摘要:

AbstractThe associations that have been noted between the clinical use of the thiazide diuretics and impairment of male sexual performance remain enigmatic. Recent studies are reviewed, in which aspects of the male sexual dysfunction in hypertensive men following treatment with thiazide diuretics were examined. The data are interpreted in light of previously published studies on the subject to suggest that penile erectile defects and decrements in sexual activities are specifically related to thiazide administration. A rodent model of thiazideinduced male sexual dysfunction is introduced that documents dose‐related impairment, by hydrochlorothiazide, of penile erectile reflexes and male copulatory performance. The etiology of thiazide‐induced male sexual dysfunction is hypothesized to result from alterations in sodium excretion that alter afferent renal nerve input to hypothalamic areas regulating male sexual respon

ISSN:0272-4391    

DOI:10.1002/ddr.430250202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe present study was designed to analyze the pharmacological characteristics and the anatomical localization of (3H)x‐dopexamine (DPX) in frozen sections of rat right and left ventricles. Moreover, the effect of DPX on 3′‐5′‐cyclic adenosine monophosphate (cAMP) generating system in membrane particles of rat left ventricle was investigated. (3H)‐DPX was specifically bound by sections of rat right and left ventricles. The binding was time‐, concentration‐, and temperature‐dependent and reversible. The pharmacological profile of (3H)‐DPX binding was consistent with the labeling of both β2‐adrenoceptors and DA2 receptors. In fact, the most potent displacer of (3H)‐DPX binding was the β2‐adrenoceptor antagonist ICI 118,551, followed by L‐propranolol, dopamine, noradrenaline, and L‐sulpiride. The β1‐adrenoceptor antagonist metoprolol and the DA1 receptor antagonist SCH 23390, even at high concentrations, were without effect on (3H)‐DPX binding. Autoradiography revealed a rather homogeneous distribution of (3H)‐DPX binding sites within both right and left ventricles. (3H)‐DPX is specifically bound by myocytes. The binding was antagonized primarily by ICI 118,551 and in lesser amounts by L‐sulpiride. ICI 118,551 and L‐sulpiride together reduced the density of silver grains to non‐specific binding. DPX dose‐dependently increased CAMP concentration in membrane particles of rat left ventricle. This effect was antagonized by ICI 11 8,551 but not by SCH 23390. The above data suggest that the cardiac actions of DPX are primarily mediated via an interaction with β2‐adrenoceptors. Moreover, a specific binding to DA2 receptors is also noticeable. The interaction with these different receptors most lik

ISSN:0272-4391    

DOI:10.1002/ddr.430250203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractCK‐1649C is a new quaternary ammonium class III antiarrhythmic agent undergoing clinical trials. The side effect profile of a class III antiarrhythmic agent is generally unknown. This study compared CK‐1649C with quinidine and lidocaine (class I), acecainide (class I/III), and clofilium (class III), in several models of smooth muscle, platelet, skeletal muscle, and central and peripheral nervous system function, to evaluate the potential side effects of this new drug. CK‐1649C was devoid of neuropharmacologic activity in the mouse and rat. CK.‐1649C did not promote gastrointestinal hypermotility in the mouse fed a charcoal meal and was also inactive in the rat carrageenan‐induced paw edema test. Ten to 30 times the antiarrhythmic dose of concentration of CK‐1649C was devoid of activity on transmural nerve stimulation and did not exhibit α1‐muscarinic, nicotinic, or β‐adrenoceptor blocking activity in canine vascular and guinea pig nonvascular smooth muscle. CK‐1649C was devoid of effects on human platelets, nonvascular smooth muscle of guinea pig vas deferens and uteri, and rabbit bronchi, responses of the anesthetized dog to intravenous acetylcholine (ACh), isoproterenol, and nicotine; cervical sympathetic transmission to the nictitating membrane of dog; and free water clearance in water‐loaded dogs. CK‐1649C (30mg/kg, i.v.) was devoid of all but transient inhibitory activity against vagal nerve stimulation in the dog. CK‐1649C should not have significant hemodynamic, neural, or smooth muscle side effects at proposed therapeutic

ISSN:0272-4391    

DOI:10.1002/ddr.430250204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe natriuretic and diuretic actions of cicletanine, a novel agent with vasorelaxant and antihypertensive properties, were examined in conscious, hydrated, normotensive rats. Cicletanine, the (+)‐ and (−)‐enantiomers of cicletanine, hydrochlorothiazide (HCTZ), or vehicle(s) were administered orally or intravenously (1, 3, 10, 30 mg base/kg) to water‐loaded (27 ml/kg) rats and 3 hr urine volume, Na+and K+were measured. Racemic cicletanine (3 mg/Kg, p.o.) caused a significant increase in urinary Na+(+174%) and K+(+46%) excretion, unaccompanied by diuresis. Diuresis was detected only with larger oral doses of racemic cicletanine (10–30 mg/kg). Oral administration of a 1‐mg/kg dose of (+)‐cicletanine caused significant natriuresis that was not detected with either racemic or (−)‐cicletanine. The (+)‐enantiomer (3–30 mg/kg) produced natriuresis and diuresis quantitatively similar to that of racemic cicletanine. By contrast, (−)‐cicletanine induced only slight natriuresis, kaliuresis, and diuresis upon administration of the largest dose (30 mg/kg, p.o.). Intravenous administration of the racemate and enantiomers of cicletanine caused natriuretic/diuretic activity that was very similar to that seen with oral administration. The natriuresis caused by a 3‐mg/kg dose of racemic cicletanine was unaffected by indomethacin. However, indomethacin attenuated the natriuresis and eliminated the diuresis produced by the 10‐ and 30‐mg/kg doses of cicletanine. Indomethacin had no effect on the kaliuretic actions of cicletanine. Indomethacin blunted the natriuresis and eliminated the diuresis caused by all doses of HCTZ. In conclusion, the natriuretic, kaliuretic, and diuretic effects of racemic cicletanine in the conscious, hydrated, normotensive rat appear to be mediated primarily by the ( + )‐enantiomer. A dose‐dependent separation exists between the natriuretic and diuretic actions of cicletanine, with only natriuresis noted at smaller doses. The natriuresis caused by racemic cicletanine has both indomethacin‐resistant and indomethacin‐sensitive components, while cicletanine‐induced diuresis appears to

ISSN:0272-4391    

DOI:10.1002/ddr.430250205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe purpose of this study was to demonstrate the in vivo activity of the novel low‐molecular‐weight superoxide dismutase (SOD)‐mimic deferoxamine‐manganese (Def‐Mn) in models of circulatory shock. Two forms of Def‐Mn were examined: the pink‐complex (NPC 14550) and the green complex (NPC 15823). Hemorrhagic shock was induced in rats (40 mmHg, 60 min) followed by autotransfusion of shed blood, and endotoxic shock (LPS, 200 μg/10g BW) was induced in mice. Significant lethality (ca. 20% survival rate at 24 hr) was observed in each model. Following hemorrhagic shock, NPC 14550 (10 mg/kg) increased the 24‐hr survival rate to 48% (P=0.03), while NPC 15823 (10 mg/kg) did not significantly alter survival rate (30%,P>0.05). Following endotoxin challenge, both NPC 14550 and NPC 15823 significantly improved the 24‐hr survival rate to 68% (P≤0.001) and 55% (P=0.002), respectively. Bovine erythrocyte SOD and polyethylene glycol‐SOD (Peg‐SOD) also afforded significant protection in these models and, as anticipated, SOD afforded transient protection, while Peg‐SOD provided significant protection for 24 hr and longer. Deferoxamine mesylate provided only transient protection. It is concluded that the SOD‐mimic Def‐Mn has beneficial effects following circulatory shock and, furthermore, these data provide additional evidence that the superoxide radical does

ISSN:0272-4391    

DOI:10.1002/ddr.430250206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractErgosine and its D‐isolysergic acid derivative ergosinine were investigated on canine saphenous veins both in vivo and in vitro. Following local i.v. infusion in vivo, about 5 times higher doses of ergosinine were necessary to produce the same venoconstrictor response as induced by ergosine. When administered orally, however, both ergot alkaloids were equi‐effective. In vitro methiothepin, a 5‐HT receptor blocker with high affinity for 5‐HT1receptors, antagonized venoconstrictor responses to 5‐HT and ergosine within the same concentration range, being significantly less potent when tested against norepinephrine. The reverse was true for the α2‐selective adrenoceptor blocker yohimbine, which was significantly more potent against norepinephrine and ergosine than against 5‐HT, suggesting that ergosine has affinity to both 5‐HT1‐like receptors and α2‐adrenoceptors. Concentration‐response curves to norepinephrine were shifted to the right in a parallel fashion when ergosine or ergosinine were present in the organ baths, suggesting competitive antagonism. The blocking potency of ergosinine increased with increasing incubation times in Krebs‐Henseleit solution becoming similar to that of ergosine when an incubation time of 2 hr was applied. It is suggested that the pharmacological activity of ergosinine is the consequence of an isomerization into its natural stereoisomer ergosine, which may occur

ISSN:0272-4391    

DOI:10.1002/ddr.430250207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractDantrolene is a unique directly acting skeletal muscle relaxant that is clinically useful in the treatment of chronic muscle spasticity and malignant hyperthermia. Azumolene is a new dantrolene‐like drug that has better aqueous solubility and that may also be of use in the treatment of acute muscle spasm. Potency of both compounds was determined in the anesthetized, curarized rat gastrocnemius (using different routes of administration) and the isolated chick biventer muscle preparations. The specificity of effects in vitro was evaluated by comparing effects in the chick biventer with those seen in the rat aortic strip. Route of administration governed potency for both drugs, with rank order i.v., i.p., and i.d. being the least potent. In vivo, dantrolene was approximately twice as potent as azumolene when administered by any of the routes tested. However, both drugs are equipotent in vitro. Reasons for the discrepancy between in vivo and in vitro potencies are discussed. The muscle relaxant effects of both azumolene and dantrolene are specific for skeletal muscle, being 10‐fold more potent in skeletal than in arterial smooth muscle. The reasons for this specificity are probably due to basic differences in the physiology of smooth and skeletal muscle. We conclude that the new agent, azumolene, is a specific, potent skeletal muscle relaxant with properties qualitatively similar to those of dantrol

ISSN:0272-4391    

DOI:10.1002/ddr.430250208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe combined use of two drugs with overtly similar action is a common therapeutic strategy. Combinations in doses that produce synergism are frequently sought. In this study, we examined the vasodilating action of diltiazem (DIL) and glyceryl trinitrate (GTN), tested in several fixed‐ratio combinations on an isolated preparation of the rabbit aorta. This pair of drugs, widely used clinically, exhibited significant superadditivity (synergism) in certain fixed‐ratio combinations tested, i.e., 30:1 and 100:1 of DIL:GTN (based on weight), and only simple additivity in other dose ratios, 1:15, 1:1, and 15:1. A demonstration of synergism requires that the total dose of the mixture needed to produce a level of effect be significantly less than the theoretically additive dose calculated; hence, statistical confidence limits of the additive value are needed. Testing of this nature has been limited for statistical reasons to drug combinations that produce parallel regressions of effect on log (dose). In this paper we illustrate the application of new statistical methodology that permits testing of drug combinations that producenonparallel assaysand report our experimental findings, which show that only certain fixed‐ratio combinations of DIL and GTN are superadditive (synergistic) in this test. Although vasodilation alone does not imply antianginal action, these findings may serve as a guide for further clinical te

ISSN:0272-4391    

DOI:10.1002/ddr.430250209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430250201

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY