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We investigated the effects of intravenous administration of conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on blood electrolytes and plasma osmolality in rats with an experimental syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The experimental SIADH rat model was developed by means of continuous administration of arginine vasopressin (AVP) via a subcutaneously implanted osmotic mini pump, and hyponatremia was induced by additional water loading. This model possesses similar characteristics to those observed in patients with SIADH, specifically decreases in blood sodium concentration and plasma osmolality. In this experimental model, intravenous administration of conivaptan (0.1, 1 mg/kg) significantly increased blood sodium concentration and plasma osmolality. On the other hand, intravenous administration of furosemide (10 mg/kg) did not increase either blood sodium concentration or plasma osmolality in the SIADH rats. Moreover, furosemide significantly lowered blood potassium concentration. These results show that conivaptan improves hyponatremia in rats with SIADH, supporting the therapeutic potential of conivaptan in treatment of patients with hyponatremia associated with SIADH.

The effects of the novel, selective endothelin-A (ET A ) receptor antagonist YM598 on both-side heart failure were investigated. Right-side heart failure secondary to pulmonary hypertension was produced by a single subcutaneous injection of 60 mg/kg monocrotaline, and post-ischemic congestive left-side heart failure (CHF) produced by surgical left coronary artery ligation. In right-side heart failure rats, oral YM598 (0.1 and 1 mg/kg for 4 weeks), but not bosentan (30 mg/kg), significantly inhibited the progression of pulmonary hypertension and the development of right ventricular hypertrophy. YM598 also improved hypoxemia and morphological pulmonary lesions in these rats. In CHF rats, moreover, long-term oral administration of YM598 (1 mg/kg/day for approximately 30 weeks) significantly ameliorated their poor survival rate (P < 0.05). In the measurement of cardio-hemodynamic parameters, YM598 improved the contractile/diastolic capacity of the left ventricle and the preload in the right ventricle to the levels seen in sham-operated rats. YM598 also markedly inhibited both ventricular hypertrophy and pulmonary congestion, as well as lowering high plasma brain natriuretic peptide levels in CHF rats. These findings suggest that YM598 may have a clinical benefit with regards to ameliorating the cardiopulmonary changes of right-side heart failure, and the cardiac dysfunction and mortality/morbidity of CHF.

We investigated the preventive and therapeutic effects of the selective endothelin ETA receptor antagonist potassium(E)-N-[6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]-2-phenylenthenesulfonamidate (YM598) on the development of pulmonary hypertension in monocrotaline-induced pulmonary hypertensive and hypoxemic rats. In the prevention study, oral administration of YM598 (0.1 and 1 mg/kg) or bosentan (30 mg/kg) for 4 weeks was started on the day following monocrotaline (60 mg/kg) injection. In the therapeutic study, oral administration of YM598 (0.1, 0.3 and 1 mg/kg) for 2 weeks was started 3 weeks after monocrotaline injection. In the prevention study, a marked increase in pulmonary arterial pressure and right ventricular hypertrophy, a decrease in right cardiac function and hypoxemia were observed. Histopathological examination indicated the presence of pulmonary remodeling, including medial wall thickening of the pulmonary microvasculature and alveolar disorders. YM598 suppressed the increase in pulmonary arterial pressure, right ventricular hypertrophy and systemic congestion, and improved the hypoxemia, but bosentan had only modest effects. Histopathological disorders were also ameliorated by YM598. In the therapeutic study, YM598 also ameliorated the pulmonary hypertension and hypoxemia in monocrotaline-treated rats. These results suggest that YM598 effectively prevented and reversed the development of pulmonary hypertension, and reduced the pulmonary vascular remodeling and parenchymal injury in monocrotaline-treated rats. YM598 also improved hypoxemia which accompanied with the severe pulmonary hypertension in these rats.

In the present article we wish to report the discovery of a novel class of ET(A)-selective endothelin (ET) receptor antagonists through the modification of the ET(A)/ET(B) non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET(A)-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET(A)-selectivity. [IC50=2.1 nM for ET(A) receptor, ET(B)/ET(A) ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.

In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ETA-selective endothelin (ET) receptor antagonists, including the compounds 1a, b. Compound 1a showed excellent oral antagonistic activities and pharmacokinetic profiles, and the monopotassium salt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wish to report the investigation of the further details of structure-activity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a. It was found that methyl substitutions at the 2-, 4- and 6-positions of the phenyl group in 1a led to the discovery of the ET(A)/ET(B) mixed antagonist (6s) with an IC50 of 2.2 nM for the ET(A) receptor. We also found that introduction of an ethyl group to the 1-position of the ethenyl group in 1a gave the ET(A) selective antagonist (6u) with an oral endothelin antagonistic activity in rats.

1. We investigated the effects of selective alpha 1-adrenoceptor antagonists on rhythmic bladder contraction and cystometrograms as representative of urinary bladder function in urethane-anesthetized rats. 2. The selective alpha 1-adrenoceptor antagonists tamsulosin (0.03-3 micrograms/kg IV), prazosin (0.03-3 micrograms/ kg IV) and bunazosin (0.03-3 micrograms/kg IV) exerted little effect on the amplitude and frequency of rhythmic bladder contraction in anesthetized rats. In contrast, the antipollakiuria agent flavoxate (5 and 10 mg/kg IV) induced a dose-dependent disappearance in frequency without affecting the amplitude of the contractions. 3. Tamsulosin (1 and 3 micrograms/kg IV), prazosin (1 and 3 micrograms/kg IV), and bunazosin (1 and 3 micrograms/kg IV) exerted no effect on the cystometrogram, either. However, flavoxate (5 and 10 mg/kg IV) raised the micturition threshold pressure and prolonged the time to micturition. 4. These results suggest that the alpha 1-adrenoceptor plays little role in urinary bladder contraction in anesthetized rats.

1. 1. The contractile activity, binding activity and localization of endothelin (ET)-1 were evaluated in human nonhyperplastic (control) and hyperplastic prostates. 2. 2. ET-1 caused contraction of both prostates in a dose-dependent manner. However, this contraction was markedly decreased in hyperplastic prostates. 3. 3. B max and K d values of hyperplastic prostates were greater than those of the control. 4. 4. The muscle and proliferative epithelium of hyperplastic prostates showed strong staining for the anti-ET-1 antibody. However, the glandular epithelium of control prostates was weakly stained. 5. 5. These findings indicate that responsiveness to ET-1 is decreased, though the ET-1 and ET-1 receptors increase in the hyperplastic prostate. Namely, the increase in ET-1 receptors is not effective in regulating the contractile response of the prostate, because its expression is rather dominant in proliferated gland. 6. 6. These suggest that ET-1 may not have an important role in the release of the obstructive symptoms of benign prostatic hypertrophy.

In the present article we wish to report the discovery of a novel class of ET(A)-selective endothelin (ET) receptor antagonists through the modification of the ET(A)/ET(B) non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET(A)-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET(A)-selectivity. [IC50=2.1 nM for ET(A) receptor, ET(B)/ET(A) ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.

In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ETA-selective endothelin (ET) receptor antagonists, including the compounds 1a, b. Compound 1a showed excellent oral antagonistic activities and pharmacokinetic profiles, and the monopotassium salt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wish to report the investigation of the further details of structure-activity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a. It was found that methyl substitutions at the 2-, 4- and 6-positions of the phenyl group in 1a led to the discovery of the ET(A)/ET(B) mixed antagonist (6s) with an IC50 of 2.2 nM for the ET(A) receptor. We also found that introduction of an ethyl group to the 1-position of the ethenyl group in 1a gave the ET(A) selective antagonist (6u) with an oral endothelin antagonistic activity in rats.

The effect of highly purified recombinant human renin (rh-renin), expressed in Chinese hamster ovary cells, on mean blood pressure (MBP) was evaluated in pithed spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Intravenous bolus injection of rh-renin produced dose-dependent increases in MBP in pithed SHR and WKY. The pressor response to rh-renin in pithed SHR was about 3 times as potent as that in pithed WKY. Intravenous infusion of rh-renin produced dose-dependent progressive increases in MBP during the first 40 min, reaching plateaus and thereafter MBP was maintained up to 120 min. This hypertensive response to rh-renin was antagonized by renin inhibitors, YM-21095 and KRI-1314, which inhibited the reaction between rh-renin and tetradecapeptide competitively, with K i values of 5.1 × 10 −10 and 4.3 × 10 −9 M, respectively. In rh-renin-infused pithed SHR, the hypotensive effect of YM-21095 was 37 times as potent as that of KRI-1314. These results suggest that rh-renin can stimulate the rat renin-angiotensin system, thereby producing hypertension. Moreover, the rh-renin-infused rat model could be useful to evaluate the effect of renin inhibitor.

We investigated the contractile response of the lower urinary tract to endothelin-1 in vitro (rabbits) and in vivo (dogs). We also assessed the effects of a selective endothelin ETA receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2, 2′-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on endothelin-1-induced contractile responses. In the in vitro study, endothelin-1 induced contractile responses in isolated rabbit bladder base, urethra, and prostate tissues. YM598 (10− 7–10− 5 M) antagonized these endothelin-1-induced contractile responses without affecting the maximal responses. In the in vivo study, endothelin-1 induced the elevation of non-prostatic urethral pressure as well as prostatic urethral pressure even in the presence of tamsulosin (10 μg/kg, i.v.) in anesthetized male dogs. YM598 (0.1–3 mg/kg, i.v.) inhibited these endothelin-1-induced contractile responses in a dose-dependent fashion. These results suggest that endothelin ETA receptors play an important role in the lower urinary tract contraction, and that the selective endothelin ETA receptor antagonist YM598 has ameliorating effects on various urinary dysfunctions, including benign prostatic hyperplasia.

Hyponatremia is a common electrolyte disorder with the potential to cause serious neurological complications. Conventional therapies for hyponatremia have been found to be inconsistently effective. Arginine vasopressin (AVP) is etiologically critical for hyponatremia, and it has been proven that AVP receptor (AVP-R) antagonists normalize serum sodium levels in hyponatremic patients. Additionally, one of these drugs showed potential for reducing mortality in patients with decompensated heart failure and for suppressing the progression of genetic renal disease in animals. The first non-peptide AVP-R antagonist has recently been approved in the United States. It is expected that this approval will accelerate the development of future clinical applications of AVP-R antagonists and open the door to a new era in the treatment of these intractable diseases.

In some diseases in which endothelin-1 (ET-1) production increases (e.g. prostate cancer), ET-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin-A receptor antagonist, YM598, on the nociception potentiated by ET-1 in formalin-induced and cancer inoculation-induced pain models in mice. The formalin-induced pain model was prepared by intraplantar injection of 0.7% formalin into the hind paws of ICR mice, and the cancer pain model was prepared by inoculation of the human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency mice. Formalin caused a biphasic pain response and paw edema in the mouse hind paw. ET-1 (10 pmol/paw) potentiated these responses, and single oral administration of YM598 (0.3-3 mg/kg) significantly inhibited this ET-1-induced potentiation of nociception and paw edema. ET-1 (10 pmol/paw) also potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3-3 mg/kg) significantly inhibited the ET-1-induced potentiation of nociception. These results suggest that selective endothelin-A receptor antagonists relieve pain in patients with various diseases in which ET-1 production increases (e.g. prostate cancer).

We investigated the effects of intravenously administered conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on cardiac function in rats with congestive heart failure following myocardial infarction, and compared results with those for the selective vasopressin V2 receptor antagonist SR121463A. Rats were subjected to left coronary artery occlusion to induce myocardial infarction, which in turn led to congestive heart failure. At 4 weeks after coronary occlusion, conivaptan (0.03, 0.1 and 0.3 mg/kg i.v.) dose-dependently increased urine volume and reduced urine osmolality in both myocardial infarction and sham-operated rats. SR121463A (0.3 mg/kg i.v.) also increased urine volume and decreased urine osmolality in myocardial infarction rats, to a degree comparable to that by conivaptan (0.3 mg/kg i.v.). At 6 weeks after surgery, myocardial infarction rats showed increases in right ventricular systolic pressure, right atrial pressure, left ventricular end-diastolic pressure and relative weights of the heart and the lungs, and a decrease in first derivative of left ventricular pressure (dP/dt(max))/left ventricular pressure, showing that congestive heart failure was well established. Conivaptan (0.3 mg/kg i.v.) significantly reduced right ventricular systolic pressure, left ventricular end-diastolic pressure, lung/body weight and right atrial pressure in myocardial infarction rats. Moreover, conivaptan (0.3 mg/kg i.v.) significantly increased dP/dt(max)/left ventricular pressure. SR121463A at a dose of 0.3 mg/kg i.v. significantly decreased left ventricular end-diastolic pressure and right atrial pressure, and tended to decrease right ventricular systolic pressure and relative lung weight in myocardial infarction rats. Although the aquaretic and preload-reducing effects of SR121463A were similar to those of conivaptan, SR121463A failed to improve dP/dt(max)/left ventricular pressure. These results suggest that dual vasopressin V1A and V2 receptor antagonists provide greater benefit than selective vasopressin V2 receptor antagonists in the treatment of congestive heart failure.

The preventive effects of the novel and selective endothelin ET(A) receptor antagonist YM598 on the development of pulmonary hypertension (PH) were investigated in chronic hypoxia-induced PH rats. Oral administration of YM598 at a dose of 1 mg/kg was started on the first day of chronic hypoxia exposure for 2 and 3 weeks to investigate the effects of this compound on hemodynamic and arterial blood gas variables, respectively. Cardiopulmonary organ weights were measured at the end of the 2-week administration period. Chronic hypoxia for 2 weeks induced a marked increase in pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary and systemic congestion, and a decrease in right cardiac diastolic function. Repeated oral administration of YM598 significantly suppressed the increase in pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary and systemic congestion. YM598 also improved the hypoxemia which was induced by 3 weeks of exposure to hypoxia. These results suggest that repeated oral administration of YM598 to rats with chronic hypoxia effectively prevented the development of PH. Oral administration of YM598 also improved hypoxemia in this model. These data strongly suggest that YM598 will be clinically useful in the treatment of patients with either primary or secondary pulmonary hypertension.

The binding affinities of (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598) for native human endothelin ETA and ETB receptors expressed in human coronary artery smooth muscle cells (CASMC) and a human melanoma cell line, SK-Mel-28, respectively, were examined, and the results compared with those for the endothelin receptor antagonists atrasentan and bosentan. The in vivo endothelin ETA receptor inhibitory activities of YM598 and atrasentan were also compared through the suppression of the big endothelin-1-induced pressor response in pithed rats. Ki values of YM598, atrasentan, and bosentan for native human endothelin ETA receptors were 0.772, 0.0551, and 4.75 nM, while those for native human endothelin ETB receptors were 143, 4.80, and 40.9 nM, respectively. The calculated selectivity ratios of YM598, atrasentan, and bosentan for endothelin ETA versus ETB receptors were 185, 87 and 8.6, respectively. In pithed rats, YM598 and atrasentan inhibited the big endothelin-1 (1 nmol/kg)-induced pressor response in a dose-dependent manner on both intravenous and oral administration. The inhibitory effect of YM598 was less potent than that of atrasentan when these agents were intravenously administered, but closely similar on oral administration. These results suggest that YM598 has high selectivity for native human ETA against ETB receptors, and that YM598 is superior to atrasentan as an ETA receptor antagonist with regard to pharmacological bioavailability in rats.

In some diseases in which endothelin-1 production increases, e.g. prostate cancer, endothelin-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin ETA receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2′-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on the nociception potentiated by endothelin-1 in a cancer inoculation-induced pain model in mice, induced by inoculation of the androgen-independent human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency (SCID) mice. No pain responses were observed in the sham-operated mice, whereas monophasic pain responses were observed in the PPC-1-inoculated mice. Endothelin-1 (1 to 10 pmol/paw) but not sarafotoxin S6c potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3 to 3 mg/kg, p.o.) significantly inhibited the endothelin-1 (10 pmol/paw)-induced potentiation of nociception in a dose-dependent manner. These results suggest that selective endothelin ETA receptor antagonists might relieve pain in patients with various diseases in which endothelin-1 production is increased, e.g. prostate cancer.

We investigated the effect of YM598, a selective endothelin ETA receptor antagonist, on blood pressure (BP) in normotensive rats (NTR), spontaneously hypertensive rats (SHR) and Dahl salt-sensitive hypertensive rats (Dahl-SS). We also examined the concomitant effect of YM598 with the L-type Ca2+ channel antagonist nifedipine on BP. Single oral administration of YM598 did not affect BP in NTR and SHR. In Dahl-SS, in contrast, YM598 slightly, but not significantly, reduced BP. Concomitant administration of YM598 with nifedipine at doses inducing slight hypotension on respective single administrations resulted in a stronger hypotensive effect than single administration of either compound alone. However, the magnitude of the concomitant hypotensive effect demonstrated only a simple additive effect of the two compounds. These results indicate that YM598 did cause slight hypotensive effects in some types of hypertension. These results also indicate the possibility of additive, but not synergic, hypotensive effects on concomitant administration of ET receptor antagonist and an L-type Ca2+ channel antagonist.

We describe here the pharmacology of (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), a novel selective endothelin ET(A) receptor antagonist synthesized through the modification of the ET(A)/ET(B) non-selective antagonist, bosentan. YM598 inhibited [125I]endothelin-1 binding to cloned human endothelin ET(A) and ET(B) receptor, with K(i) of 0.697 and 569 nM, and inhibited endothelin-1-induced increases in intracellular Ca(2+) concentration in human and rat endothelin ET(A) receptor. YM598 also inhibited endothelin-1-induced vasoconstriction in isolated rat aorta with a pA(2) value of 7.6. In vivo, YM598 inhibited the pressor response to big endothelin-1, a precursor peptide of endothelin-1. DR(2) values of YM598 in pithed rats were 0.53 mg/kg, i.v. and 0.77 mg/kg, p.o., and its antagonism in conscious rats was maintained for more than 6.5 h at 1 mg/kg, p.o. In contrast, YM598 had no effect on the sarafotoxin S6c-induced depressor or pressor responses. YM598 showed not only superior antagonistic activity and higher-selectivity for endothelin ET(A) receptor in vitro, but at least a 30-fold higher potency in vivo than bosentan. In conclusion, YM598 is a potent and orally active selective endothelin ET(A) receptor antagonist.

In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ET(A)-selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative (2b). In this paper, we wish to report further details of structure-activity relationships (SARs) of the two regions of the molecule in compound 2b, which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group (6e) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group (6l) or 2-phenylethanesulfonamide group (6q) were well tolerated both in the ET(A) binding affinity and ET(A) selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3mg /kg with a duration of >6.5h. Compound 6e also exhibited a potent antagonistic activity in the pithed rats.

1. The effects of YM435, a dopamine DA1 receptor agonist, were evaluated in a canine model of acute congestive heart failure. 2. The model was induced in open-chest anesthetized dogs by left anterior descending coronary artery ligation, volume loading, and intravenous infusion of angiotensin II. This resulted in a moderate and stable congestive heart failure characterized by reduction in cardiac output and increases in left ventricular end-diastolic pressure and total peripheral vascular resistance. 3. Intravenous infusion of YM435 (1 microgram/kg/min) significantly decreased left ventricular end-diastolic pressure, total peripheral vascular resistance and mean blood pressure and significantly increased cardiac output and renal blood flow in this model. 4. These results indicate that intravenous infusion of YM435 can improve hemodynamics and cardiac function in a canine model of acute congestive heart failure. YM435 may be a useful therapeutic agent for the treatment of congestive heart failure.

1. We compared the responsiveness of smooth muscle in the lower urinary tract and prostate from rabbits to the agonists noradrenaline, phenylephrine, clonidine, acetylcholine, prostaglandin F2 alpha, and histamine. 2. These agonists contracted smooth muscle in the lower urinary tract and prostate. In terms of maximal developed tension, contractile responses to the agonists were produced in the following order of potency: acetylcholineprostaglandin F2 alphahistamineor = phenylephrineor = noradrenalineclonidine in the urinary bladder body; acetylcholine = noradrenaline = phenylephrineprostaglandin F2 alphahistamineor = clonidine in the urinary bladder base; noradrenalineor = phenylephrineor = clonidineacetyl-cholineprostaglandin F2 alphaor = histamine in the urethra; and noradrenalineor = phenylephrinehistamine = acetylcholine = clonidine = prostaglandin F2 alpha in the prostate. 3. These results suggest that considerable responsiveness variation occurs in the lower urinary tract and prostate and support the idea that the urinary bladder body is primarily governed by cholinergic mechanisms (parasympathetic nerves), whereas the urethra and prostate are regulated by alpha 1-adrenergic mechanisms (sympathetic nerves) and the bladder base by both.

The adrenoceptor antagonistic and antihypertensive effects of amosulalol, 5-[1-hydroxy-2-[[2-(o- methoxy)ethyl]-2-ethylbenzenesulfonamide HCl, a combined alpha- and beta-adrenoceptor antagonist, were examined in hypertensive rats. Oral administration of amosulalol (1-30 mg/kg) produced a dose-dependent antihypertensive effect without reflex tachycardia in conscious spontaneously hypertensive rats (SHR) with a duration > 10 h after the higher doses (10 and 30 mg/kg). Amosulalol was approximately threefold more potent than labetalol and arotinolol in decreasing blood pressure (BP) in conscious SHR. Oral (p.o.) administration of amosulalol 10 mg/kg produced equally potent reductions in mean arterial BP (MBP) without reflex tachycardia in deoxycorticosterone acetate-salt rats (DHR) and renal hypertensive rats (RHR) as it did in SHR. Repeated oral administration (1, 4, 8, or 12 weeks) of amosulalol 10 mg/kg elicited an antihypertensive effect without evidence of tolerance in conscious SHR and produced a rightward shift in phenylephrine (PE)-induced vasopressor and isoproterenol (ISO)-induced positive chronotropic responses with dose ratios of 3.3-12.5 and 3.7-6.4, respectively, in pithed SHR. In addition, single p.o. administration of amosulalol 10 mg/kg produced a rightward shift in these responses with dose ratios of 12.1 and 3.5, respectively, in pithed SHR. Amosulalol exerted antihypertensive activity without tachycardia through blockade of vascular alpha- and cardiac beta-adrenoceptors, and its activities were constant even after repeated p.o. administration.

1. Effects of the individual optical isomers of YM-12617 (R, S 5-[2-[[2-(o-ethoxyphenoxy)ethyl]-amino]propyl]-2- methoxybenzenesulphonamide HCl, (+/-)-YM), a potent selective alpha 1-adrenoceptor antagonist, on the increase in intraurethral pressure (IUP) and diastolic blood pressure (DBP) induced by phenylephrine were evaluated in pentobarbital-anaesthetized female dogs. 2. Phenylephrine (0.1-30 micrograms kg-1 i.v.), an alpha 1-adrenoceptor agonist, dose-dependently increased IUP and DBP. 3. alpha-adrenoceptor antagonists (i.v.) dose-dependently antagonized the increase in IUP and DBP induced by phenylephrine, with a potency ranking of R(-)-YM greater than (+/-)-YM greater than prazosin greater than phentolamine greater than S(+)-YM greater than yohimbine. 4. These results suggest that the alpha 1-adrenoceptor mediates the increase in IUP as well as DBP in anaesthetized dogs, and that alpha 1-adrenoceptors in the urethra and arteries show a stereochemical preference for R(-)-YM.