Phlorizin prevents electrically-induced ventricular tachyarrhythmia during ischemia in langendorff-perfused guinea-pig hearts.

Phlorizin is a type of flavonoids and has a peroxynitrite scavenging effect. This study aimed to elucidate the effects of phlorizin on ischemia-induced ventricular tachyarrhythmia (VT). Optical signals from the epicardial surface of the ventricle or left ventricular end diastolic pressure (LVEDP) were recorded during acute global ischemia in 42 Langendorff-perfused guinea pig hearts. Experiments were performed in the control condition and in the presence of phlorizin or N-2-mercaptopropionylglycine (2-MPG), a peroxynitrite scavenger, respectively. Mean action potential duration at 20 min of ischemia did not differ among the three interventions. Impulse conduction time-dependently slowed during 20 min of ischemia in the control. Phlorizin but not 2-MPG improved the ischemic conduction slowing at 15 and 20 min of ischemia. Programmed stimulation induced VT at 20 min of ischemia in the control and in the presence of 2-MPG but not in the presence of phlorizin (p<0.05). LVEDP was increased during 30 min of ischemia in the control and in the presence of 2-MPG but not in the presence of phlorizin. These results indicate that phlorizin prevents VT through the improvement of impulse conduction slowing during ischemia. Phlorizin may be more useful for ischemia-induced VT than 2-MPG.

A Contractile Network of Interstitial Cells of Cajal in the Supratarsal Mueller's Smooth Muscle Fibers With Sparse Sympathetic Innervation.

BACKGROUND: We previously reported that the supratarsal Mueller's muscle is innervated by both sympathetic efferent fibers and trigeminal proprioceptive afferent fibers, which function as mechanoreceptors-inducing reflexive contractions of both the levator and frontalis muscles. Controversy still persists regarding the role of the mechanoreceptors in Mueller's muscle; therefore, we clinically and histologically investigated Mueller's muscle. METHODS: We evaluated the role of phenylephrine administration into the upper fornix in contraction of Mueller's smooth muscle fibers and how intraoperative stretching of Mueller's muscle alters the degree of eyelid retraction in 20 patients with aponeurotic blepharoptosis. In addition, we stained Mueller's muscle in 7 cadavers with antibodies against α-smooth muscle actin, S100, tyrosine hydroxylase, c-kit, and connexin 43. RESULTS: Maximal eyelid retraction occurred approximately 3.8 minutes after administration of phenylephrine and prolonged eyelid retraction for at least 20 minutes after administration. Intraoperative stretching of Mueller's muscle increased eyelid retraction due to its reflexive contraction. The tyrosine hydroxylase antibody sparsely stained postganglionic sympathetic nerve fibers, whereas the S100 and c-kit antibodies densely stained the interstitial cells of Cajal (ICCs) among Mueller's smooth muscle fibers. A connexin 43 antibody failed to stain Mueller's muscle. CONCLUSIONS: A contractile network of ICCs may mediate neurotransmission within Mueller's multiunit smooth muscle fibers that are sparsely innervated by postganglionic sympathetic fibers. Interstitial cells of Cajal may also serve as mechanoreceptors that reflexively contract Mueller's smooth muscle fibers, forming intimate associations with intramuscular trigeminal proprioceptive fibers to induce reflexive contraction of the levator and frontalis muscles.

Decrease in the density of t-tubular L-type Ca2+ channel currents in failing ventricular myocytes.

In some forms of cardiac hypertrophy and failure, the gain of Ca(2+)-induced Ca(2+) release [CICR; i.e., the amount of Ca(2+) released from the sarcoplasmic reticulum normalized to Ca(2+) influx through L-type Ca(2+) channels (LTCCs)] decreases despite the normal whole cell LTCC current density, ryanodine receptor number, and sarcoplasmic reticulum Ca(2+) content. This decrease in CICR gain has been proposed to arise from a change in dyad architecture or derangement of the t-tubular (TT) structure. However, the activity of surface sarcolemmal LTCCs has been reported to increase despite the unaltered whole cell LTCC current density in failing human ventricular myocytes, indicating that the "decreased CICR gain" may reflect a decrease in the TT LTCC current density in heart failure. Thus, we analyzed LTCC currents of failing ventricular myocytes of mice chronically treated with isoproterenol (Iso). Although Iso-treated mice exhibited intact t-tubules and normal LTCC subunit expression, acute occlusion of t-tubules of isolated ventricular myocytes with osmotic shock (detubulation) revealed that the TT LTCC current density was halved in Iso-treated versus control myocytes. Pharmacological analysis indicated that kinases other than PKA or Ca(2+)/calmodulin-dependent protein kinase II insufficiently activated, whereas protein phosphatase 1/2A excessively suppressed, TT LTCCs in Iso-treated versus control myocytes. These results indicate that excessive ß-adrenergic stimulation causes the decrease in TT LTCC current density by altering the regulation of TT LTCCs by protein kinases and phosphatases in heart failure. This phenomenon might underlie the decreased CICR gain in heart failure.

Nicorandil ameliorates impulse conduction disturbances during ischemia in isolated arterially perfused canine atria.

BACKGROUND: Nicorandil has protective effects on the ischemic atrial myocardium. However, effects of nicorandil on ischemia-induced impulse conduction disturbances are still uncertain. METHODS: Optical action potentials were recorded from 256 sites of the left atrium in isolated arterially perfused canine atria during the left atrial ischemia. Constant pacing (BCL = 350 ms) from the left superior pulmonary vein (LSPV) and the posterior left atrium (PLA) was performed, and local conduction velocity (CV) was calculated at the LSPV-left atrial (LA) junction and the right inferior PV (RIPV)-LA junction. Impulse conduction failure was elucidated within the optical mapping field during sinus rhythm. RESULTS: In the control, ischemia slowed the local CV at both regions regardless of the pacing site, and impulse conduction failure occurred within the mapping field during sinus rhythm. Nicorandil suppressed the ischemic conduction slowing at both regions and prevented the conduction failure. Nicorandil also reduced the dispersion of local CV during ischemia. HMR1098, a blocker of cardiac sarcolemmal K(ATP) channels abolished suppression of the ischemic conduction slowing by nicorandil at the RIPV-LA junction but not at the LSPV-LA junction and induced the conduction failure. 5-HD, a blocker of mitochondrial K(ATP) channels also abolished it at both regions and induced the conduction failure. 5-HD abolished the decreased dispersion of local CV by nicorandil, and HMR1098 further increased the dispersion of local CV compared with the control. CONCLUSIONS: These results indicate that nicorandil suppresses ischemia-induced impulse conduction disturbances by its action on both the mitochondrial and sarcolemmal K(ATP) channels.

Selective alpha 1A-adrenoceptor stimulation induces Mueller's smooth muscle contraction in an isolated canine upper eyelid preparation.

PURPOSE: It has been demonstrated that in patients with aponeurotic blepharoptosis, alpha(1)-adrenoceptor stimulation causes the contraction of the upper eyelid tarsal smooth muscle (Mueller's muscle) and opening of the eye. However, alpha(1)-adrenoceptor subtypes mediating the contraction of Mueller's muscle are still unclear. This study was designed to identify the alpha(1)-adrenoceptor subtypes in Mueller's muscle. MATERIALS AND METHODS: A newly developed canine upper eyelid preparation was retrogradely perfused with a drug-containing Krebs-Henseleit solution through the angular vein in a temperature-controlled organ chamber. The contraction of the preparation was measured with a force-displacement transducer. RESULTS: Phenylephrine, an alpha(1)-adrenoceptor agonist, increased the upper eyelid contractile force in a dose-dependent manner (K(0.5) = 110 nmol). Interestingly, the contraction in response to phenylephrine was persistent and hardly recovered to a base line level for more than 100 min after washout of the drug. WB4101 (100 nM), an alpha(1A)- and alpha(1D)-adrenoceptor antagonist, but not BMY7378 (100 nM), a selective alpha(1D)-adrenoceptor antagonist, competitively inhibited the phenylephrine-induced contraction. ABT-866, a selective alpha(1A)-adrenoceptor agonist, increased the upper eyelid contractile force as effectively as phenylephrine in a dose-dependent manner (K(0.5) = 190 nmol), and the contraction continued again for more than 100 min. CONCLUSION: These results suggest that selective alpha(1A)-adrenoceptor agonists, such as ABT-866, induce the sustained Mueller's muscle contraction and may be useful in pharmacological treatment of blepharoptosis.

Mechanisms of preventive effect of nicorandil on ischaemia-induced ventricular tachyarrhythmia in isolated arterially perfused canine left ventricular wedges.

Whether nicorandil is effective at preventing ventricular tachyarrhythmia (VT) during acute myocardial ischaemia is still controversial. We examined effects of nicorandil on the induction of VT during acute myocardial ischaemia. Optical action potentials were recorded from the entire transmural wall of arterially perfused canine left ventricular wedges. Ischaemia was produced by arterial occlusion for 20 min. During endocardial pacing, nicorandil shortened mean action potential duration (APD) in the transmural wall before ischaemia and further shortened it during ischaemia without increasing dispersion of APD. HMR1098, a selective blocker of sarcolemmal ATP-sensitive K(+) channels, inhibited the shortening of APD by nicorandil before and during ischaemia. Ischaemia decreased transmural conduction velocity (CV). Nicorandil partially restored CV to a similar extent in the absence and presence of HMR1098. In contrast, HMR1098 did not suppress the ischaemic conduction slowing in the absence of nicorandil. Nicorandil suppressed the increased dispersion of local CV during ischaemia. Isochrone maps on the initiation of VT showed that reentry in the transmural surface resulted from the excitation of the epicardial region of transmural surface. Nicorandil significantly increased the size of non-excited area in the epicardial region of the transmural wall, thereby significantly reducing the incidence of VT induced during ischaemia. HMR1098 inhibited this effect of nicorandil. These results suggest that nicorandil prevents VT during acute global ischaemia primarily by augmenting the inactivation of epicardial muscle through the activation of sarcolemmal K(ATP) channels.

Alternative etiology and surgical correction of acquired lower-eyelid entropion.

When increased contraction of the levator muscle accompanied by the superior rectus muscle compensates for aponeurotic blepharoptosis, increased contraction of the inferior rectus muscle for foveation retracts the lower eyelid through the capsulopalpebral fascia, showing the lower sclera. We hypothesized that in patients with aponeurotic blepharoptosis, the capsulopalpebral fascia excessively retracts the posterior lamella of the lower eyelid alone while keeping the anterior lamella unretracted, especially in patients with both weak extension of the capsulopalpebral fascia to the pretarsal anterior lamella and increased contraction of the orbicularis oculi muscle, resulting in entropion. Aponeurotic reinsertion to the tarsus for the upper eyelid improved entropion in 15 younger patients. Surgical disinsertion of the capsulopalpebral fascia from the tarsus and creation of a cicatricial connection between the pretarsal skin and the tarsus for the lower eyelid corrected entropion in 15 elderly patients. Both procedures also corrected the lower scleral show.