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The aim of the present study was to investigate the effects of tamsulosin, an α 1 -adrenoceptor antagonist, on hypogastric nerve stimulation-induced intraurethral pressure elevation in anesthetized male and female dogs and to evaluate sex differences in these effects. Additionally, the effects of tamsulosin were also compared with those of other α 1 -adrenoceptor antagonists, namely prazosin, naftopidil and urapidil. Tamsulosin dose-dependently inhibited hypogastric nerve stimulation-induced intraurethral pressure elevation, with doses required to induce 50% inhibition of the elevation (ED 50 values) of 0.72 and 0.74 μg/kg i.v. in anesthetized male and female dogs, respectively. Mean arterial blood pressure slightly decreased after administration of tamsulosin at a dose which inhibited intraurethral pressure elevation almost completely. Prazosin, naftopidil and urapidil also inhibited increases in intraurethral pressure in a dose-dependent fashion, but caused decreases in mean arterial blood pressure at the same doses. The estimated rank order of inhibitory potency for urethral response was tamsulosin>prazosin>naftopidil=urapidil. In conclusion, tamsulosin dose-dependently inhibited increases in intraurethral pressure with little effect on mean arterial blood pressure in both male and female dogs, and these effects were almost equipotent. These results indicate that tamsulosin will be useful in the treatment of dysuria associated with lower urinary tract symptoms in women as well as men.

T-0156 (2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride) is a newly synthesized phosphodiesterase type 5 inhibitor, and its potency and selectivity are higher than those of sildenafil in an enzyme assay. In the present study with anesthetized dogs, we examined the effects of intravenous T-0156 or sildenafil on the pelvic nerve stimulation-induced penile tumescence and light-adapted flicker stimulation-induced electroretinogram, parameters of which are reported to be indicators for inhibition of phosphodiesterase type 5 and type 6, respectively. Both compounds potentiated the penile tumescence in a dose-dependent manner. T-0156 at 10 microg/kg and sildenafil at 100 microg/kg showed almost the same potentiating percentage (181.5+/-31.1% and 190.0+/-37.9%) in spite of the plasma concentration of T-0156 being about five times lower than that of sildenafil (16.7+/-1.6 and 78.8+/-5.3 ng/ml), indicating that the effect of T-0156 on tumescence is more potent than that of sildenafil. While the high dose of T-0156 (1000 microg/kg) reduced the amplitude and increased the latency of the electroretinogram positive wave, the effects of T-0156 were conversely weaker than those of sildenafil (reduction of amplitude; T-0156: 41.1+/-8.0%, sildenafil: 71.7+/-3.9%, increase of latency; T-0156: 3.9+/-0.6%, sildenafil: 14.5+/-1.4%, at 1000 microg/kg). These results clearly showed the difference in the properties of T-0156 and sildenafil in pharmacological studies with anesthetized dogs, and the difference appeared to correspond with their inhibitory potencies for phosphodiesterase type 5 and type 6. It was concluded that T-0156 would be a useful pharmacological tool as a potent and highly selective phosphodiesterase type 5 inhibitor.

CP-99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] is a selective tachykinin NK(1) receptor antagonist that inhibits cough in guinea pigs and cats. This study examined the antitussive effects of CP-99994 in dogs produced by mechanical stimulation of the intrathoracic trachea. CP-99994 (10 mg/kg, p.o.) inhibited cough frequency by 52% at 2 h, 31% at 6 h and by 21% at 24 h. Cough amplitude was inhibited by 45% at 6 h but unchanged at 2 and 24 h after CP-99994. Plasma levels of CP-99994 were highest at 2 h (75+/-26 ng/ml) and fell to 22+/-6 ng/ml at 6 h. These results demonstrate antitussive activity of CP-99994 in dogs at a dose proven to antagonize tachykinin NK(1) receptors in this species.

Several prostanoids were investigated for their ability to induce emesis and/or defecation and tenesmus in the ferret. The rank order of emetic potency (dose producing four episodes, D4) was: sulprostone (5 microg/kg)11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 8 microg/kg)misoprostol (27 microg/kg)17-phenyl-omega-trinor prostaglandin E2 (53 microg/kg)prostaglandin E2 (94 microg/kg)5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C; 148 microg/kg)prostaglandin F(2alpha) (13,500 microg/kg). Emesis was also induced by iloprost (D4 not determined) and prostaglandin E2 methyl ester (D4=350 microg/kg). Cicaprost and fluprostenol were virtually inactive; they also failed to modify copper sulphate (100 mg/kg, intragastric)-induced emesis (P0.05), although cicaprost potentiated apomorphine (0.25 mg/kg, s.c.)-induced emesis (P0.05). U46619-induced emesis was antagonised by vapiprost (P0.05). The rank order of potency to produce defecation and tenesmus (dose producing three episodes) was: sulprostone (12 microg/kg)misoprostol (15 microg/kg)17-phenyl-omega-trinor prostaglandin E2 (94 microg/kg)prostaglandin E2 (113 microg/kg)fluprostenol (158 microg/kg)z.Gt;prostaglandin F(2alpha) (1759 microg/kg); prostaglandin E2 methyl ester also induced defecation (196 microg/kg). Data are discussed in relation to mechanisms involved in emesis and defecation.

Anesthetized open-chest dogs were subjected to 15-min myocardial ischemia followed by 2-h reperfusion to induce myocardial stunning. A novel Na(+)/H(+) exchange inhibitor 6,7,8,9-tetrahydro-2-methyl-5H-cyclohepta[b]pyridine-3-carbonylguanidine maleate (TY-12533), administered 10 min before or 10 min after start of ischemia (3 mg/kg/10 min, i.v.), did not affect reductions in regional myocardial wall thickening, blood flow and pH during ischemia, but it significantly improved recovery of the wall thickening and blood flow after reperfusion. These results indicate that TY-12533, even when administered during ischemia, could prevent myocardial stunning without affecting myocardial dysfunction or acidosis induced by brief ischemia.

Cilostazol prevents neointimal formation, but its mechanism has remained unclear. We investigated whether intimal formation in dog grafted veins is suppressed by cilostazol, and studied the effect of cilostazol on angiotensin II-forming enzymes. The external jugular vein was grafted to the carotid artery, and cilostazol (60 mg/kg/day) was administered orally. By 28 days after the surgery, the intimal cross-sectional area of the grafted vein was reduced to 16.7% by treatment of cilostazol, and the activities of angiotensin II-forming enzymes were suppressed significantly. The inhibitory effect of cilostazol in intimal formation may be dependent on inhibition of angiotensin II-forming enzymes.

The effect of the K(ATP) channel opener ZD6169 [(S)-N-(4-benzoyl-phenyl)-3,3, 3-trifluoro-2-hydroxy-2-methyl-propionamide] currently under development for the treatment of urinary incontinence was explored in acutely isolated adult feline ventricular myocytes. ZD6169 activated a current over a wide range of concentrations (0.1-100 microM) that is completely blocked by 10 microM glyburide thereby identifying it as I(K(ATP)). The maximum activation of K(ATP) current was observed at 10 microM; higher concentrations decreased current activation. In contrast, the standard K(ATP) channel opener cromakalim showed a more usual concentration-response relationship, with increasing current for increased concentrations and no signs of saturation or reversal. The bell-shaped dose-response relationship for ZD6169 activation of I(K(ATP)) has also been seen in bladder myocytes, albeit at a lower concentration, and it has been proposed to contribute to the reported lack of in vivo cardiovascular side effects. We compared the effects of ZD6169 to cromakalim and showed that both compounds dramatically shorten cardiac myocyte action potential duration and that ZD6169 does so in spite of the bell-shaped concentration-response relationship for activation of K(ATP) current.

CP-060 S, (-)-( S)-2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N-methyl-N-[2-(3 ,4-methylenedioxyphenoxy)ethyl]-amino]propyl]-1,3-thiazolidin++ +-4-one hydrogen fumarate, is a novel cardioprotective drug which prevents Na+-, Ca2+-overload and has Ca2+ channel blocking activity. We compared the anti-ischemic effects of CP-060S with those of diltiazem, a Ca2+ channel blocker, and R56865, N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazo lamine, a Na+-, Ca2+-overload inhibitor, in a canine pacing-induced ischemia model. CP-060S 100 microg kg(-1) significantly suppressed the pacing-induced ischemic epicardial ST-segment elevation by maximally 75%, while diltiazem 100 microg kg(-1) suppressed it by maximally 35%. R56865 100 microg kg(-1) significantly suppressed the ST-segment elevation by maximally 30%. In addition, diltiazem 100 microg kg(-1) caused synergistic suppression of ST-segment elevation by 70% when administered simultaneously with R56865 100 microg kg(-1). These results suggest that a Na+-, Ca2+-overload preventive action and a Ca2+ channel blocking action independently contribute to the suppression of the ST-segment elevation. Therefore, CP-060S may suppress pacing-induced ST-segment elevation by a dual action by preventing Na+-, Ca2+-overload and the Ca2+ channel blockade.

We compared the cumulative dose–response relations of verapamil (0.1, 0.2 and 0.4 mg kg−1) in different R/S enantiomer ratios (100/0, 90/10, 80/20, 50/50 and 20/80) on the electrophysiological and hemodynamic characteristics of the heart using the conscious dogs. A reduction of mean arterial pressure occurred with 20R/80S producing a 3-times greater decrease than 100R/0S, but an increase in heart rate occurred with 20R/80S producing a 9-times greater increase than 100R/0S. Increased heart rate was concurrent with decreased mean arterial pressure most prevalent with a higher ratio of S-isomer that produced a greater reduction in mean arterial pressure and increase in heart rate at lower overall verapamil doses. Atrio-ventricular conduction time increased 3–5 min after each infusion, with 20R/80S producing a 4-times greater effect than 100R/0S. These results indicate that the peripheral and cardiac electrophysiologic properties of various nonracemic verapamil mixtures are mainly attributable to the concentration of S-isomer.

Lecithinized superoxide dismutase, a lecithin derivative bound to recombinant human CuZn superoxide dismutase, has a higher affinity for cells such as polymorphonuclear leukocytes and endothelial cells than recombinant human CuZn superoxide dismutase has. We determined the protective effects of lecithinized superoxide dismutase on the increased microvascular permeability induced by phorbol myristate acetate (PMA) in isolated dog lungs. Microvascular permeability was assessed by the capillary filtration coefficient (Kf,c) and solvent drag reflection coefficient (sigma(f)). PMA (13.3 microg) increased microvascular permeability, as evidenced by an increase in Kf,c and the small sigma(f) value. Lecithinized superoxide dismutase at both low (4800 U) and high doses (48,000 U) inhibited the PMA-induced increase in Kf,c, but only the high dose of lecithinized superoxide dismutase attenuated the decrease in sigma(f). Recombinant human CuZn superoxide dismutase did not affect the PMA-induced increase in vascular permeability at either a low (4800 U) or a high dose (48,000 U). These findings suggest that lecithinized superoxide dismutase has a protective effect against oxygen radical-induced lung injury in isolated dog lungs.

The present study was undertaken to investigate the effects of intracavernosal injections of adrenomedullin, a novel hypotensive peptide, on penile erection in anesthetized cats. Responses to adrenomedullin were compared to those elicited by intracavernosal injection of the control triple-drug combination (1.65 mg papaverine, 25 micrograms phentolamine, and 0.5 microgram prostaglandin E1). Intracavernosal injections of adrenomedullin in doses of 0.1-1.0 nmol elicited dose-related increases in cavernosal pressure and penile length. The maximal effect of adrenomedullin injection on cavernosal pressure was an 8-fold increase in pressure, which was 74% of that induced by the triple-drug combination. The maximal effect on penile length was a 43% increase when compared to baseline value, which was comparable to that induced by the triple-drug combination. The duration of the peak pressure and total duration of the peptide effect were significantly shorter in response to the 1 nmol dose of adrenomedullin than was observed with the control triple-drug combination. Intracavernous injection of the control triple-drug combination resulted in a significantly greater decrease in systemic arterial blood pressure than did adrenomedullin. Erectile responses to adrenomedullin were not altered following administration of the nitric oxide synthase inhibitor. N omega-nitro-L-arginine, at a time when erectile responses to acetylcholine were significantly reduced. These data demonstrate that intracavernous injection of adrenomedullin induces a short-lived erection in cats that is not due to the release of nitric oxide.

The role of substance P in the cerebral parenchymal circulation was examined in 19 anesthetized cats. The local cerebral blood volume in the temporoparietal cortex was measured by our photoelectric method. Cerebral blood volume reflects the cumulative dimensions of the parenchymal microvessels. Intravenous injection of 0.01, 0.1, and 1 mg/kg FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide) , a selective tachykinin NK1 receptor antagonist, had no significant effects (compared to the vehicle, ethanol) on cerebral blood volume and mean arterial blood pressure. Intracarotid injection of 1, 10, 100 pmol/kg, and 1 nmol/kg substance P increased cerebral blood volume (P < 0.01) in a dose-dependent manner (maximal increase of 6.5% at 5 min). Following injection of 1 nmol/kg substance P, cerebral blood volume was initially reduced, possibly due to the marked fall in mean arterial blood pressure (P < 0.01). The cerebral blood volume increase elicited by 1 nmol/kg substance P was strongly blocked (P < 0.05) by prior injection of 1 mg/kg FK888. However, the depressor effect of 1 nmol/kg substance P (-24 +/- 4 mm Hg at 30 s, P < 0.01) was partially inhibited (P < 0.01) by FK888. We conclude that endogenous substance P may not have a significant role in the maintenance of resting tone of cerebral parenchymal vessels. Intravascular substance P, however, dilates the small microvessels through a specific tachykinin NK1 receptor and could be involved in the development of pathologic processes such as migraine headache.

This study examined the effect of carvedilol, a vasodilating beta-adrenoceptor antagonist and antioxidant, on lethal reperfusion injury in feline hearts subjected to 40 min of regional ischemia and 180 min of reperfusion. 30 open chest anaesthetized cats were randomized into three groups. A control (n = 10) was compared with a group given carvedilol before coronary artery occlusions (n = 10) and a group given carvedilol immediately before and during early reperfusion (n = 10). Regional myocardial function was measured by sonomicrometry. Infarct size was determined by staining the left ventricle with triphenyl tetrazolium chloride. Myocardial blood flow was measured by radiolabeled microspheres. Tissue levels of glutathione were measured after reperfusion. Infarct size was significantly reduced compared to control both when carvedilol was given before ischemia (0.2 +/- 0.1 vs. 17.6 +/- 3.6%, P0.05). and when given immediately before reperfusion (3.7 +/- 1.3 vs. 17.6 +/- 3.6%, P0.05). Regional shortening improved significantly and the incidence of ventricular fibrillation during early reperfusion was reduced in both groups treated with carvedilol compared to control. Oxidized glutathione did not differ between groups in the post-ischaemic myocardium. This study supports that lethal reperfusion injury is a significant phenomenon. Furthermore, carvedilol reduces infarct size and reperfusion arrhythmias, and improves post-ischaemic regional myocardial function by protecting against both ischaemic and lethal reperfusion injury. The present study does not answer whether it is the non-selective beta- or alpha 1-receptor antagonism, the antiarrhythmic or the antioxidant actions of carvedilol that is responsible for the protective effect.

We have shown previously in dogs with right heart failure that the reduction of myocardial beta-adrenoceptor density occurs only in the failing right ventricle, while cardiac inotropic responses to beta-adrenergic stimulation are reduced in both the right and left ventricles. The purpose of the present study was to determine whether a post-receptor defect in the guanine nucleotide-binding regulatory proteins (G-proteins) existed which would explain, at least in part, the adrenergic subsensitivity in both ventricles of the heart failure dogs. Using both immunoblotting technique and the bacterial toxin-mediated ADP ribosylation assays, we found that the stimulatory G-protein (Gs) was reduced in both ventricles of the heart failure dogs. In contrast, there were no changes in the inhibitory G-protein (Gi). In addition, receptor subtype analysis showed that only beta(1)-adrenoceptors were reduced in the failing right ventricle of the heart failure animals. This study demonstrated that the reduction of beta-adrenoceptors in right heart failure was chamber-specific whereas the reduction of Gs was non-selective, occurring in both ventricles of right heart failure dogs. The findings further suggest that the reduction of Gs probably was caused by systemic neurohormonal activation, independent of local ventricular stress.

We studied the cardiac electrophysiological effects of falipamil, a specific bradycardic agent, in conscious dogs, in comparison with those of alinidine. Sinus rate, corrected sinus recovery time, and Wenckebach point were measured in six intact dogs. Atrial rate, ventricular rate, and atrial effective refractory period were measured in six atrioventricular-blocked dogs. In both groups, blood pressure was also monitored. Each dog received, with at least a three-day interval, falipamil (hydrochloride) and alinidine (hydrobromide) in four successive intravenous injections, 30 min apart, at 0.5, 0.5, 1, and 2 mg kg −1 . Falipamil increased sinus rate and atrial rate, but decreased ventricular rate, whereas alinidine decreased sinus rate and ventricular rate, but increased atrial rate. Falipamil shortened corrected sinus recovery time and increased Wenckebach point, whereas alinidine lengthened corrected sinus recovery time and decreased Wenckebach point. Falipamil and alinidine increased atrial effective refractory period. Neither falipamil nor alinidine modified mean blood pressure in either group. Overall, these results show that (a) falipamil exhibits effects on the electrical activity of the heart, reflecting the predominant direct vagolytic effect of this drug, (b) alinidine exhibits effects reflecting the marked antiarrhythmic potential of this agent, and (c) thus indicate that two drugs with almost identical specific bradycardic properties can produce quite different electrophysiological effects in the conscious dog.

The effects of the selective prostaglandin DP receptor antagonist BW A868C ((+/-)-3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamin o)- hydantoin), 3.0 nM to 0.3 microM) were examined against prostaglandin D2 and BW245C ((+/-)-5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin)-in duced smooth muscle relaxation on dog isolated vascular preparations pre-contracted with a sub-maximal concentration of KCl (50 mM). In dog dorsal nasal vein BW245C was found to be more potent than prostaglandin D2 with p[A]50 estimates of 7.6 +/- 0.1 (S.E.M., n = 8) and 5.8 +/- 0.1 (n = 5), respectively. BW A868C, up to 0.3 microM, displaced the relaxant concentration-effect curves to BW245C in dog dorsal nasal vein in an apparently competitive manner with parallel rightward shifts and no significant changes in the upper asymptotes. The data were analysed by using a modified Schild equation which not only gives equal weight to all agonist concentration-effect data but also allows a direct plot in Clark plot space. A pKB estimate of 7.3 +/- 0.8 (n = 20) was obtained with a unity Schild plot slope (b = 1.0 +/- 0.1). This affinity estimate, however, is lower than the values previously reported in other studies. The affinity estimates of BW A868C against BW245C and prostaglandin D2 obtained from dog dorsal nasal vein, major palatine artery and saphenous vein were found to be consistent. The relatively low affinity estimates of BW A868C at DP receptors as observed in the present study may be due to species- or tissue-related variations or may be indicative of the possible existence of DP receptor subtypes.

To determine whether a hyperpolarization-activated current (If) participates in ventricular tachyarrhythmias, we investigated the effects of zatebradine, an I(f) inhibitor, on the ventricular tachyarrhythmias induced by ouabain, two-stage coronary ligation and epinephrine infusion in the dog heart. We determined atrial rate, ectopic ventricular rate, total heart rate and arrhythmic ratio (the number of ectopic ventricular beats divided by total heart beats). Zatebradine (0.15, 0.5 and 1.5 mg/kg, i.v.) dose dependently decreased the arrhythmic ratio, ectopic ventricular rate and atrial rate of the ouabain-induced ventricular tachyarrhythmias in pentobarbital-anesthetized dogs. The inhibition by zatebradine of the ventricular arrhythmias needed larger doses than the inhibition of the atrial rate. Zatebradine weakly depressed the ectopic ventricular rate but not the arrhythmic ratio of the ventricular arrhythmias induced by two-stage coronary ligation 24 h after the ligation in conscious dogs. Although neither the ectopic ventricular rate nor the arrhythmic ratio of the epinephrine-induced ventricular arrhythmias was affected by zatebradine, after treatment with zatebradine, the arrhythmias elicited by epinephrine developed more slowly. Together with the previously reported spectra of the effects of the antiarrhythmic agents in three ventricular tachyarrhythmia models, our results suggest that zatebradine may improve automaticity-related ventricular tachyarrhythmias due to I(f) inhibition or to other undetermined mechanisms in the heart.

In vitro autoradiography was performed on sections of cat brain stem and spinal cord using [3H]sumatriptan. Localization studies using 20–25 nM [3H]sumatriptan showed specific binding to cells in the trigeminal nucleus caudalis and nucleus tractus solitarius of the brain stem and the dorsal horn of the spinal cord. This binding was unaffected by 8-hydroxy-dipropylaminotetralin (20 nM), but was abolished by 5-carboxyamidotryptamine (200 nM). Ketanserin displaced total specific binding in the brain stem with a pIC50 of 6.2 but no apparent regional specificity. These results indicate that [3H]sumatriptan labels predominantly 5-HT1Dα and/or 5-HT1Dβ (but not 5-HT1A or 5-HT1F) receptor subtypes in cat brain stem and spinal cord.

The effects of the selective prostaglandin D2 (DP) receptor agonists, 572C85 ((+/-)-5-(3-carboxypropylthio)-1-(2-cyclohexyl-2-hydroxyethyl- amino)hexahydrocyclopenta(d)imidazol-2(1H)-one) and 192C86 ((+/-)-5-(3-carboxypropylthio)-1-(2-cyclohexyl-2-hydroxyethylidene - amino)-3-ethylhexahydrocyclopenta(d)imidazol-2(1H)-one), were determined on intraocular pressure regulation in rabbits and cats. 572C85 (50 micrograms) in rabbits maximally lowered intraocular pressure by 4.3 mm Hg, and significantly for 4 h compared to control. In cats 572C85 had a similar effect. 192C86 (50 micrograms) reduced intraocular pressure by 2.8 mm Hg for 2 h in rabbits. Following exposure to the specific DP receptor antagonist, BW A868C ((+/-)-3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamin o)- hydantoin; 50 micrograms), which had no effect on intraocular pressure by itself, 572C85 (50 micrograms) did not reduce intraocular pressure in rabbits and cats. The intraocular pressure lowering effect of the mixed DP and EP receptor agonist, BW245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin; 50 micrograms), in cats was suppressed by only 64% by BW A868C (50 micrograms). These results clearly show that the DP receptors in rabbit and cat eyes are involved in intraocular pressure regulation. However, under baseline conditions DP receptor activity does not contribute to this regulation.

Responses to adrenomedullin, a newly discovered hypotensive peptide isolated from human pheochromocytoma cells, and the carboxy terminal 15–52 (adrenomedullin-(15–52)) and 22–52 (adrenomedullin-(22–52)) amino acid fragments of adrenomedullin were investigated in the mesenteric vascular bed of the cat. Under constant flow conditions, injections of adrenomedullin, adrenomedullin-(15–52), and calcitonin gene-related peptide (CGRP) in doses of 0.003–1 nmol into the perfused superior mesenteric artery caused significant dose-related decreases in mesenteric arterial perfusion pressure. Mesenteric vasodilator responses to adrenomedullin and adrenomedullin-(15–52) were similar in magnitude and duration, while vasodilator responses to CGRP were greater in magnitude and longer in duration than those produced by adrenomedullin or adrenomedullin-(15–52) when these agents were injected in doses of 0.1–1 nmol. Adrenomedullin-(22–52) caused no significant change in mesenteric arterial perfusion pressure when injected in doses up to 10 nmol. These results suggest that amino acids 15–52 and the six-membered ring structure of adrenomedullin are important for the expression of vasodilator activity in the mesenteric vascular bed of the cat.

The effects of tilisolol on ischemic myocardial energy and carbohydrate metabolism were examined, and compared with those of propranolol. Ischemia was induced by ligating the left anterior descending coronary artery for 3 or 30 min in anesthetized open-chest dogs, 5 min after saline, tilisolol (0.2 mg.kg-1, i.v.), or propranolol (1 mg.kg-1, i.v.) injection. During ischemia, the myocardial energy stores were depleted, and the levels of glycolytic intermediates were altered, associated with ST segment elevation and TQ segment depression of the epicardial electrocardiogram. Tilisolol prevented the myocardial energy depletion and alterations of carbohydrate metabolism caused by 3 min of ischemia, to the same extent as did propranolol. Even 30 min after ischemia, the prevention of these ischemic changes was sustained by tilisolol, but not by propranolol. Tilisolol briefly reduced the ST segment elevation and TQ segment depression induced by ischemia. These results suggest that the protective effects of tilisolol on the ischemic myocardium are more potent and long-lasting than those of propranolol.

The involvement of visceral afferent fibers and 5-HT3 or 5-HT4 receptors in the vomiting induced by oral administration of copper sulfate was investigated in beagle dogs. Vomiting induced by copper sulfate (100 mg/kg) was inhibited markedly by bilateral abdominal vagotomy and bilateral greater splanchnic nerve section. The vomiting induced by copper sulfate was inhibited by blocking 5-HT4 receptors with high doses (1 and 3 mg/kg, i.v.) of ICS 205-930. On the other hand, blocking 5-HT3 receptors with MDL 72222 (0.5 and 5 mg/kg, i.v.) or low doses (0.01 and 0.1 mg/kg, i.v.) of ICS 205-930 had no apparent effect on the vomiting induced by copper sulfate. Oral administration of a 5-HT4 receptor agonist, 5-methoxytryptamine (5-MT), caused vomiting at a dose of 100 mg/kg, and the vomiting was inhibited markedly by abdominal visceral nerve section or a high dose (1 mg/kg, i.v.), but not a low dose (0.01 mg/kg, i.v.), of ICS 205-930. Intravenous administration of 5-MT (10 mg/kg) failed to induce vomiting. These results suggest that the abdominal visceral afferent fibers and possibly peripheral 5-HT4 receptors play an important role in the vomiting induced by oral administration of copper sulfate in dogs.

Responses to pituitary adenylate cyclase activating polypeptide (PACAP)-38 were investigated and compared with responses to PACAP-27 and vasoactive intestinal polypeptide (VIP) in the hindquarters vascular bed of the cat under constant flow conditions. Injections of PACAP-38 into the hindquarters perfusion circuit caused dose-related, biphasic changes characterized by initial decreases followed by increases in both hindquarters perfusion and systemic arterial pressure. In relative terms, PACAP-38 was less potent then PACAP-27 and VIP in dilating the hindquarters vascular bed, with the order of related potency being VIP > PACAP-27 > PACAP-38 when the doses required to decrease hindquarters perfusion pressure by 25 mm Hg were compared. When comparing the relative vasoconstrictor activity of PACAP-38 to that of PACAP-27 and norepinephrine, PACAP-38 was approximately 3-fold less potent than PACAP-27 and 10-fold less potent than norepinephrine. The vasoconstrictor component of the response to PACAP-38 and, as shown previously, for PACAP-27 was blocked by phentolamine in a dose that significantly reduced pressor responses to norepinephrine in the hindquarters vascular bed. The present data show that PACAP-38 has significant vasodilator and vasoconstrictor activity in the hindquarters vascular bed of the cat, and that the 27 amino acid form of the peptide has greater depressor and pressor activity than PACAP-38.

Ifenprodil, phentolamine, yohimbine or idazoxan, 1 mg/kg i.v., administered 5 min prior to 5-min global cerebral ischemia, completely prevented the post-ischemic dysfunction of the vagal baroreflex in anesthetized dogs. Idazoxan, 0.1 mg/kg i.v., was cerebroprotective against mild ischemia, but ineffective against severe ischemia. The post-ischemic administration of idazoxan, 1 mg/kg i.v., failed to restore the damaged vagal baroreflex. These results suggest that blockade of α 2 -adrenoceptors during ischemia and the early reperfusion period may protect the vagal component of baroreflex from cerebral ischemia.

The antiarrhythmic effects of bisaramil were examined in canine models of digitalis-, adrenaline- and two-stage coronary ligation- induced arrhythmia. Bisaramil (0.3–1.5 mg/kg i.v.) suppressed all the arrhythmias. The antiarrhythmic plasma concentration (IC 50 ) for arrhythmias induced by digitalis, adrenaline, and 24 h two-stage coronary ligation were 0.11, 0.81, and 0.75 μg/ml, respectively. Bisaramil is a potent class I agent, judging from its low antiarrhythmic plasma concentrations. Oral bisaramil (10 mg/kg) also suppressed 24-h coronary ligation-induced arrhythmia. These results indicate that bisaramil may be a useful drug for the treatment of various clinical ventricular arrhythmias.

We investigated the effect of cromakalim, a K + channel opener, that activates indirectly the Na + -K + pump, in association with increased K + conductance in the mesenteric arteries. In 65% of human mesenteric arteries tested, the concentration-dependent relaxation curves for cromakalim were biphasic: the low concentration ( −7 M) effect was preferentially inhibited by ouabain, whereas the higher concentration effect was significantly inhibited by glibenclamide. In branches of canine mesenteric artery, the cromakalin-induced relaxation was inhibited by pretreatment with ouabain (1 μM) as well as by glibenclamide (1 μM). The reduction in contraction of human and canine mesenteric arterial strips caused by cromakalim was totally reversed by pretreatment with ouabain (1 μM) or glibenclamide (1 μM). On the other hand, in canine mesenteric artery, cromakalim caused a significant stimulation of 22 Na + influx and ouabain-sensitive 86 Rb + uptake in association with increased 86 Rb + efflux, all of which were inhibited by glibenclamide (1 μM). Thus, it is suggested that cromakalim possesses the additional property to stimulate the Na + -K + pump through an elevation in intracellular Na + , resulting in strong relaxation of blood vessels.

We examined dependencies of amygdala central nucleus neuronal discharge to the cardiac and respiratory cycles in freely behaving cats following local microinjection of cocaine (100 micrograms/0.2 microliter). Cross-correlation histograms showed cycle-by-cycle dependencies between neuronal discharge and the cardiac and respiratory cycles in 10 of 30 cells and 7 of 30 cells, respectively, during baseline periods. After cocaine delivery, the discharge rate of half of the central nucleus of the amygdala cells (16/30, 53%) were partly or completely inhibited in a reversible manner. Excluding cardiac- and respiratory-dependent neurons which ceased firing after cocaine, more than half (5/8) of the remaining cardiac and two-thirds (4/6) of respiratory-dependent neurons altered discharge dependencies following cocaine administration. Of the cells that did not exhibit cardiac and respiratory dependencies pre-cocaine, 2 of 20 developed cardiac correlations and 3 of 23 developed respiratory correlations following cocaine administration. We speculate that a portion of the cardiac and respiratory responses induced by cocaine may be mediated through the central nucleus of the amygdala.

Using standard microelectrode techniques, the developmental cellular electrophysiologic effects of moricizine HCl on adult and neonatal canine Purkinje fibers were studied. Steady state and rate-related changes in the transmembrane action potentials produced by moricizine HCl in both age groups were characterized and compared. Also, the rate of barium-induced abnormal automaticity before and after drug was also investigated in neonatal and adult Purkinje fibers. The major findings of this study are as follows. (1) The steady state and rate-related depressant effects of moricizine HCl on Vmax were similar in both age groups. (2) Moricizine HCl shortened APD90 in the adult fibers to a greater extent than in the neonate. (3) The concentration of moricizine HCl required to significantly reduce the rate of abnormal automaticity was less in the neonate than in the adult. The effect of moricizine HCl on APD90 of individual Purkinje fibers is influenced both by their control APD90 value as well as by maturational factors. It is less clear whether developmental differences in the effects of moricizine HCl on abnormal automaticity are solely a result of differences in control rates of abnormal automaticity between the two age groups.

Previous in vitro and in vivo studies demonstrate that mebeverine, administered to isolated smooth muscle preparations or given intravenously, (i.v.), acts as an antispasmodic agent and may be useful in treating intestinal hypermotility. Whether mebeverine affects intestinal mucosal transport is, however, unknown. The aim of the present study was to characterize the effect of mebeverine on both small intestinal motor activity and electrogenic epithelial transport in the urethane anesthetized ferret. The effects of mebeverine were compared following i.v. and intrajejunal (i.j.) administration. Following both routes of drug administration mebeverine dose dependently inhibited jejunal motility, with the i.j. route being more potent. However, when administered i.v. but not i.j., the doses of mebeverine that inhibited jejunal motility also significantly reduced heart rate and arterial blood pressure. Mebeverine (0.1-10 mg/kg) administered i.v. had no significant effect on epithelial transport as measured by a change in transmural potential difference. However, when dosed i.j., mebeverine (0.1-10 mg/kg) induced a decrease in potential difference towards lower lumen negativity, which was suggestive of a decrease in fluid secretion or enhancement of absorption. In conclusion, the results confirm in vivo the antispasmodic effect of mebeverine and suggested that mebeverine can influence epithelial transport, probably in the direction of enhanced intestinal absorption.

The effect of endotoxin on the release of endothelin, a novel potent vasoconstrictor peptide, was examined in anesthetized dogs and in cultured endothelial cells. Administration of 2.63 mg lipopolysaccharide, E. coli 0111:B4/kg body weight caused shock in the animals and produced a long-lasting increase in the plasma immunoreactive endothelin-1 level that remained higher than the basal level (1.83 pg/ml as mean level) from 30 to 120 min after the injection, with a peak at 90 min (8.15 pg/ml as mean level). In vitro immunoreactive endothelin-1 in a culture medium, in which calf pulmonary artery endothelial cells were incubated in the presence of 10% fetal bovine serum, increased dose dependently with the concentration of added lipopolysaccharide between 0.01 and 10 micrograms/ml. These data indicate that plasma endothelin increases during endotoxin shock and that stimulation by endotoxin, per se, in the presence of serum participates at least partially in the mechanism for its release.

Pulmonary vasodilator responses to the K + ATP channel opener, RP 52891, were investigated in the intact-chest cat under constant flow conditions. When pulmonary vascular tone was increased with U46619, intralobar injections of RP 52891 caused dose-related decreases in lobar arterial and systemic arterial pressures without altering left atrial pressure. RP 52891 was more potent than pinacidil but less potent than cromakalim in dilating the pulmonary vascular bed. Pulmonary vasodilator responses to RP 52891, cromakalim and pinacidil, but not to acetylcholine, nitroprusside or isoproterenol, were blocked by glibenclamide. These data demonstrate that RP 52891 has potent pulmonary vasodilator activity in the cat and suggest that responses are due to opening of a glibenclamide-sensitive + ATP channel.

Whereas isolated heart preparations or anesthetized animals have been used to assess the actions of beta-adrenoceptor antagonists upon reperfusion-induced arrhythmias, this study evaluated the possible antiarrhythmic effects of beta-adrenoceptor antagonism in conscious animals. Conscious, chronically instrumented dogs were subjected to a temporary occlusion of the left anterior descending coronary artery for 4 h. After the first hour of reperfusion, flestolol (N-(1,1-dimethyl-2- ureidoethyl)-2-hydroxy-3-(O-fluorobenzoyloxy)-propylamine sulfate), an ultra short-acting beta-adrenoceptor antagonist, was administered i.v. at infusion rates of 1 and 2.6 micrograms/kg per min. A control group received the equivalent volume of saline during this period. Delayed reperfusion-induced arrhythmias were evaluated by using a computerized analysis system. Treatment with flestolol did not affect the total number of beats, the number of normal and ectopic beats, and the arrhythmic ratio, i.e. the ratio of ectopic beats to the total number of beats. Hence, beta-adrenoceptor antagonism does not appear to suppress delayed ectopic activity during coronary reperfusion in conscious dogs.

The effects of MC1-154, a cardiotonic agent which has direct effects on cardiac myofilaments, on postischemic contractile dysfunction were studied in dog heart subjected to a 30-min occlusion of the left anterior descending coronary artery followed by reperfusion, and compared with the effects of milrinone and dobutamine, that have largely cyclic AMP-dependent mechanisms of action. Regional myocardial contractility (segment shortening) and tissue ATP levels were severely depressed in reperfused myocardium. MCI-154 (0.3 and 1 μg/kg per min) improved the regional function of postischemic myocardium and decreased left ventricular end-diastolic pressure and systemic aortic pressure when infused i.v. from 30 min after reperfusion. The improvement of regional function caused by MCI-154 (1 μg/kg per min) was more pronounced than that caused by milrinone (1 μg/kg per min) or dobutamine (1 μg/kg per min), although the drugs produced an equal increase in cardiac performance (peak positive left ventricular dP/dt). These results suggest that MCI-154 produces a more pronounced improvement of regional myocardial function than milrinone and dobutamine, presumably by increasing the responses of the contractile protein system to Ca2+. In this respect, MCI-154 would be of much benefit for the treatment of postischemic left ventricular dysfunction.

Effects of fluorine (F) substitution on the 2- and 6-positions of the catechol ring of epinephrine (Epi) on its alpha- and beta-adrenoceptor agonist activities were studied in anesthetized dogs. Increments in heart rate and contractile force were used as measures of beta 1-adrenoceptor activity, while increases and decreases in blood pressure and decreases and increases in femoral blood flow were used as measures of alpha- and beta 2-adrenoceptor activities, respectively. F substitution on the 2- and 6-positions of the catechol ring yielded compounds with opposite receptor selectivities: 2-FEpi was a selective beta-adrenoceptor agonist with little agonist activity at alpha-adrenoceptors, while the 6-F analog was a selective a-adrenoceptor agonist with no significant beta-adrenoceptor effects. Of added significance, 2-FEpi was more potent than Epi as a beta 1-adrenoceptor agonist, while 6-F Epi was more potent than the parent compound as an alpha-adrenoceptor agonist. The possible mechanisms for the effects of ring fluorination on the adrenoceptor activities of Epi and other sympathomimetic amines are discussed.

Our previous studies demonstrated that subcutaneous injection of agmatine inhibits tolerance to and physiological dependence on morphine in mice and rats. In the present study we further evaluated the effects of intragastric (i.g.) administration of agmatine on morphine-induced physiological dependence in mice, rats, beagle dogs and rhesus monkeys. When agmatine (5-40 mg/kg, i.g.) was co-administered with morphine during the development of morphine-induced physiological dependence, it inhibited the abstinent syndrome precipitated by naloxone in mice, rats and beagle dogs. In addition, agmatine (40 mg/kg, i.g.) inhibited the abstinent syndrome precipitated by naloxone in mice when it was administered on the test day. In naloxone precipitated and naturally abstinent morphine dependent model in rhesus monkeys, agmatine (40 or 80 mg/kg, i.g.) inhibited the development of physiological dependence when it was co-administered with morphine. After the development of morphine dependence, agmatine (80 mg/kg, i.g.) inhibited the naturally abstinent syndrome during the 7-d abstinent period. All these results suggested that intragastric administration of agmatine inhibits morphine-induced physiological dependence in animal models.

Acquired urinary incontinence is a significant, incurable problem, prevalent in neutered bitches but rarely seen in entire bitches or males. Decreased urethral closure pressure has been proposed as a causative factor for altered detrusor contractility in the neutered bitch. In post menopausal women, acquired urinary incontinence is associated with acquired urinary incontinence and changes in collagen deposition within the bladder wall. The aim of this study was to determine effects of neutering on smooth muscle in the canine urinary bladder. Tissue bath studies were used to assess contractile function and morphometric analysis to determine percentage of collagen in the bladder wall from male and female, neutered and entire canines. Maximal response to both carbachol and neurogenic stimulation was significantly lower in bladder strips from neutered animals of both sexes. Sensitivity to carbachol was also significantly reduced by neutering in both sexes. The percentage of collagen was significantly higher in the bladder wall from neutered vs. entire females, which were similar to that of both neutered and entire males. Neutering a canine decreases urinary bladder responsiveness to muscarinic stimulation in vitro, in both sexes, but only increases the percentage of collagen in the bladder wall in females. While increased percentage collagen may predispose bitches to acquired urinary incontinence, the sex difference in this parameter indicates that more than one mechanism underlies the changes in bladder responsiveness seen following neutering. This alternative effect of neutering may be in the muscarinic receptor effector pathway and act as a therapeutic target for acquired urinary incontinence treatment.

Structural in addition to electrical remodeling may be induced by persistent atrial fibrillation per se and make atrial fibrillation refractory to antiarrhythmic drug therapy. Matrix metalloproteinases (MMPs) contribute to structural remodeling in the interstitial space. Amiodarone is effective in treating persistent atrial fibrillation compared with other antiarrhythmic drugs. In mongrel dogs, right atrial pacing at 540 beats/min (bpm) was performed along with ventricular pacing at 100 bpm for 6 weeks after atrioventricular node ablation. Right atrial pacing at 400 bpm was continued for 4 weeks with (n=5) or without (n=5) oral amiodarone (30 mg/kg/day). In sham dogs, only ventricular pacing was done with (n=4) or without (n=6) amiodarone. In atrial pacing without amiodarone group, electrical remodeling characterized by monophasic action potential duration shortening, loss of action potential duration-rate adaptation and depressed conduction velocity and structural remodeling characterized by slightly but significantly increased interstitial fibrosis and enhanced MMP-2 activity compared with sham group were observed, and sustained atrial fibrillation was easily induced. In atrial pacing with amiodarone group, both electrical and structural remodeling were reversed and sustained atrial fibrillation was not induced. In sham group with amiodarone, action potential duration prolongation and depressed conduction velocity compared with sham without amiodarone were observed, but either increased fibrosis or enhanced MMP-2 activity was not observed. Not only electrical but structural remodeling were induced in a canine persistent atrial fibrillation model. Amiodarone reversed both of them, which may be related to its high efficacy in preventing recurrence of persistent atrial fibrillation.

Bupropion is a non-nicotinic drug used in smoking cessation therapy. However, its acute effects remain unclear. In this study, we investigated the effects of bupropion on hemodynamic parameters in pentobarbital-anesthetized mongrel dogs. Bupropion administered either in bolus injections (3 or 6 mg/kg, i.v.) or in cumulative doses of 0.01, 0.1, 1, 3 and 10 mg/kg showed, in both studies, a significant increase of mean pulmonary arterial pressure and pulmonary vascular resistance index. These results show that bupropion can elevate the pulmonary pressure. Further investigations should be done to test this effect in smokers with chronic obstructive pulmonary disease.

Activation of the Na+/Ca2+ exchanger may contribute to Ca2+ overload during reperfusion after transient ischemia. We examined the effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a selective inhibitor of Na+/Ca2+ exchange, on a canine model of ischemia/reperfusion injury (myocardial stunning). Myocardial stunning was induced by a 15-min occlusion of the left anterior descending coronary artery followed by a 4-h reperfusion in anesthetized open-chest dogs. Reperfusion gradually restored myocardial percent segment shortening but remained depressed during a 4-h reperfusion period. A bolus intravenous injection of SEA0400 (0.3 or 1.0 mg/kg), given 1 min before reperfusion, improved significantly the recovery of percent segment shortening in the ischemic/reperfused myocardium. SEA0400 did not affect the hemodynamics and electrocardiogram parameters. In addition, SEA0400 did not affect reperfusion-induced change in coronary blood flow. These results suggest that the Na+/Ca2+ exchanger is involved in the stunned myocardium of dogs after reperfusion, and that SEA0400 has a protective effect against myocardial stunning in dogs.

The action of ondansetron (1 mg/kg, i.p.) and (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994; 10 mg/kg, i.p.) on spontaneous behavior and the emesis induced by cisplatin (10 mg/kg, i.p.) was studied in the ferret. Ondansetron was inactive to modify behavior, but CP-99,994 reduced spontaneous locomotor activity and lip licking by 48% (P

SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline), a novel and selective inhibitor of Na+/Ca2+ exchanger, was investigated for its possible antiarrhythmic effects on arrhythmias of Ca2+ overload induced by coronary ligation/reperfusion and by digitalis in the dog. SEA0400 (1.0 mg/kg) did not change the hemodynamics but slightly prolonged the QRS duration (P

A 20-min period of treadmill exercise in dogs, sufficient to increase heart rate by 90–100 beats min −1 , markedly decreases the severity of the life-threatening ventricular arrhythmias that result when, following anaesthesia 24 h later, the left coronary artery is occluded. This protection was unaffected by the administration of the selective cyclooxygenase-2 inhibitor celecoxib (two times 3 mg kg −1 given intravenously). These results show that prostacyclin, derived from cyclooxygenase-2, plays no role in this pronounced delayed cardioprotection.

This study investigated the effects of antigen challenge on the cough reflex in dogs that were neonatally sensitized to ragweed. Tidal volume (V(T)), respiratory rate (f), pulmonary resistance (R(L)), dynamic lung compliance (C(Dyn)) and the number and amplitude (increase in mean peak expiratory pressure) of coughs induced by mechanical stimulation of the intrathoracic trachea were measured in propofol-anesthetized dogs. Aerosolized ragweed challenge had no effect to induce spontaneous cough but increased f and R(L) and reduced V(T) and C(Dyn). Mechanical stimulation of the intrathoracic trachea at this time produced 19+/-5 coughs with an average increase in cough amplitude of 11+/-1 cm H(2)O which differed significantly from the number (9+/-2 coughs) and amplitude (30+/-5.5 cm H(2)O) of mechanically induced coughs after treatment with aerosolized saline. Both the number and amplitude of mechanically induced coughs returned to baseline values by 24-48 h after the ragweed challenge. Similar results were obtained after challenge with aerosolized histamine (0.3-1% histamine) that did not induce spontaneous coughs but increased f, reduced V(T) and decreased C(Dyn) and increased the number but reduced the amplitude of the mechanically induced coughs. In conclusion, both antigen and histamine bronchoprovocation changed the characteristics of the mechanically induced cough in dogs to a response of increased cough number but reduced mean expiratory cough amplitude.

The Na(+)/Ca(2+) exchanger (NCX) is involved in myocardial ischemia-reperfusion injuries. We examined the effects of 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a potent and selective inhibitor of NCX, on myocardial ischemia-reperfusion injury models. In canine cardiac sarcolemmal vesicles and rat cardiomyocytes, SEA0400 potently inhibited the Na(+)-dependent 45Ca(2+) uptake with an IC(50) value of 90 and 92 nM, compared with 2-[2-[4-(4-nitrobenzyloxy)phenyl]isothiourea (KB-R7943, 7.0 and 9.5 microM), respectively. In rat cardiomyocytes, SEA0400 (1 and 3 microM) attenuated the Ca(2+) paradox-induced cell death. In isolated rat Langendorff hearts, SEA0400 (0.3 and 1 microM) improved the cardiac dysfunction induced by low-pressure perfusion followed by normal perfusion. In anesthetized rats, SEA0400 (0.3 and 1 mg/kg, i.v.) reduced the incidence of ventricular fibrillation and mortality induced by occlusion of the left anterior descending coronary artery followed by reperfusion. These results suggest that SEA0400 is a most potent NCX inhibitor in the heart and that it has protective effects against myocardial ischemia-reperfusion injuries.

The effect of (+)-momocalcium bis[(2S,3a,7a-cis)-α-benzylhexahydro-γ-oxo-2-isoindolinebutyrate]dihydrate (KAD-1229), a novel hypoglycemic agent with a chemical structure different from that of the sulfonylureas, on myocardial stunning was assessed in anesthetized dogs by comparison with that of glibenclamide, a sulfonylurea. Even though their hypoglycemic effects were of similar magnitude, glibenclamide (1 mg/kg, i.v.), but not KAD-1229, exacerbated the myocardial stunning induced by occlusion/reperfusion of the descending coronary artery. In a receptor-binding experiment, unlabeled glibenclamide completely inhibited [3H]glibenclamide binding to the myocardium, but KAD-1229 did not. These results suggest that the difference in binding properties of KAD-1229 and glibenclamide toward cardiac sulfonylurea receptors is one of the causes of their different effects on myocardial stunning. It is likely that KAD-1229 is highly specific for pancreatic sulfonylurea receptors and is speculated to be a safer hypoglycemic agent than, at least, glibenclamide.

Transient lower esophageal sphincter relaxation is the major cause of gastroesophageal reflux. Mechanisms underlying transient lower esophageal sphincter relaxation are poorly understood although gastric mechanosensitive vagal afferent pathways play a central role. Glutamate is a key transmitter of vagal afferents acting partly on NMDA receptors. The aim of this work was to study the effects on transient lower esophageal sphincter relaxation in awake dogs (n=5) of the competitive NMDA receptor antagonist cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755; 0.3 and 3 mg/kg i.v., the high dose was given at two separate occasions to each dog). Transient lower esophageal sphincter relaxations were evoked by intragastric infusion of a liquid meal followed by air insufflation and were scored during a 45-min period. Neither dose produced any significant effect on the group average number of transient lower esophageal sphincter relaxations. Synchronous contractions of the esophagus were commonly seen during transient lower esophageal sphincter relaxation and CGS 19755 at both doses greatly reduced their occurrence. The findings indicate that NMDA receptor antagonism selectively inhibits the esophageal component of transient lower esophageal sphincter relaxation although the rate of transient lower esophageal sphincter relaxations is not consistently affected.

The metabotropic γ-aminobutyric acid (GABA) receptor (GABA B receptor) agonist baclofen inhibits transient lower esophageal sphincter relaxation in dogs, ferrets, and humans. Since transient lower esophageal sphincter relaxations are the major cause of gastroesophageal reflux, GABA B receptor agonists may have a therapeutic value in the treatment of gastroesophageal reflux disease. However, repeated stimulation of the GABA B receptor may induce receptor desensitization which, depending on the magnitude, would limit the therapeutic effect. The aim of the present study was to follow the effects of baclofen on transient lower esophageal sphincter relaxation in the dog after repeated administration. The effect of 7 μmol/kg baclofen b.i.d. (given intragastrically) on transient lower esophageal sphincter relaxation and related parameters was determined in four dogs. Transient lower esophageal sphincter relaxations stimulated by infusion of liquid nutrient and insufflation of air were quantified after placebo and then after the 1st, 13th, and 27th dose. Baclofen reduced the number of transient lower esophageal sphincter relaxations without affecting their duration, and the latency to the first transient lower esophageal sphincter relaxation was prolonged. Basal sphincter pressure was unaffected by baclofen, and the number of reflux episodes and esophageal acid exposure decreased. There was a statistically insignificant numerical decrease (approximately 30%) in the effect of baclofen on transient lower esophageal sphincter relaxation after the seventh dose but this was not further accentuated after the 27th dose. The effect on latency was also reduced with repeated dosing, but again, the effects after the 1st, 13th, and 27th doses were not statistically significant. The attenuation of acid exposure and reflux episodes was unaltered after repeated dosing. Three of the dogs greatly reduced their food intake within the first 2–3 days but this side effect was resolved subsequently. It is concluded that repeated dosing of baclofen leads to mild tolerance development in terms of the effects on transient lower esophageal sphincter relaxation, but that the tolerance is much less pronounced than that previously reported in other animal models.

Modulation of the vasoinhibitory effect of NKY-722 by vascular endothelial cells was studied in canine mesenteric arteries. A high concentration of NKY-722 accumulated in the endothelium-intact arteries and its accumulation in endothelium-removed arteries was significantly less. The vasoinhibitory effect of NKY-722 in endothelium-intact arteries was significantly weaker than that in endothelium-removed arteries. These results suggest that endolhelial cells can attenuate the vasoinhibitory effect of NKY-722.

Intravenous infusions of nicardipine in a dose insufficient to lower blood pressure prevented the generation of the basilar artery spasm provoked by oxyhemoglobin (oxyHb) injected intracisternally in anesthetized dogs. The plasma concentration of nicardipine was comparable to that sufficient to suppress the oxyHb-induced contraction in isolated dog basilar arteries. Nicardipine appears to be similarly effective in antagonizing the vasoconstrictor action of oxyHb in vivo and in vitro.

The effects of chronic stress both alone and in combination with the antidepressant, nefazodone, which possesses antagonistic activity at the 5-HT2A receptor, were examined on the 5-HT2A receptor-mediated behaviour, wet dog shaking and sexual behaviour. Ovariectomized female rats received either a chronic stressor or no stress for 30 days, and half of each group received concurrent nefazodone treatment (100 mg/kg/day). Following treatment with either estrogen, or estrogen combined with progesterone, sexual behaviour and wet dog shaking were recorded. Chronic stress alone was found to facilitate sexual behaviour and increase wet dog shaking, while nefazodone administration alone was without effect. Furthermore, nefazodone completely attenuated the stress-induced facilitation of wet dog shaking, but not sexual behaviour.