Biomedical subjects

K Shigenobu

Publications and source records attributed to K Shigenobu.

At least 55 records · Page 3Linked to original sources

PubMed1999

Role of MaxiK channels in vasoactive intestinal peptide-induced relaxation of rat mesenteric artery.

We investigated the functional relevance of large conductance voltage-dependent and Ca(2+)-sensitive K(+)(MaxiK) channels in vasoactive intestinal peptide (VIP)-induced relaxation of rat mesenteric artery. VIP, which is known to increase cAMP levels, produced a concentration-dependent relaxation in endothelium-denuded arteries. Iberiotoxin, a MaxiK channel blocker, greatly diminished the VIP-induced relaxation. In a similar manner, a significant portion of the relaxant response to dibutyryl-cAMP (DBcAMP), a membrane-permeable analog of cAMP, was inhibited by iberiotoxin. These results suggest that activation of MaxiK channels significantly contributes to the relaxant response of rat mesenteric artery to VIP, possibly via cAMP-mediated pathways.

Animals↗

PubMed1999

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↗

PubMed1999

Endothelium is involved in the vasorelaxation by an ATP-sensitive K+ channel opener, NIP-121.

Possible involvement of endothelium was examined in the vasorelaxation of rat aorta in response to NIP-121 ((+)-7,8-dihydro-6,6-dimethyl-7-hyroxy-8-(2-oxo-1-piperidinyl)-6H- pyrano[2,3-f]benz-2,1,3-oxadiazole), an ATP-sensitive K+ (K(ATP)) channel opener. The NIP-121-induced vasorelaxation was greater in endothelium-intact preparations than in endothelium-denuded ones. In the presence of glibenclamide, which inhibits K(ATP) channels, NIP-121-induced vasorelaxations were of a similar extent in both endothelium-intact and -denuded preparations. These findings suggest that the presence of endothelium plays a role in the vasorelaxation in response to K(ATP) channel openers.

Adenosine Triphosphate↗

PubMed1999

Evidence for a contribution of store-operated Ca2+ channels to NO-mediated endothelium-dependent relaxation of guinea-pig aorta in response to a Ca2+ ionophore, A23187.

A23187 (6S-[6alpha,8beta,9beta,11alpha]-5-(methylamino) -2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1,7- dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazolecarboxylic acid, calcimycin), an antibiotic Ca2+ ionophore, produces an endothelium-dependent vascular relaxation. In the present study, pharmacological features were functionally characterized of endothelium-dependent relaxant response of guinea-pig aorta to A23187, especially focusing on the possible Ca2+ source and Ca2+ mobilization mechanisms in endothelial cells responsible for the vasorelaxant response to the Ca2+ ionophore. A23187-induced endothelium-dependent relaxation was suppressed profoundly by N(G)-nitro-L-arginine (L-NNA; 3 x 10(-4) M) or calmidazolium (3 x 10(-5) M), suggesting that nitric oxide (NO) produced by the enhanced activation of Ca2+/calmodulin-dependent endothelial NO synthase (eNOS) is largely responsible for the relaxant response of this artery to A23187. In the Ca2+-free solution without EGTA, NO-mediated endothelium-dependent relaxation induced by A23187 was almost abolished, which suggests that Ca2+ entry from extracellular space into endothelial cells plays the key role in the A23187-induced functional vasorelaxation. On the other hand, SK&F96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole; 5 x 10(-5) M) and Ni2+ (3 x 10(-4) M), both of which inhibit capacitative Ca2+ influx through store-operated Ca2+ channels (SOCCs), attenuated significantly NO-mediated endothelium-dependent relaxation by A23187. Furthermore, A23187-induced endothelium-dependent relaxation was suppressed more strongly than endothelium-independent relaxation induced by SIN-1 (3-morpholino-sydnonimine), an NO donor, when aortic preparation was preconstricted with high KCl instead of agonistic stimulation (prostaglandin F2alpha). These findings suggest that NO-mediated endothelium-dependent relaxant response of guinea-pig aorta to A23187 is preceded by the increase in endothelial cytosolic free Ca2+ concentration ([Ca2+]cyt) due to the enhanced Ca2+ influx from extracellular space. In the enhanced Ca2+ entry leading to the stimulation of eNOS and NO-mediated functional relaxant response of guinea-pig aorta to A23187, activation of SOCCs but not the Ca2+ entry through plasma membrane Ca2+-specific routes made by A23187 seems to play the predominant role. It is most likely that A23187 acts primarily at the Ca2+ store sites in endothelial cells, which subsequently depletes stored Ca2+ to activate SOCCs via unidentified mechanisms.

Animals↗

PubMed1999

Effects of hirsutine and dihydrocorynantheine on the action potentials of sino-atrial node, atrium and ventricle.

The effects of hirsutine, an indole alkaloid from Uncaria rhynchophylla MIQ. JACKSON with antihypertensive, negative chronotropic and antiarrhythmic activity, and its C3 structural epimer, dihydrocorynantheine, on membrane potentials of rabbit sino-atrial node and guinea-pig right ventricle and left atrium were studied with microelectrode techniques. In sino-atrial node preparations, hirsutine and dihydrocorynantheine (0.1 microM to 10 microM) concentration-dependently increased cycle length, decreased slope of the pacemaker depolarization (phase 4 depolarization), decreased maximum rate of rise and prolonged action potential duration. In atrial and ventricular preparations, both compounds (0.1 microM to 30 microM) concentration-dependently decreased maximum rate of rise and prolonged action potential duration. These results indicate that hirsutine and dihydrocorynantheine have direct effects on the action potential of cardiac muscle through inhibition of multiple ion channels, which may explain their negative chronotropic and antiarrhythmic activity.

Action Potentials↗

PubMed1999

Significant role of neuronal non-N-type calcium channels in the sympathetic neurogenic contraction of rat mesenteric artery.

1. The possible involvement of pre-junctional non-N-type Ca2+ channels in noradrenaline (NA)-mediated neurogenic contraction by electrical field stimulation (EFS) was examined pharmacomechanically in the isolated rat mesenteric artery. 2. EFS-generated contraction of endothelium-denuded mesenteric artery was frequency-dependent (2 - 32 Hz) and was abolished by tetrodotoxin (TTX, 1 microM), guanethidine (5 microM) or prazosin (100 nM), indicating that NA released from sympathetic nerve endings mediates the contractile response. 3. NA-mediated neurogenic contractions to lower frequency stimulations (2 - 8 Hz) were almost abolished by an N-type Ca2+ channel blocker, omega-conotoxin-GVIA (1 microM) whereas the responses to higher frequency stimulations (12 - 32 Hz) were less sensitive to omega-conotoxin-GVIA. The omega-conotoxin-GVIA-resistant component of the contractile response to 32 Hz stimulation was inhibited partly (10 - 20%) by omega-agatoxin-IVA (10 - 100 nM; concentrations which are relatively selective for P-type channels) and to a greater extent by omega-agatoxin-IVA (1 microM) and omega-conotoxin-MVIIC (3 microM), both of which block Q-type channels at the concentrations used. 4. omega-Agatoxin-IVA (10 - 100 nM) alone inhibited 32 Hz EFS-induced contraction by 10 approximately 20% whereas omega-conotoxin-MVIIC (3 microM) alone inhibited the response by approximately 60%. 5. These omega-toxin treatments did not affect the contractions evoked by exogenously applied NA. 6. These findings show that P- and Q-type as well as N-type Ca2+ channels are involved in the sympathetic neurogenic vascular contraction, and suggest the significant role of non-N-type Ca2+ channels in NA release from adrenergic nerve endings when higher frequency stimulations are applied to the nerve.

Animals↗

PubMed1999

Possible involvement of Ca2+ entry and its pharmacological characteristics responsible for endothelium-dependent, NO-mediated relaxation induced by thapsigargin in guinea-pig aorta.

Thapsigargin, a specific inhibitor of Ca(2+)-pump Ca(2+)-ATPase in the sarcoplasmic/endoplasmic reticulum (SR/ER), produces an endothelium-dependent vascular relaxation. In the present study, pharmacological features of thapsigargin-induced endothelium-dependent relaxation were functionally characterized in the isolated guinea-pig aorta especially focusing on the Ca2+ mobilization mechanisms in endothelial cells. Thapsigargin-induced endothelium-dependent vascular relaxation was markedly suppressed by N(G)-nitro-L-arginine (L-NNA) and calmidazolium, suggesting that the vascular relaxation to thapsigargin is largely attributable to endothelium-derived nitric oxide (NO) produced as a result of the activation of Ca2+, calmodulin-dependent NO synthase (NOS). Removal of Ca2+ from the external solution abolished the endothelium-dependent relaxation of guinea-pig aorta in response to thapsigargin. Thapsigargin-induced endothelium-dependent relaxation was inhibited more strongly compared with the endothelium-independent relaxation to an NO donor, SIN-1 (3-(4-morpholinyl)-sydnonimine), when the artery preparation was preconstricted with a high concentration (80 mM) of KCl instead of agonistic stimulation. Endothelium-dependent relaxation induced by thapsigargin was not affected by diltiazem, a blocker of L-type voltage-gated Ca2+ channels. SK&F96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1 H-imidazole) and Ni2+, both of which block capacitative Ca(2+) entry, did not show any appreciable inhibitory effects on the endothelium-dependent relaxation to thapsigargin. These findings suggest that in guinea-pig aorta, endothelium-dependent NO-mediated relaxation induced by thapsigargin is preceded by the increase in the cytosolic free Ca2+ concentrations ([Ca2+]cyt) following the depletion of stored Ca2+ in thapsigargin-sensitive store sites in endothelial cells. Although the increase in [Ca2+]cyt responsible for the activation of endothelium NOS leading to thapsigargin-induced vascular relaxation may be ascribed to the capacitative Ca2+ entry from extracellular space, the Ca2+ entry mechanism stimulated with thapsigargin is deficient in sensitivity to SK&F96365 and Ni2+ in the endothelium of guinea-pig aorta.

Animals↗

PubMed1999

Pharmacologic characteristics of non-prostanoid, non-nitric oxide mediated and endothelium-dependent relaxation of guinea-pig aorta in response to substance P.

The pharmacologic characteristics of the non-prostanoid (prostacyclin, PGI2), non-nitric oxide (NO) mediated endothelium-dependent relaxation in response to substance P were examined in the guinea-pig aorta. Substance P, in a concentration-dependent manner, relaxed the ring preparations of guinea-pig thoracic aorta preconstricted with norepinephrine (NE) in an endothelium-dependent manner. Substance P-induced endothelium-dependent relaxation was not affected by indomethacin (3 x 10(-6) M) as in the case of acetylcholine (ACh)-induced endothelium-dependent relaxation. Although N(G)-nitro-L-arginine (L-NNA, 3 x 10(-5) M), an inhibitor of nitric oxide (NO) synthase, significantly inhibited substance P-induced endothelium-dependent relaxation in the presence of indomethacin, about 50% of the vasorelaxant response to substance P remained in the combined presence of L-NNA and indomethacin. By comparison, indomethacin-resistant component of endothelium-dependent relaxation to ACh was mostly suppressed by the treatment with L-NNA plus indomethacin. Substance P-induced non-PGI2, non-NO mediated vascular relaxation was attenuated markedly in high (40 mM) KCl solution or by tetraethylammonium (TEA, 5 x 10(-3) M). Furthermore, substance P-induced non- PGI2, non-NO mediated vascular relaxation was not appreciably affected by glibenclamide (10(-6) M), apamin (10(-7) M), iberiotoxin (1(-7) M), but was greatly attenuated by the combined treatment with charybdotoxin (10(-7) M) plus apamin (10(-7) M), which suggesting that endothelium-derived hyperpolarizing factor(s) (EDHF(s)) mediates the response. Interestingly, after applied repetitively, the substance P-induced vasorelaxant component remaining in the combined presence of indomethacin and L-NNA was decreased more profoundly than the response to substance P in the presence of indomethacin alone. Possible contribution of non-PGI2, non-NO vasorelaxant(s) (EDHF(s)) from the endothelium to the total relaxation response to substance P was greater in thoracic aorta isolated from adult guinea-pigs than that from neonatal ones. These findings suggest that 1) endothelium-dependent vascular relaxation of guinea-pig thoracic aorta in response to substance P is attributable to the release of both NO and EDHF(s); 2) possible release of EDHF(s) from the endothelium of guinea-pig thoracic aorta decreases after repetitive stimulation with substance P; and 3) contribution of EDHF(s) to substance P-induced functional relaxation of the thoracic aorta is greater in adult guinea-pigs than neonatal ones.

Aging↗

PubMed1999

Glycyrrhetinic acid-sensitive mechanism does not make a major contribution to non-prostanoid, non-nitric oxide mediated endothelium-dependent relaxation of rat mesenteric artery in response to acetylcholine.

Pharmacological characteristics of non-prostanoid (PGI2), non-NO mediated endothelium-dependent relaxation in response to acetylcholine (ACh) were examined in the isolated rat mesenteric artery, especially focusing on the possible contribution of the gap junctional communication in the response. ACh produced an endothelium-dependent relaxation of the isolated rat mesenteric artery with functional endothelium in the presence of both indomethacin (3 x 10(-6) M) and N(G)-nitro-L-arginine methyl ester (L-NAME) (10(-4) M), an inhibitor of nitric oxide synthase (NOS). ACh-induced relaxation of the rat mesenteric artery in the presence of indomethacin and L-NAME was strongly attenuated in the solution containing high (80 mM) KCl, tetraethylammonium (TEA) (10(-2) M), which suggests the involvement of endothelium-derived relaxing factor(s) (EDHF(s)) in the response. Non-PGI2, non-NO mediated endothelium-dependent relaxation to ACh was not profoundly affected by glibenclamide (10(-6) M), 4-aminopyridine (4-AP) (10(-4) M), iberiotoxin (10(-7) M), agitoxin-2 (10(-8) M), or apamin (10(-7) M), but was abolished by the treatment with apamin (10(-7) M) plus charybdotoxin (10(-7) M). Non-PGI2, non-NO mediated endothelium-dependent relaxation to ACh was not substantially affected by arachidonic acid (AA) (10(-4) M) or ONO-RS-082 (10(-5) M), an inhibitor of phospholipase A2, which rules out the involvement of AA metabolites in the vascular response. Furthermore, a gap junction inhibitor, 18alpha-glycyrrhetinic acid (18alpha-GA) did not show dramatic inhibitory effect on non-PGI2, non-NO mediated endothelium-dependent relaxation induced by ACh. These findings suggest that 1) metabolites of AA are not involved in non-PGI2, non-NO mediated endothelium-dependent relaxation to ACh in the isolated rat mesenteric artery; 2) Heterocellular gap junctional communication does not mainly account for non-PGI2, non-NO mediated endothelium-dependent relaxation evoked by ACh in this artery.

Acetylcholine↗

PubMed1999

Calcium channel antagonistic effects of AH-1058, a novel antiarrhythmic drug, on guinea-pig myocardium.

Effects of AH-1058, a novel cyproheptadine derivative with high antiarrhythmic activity in in vivo arrhythmia models, were studied in guinea-pig myocardium. In coronary-perfused right ventricular tissue preparations, AH-1058 (10(-5) M) shortened the action potential duration with little effect on the resting membrane potential, maximum rate of rise and overshoot. AH-1058, 10(-7) M to 10(-5) M, concentration-dependently decreased the contractile force. The increase in contractile force by Ca2+ was markedly inhibited by 3 x 10(-6) M AH-1058 while that by isoproterenol was only slightly affected. In isolated ventricular myocytes, AH-1058 concentration-dependently decreased the nicardipine sensitive transient inward current with no effect on steady state currents, and decreased the amplitude of the evoked Ca2+ transient. These results suggest that AH-1058 has Ca2+ channel antagonistic effects which may contribute to its antiarrhythmic activity.

Action Potentials↗

PubMed1999

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↗

PubMed1999

Effects of mibefradil, a selective T-type Ca2+ channel antagonist, on sino-atrial node and ventricular myocardia.

The effects of mibefradil, a non-dihydropyridine Ca2+ channel antagonist, on the action potential configuration of isolated rabbit sino-atrial node preparations, membrane currents of guinea-pig ventricular myocytes and the contractile force of isolated ventricular papillary muscles were examined. In sino-atrial node preparations, 10 microM mibefradil decreased the slope of the pacemaker depolarization (phase 4 depolarization) and maximum rate of rise, and shifted the threshold potential to the positive direction with no effect on action potential duration. In ventricular myocytes, 1 microM mibefradil inhibited the T-type Ca2+ current by about 40% while it had no effect on the L-type Ca2+ current. At 10 microM, mibefradil inhibited the L-type and T-type Ca2+ currents by about 40% and 90%, respectively. Mibefradil had no effect on contractile force at concentrations up to 1 microM. Thus, mibefradil was shown to produce potent prolongation of the pacemaker depolarization, mainly through inhibition of the T-type Ca2+ current. It is suggested that the T-type Ca2+ current may not be involved in ventricular contraction.

Action Potentials↗

PubMed1998

Inhibitory actions of various vasorelaxants on the myogenic contraction induced by quick stretch studied in canine cerebral artery.

Quick stretch at a rate of 10 cm/s with the amount of 30% of the initial muscle length (= 100%) produced a myogenic contraction in canine cerebral artery. The inhibitory actions of various vasorelaxants on the stretch-induced contraction were investigated. Ca2+ channel blockers (nicardipine, D-cis-diltiazem) inhibited the stretch-induced contraction by 50-60% at the concentrations which abolished high KCl-induced contraction. Inhibitions of the stretch-induced contraction by nitro-compounds (nitroglycerin, sodium nitroprusside) were about 50%. In contrast, inhibitions by the compounds which activate ATP-sensitive K+ channels (cromakalim, nicorandil, pinacidil) of the myogenic contraction in response to quick stretch were only 20%. Papaverine totally abolished the stretch-induced contraction. It is likely that all the vasorelaxant compounds tested in the present study except papaverine are beneficial in the sense that they do not suppress the intrinsic myogenic contraction, which may be related to the autoregulation of local blood flow.

Animals↗

PubMed1998

Inhibition of myocardial L- and T-type Ca2+ currents by efonidipine: possible mechanism for its chronotropic effect.

Effects of efonidipine, a dihydropyridine phosphonate Ca2+ channel antagonist, on the guinea-pig heart were compared with those of nifedipine. In the sino-atrial node, 1 microM efonidipine produced increase in cycle length accompanied by prolongation of the phase 4 depolarization which was not prominent with 0.1 microM nifedipine. In ventricular myocytes, both efonidipine and nifedipine produced inhibition of the L-type Ca2+ current, nifedipine being tenfold more potent than efonidipine. Efonidipine also inhibited the T-type Ca2+ current at higher concentrations but nifedipine did not. Both Ca2+ channel antagonists had no or only a weak effect on K+ currents. In addition, 40 microM Ni2+, which selectively inhibited the T-type Ca2+ current, had no effect on myocardial Ca2+ transients and contractile force. In conclusion, efonidipine was shown to have inhibitory effects on both L- and T-type Ca2+ currents, which may contribute to its high negative chronotropic potency.

Action Potentials↗

PubMed1998

Intrasarcomere [Ca2+] gradients and their spatio-temporal relation to Ca2+ sparks in rat cardiomyocytes.

1. Line-scan analyses of spontaneous Ca2+ sparks, non-propagating local rises in Ca2+ concentration, and the early phase of Ca2+ transients in cardiomyocytes were performed with a rapid-scanning laser confocal microscope (Nikon RCM8000) and fluo-3. 2. On electrical stimulation, points at which rise in Ca2+ began earliest were observed at regular spacings of 1.82 +/- 0.26 micron (mean +/- S.D.) along the longitudinal axis of the cell. The points were heavily stained with di-2-ANEPEQ, which stains the T-tubules, indicating that they were at the Z-line. 3. The points where spontaneous Ca2+ sparks originated coincided with the points which showed faster Ca2+ elevation, i.e. the Z-line. 4. In some cases where a Ca2+ spark had occurred within about 30 ms before the evoked Ca2+ transient, fast elevation of Ca2+ was not observed at the corresponding Z-line, indicating the presence of a refractory period in Ca2+ release from the SR. 5. The present results provide visual evidence for Ca2+ release from the junctional sarcoplasmic reticulum in cardiomyocytes. The presence of a refractory period in Ca2+ release after Ca2+ sparks provided new evidence that the normal Ca2+ transient may be the summation of Ca2+ sparks.

Aniline Compounds↗

PubMed1998

Involvement of maxi-K(Ca) channel activation in atrial natriuretic peptide-induced vasorelaxation.

Large conductance, voltage- and Ca2+-sensitive K+ (maxi-K(Ca)) channels play an important role in the regulation of vascular smooth muscle excitability and contractility. The activity of maxi-K(Ca) channels is modified by a variety of intracellular messengers including cGMP, as well as by voltage and Ca2+. In the present study, we investigated the functional relevance of maxi-K(Ca) channels in atrial natriuretic peptide (ANP)-mediated vasorelaxation in the isolated rat mesenteric artery. ANP produced concentration-dependent relaxation in the de-endothelialized rat mesenteric artery. Iberiotoxin, a specific blocker of maxi-K(Ca) channels, greatly attenuated the ANP-induced vasorelaxation. Similarly, a large portion of the vascular relaxation induced by 8-Bromo-cGMP, a membrane permeable analogue of cGMP, was inhibited by iberiotoxin. These results indicate that activation of maxi-K(Ca) channels contributes substantially to the vascular relaxation produced by ANP in the rat mesenteric artery. Intracellular cGMP, increased by ANP, and the subsequent activation of cGMP-dependent protein kinase (PKG) may play a central role in the activation of maxi-K(Ca) channels in the ANP-produced vascular relaxation.

Animals↗

PubMed1998

Possible involvement of nitric oxide-cGMP pathway in the negative chronotropic effect of CD-832, a novel dihydropyridine derivative.

Effects of zaprinast, an inhibitor of guanosine 3', 5'-cyclic monophosphate (cGMP)-specific phosphodiesterase, and methylene blue, an inhibitor of soluble guanylate cyclase, on the negative chronotropic response to CD-832, a novel dihydropyridine derivative with a nitrate moiety, and nifedipine were examined with isolated guinea-pig right atria in the presence and absence of isoproterenol. CD-832 and nifedipine produced concentration-dependent negative chronotropic effects both in the absence and presence of isoproterenol. In the absence of isoproterenol, the concentration-response curves for CD-832 and nifedipine were neither potentiated by zaprinast nor inhibited by methylene blue. In the presence of isoproterenol (10[-8] M), zaprinast produced a three-fold leftward shift of the concentration-response curve for CD-832, while methylene blue produced a three-fold rightward shift. The concentration-response curve for nifedipine was not affected by these agents. SIN-1, a nitric oxide (NO) donor, had no chronotropic effect in the absence of isoproterenol, but had a concentration-dependent negative chronotropic effect in the presence of isoproterenol: the beating rate decreased to values close to that in the absence of isoproterenol. These findings suggest that NO-cGMP mediated pathway is involved in the negative chronotropic actions of CD-832 under beta-adrenergic stimulation.

Animals↗

PubMed1998

Differential sensitivity to ATP-sensitive potassium channel openers of norepinephrine-induced contraction of guinea pig and rat aorta.

Vasorelaxant effects of ATP-sensitive potassium (K(ATP)) channel openers were examined on the tonic phase of vascular contraction induced by norepinephrine (NE) in guinea pig and rat aorta. K(ATP) channel openers, NIP-121 and cromakalim, produced glibenclamide-sensitive and concentration-dependent relaxations in guinea pig and rat aorta preconstricted with NE. However, the vascular relaxations induced by both K(ATP) channel openers were less pronounced in guinea pig aorta than in rat aorta. D-cis-Diltiazem, at the concentration up to 10(-5) M, did not appreciably inhibit the NE-induced contraction of guinea pig aorta, whereas the compound almost completely inhibited the NE-induced contraction of rat aorta at the same concentration. By contrast, sodium nitroprusside relaxed the NE-induced contractions in both guinea pig and rat aorta with similar potencies. These findings suggest that vasorelaxant effects of K(ATP) channel openers on the NE-induced sustained contraction in guinea pig aorta is not attributable to the subsequent inhibition of Ca2+ influx through L-type voltage-gated Ca2+ channels. Lower sensitivity of guinea pig aortic smooth muscle to K(ATP) channel openers is most likely due to the low dependence of NE-induced contraction on the Ca2+ influx in this vascular smooth muscle.

Adenosine Triphosphate↗