Effects of topical nipradilol, a beta-blocking agent with alpha-blocking and nitroglycerin-like activities, on aqueous humor dynamics and fundus circulation.

PURPOSE: To study the effects of nipradilol, a nonselective beta-blocker with alpha 1-blocking activity and nitroglycerin-like activity, on aqueous humor dynamics and optic nerve head (ONH) circulation in albino rabbits. METHODS: Experiments were carried out during the dark phase, in conscious rabbits conditioned to a schedule of alternating 12-hour periods of light and dark. The blood-aqueous barrier permeability and the aqueous flow rate were determined fluorophotometrically. The effect on outflow to general blood circulation and uveoscleral outflow were determined by using the fluorophotometric Diamox technique, and the effect on the uveoscleral outflow was further assessed by using the anterior chamber perfusion method. The ONH circulation was estimated by using the laser speckle method. RESULTS: Unilateral topical administration of 0.25% nipradilol solution lowered intraocular pressure (IOP) with relatively weak contralateral effects in a dose-dependent manner with a maximum reduction of 6 mm Hg and an effect duration of 6 hours. Twice-daily instillation for 14 days showed no attenuation of the effects. Single instillation of 0.25% nipradilol showed no significant effect on blood-aqueous barrier permeability and decreased aqueous flow rate in the treated eye (17%; P < 0.01) and in the contralateral eye (9%, P < 0.05). Nipradilol produced no significant effect on outflow facility to general blood circulation, whereas it substantially increased uveoscleral outflow. Twice-daily 0.25% nipradilol instillation increased ONH tissue blood velocity by 13% (P < 0.01), which was probably attributable to locally penetrating drug. CONCLUSIONS: Because of its ability to lower IOP and to increase uveoscleral outflow and optic nerve head circulation in rabbits, further studies are warranted to determine whether nipradilol has potential as an antiglaucoma agent in humans.

Cardiovascular effects of (2RS,3SR)- 2-aminomethyl-2,3,7,8-tetrahydro-2,3,5,8,8-pentamethyl-6H-furo- [2,3-e]indol-7-one hydrochloride (UK-1745), a novel cardiotonic agent with vasodilatory and antiarrhythmic properties.

The cardiovascular effects of (2RS,3SR)-2-aminomethyl-2,3,7,8- tetrahydro-2,3,5,8,8-pentamethyl-6H-furo[2,3-e]indol-7-one hydrochloride (CAS 170684-14-7, UK-1745), a novel cardiotonic agent, were investigated using in vitro and in vivo preparations. In paced left atria isolated from guinea pigs, both UK-1745 and vesnarinone (CAS 81840-15-5) showed a concentration-dependent positive inotropic effect. In spontaneously beating guinea pig right atria, both agents caused only a minimal chronotropic effect. In isolated, blood-perfused canine papillary muscle preparations, UK-1745 and vesnarinone injected intra-arterially into the anterior septal artery (ASA) increased the developed tension in a dose-dependent manner. In isolated, blood-perfused canine sinoatrial node preparations, both agents injected into the right coronary artery (RCA) did not cause any appreciable changes in the sinus rate. UK-1745 increased the blood flow through the ASA and the RCA in a dose-dependent manner, whereas vesnarinone did not. In anesthetized open-chest dogs, UK-1745 injected intravenously increased cardiac contractility and cardiac output, and decreased left ventricular end-diastolic pressure, systemic vascular resistance and heart rate. In experimentally induced acute heart failure in anesthetized open-chest dogs, intravenously injected UK-1745 effectively improved hemodynamic functions. In conscious instrumented dogs, orally administered UK-1745 increased LV dP/dtmax with insignificant changes in systemic blood pressure and heart rate. In mice, orally administered UK-1745 protected the development of ventricular fibrillation induced by chloroform inhalation, whereas vesnarinone did not. Thus, in respect of inotropic and chronotropic effects, UK-1745 closely resembled vesnarinone, but differed from vesnarinone in respect of coronary vasodilating and antiarrhythmic effects. The results suggest that UK-1745 is a novel positive inotropic agent with vasodilatory and antiarrhythmic properties, without significant chronotropic action, and may be beneficial for the treatment of congestive heart failure.

Vasodilator effects of cepharanthine, a biscoclaurine alkaloid, on cutaneous microcirculation in the rabbit.

Cutaneous microcirculatory responses to intravenous administration of cepharanthine (CT), a biscoclaurine alkaloid, isolated from Stephania cepharantha, were studied in a transparent round chamber installed in a rabbit ear, under conscious conditions. Vital-microscopic observations were made visually with a microscope-closed TV system and microphotoelectric plethysmography. Following the CT administration in doses of 1.0 and 3.0 mg/kg, an enhancement of rhythmic perfusion of microvascular blood due to vasomotion was developed for a period of 1 h or longer, although no appreciable change was observed following CT administration at 10.0 mg/kg. The microvascular dilator effect of CT appeared to have no direct association with systemic hemodynamics, based on the additional measurements of heart rate, blood pressure, carotid blood flow and auricular arterial blood flow.

Cardiovascular effects of nipradilol, a beta-adrenoceptor blocker with vasodilating properties.

In anesthetized dogs, an intravenous injection of nipradilol produced a long lasting fall in mean arterial blood pressure which was accompanied by transient decreases in peripheral vascular resistance and sustained decreases in heart rate, cardiac output and left ventricular (LV) dP/dt. LV end-diastolic pressure (LVEDP) was not changed while LV diameters and central venous pressure were slightly increased. Under propranolol pretreatment conditions, nipradilol no longer affected the heart rate, but the drug still induced a transient reduction in peripheral vascular resistance, and sustained decreases in arterial blood pressure and cardiac output. Furthermore, indicators of LV preload (LVEDP, LV end-diastolic diameter and central venous pressure) were significantly reduced, suggesting a direct dilating action of nipradilol on capacitance vessels. In intact conscious dogs, nipradilol caused a sustained reduction in LVEDP, while propranolol increased LVEDP. After administration of nipradilol, coronary blood flow in anesthetized dogs decreased in association with diminished myocardial oxygen consumption, and large coronary vessel resistance also decreased. Nipradilol competitively antagonized the isoproterenol-induced positive chronotropic response (DR10: 0.04 mg/Kg, i.v.) and the phenylephrine-induced vasopressor response (DR10: 3.95 mg/Kg, i.v.). In conclusion, nipradilol, in contrast to propranolol, possesses the properties to decrease arterial blood pressure, LV preload and large coronary vessel resistance through its dilating action on arterial and venous vessels. It is proposed that nipradilol may be beneficial for the treatment of hypertension and coronary heart disease.

Cutaneous microcirculatory effects of various vasodilator agents on the conscious rabbit, with special regard to changes in the rhythmic property of vasomotion.

Microcirculatory effects of intravenous administrations in the appropriate doses of phenoxybenzamine (POBA), phentolamine (PTA), nicotinic acid (NAc), trimetazidine (TMZ), dilazep (DZ), cepharanthine (CT), alpha-tocopheryl acetate (TP-A), and alpha-tocopheryl nicotinate (TP-N) as vasodilator agents were investigated in the subcutaneous tissue within a transparent ear chamber of the normal conscious rabbit. The intra-vital microscopic findings obtained following administration of the drugs were as follows: POBA, a marked and long-lasting vasodilatation without vasomotion (more than 1 hour); PTA, a quite brief vasodilatation followed by a marked and long-lasting vasoconstriction without vasomotion (more than 1 hour); NAc, a short-lasting vasodilatation with slightly blunted vasomotion (less than 10 minutes); TMZ, DZ, CT, TP-A, and TP-N, a similar notable and transient vasodilatation with vasomotion (about 1 hour or more). Some physiological implications on the microcirculatory changes induced by administrations of the drugs were discussed especially in relation to the significance of sustaining the rhythmic fluctuations of blood flow due to vasomotion.