Macula Densa Nitric Oxide Synthase 1ß Protects against Salt-Sensitive Hypertension.

Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α-, ß-, and γ-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1ß expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1ß expression in the macula densa affects sodium excretion and salt-sensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1ß mRNA and protein were 30- and five-fold higher, respectively, than those of NOS1α in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1α-knockout (NOS1αKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P<0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P<0.01) fed a high-salt diet. These results indicate that NOS1ß is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.

Cardiac myocyte neuronal nitric oxide synthase. New therapeutic target in heart failure?

Although nitric oxide-dependent regulation of contractile function is altered in the diseased and failing heart, several aspects of nitric oxide (NO) signalling in the myocardium remain poorly understood. Some apparently contrasting findings may have arisen from the use of non-isoform-specific inhibitors of NO synthase isoforms (NOS) as compared to the use of mouse models genetically deficient or overexpressing the NOS thought to be responsible for the increase in NO production in heart failure (mainly NOS2 and NOS3). In recent years, identification of the neuronal NOS (NOS1) isoform in cardiac myocytes and the recognition of the importance of its subcellular localisation have greatly advanced the understanding of the critical role of NOS1-derived NO in the control of myocardial contractility both in the normal and failing heart. The challenge is now to confirm these emerging findings on the critical role of NOS1-derived NO in human cardiac physiology and hopefully translate them into therapy.