cyclic-gmp and fasudil

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Cilostazol; Cyclic AMP; Cyclic GMP; Depression, Chemical; Isoquinolines; Nicardipine; Platelet Aggregation Inhibitors; Tetrazoles; Vasodilator Agents; Vinca Alkaloids

Pulmonary hypertension (PH) in left ventricular dysfunction is attributable not only to backward failure of the left ventricle, but also to increased pulmonary vascular resistance (PVR) in some patients. Recently, Rho-kinase has been known as a potent growth stimulator and mediator of vasoconstriction, and Rho-kinase inhibitors could ameliorate PVR, little is known about the role of Rho-kinase in left ventricular dysfunction-induced PH. We utilized the ascending aortic-banded rat and assessed the effect of Rho-kinase inhibitor fasudil on the development of PH secondary to left ventricular dysfunction. Subsequently, in rats subjected to aortic banding for 6 weeks, there were increases in mean pulmonary arterial pressure, pulmonary arteriolar medial thickness, active RhoA, Rho-kinase II, Rho-kinase activity, endothelial nitric oxide synthase (eNOS) and endothelin-1(ET-1) concomitant with decreased levels in NO and cGMP in the lung. Treatment with fasudil at a dose of 30 mg/kg/day from days 1 to 28 or from days 29 to 42 decreased the mean pulmonary arterial pressure by 57% and 56%, right ventricular hypertrophy by 31% and 30%, pulmonary arteriolar medial thickness by 50% and 50%, and pulmonary expression of Rho-kinase II by 41% and 28%, respectively, as well as augmented pulmonary expression of eNOS by 16% and 31% and NO by 50% and 76%, respectively, when compared with the vehicle controls. In conclusion, these results suggest that inhibition of Rho-kinase may provide therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction. Further translational study in human is needed to substantiate the findings.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Arterioles; Cyclic GMP; Endothelin-1; Hypertension, Pulmonary; Lung; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Protein Kinase Inhibitors; Pulmonary Artery; Rats; Rats, Wistar; rho-Associated Kinases; Treatment Outcome; Ventricular Dysfunction, Left

Vasomotion is linked to the rapid oscillations of intracellular calcium levels. In rat pulmonary artery, this activity can manifest as a slow periodic on-off pattern, the timing of which depends on the type and intensity of pharmacological stimuli employed. In this study, we have sought to characterize a slow-wave vasomotor activity pattern induced in isolated arterial ring preparations by simultaneous exposure to the α(1) -adrenoceptor agonist phenylephrine (1-10 nm) and the L channel agonist S(-)-Bay K 8644 (3-20 nm). Treated tissues responded with a stable on-off pattern of vasomotion persisting for >5 h at 5-6 cycles/h. In intact rings, this response was suppressed by methacholine and restored or enhanced by N(ω) -nitro-l-arginine methyl ester. Analogous inhibitory effects were obtained with high Mg(2+) , 8-Br-cGMP (but not 8-Br-cAMP), riluzole, ryanodine, chelerythrine, and fasudil. Pinacidil (30 nm) increased off-cycle length without change in slow-wave amplitude. Conversely, tetraethylammonium (1.0-3.0 mm) augmented the latter without affecting periodicity. Carbenoxolone (10 μm) abolished slow-wave activity, while raising basal tone and inducing random phasic activity. In endothelium-denuded rings, the threshold of agonist-induced slow-wave vasomotion was lowered and a similar inhibitory effect obtained with carbenoxolone. In conclusion, the slow-wave pattern of vasomotion described here is (i) subject to inhibitory modulation by endothelial NO and an array of voltage-gated and leak K conductances yet to be fully characterized; (ii) dependent on Ca(2+) from both extracellular and sarcoendoplasmatic sources; (iii) controlled by kinase (Rho and PKC)-mediated regulation of myosin light chain phosphatase; and (iv) synchronized via intermyocyte gap junctions.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; 8-Bromo Cyclic Adenosine Monophosphate; Adrenergic alpha-1 Receptor Agonists; Animals; Benzophenanthridines; Calcium Channel Agonists; Calcium Signaling; Carbenoxolone; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Endothelium, Vascular; Gap Junctions; In Vitro Techniques; Male; Methacholine Chloride; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Phenylephrine; Pinacidil; Potassium Channels; Protein Kinase C; Protein Kinase Inhibitors; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Riluzole; Ryanodine; Tetraethylammonium; Vasomotor System