MaxiK, c-Src and vasoconstriction.
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CSK Tyrosine-Protein Kinase↗
Biomedical subjects
K Nishimaru
Publications and source records attributed to K Nishimaru.
Decreased expression of voltage- and Ca(2+)-activated K(+) channels in coronary smooth muscle during aging.
Aging is the main risk factor for coronary artery disease. One characteristic of aging coronary arteries is their enhanced contractile responses to endothelial vasoconstricting factors, which increase the risk of coronary vasospasm in older people. Because large-conductance voltage- and Ca(2+)-activated K(+) channels (MaxiK) are key regulators of vascular tone, we explored the possibility that this class of channels is diminished with increasing age. Using site-directed antibodies recognizing the pore-forming alpha subunit and electrophysiological methods, we demonstrate that the number of MaxiK channels is dramatically diminished in aged coronary arteries from old F344 rats. Channel density was reduced from 52+/-9 channels/pF (3 months old) to 18+/-5 channels/pF (25 to 30 months old), which represents a 65% reduction in the older population. Pixel intensity of Western blots was also diminished by approximately 50%. Moreover, the age-related decrease in the channel protein expression was also evident in humans, which showed approximately 80% reduction in 61- to 70-year-old subjects compared with 3- to 18-year-old youngsters and approximately 45% reduction compared with 19- to 56-year-old adults. In agreement with a reduction of MaxiK channel numbers in aging coronary arteries, old coronary arteries from F344 rats contract less effectively ( approximately 70% reduction) than young coronary arteries when exposed to the MaxiK channel blocker iberiotoxin. The contraction studies indicate that under physiological conditions, MaxiK channels are tonically active, serving as a hyperpolarizing force that opposes contraction. Thus, reduced expression of MaxiK channels in aged coronary arteries would lead to a decreased vasodilating capacity and increased risk of coronary spasm and myocardial ischemia in older people.
Adolescent↗
Acetylcholine-induced positive inotropy mediated by prostaglandin released from endocardial endothelium in mouse left atrium.
The possible involvement of the endocardial endothelium in the positive inotropic response of the mouse left atrium to acetylcholine was examined pharmacologically. In mouse left atria, acetylcholine produced a biphasic inotropic response: a transient decrease in contractile force followed by a late increase. The positive response was not affected by the presence of phentolamine and propranolol, but was almost abolished by pretreatment of the preparation with 1% Triton X-100, which denudes the endocardium of its endothelium. Nordihydroguaiaretic acid, NG-nitro-L-arginine, BQ-123 and BQ-788 had no effect on the inotropic responses to acetylcholine, but indomethacin completely abolished the positive response. Prostaglandins and their analogues had a positive inotropic effect with a potency order PGF2alpha>PGD2>PGE2>U46619, whereas beraprost had no effect. Neither Triton X-100 pretreatment nor the presence of indomethacin affected the positive inotropic effect of PGF2alpha. Acetylcholine and PGF2alpha prolonged the action potential duration similarly. These results suggest that the acetylcholine-induced positive inotropic response in mouse left atria is mediated by prostaglandin released from the endocardial endothelium.
Acetylcholine↗
alpha-Adrenoceptor stimulation-mediated negative inotropism and enhanced Na(+)/Ca(2+) exchange in mouse ventricle.
Mechanisms underlying the negative inotropic response to alpha-adrenoceptor stimulation in adult mouse ventricular myocardium were studied. In isolated ventricular tissue, phenylephrine (PE), in the presence of propranolol, decreased contractile force by approximately 40% of basal value. The negative inotropic response was similarly observed under low extracellular Ca(2+) concentration ([Ca(2+)](o)) conditions but was significantly smaller under high-[Ca(2+)](o) conditions and was not observed under low-[Na(+)](o) conditions. The negative inotropic response was not affected by nicardipine, ryanodine, ouabain, or dimethylamiloride (DMA), inhibitors of L-type Ca(2+) channel, Ca(2+) release channel, Na(+)-K(+) pump, or Na(+)/H(+) exchanger, respectively. KB-R7943, an inhibitor of Na(+)/Ca(2+) exchanger, suppressed the negative inotropic response mediated by PE. PE reduced the magnitude of postrest contractions. PE caused a decrease in duration of the late plateau phase of action potential and a slight increase in resting membrane potential; time courses of these effects were similar to that of the negative inotropic effect. In whole cell voltage-clamped myocytes, PE increased the L-type Ca(2+) and Na(+)/Ca(2+) exchanger currents but had no effect on the inwardly rectifying K(+), transient outward K(+), or Na(+)-K(+)-pump currents. These results suggest that the sustained negative inotropic response to alpha-adrenoceptor stimulation of adult mouse ventricular myocardium is mediated by enhancement of Ca(2+) efflux through the Na(+)/Ca(2+) exchanger.
Action Potentials↗
Pharmacological properties of excitation-contraction mechanisms in isolated mouse left atria.
Effects of 4-aminopyridine (4-AP), nicardipine and ryanodine on the action potential and contractile force were examined in isolated mouse left atria. The mouse left atria had an action potential with an extremely short duration and two phases of repolarization; action potential duration at 50% repolarization was 6.7 +/- 0.4 ms (n = 15). The action potential duration, as well as contractile force, was increased by 4-AP (at 100 micromol/l and 1 mmol/l). Nicardipine (3 micromol/l), which is known to greatly reduce the contractile force in atria of most other experimental animal species, had no significant effect on the action potential and decreased contractile force by only 40% in mouse atria. Ryanodine (10 nmol/l) decreased the contractile force by 90% of basal value. At 100 nmol/l, ryanodine slightly affected the action potential configuration, which could be explained by indirect effects through inhibition of Ca(2+) release from the sarcoplasmic reticulum. The extremely short action potential duration and the highly sarcoplasmic reticulum-dependent contraction of the mouse atria appear to underlie its unique response to agonists.
4-Aminopyridine↗
Effect of ethanol on hemorheology in patients with ischemic cerebrovascular disease and elderly healthy men.
Changes in hemorheological parameters were studied in patients with ischemic cerebrovascular disease and elderly healthy men who ingested ethanol at 0.5 and 1 g/kg body weight. Following ingestion of 1 g/kg, but not 0.5 g/kg of ethanol, there were significant changes in hemorheologic factors. Whole blood viscosity (WBV, shear rate: 18.8, 37.5, 75, 150, 350 sec(-1)) and blood viscosity corrected for hematocrit (BVC) were increased. WBV and BVC at high shear rate were increased and red blood cell deformability impaired in patients with ischemic cerebrovascular disease, while those factors were not significantly changed in healthy men. It is considered that ethanol ingestion could has bad influences for the microcirculation in patients with ischemic cerebrovascular disease.
Acetaldehyde↗
Positive and negative inotropic effects of muscarinic receptor stimulation in mouse left atria.
In isolated mouse left atria, acetylcholine (ACh) produced a biphasic inotropic response; a transient decrease in developed tension was followed by an increase. Both negative and positive responses were concentration dependent and were inhibited by atropine. The negative and positive inotropic responses were also observed with a nonselective muscarinic stimulant, oxotremorine-M, but not with an M1-receptor selective stimulant, McN-A343. Pirenzepine, an M1-receptor antagonist, inhibited both negative and positive inotropic responses at high concentrations. Gallamine, an M2-receptor antagonist, inhibited the negative response. Hexahydro-siladifenidol hydrochloride, p-fluoro analog (p-F-HHSiD), an M3-receptor antagonist, inhibited the positive response with no effect on the negative phase. In pertussis toxin (PTX) treated preparations, negative inotropic response to ACh was not observed. These results suggest that the negative and positive inotropic responses to acetylcholine in mouse atria are mediated by M2 and M3 receptors, respectively. The negative phase, but not the positive phase, was mediated by a PTX-sensitive G protein.
Acetylcholine↗
Deep white matter lesions on MRI, and not silent brain infarcts are related to headache and dizziness of non-specific cause in non-stroke Japanese subjects.
OBJECTIVE: Silent or asymptomatic cerebrovascular disease is believed to be an important risk factor for symptomatic stroke and vascular dementia. Although non-specific complaints such as mild to moderate headache and/or dizziness may also be caused by silent stroke, which remains a topic of controversy. METHODS: To investigate the relationship between silent brain infarcts and non-specific complaints, we assessed findings on magnetic resonance images using a common protocol in the following three groups of subjects; Group 1:78 subjects with non-specific complaints, Group 2:47 subjects with vascular risk factors, and Group 3:75 normal subjects without any subjective complaints or vascular risk factors. In addition to silent stroke, deep white matter lesions on MRI were also evaluated. All subjects were recruited from 12 institutes of the study group located at various parts of Japan. RESULTS: Silent brain infarcts were demonstrated in 44%, 43%, and 20% of subjects in Groups 1, 2, and 3, respectively. In Group 1, the average number of infarcts per individual who had silent brain infarction was 1.8, which was significantly fewer than 3.8 in Group 2 or 3.5 in Group 3 (p<0.0167). White matter lesions were found in 68%, 49%, and 11% in Groups 1, 2, and 3, respectively, indicating that non-specific complaints are more closely related to deep white matter lesions than to silent infarct lesions. Such white matter lesions were found more frequently in subjects with depressive state than in non-depressed subjects (67% vs. 39%, p=0.0155). CONCLUSION: The present results suggest that deep white matter lesions, rather than silent brain infarcts, appear to be important in producing headache and/or dizziness of non-specific cause and also to be related to the depressive state.
Aged↗
Developmental conversion of inotropism by endothelin I and angiotensin II from positive to negative in mice.
Inotropic effects on isolated neonatal and adult mouse myocardium of endothelin I and angiotensin II were examined. Endothelin I produced a sustained positive inotropic response in the neonate but a sustained negative response in the adult. Both were concentration-dependent and were inhibited by the endothelin ETA receptor antagonist, BQ-123 (Cyclo(D-a-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl)). Angiotensin II produced a sustained positive inotropic response in the neonate while a sustained negative response in the adult. Both were concentration-dependent and were inhibited by the angiotensin AT1 receptor antagonist, YM358 (2,7-diethyl-5-((2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl-5H-pyrazolo(1,5-b)(1,2,4)tria zole potassium salt monohydrate). These results indicate that inotropic responses of the mouse heart to cardioactive peptides are unique among experimental animal species and may be reversed during development.
Age Factors↗
Temperature sensitive effects of alpha-adrenergic stimulation in mouse ventricular myocardia.
The effects of alpha- and beta-adrenergic stimulation on the contractile force and L-type Ca2+ channel current were studied in mouse ventricular myocardia at two different temperatures. In ventricular tissue, at 35-36 degrees C, phenylephrine, in the presence of propranolol, produced a sustained negative inotropic response with no change in the time course of contraction and relaxation. These effects were greatly reduced at 22-23 degrees C. Isoproterenol produced marked positive inotropic responses accompanied by shortening of the time required for relaxation. In isolated ventricular myocytes, phenylephrine, in the presence of propranolol, significantly increased the L-type Ca2+ channel current (I(Ca)) at 35-36 degrees C, but the effect was small at 22-23 degrees C. Isoproterenol increased I(Ca) similarly at both temperatures. These results suggest that, in mouse ventricular myocardia, alpha-adrenoceptor mediated regulation of the contractile force and I(Ca) involve temperature-dependent mechanisms different from those of beta-adrenoceptor-mediated mechanisms.
Adrenergic Agonists↗
Role of sarcoplasmic reticulum in myocardial contraction of neonatal and adult mice.
Changes in action potential parameters by and inotropic responses to nicardipine, verapamil, ryanodine and cyclopiazonic acid were examined in isolated ventricular myocardial preparations from neonatal and adult mice. The action potential of both neonatal and adult mice had a unique configuration with little evidence of a plateau at depolarized membrane potential; the action potential duration was significantly larger in neonatal preparations. Nicardipine had no effect on action potential parameters in the adult while it significantly shortened the action potential duration at 50% repolarization in the neonate. Ryanodine significantly shortened the action potential duration at 80% repolarization at both ages: the shortening was significantly larger in the adult when compared with the neonate. The contraction of ventricular preparations from adult mice were relatively resistant to nicardipine and verapamil. Nicardipine or verapamil, even at 10(-5) M, only decreased the contractile force to 70% of control values; the decrease was much less than that reported in other experimental species such as chick, guinea pig or rabbit. In the neonate, 10(-5) M nicardipine or verapamil decreased the contractile force to 30% of control values. Ryanodine had a potent negative inotropic effect both in the neonate and adult; the effect was significantly larger in the adult. Cyclopiazonic acid produced a decrease in contractile force and prolongation of the time required for relaxation; both effects were significantly larger in the adult. These results suggest that the contraction of the adult mouse myocardium is highly dependent on SR function and less dependent on transsarcolemmal Ca2+ influx when compared with the myocardium of the neonatal mouse and that of other species.
Age Factors↗
[Significance of pontine high signal intensity lesions on magnetic resonance imaging in patients with cerebral infarction].
We reviewed MRI findings in a series of 211 patients with cerebral infarction. A high signal in the basis pontis bilaterally in T2 weighted images (Central Pontine Hyperintensity, CPH), with almost-normal T1 weighted images, was present in 29 cases (12.9%). CPH findings were present more frequently in elderly patients, and were significantly associated with a previous history of cerebrovascular accident, although not with other arteriosclerotic risk factors. In patients with CPH. periventricular hyperintensity was severe and the number of infarctions of the thalamus was higher. These results suggest that a) CPH may arise from ischemia in subcortical areas or in the territory of the vertebrobasilar system, and that b) chronic brain ischemia, which may be partially due to aging, may play a more important role in cerebral infarction than the usual arteriosclerotic risk factors.
Adult↗
[A case of HTLV-I associated polyradiculoneuropathy and cerebral white matter lesions with smouldering type adult T cell leukemia].
A 45-year-old female was admitted to our hospital complaining of abnormal sensation in the upper and lower extremities. She was given a diagnosis of smouldering type adult T cell leukemia 9 months before admission. On admission, neurological examination revealed sensory disturbance of polyneuropathy type, and generalized hyporeflexia. Nerve conduction study demonstrated decreased F wave appearance rate. Motor unit potentials in electromyelography had long duration and high amplitude. MR imaging of the brain showed multiple abnormal lesions in the periventricular and subcortical white matter. CSF protein was mildly increased, and anti-HTLV-I antibody was positive. Treatment with corticosteroid was effective, resulting in disappearance of sensory symptoms and normalization of F wave appearance. The present case is different from HAM, and the above clinical features may fit to the disease entity of HTLV-I associated polyradiculoneuropathy and cerebral white matter lesions.
Anemia, Refractory, with Excess of Blasts↗
Two-dimensional millisecond analysis of intracellular Ca2+ sparks in cardiac myocytes by rapid scanning confocal microscopy: increase in amplitude by isoproterenol.
Two dimensional images of myocardial Ca2+ sparks, non-propagating local rises in cytoplasmic Ca2+ concentration, were obtained at 4 msec intervals with a rapid-scanning confocal laser microscope, Nikon RCM 8000, and fluo-3. Spontaneous Ca2+ sparks were observed at apparently random sites throughout the cytoplasm of rat ventricular cells. The duration of sparks was 30 to 40 msec and the time to peak intensity about 10 msec. Ryanodine (1 microM) completely inhibited Ca2+ sparks while nicardipine (3 microM) had no effect. Isoproterenol (1 microM) had no effect on the frequency and distribution of Ca2+ sparks but significantly increased their amplitude. These results suggest that myocardial Ca2+ sparks are the result of spontaneous release of Ca2+ from the sarcoplasmic reticulum and that beta-adrenergic stimulation may result in functional modification of the ryanodine receptor channel.
Adrenergic beta-Antagonists↗
[A case of sarcoidosis with cranial mononeuritis multiplex and peripheral polyneuropathy].
A 67-year-old woman with sarcoidosis, cranial mononeuritis multiplex and peripheral neuropathy was reported. The initial presentation of her sarcoidosis was a subcutaneous nodule of left knee joint on June, 1990. The number of subcutaneous nodules increased. Sarcoidosis was diagnosed by biopsy of the subcutaneous nodule. Paresthesia of the face and limbs appeared from November, 1991 and one month later, left abducens palsy and hearing disturbances were added. Alternate day therapy of 20mg prednisolone was effective in improvement of symptoms. The case of sarcoidosis with cranial mononeuritis multiplex and peripheral polyneuropathy was rarely found in 6 to 25% of patients with sarcoid neuropathy in the previous reports. Angiotensin-converting enzyme (ACE) in cerebro-spinal fluid not only raised on exacerbation also lowered with improvement of symptoms after steroid therapy. The ACE, which had a selective activity in the central nervous system, seemed to contribute to the index of treatment for sarcoidosis.
Aged↗
[Clinical profiles of patients with thalamic hemorrhage].
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Adult↗
[Asymptomatic cerebral infarction of the vertebrobasilar system].
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Aged↗