)* in non-renal neurons. However, exposed to the chemokine, renal DRG neurons exhibited significantly to a lesser degree tonic firing (35,6% [35 of 101] vs. 57% [23 of 41], *p<0,05) but instead an increased occurrence of phasic firing. Renal DRG neurons with phasic firing pattern showed a significantly lower threshold for AP-firing (600pA [320-1000] vs.1000pA [400-3200]) and a significantly shorter AP-duration at threshold-level (2,095ms [1,75-4,25] vs. 5,15ms [4,3- 8,7]) after exposure to CXCL1. Conclusion: We could show that after exposure to a proinflammatory mediator like CXCL1, renal afferent DRG neurons exhibited a significantly higher proportion of neurons with a phasic pattern (<5 APs) and decreased excitability as compared to control conditions. Significant changes in action potential properties of phasic neurons point to an altered sodium channel expression likely inducing a faster inactivation of these channels with decreased firing activity.
Introduction: Renal denervation has been shown to be effective in patients with hypertension. Recently, we found that afferent renal neurons show a distinctive feature, exhibiting predominantly a sustained firing upon current injection due to a specific expression of TTX resistant Na-channels. So far, the activity of these specific sensory neurons in hypertension is unclear. Hence we wanted to test the hypothesis that the firing pattern of renal afferent neurons is altered in the 2K/1C model of hypertension. Methods: Hypertension was induced by unilateral clipping of the renal artery in Sprague Dawley rats 3 weeks prior to experiments. Blood pressure was confirmed by an intraarterial measurement. Retrograde labelling (DiI) allowed the identification of renal afferent neurons in the Dorsal root ganglion (DRG Th11-L2). Current clamp was used to characterize neurons as “tonic”, i.e. sustained action potential (AP) firing or “phasic”, i.e. <5 APs according to their firing upon current injections. Electrophysiological parameters and AP properties were determined in neurons of hypertensive animals and controls. Renal morphology was investigated. Results: Renal DRG neurons of hypertensive animals (n=88) showed a significant decrease in tonic firing pattern compared to controls (n=84) (44.3% [39/88] vs. 59.5% [50/84], p< 0.05). Current Clamp analysis revealed no significant change in action potential shape in hypertensive animals (overshoot, firing threshold, AP- duration). Tonic cells revealed a higher capacity in hypertensive rats (124pF vs. 87.8pF, p<0.01), all other parameters (resting potential, resistances) were equal in both groups. No differences in renal pathomorphology could be observed between clipped and non-clipped kidney in hypertensive animals. (BP: 187.5 mmHg versus controls: 106.5mmHg) Conclusion: Hence the excitability of afferent renal neurons in a model of renovascular hypertension is significantly altered, as renal afferent DRG neurons exhibit less sustained firing upon stimulation. Sustained high blood pressure is possibly rather characterized by a generally decreased afferent renal activity with impaired sympathoinhibition than by activated sympathoexcitatory fibers from the clipped kidney.
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