A comparison of the electrophysiological actions of phentolamine with those of some other antiarrhythmic drugs on tissues isolated from the rat heart

1 The effects of phentolamine, an ax-adrenoceptor blocking agent and amosulalol, an a1 and fadrenoceptor antagonist on hypoxia-induced impairment in cardiac function and metabolism were examined using the isolated heart Langendorff preparation of the rabbit. 2 Hypoxia induced cessation of cardiac contractile force, a rise in resting tension, a decrease in myocardial high-energy phosphates, an increase in tissue calcium content and the release of ATP metabolites from the heart. Subsequent reoxygenation resulted in little recovery of cardiac contractile force, and there were further increases in tissue calcium content and in the release of creatine kinase from the heart. 3 Treatment of hypoxic hearts with either 83 yM phentolamine or 45 gM amosulalol resulted in a suppression of the rise in resting tension, the tissue calcium accumulation and the release of creatine kinase and ATP metabolites during hypoxia. This treatment also elicited significant recovery of cardiac contractile force, restoration of myocardial high-energy phosphates, suppression of the release of creatine kinase and the accumulation of tissue calcium during reoxygenation. Both 83 Mm phentolamine and 45 Mm amosulalol exerted a significant prolongation of the effective refractory period of rabbit isolated atria.4 Lower concentrations of phentolamine (16jMm) and amosulalol (9 Mm), which are sufficient to exert an a-adrenoceptor blocking action, did not elicit an appreciable effect on the post-hypoxic recovery of cardiac contractile force. 5 These results suggest that phentolamine and amosulalol are capable of protecting the myocardium from hypoxia-induced derangements in cardiac function and metabolism. This effect is probably attributable to their membrane stabilizing effect, rather than to their a-adrenoceptor blocking action. IntroductionOxygen deficiency primarily induces functional and metabolic impairments in cardiac cells, which are believed to be dependent on the period and the severity of oxygen deficiency used (Hearse & Humphrey, 1975;Hearse et al., 1977;Nayler et al., 1979;Nayler, 1983;Murry et al., 1986;Allen & Orchard, 1987). Several investigators have demonstrated a cardioprotective action of both calcium antagonists (Fleckenstein, 1971; Aschraf & Kahamathra, 1984) and fI-adrenoceptor blocking agents in ischaemic hearts (Nayler et al., 1978b;Wrangler et al. 1984). We have also shown that experimentally-induced hypoxic insults produce cardiac contractile failure, 1 Author for correspondence at present address: 1432-1, Horinouchi, Hachioji, Japan. impairments in myocardial energy metabolism and changes in cell membrane permeability, which can be prevented by diltiazem, verapamil (Takeo et al., 1988c) and coenzyme Q10 (Takeo et al., 1987). aAdrenoceptor blocking agents such as phentolamine and prazosin have been shown to be effective in protecting against post-ischaemic reperfusion-induced calcium accumulation in cat and rat hearts (Sharma et al., 1983;Nayler et al., 1985). This suggests that aand/or fi-adrenoceptor antagonists are...

Section: Discussionsupporting

confidence: 51%

Beneficial effect of amosulalol and phentolamine on post‐hypoxic recovery of contractile force and energy metabolism in rabbit hearts

Tanonaka

Matsumoto

Minematsu

et al. 1989

“…Previous studies showed that the V'max of steady-state action potentials of Purkinje fibres, sinoatrial node or ventricular muscle cells is suppressed by prazosin (Dukes & Vaughan Williams, 1984;Rosen et al, 1984), phentolamine (Ledda & Marchetti, 1971;Northover, 1983), yohimbine (Azuma et al, 1978;Rosen et al, 1984;Briggs & Meier, 1986) and by urapidil, a new a,-adrenoceptor antagonist (Gulch et al, 1986;Kotake et al, 1988). Hasegawa et al (1988) against a2-adrenoceptors (Kameda et al, 1982a,b;Yamanaka et al, 1984) or the low affinity state of x2-adrenoceptors (Yamanaka et al, 1985) and to reverse the a-adrenergic inhibition of insulin release from the pancreatic islet cells (Kameda et al, 1982b).…”

Section: Discussionmentioning

confidence: 99%

“…Northover (1983) considered the antiarrhythmic effects of prazosin, yohimbine, tolazoline, dibenamine and phenoxybenzamine to be produced by interaction with the cell membrane and not by direct inhibition of the a-adrenoceptors. Hasegawa et al (1988) described the suppressive effect of aadrenoceptor antagonists on transient depolarization and triggered activity, and its protective effect against further deterioration of abnormal automatic activity during hypoxia.…”

Section: Introductionmentioning

confidence: 99%

Effects of midaglizole, a new hypoglycaemic drug on the electrophysiological properties of guinea‐pig papillary muscle

Noguchi

Hasegawa

Mashiba

1991

1 The electrophysiological effects of midaglizole, a new oral hypoglycaemic agent which is an a2-adrenoceptor antagonist, were assessed in the reserpinized ventricular myocardium of the guinea-pig.2 Midaglizole suppressed the maximal rate of rise (V'mx) and the amplitude of action potentials (APA) of the fast and the slow responses in a concentration-dependent manner without influencing the resting potentials.3 Voltage-dependency of the Pmax block of the action potentials by midaglizole (10puM) did not appear in solutions containing various concentrations of KCL. 4 It is concluded that midaglizole has inhibitory effects on the fast Na+ and slow Ca2+ currents of the membrane independent of the blockade of myocardial a-adrenoceptors, and that these effects may be significant in some clinical uses of the drug.

“…In contrast, the prolongation of the action potential duration produced by most class III antiarrhythmic drugs decreased at fast rates, i.e., they exhibited a 'reversed usedependence' (Hondeghem & Snyders, 1990). Even when in some studies the inhibitory effects of phentolamine and prazosin on Vmass increased with the frequency of stimulation (Sada, 1978;Northover, 1983;Tohse et al, 1986) the frequency-dependent effects of ax-adrenoceptor antagonists on V,,,lX and APD have not been thoroughly studied.…”

Section: Introductionmentioning

confidence: 99%

“…Previous electrophysiological studies in different animal species have demonstrated that al-adrenoceptor antagonists inhibited the maximum upstroke velocity (V,,.~) and lengthened the action potential duration (Quadbeck & Reiter, 1975;Sada, 1978;Northover, 1983;Dukes & Vaughan Wilhans, 1984; Rosen et al, 1984;Tohse et at., 1986;Himmel et al, 1991). These results suggested that o1-adrenoceptor antagonists may exhibit class I (Na channel blocking properties) and class III antiarrhythmic properties, respectively, according to the classification of Vaughan Williams (1984).…”

Section: Introductionmentioning

confidence: 99%

Class I and III antiarrhythmic actions of prazosin in guinea‐pig papillary muscles

Pérez

Valenzuela

Delpón

et al. 1994

1 The electrophysiological effects of prazosin, a highly specific ax-adrenoceptor antagonist, on transmembrane action potential characteristics were studied in guinea-pig papillary muscles. 2 At concentrations between 10-6 M and 10-5 M, prazosin produced a concentration-dependent decrease in the maximum upstroke velocity (V,,,.) and a progressive lengthening of the action potential duration at 50% (APDm) and 90% (APD90) of repolarization. The prolongation of the APD5o and APD91 values was independent of the frequency of stimulation. The prolongation of the APD9o was accompanied by a parallel lengthening of the effective refractory period (ERP) and thus, the ERP/APD9( ratio remained unaltered at all drug concentrations tested. 3 In the presence of prazosin, 5 x 10-6 M, the percentage of 1,, block increased with the frequency of stimulation, the inhibitory effect being more marked at fast driving rates (frequency-dependent V,,,C,, block). At 3 Hz,, the onset kinetics of the frequency-dependent Vmax block was better fitted by a biexponential function, the K values of the fast (K1) and slow components (K2) being 0.254 ± 0.037 APà nd 0.045 ± 0.010 AP-', respectively. However, prazosin did not produce tonic V,.. block. 4 The recovery time constant (Tre) from the frequency-dependent V.,.z block was prolonged from 19.6 ± 2.5 ms to 24.4 ± 5.5 s. This result indicated that prazosin can be considered as a slow kinetics Na channel blocker.5 Prazosin, 5 x 10-6 M, shifted the membrane responsiveness curve in a hyperpolarizing direction, which indicated that the blockade of sodium channels increased at less negative potentials (voltagedependent . block). 6 It is concluded that in guinea-pig papillary muscles, prazosin inhibited the V,,,, and lengthened the duration of the action potentials, thus exhibiting both class I and class III antiarrhythmic actions, respectively, that were possibly unrelated to blockade of myocardial al-adrenoceptors.