Nitric Oxide Mediates Stretch-Induced Ca2+ Release via Activation of Phosphatidylinositol 3-Kinase-Akt Pathway in Smooth Muscle

Hollow smooth muscle organs such as the bladder undergo significant changes in wall tension associated with filling and distension, with attendant changes in muscle tone. Our previous study indicated that stretch induces Ca(2+) release occurs in the form of Ca(2+) sparks and Ca(2+) waves in urinary bladder myocytes. While, the mechanism underlying stretch-induced Ca2+ release in smooth muscle is unknown.We examined the transduction mechanism linking cell stretch to Ca(2+) release. The probability and frequency of Ca(2+) sparks induced by stretch were closely related to the extent of cell extension and the time that the stretch was maintained. Experiments in tissues and single myocytes indicated that mechanical stretch significantly increases the production of nitric oxide (NO) and the amplitude and duration of muscle contraction. Stretch-induced Ca(2+) sparks and contractility increases were abrogated by the NO inhibitor L-NAME and were also absent in eNOS knockout mice. Furthermore, exposure of eNOS null mice to exogenously generated NO induced Ca(2+) sparks. The soluble guanylyl cyclase inhibitor ODQ did not inhibit SICR, but this process was effectively blocked by the PI3 kinase inhibitors LY494002 and wortmannin; the phosphorylation of Akt and eNOS were up-regulated by 204+/-28.6% and 258+/-36.8% by stretch, respectively. Moreover, stretch significantly increased the eNOS protein expression level.Taking together, these results suggest that stretch-induced Ca2+ release is NO dependent, resulting from the activation of PI3K/Akt pathway in smooth muscle

Muscle Sympathetic Nerve Activity Is Related to a Surrogate Marker of Endothelial Function in Healthy Individuals

BACKGROUND: Evidence from animal studies indicates the importance of an interaction between the sympathetic nervous system and the endothelium for cardiovascular regulation. However the interaction between these two systems remains largely unexplored in humans. The aim of this study was to investigate whether directly recorded sympathetic vasoconstrictor outflow is related to a surrogate marker of endothelial function in healthy individuals. METHODS AND RESULTS: In 10 healthy normotensive subjects (3 f/7 m), (age 37+/-11 yrs), (BMI 24+/-3 kg/m(2)) direct recordings of sympathetic action potentials to the muscle vascular bed (MSNA) were performed and endothelial function estimated with the Reactive Hyperaemia- Peripheral Arterial Tonometry (RH-PAT) technique. Blood samples were taken and time spent on leisure-time physical activities was estimated. In all subjects the rate between resting flow and the maximum flow, the Reactive Hyperemic index (RH-PAT index), was within the normal range (1.9-3.3) and MSNA was as expected for age and gender (13-44 burst/minute). RH-PAT index was inversely related to MSNA (r = -0.8, p = 0.005). RH-PAT index and MSNA were reciprocally related to time (h/week) spent on physical activity (p = 0.005 and p = 0.006 respectively) and platelet concentration (PLT) (p = 0.02 and p = 0.004 respectively). CONCLUSIONS: Our results show that sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy normotensive individuals, indicating that sympathetic outflow may be modulated by changes in endothelial function. In this study time spent on physical activity is identified as a predictor of sympathetic nerve activity and endothelial function in a group of healthy individuals. The results are of importance in understanding mechanisms underlying sympathetic activation in conditions associated with endothelial dysfunction and emphasise the importance of a daily exercise routine for maintenance of cardiovascular health

The negative inotropic effect of sevoflurane is not mediated through nitric oxide synthase in rat papillary muscle

Sevoflurane has dose-dependent negative inotropic effects on myocardial contractility. The current study investigated whether the nitric oxide pathway is involved in these effects. A laboratory, ex-vivo experiment was performed on 66 isolated papillary muscles. Effects of increasing concentrations of sevoflurane (1, 2 and 3 MAC) were assessed in control conditions, in the presence of Nw-nitro-L-arginine (L-NOARG) and in beta-adrenergic stimulated rat papillary muscles. Contractility was assessed by total developed tension. In baseline conditions, the administration of increasing concentrations of sevoflurane caused a dose-dependent reduction in contractility of respectively 8.6 +/- 1.7%, 14.4 +/- 4.8% and 23.6 +/- 3.9%. This negative inotropic effect was not significantly altered by the administration of the NO-synthase inhibitor L-NOARG (p = 0.09). Under continuous administration of 3 MAC sevoflurane, 4 consecutive concentrations of isoproterenol induced a mean increase of contractility of respectively 43.0 +/- 13.7%, 65.9 +/- 22.6%, 131.2 +/- 25.6% and 122.3 +/- 31.2%. After administration of L-NOARG, the 4 consecutive concentrations of isoproterenol induced a mean increase in contractility of respectively 36.0 +/- 8.5%, 75.0 +/- 17.8%, 143.0 +/- 42.8% and 120.0 +/- 51.4% (p = 0.85). These data indicated that the negative inotropic effects of sevoflurane in rat papillary muscles, both in basic as in beta-adrenergic stimulated conditions, were not altered by blocking the NO-cGMP-syste