A recent study suggests that exogenous ghrelin administration might decrease renal sympathetic nerve activity in conscious rabbits. In the present study, we investigated whether ghrelin administration would attenuate left ventricular (LV) remodeling following myocardial infarction (MI) via the suppression of cardiac sympathetic activity. Ghrelin (100 μg/kg sc, twice daily, n = 15) or saline ( n = 15) were administered for 2 wk from the day after MI operation in Sprague-Dawley rats. The effects of ghrelin on cardiac remodeling were evaluated by echocardiographic, hemodynamic, histopathological, and gene analysis. In addition, before and after ghrelin (100 μg/kg sc, n = 6) was administered in conscious rats with MI, the autonomic nervous function was investigated by power spectral analysis obtained by a telemetry system. In ghrelin-treated rats, LV enlargement induced by MI was significantly attenuated compared with saline-treated rats. In addition, there was a substantial decrease in LV end-diastolic pressure and increases in the peak rate of the rise and fall of LV pressure in ghrelin-treated MI rats compared with saline-treated MI rats. Furthermore, ghrelin attenuated an increase in morphometrical collagen volume fraction in the noninfarct region, which was accompanied by the suppression of collagen I and III mRNA levels. Importantly, a 2-wk administration of ghrelin dramatically suppressed the MI-induced increase in heart rate and plasma norepinephrine concentration to the similar levels as in sham-operated controls. Moreover, acute administration of ghrelin to MI rats decreased the ratio of the low-to-high frequency spectra of heart rate variability ( P < 0.01). In conclusion, these data suggest the potential usefulness of ghrelin as a new cardioprotective hormone early after MI.

Schwenke DO, Pearson JT, Umetani K, Kangawa K, Shirai M. Imaging of the pulmonary circulation in the closed-chest rat using synchrotron radiation microangiography. J Appl Physiol 102: [787][788][789][790][791][792][793] 2007. First published October 12, 2006; doi:10.1152/japplphysiol.00596.2006.-Structural changes of the pulmonary circulation during the pathogenesis of pulmonary arterial hypertension remain to be fully elucidated. Although angiography has been used for visualizing the pulmonary circulation, conventional angiography systems have considerable limitations for visualizing small microvessels (diameters Ͻ 200 m), particularly within a closed-chest animal model. In this study we assess the effectiveness of monochromatic synchrotron radiation (SR) for microangiography of the pulmonary circulation in the intact-chest rat. Male adult Sprague-Dawley rats were anesthetized, and a catheter was positioned within the right ventricle, for administering iodinated contrast agent (Iomeron 350). Subsequently, microangiography of pulmonary arterial branches within the left lung was performed using monochromatic SR. Additionally, we assessed dynamic changes in vessel diameter during acute hypoxic (10% and 8% O 2 for 4 min each) pulmonary vasoconstriction (HPV). Using SR we were able to visualize pulmonary microvessels with a diameter of Ͻ100 m (the 4th generation of branching from the left axial artery). Acute hypoxia caused a significant decrease in the diameter of all vessels less than 500 m. The greatest degree of pulmonary vasoconstriction was observed in vessels with a diameter between 200 and 300 m. These results demonstrate the effectiveness of SR for visualizing pulmonary vessels in a closed-chest rat model and for assessing dynamic changes associated with HPV. More importantly, these observations implicate SR as an effective tool in future research for assessing gross structural changes associated with the pathogenesis of pulmonary arterial hypertension. pulmonary microvessels; hypoxia; intact chest STRUCTURAL AND FUNCTIONAL changes of the pulmonary circulation, particularly during the pathogenesis of pulmonary arterial hypertension (PAH), remain to be fully elucidated. Specifically, the small peripheral pulmonary arteries (Ͻ500 m) are believed to be most susceptible to structural changes during, for example, chronic exposure to hypoxia (1,6,7,15,19,32).To date, most small-animal studies that have described the anatomic geometry of the pulmonary circulation have been limited to the use of in vitro or ex vivo preparations. While such data have aided our understanding concerning the pulmonary microcirculation, such invasive procedures ultimately disrupt the natural physiological milieu of the lung. Ideally, a technique of visualizing the pulmonary circulation within a closed-chest model, i.e., under intact neurohumoral regulation, is required to fully understand the structural and functional properties of the microcirculation in the normal lung as well as understand the dynamic changes that occur in pathologic...

Background-Mice lacking guanylyl cyclase-A (GC-A), a natriuretic peptide receptor, have pressure-independent cardiac hypertrophy. However, the mechanism underlying GC-A-mediated inhibition of cardiac hypertrophy remains to be elucidated. In the present report, we examined the role of regulator of G-protein signaling subtype 4 (RGS4), a GTPase activating protein for G q and G i , in the antihypertrophic effects of GC-A. Methods and Results-In cultured cardiac myocytes, treatment of atrial natriuretic peptide stimulated the binding of guanosine 3Ј,5Ј-cyclic monophosphate-dependent protein kinase (PKG) I-␣ to RGS4, PKG-dependent phosphorylation of RGS4, and association of RGS4 and G␣ q . In contrast, blockade of GC-A by an antagonist, HS-142-1, attenuated the phosphorylation of RGS4 and association of RGS4 and G␣ q . Moreover, overexpressing a dominant negative form of RGS4 diminished the inhibitory effects of atrial natriuretic peptide on endothelin-1-stimulated inositol 1,4,5-triphosphate production, [ 3 H]leucine incorporation, and atrial natriuretic peptide gene expression. Furthermore, expression and phosphorylation of RGS4 were significantly reduced in the hearts of GC-A knockout (GC-A-KO) mice compared with wild-type mice. For further investigation, we constructed cardiomyocyte-specific RGS4 transgenic mice and crossbred them with GC-A-KO mice. The cardiac RGS4 overexpression in GC-A-KO mice significantly reduced the ratio of heart to body weight (PϽ0.001), cardiomyocyte size (PϽ0.01), and ventricular calcineurin activity (PϽ0.05) to 80%, 76%, and 67% of nontransgenic GC-A-KO mice, respectively. It also significantly suppressed the augmented cardiac expression of hypertrophy-related genes in GC-A-KO mice. Conclusions-These results provide evidence that GC-A activates cardiac RGS4, which attenuates G␣ q and its downstream hypertrophic signaling, and that RGS4 plays important roles in GC-A-mediated inhibition of cardiac hypertrophy.

Elevated sympathetic nerve activity (SNA) coupled with dysregulated b-adrenoceptor (b-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the b-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to b-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular b 1 -AR and G s (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial b 2 -AR and G i (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac b-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart.