The endogenous cannabinoid receptor agonist anandamide is present in central and peripheral tissues. As the kidney contains both the amidase that degrades anandamide and transcripts for anandamide receptors, we characterized the molecular components of the anandamide signaling system and the vascular effects of exogenous anandamide in the kidney. We show that anandamide is present in kidney homogenates, cultured renal endothelial cells (

The vascular effects of carbon monoxide (CO) resemble those of nitric oxide (NO), but it is unknown whether the two messengers converge or exhibit reciprocal feedback regulation. These questions were examined in microdissected perfused renal resistance arteries (RRA) studied using NO-sensitive microelectrodes. Perfusion of RRA with buffers containing increasing concentrations of CO resulted in a biphasic release of NO. The NO response peaked at 100 nM CO and then declined to virtually zero at 10 microM. When a series of 50-s pulses of 100 nM CO were applied repeatedly (150-s interval), the amplitude of consecutive NO responses was diminished. NO release from RRA showed dependence on L-arginine but not D-arginine, and the responses to CO were inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthases (NOS). CO (100 nM) also suppressed NO release induced by 100 microM carbachol, a potent agonist for endothelial NOS (eNOS). RRA from rats in which endogenous CO production from inducible HO was elevated (cobalt chloride 12 h prior to study) also showed suppressed responses to carbachol. Furthermore, responses consistent with these findings were obtained in juxtamedullary afferent arterioles perfused in vitro, where the vasodilatory response to CO was biphasic and the response to acetylcholine was blunted. Collectively, these data suggest that the CO-induced NO release could be attributed to either stimulation of eNOS or to NO displacement from a cellular storage pool. To address this, direct in vitro measurements with an NO-selective electrode of NO production by recombinant eNOS revealed that CO dose-dependently inhibits NO synthesis. Together, the above data demonstrate that, whereas high levels of CO inhibit NOS activity and NO generation, lower concentrations of CO induce release of NO from a large intracellular pool and, therefore, may mimic the vascular effects of NO.

In the kidney, nitric oxide synthase (NOS) of the neuronal isoform (nNOS) is predominantly located in the macula densa cells. Unspecific chronic NOS inhibition in rats leads to elevated blood pressure (P A ), associated with increased renal vascular resistance. This study was designed to examine the effect of chronic selective inhibition of nNOS with 7-nitro indazole (7-NI) on P A , GFR, and the tubuloglomerular feedback (TGF) system. P A was repeatedly measured by a noninvasive tail-cuff technique for 4 wk in rats treated orally with 7-NI, and in control rats. After treatment, the animals were anesthetized and renal excretion rates, GFR, and TGF activity were determined. After 1 wk of 7-NI treatment P A was increased from 129 Ϯ 4 to 143 Ϯ 2 mmHg. GFR (1.85 Ϯ 0.1 vs. 1.97 Ϯ 0.2 ml/min in controls) was unchanged, but micropuncture studies revealed a more sensitive TGF than in controls. After 4 wk of 7-NI treatment P A was 152 Ϯ 4 mmHg, but no change in GFR (1.90 Ϯ 0.5 ml/min) or TGF sensitivity was detected. Acute administration of 7-NI to nontreated rats did not affect P A , but decreased GFR (1.49 Ϯ 0.1 ml/min) and increased TGF sensitivity. In conclusion, chronic nNOS inhibition leads to increased P A . Our results suggest that the elevated P A could be caused by an initially increased TGF sensitivity, leading to decreased GFR and an increased body fluid volume.

Nitric oxide (NO) is produced by enzymes called nitric oxide synthases (NOS). At least three different isoforms of NOS have been identified in the kidney. This study examines the effects of selective inhibition of the inducible isoform (iNOS) and the neuronal isoform (bNOS) on the glomerular capillary pressure (PGC), through studies of the tubuloglomerular feedback (TGF) mechanism in anaesthetized rats. The proximal tubular stop-flow pressure (PSF) was measured to estimate changes in PGC obtained after activation of the TGF system by varying the loop of Henle perfusion rate with artificial ultrafiltrate including vehicle, NOS inhibition or L-arginine. Infusion of nonspecific NOS inhibition (N omega-Nitro-L-arginine) increased maximal TGF responses (delta PSF) by 84% and L-arginine decreased delta PSF by 37%. Aminoguanidine, a selective iNOS-inhibitor, failed to increase delta PSF, whereas the nonspecific NOS inhibitor methylguanidine increased delta PSF by 64%. 7-Nitro indazole (7-NI), a selective bNOS inhibitor, increased delta PSF by 57% when infused intratubularly, and intraperitoneal administration of 7-NI increased delta PSF by 78%, without any change in blood pressure. Since bNOS is exclusively located in the macula densa (MD) cells, these results confirm and strengthen the obligatory role of MD-produced NO in regulation of TGF and PGC, which has been suggested earlier. iNOS, widely expressed in the kidney, does not seem to play any important role in regulation of PGC.

Objective. To evaluate the treatment outcome for sino-nasal carcinomas in Denmark from 1995-2004 and compare the results to the previous Danish survey covering 1982-1991. Design. Retrospective follow-up. Materials and methods. In the fi ve Danish head and neck oncology centres, charts of all consecutive patients with sino-nasal carcinomas were reviewed and data extracted to a common database. Altogether 242 patients from the period 1995-2004 were identifi ed. Of these 162 (67%) were male and 80 (33%) female. Histologies included squamous cell carcinoma (55%), adenocarcinoma (28.5%), adenoid-cystic carcinoma (5.0%), undifferentiated carcinoma (4.5%), transitiocellular carcinoma (1.7%), mucoepidermoid carcinoma (0.8%), neuroendocrine carcinoma (2.5%), small cell carcinomas (1.2%) and carcinomas not otherwise specifi ed (0.8%). Treatments included radiotherapy alone 79 (33%), surgery alone 29 (12%), combined surgery and radiotherapy 96 (40%), palliative/no treatment 38 (16%). A total of 204 (86%) patients were treated with curative intent. Results. Of the 204 patients treated with curative intent, 94 (46%) relapsed. Most failures were in T-site (63, 30%). N-site failures were 10 (5%) and M-site failures six (3%). Failure occurring in TϩN-site, TϩM-site, NϩM-site and TϩNϩM-site were seven (3%), two (1%), one (0.5%) and fi ve (3%) respectively. The 5-year actuarial local, nodal and loco-regional control rates were 55Ϯ4%, 86Ϯ3%, 49Ϯ4%, respectively. The overall 5-year actuarial survival rate for the entire cohort was 47Ϯ3%, and the corresponding cancer-specifi c 5-year actuarial survival rate was 57Ϯ3%. Female gender, nasal cavity tumour, adenocarcinoma and low clinical stage were signifi cant positive prognostic factors in univariate analysis. A Cox multivariate analysis showed that only tumour site and clinical stage were independent signifi cant prognostic factors. Conclusion. The current series has confi rmed stage and tumour site as independent prognostic factors. Compared to the previous Danish survey covering the period 1982-1991, the overall survival and cancer-specifi c survival rates have improved signifi cantly.