Effects of tedisamil on cardiovascular tissues isolated from normo- and hypertensive rats.

BACKGROUND: This study was undertaken to characterize the effects of tedisamil on isolated rat cardiovascular tissues, and identify actions that could be beneficial or detrimental in the treatment of cardiac disease. RESULTS: Tedisamil prolonged the Wistar Kyoto normotensive rat (WKY) left ventricular action potential and augmented the force of contraction of left ventricle strips. On the 12-month-old SHR model of cardiac hypertrophy, the augmenting effects of tedisamil at 10(-6) and 3 x 10(-6) M were reduced. On the 21-month-old SHR model of heart failure, the augmenting effects of tedisamil at 10(-6) and 3 x 10(-6) M were further reduced. The augmenting effect of tedisamil at 10(-5) M was reduced to 47%. The rate of the right atrium of 16- to 17-month-old WKY was reduced by tedisamil at 10(-5) and 10(-4) M, and tedisamil had a similar effect on the SHR right atrium. Tedisamil at 10(-6)--3 x 10(-5) M contracted the portal veins of WKY and aortae of 12-month-old WKY and SHR. CONCLUSIONS: The positive inotropic and negative chronotropic effects of tedisamil in the rat, which are partially or fully maintained in hypertrophied or failing myocardium would be beneficial in the treatment of heart failure. In contrast, the vasoconstrictor action of tedisamil will be detrimental in heart failure.

Effects of azimilide on cardiovascular tissues from normo- and hypertensive rats.

We tested whether azimilide has potential for use in the treatment of heart failure. Azimilide, > or =3 x 10(-5) M, had no effect on the quiescent Wistar-Kyoto (WKY) rat aorta, or mesenteric and intralobar pulmonary arteries. Azimilide > or =3 x 10(-5) M relaxed the KCl-contracted aorta and portal vein. Azimilide, 10(-7)-10(-5) M, prolonged the WKY left ventricular action potential and augmented the force of contraction of left ventricle strips from 12- and 22-month-old WKY rats. Spontaneously hypertensive rats (SHRs), at ages 12 and 22 months, are models of cardiac hypertrophy and failure, respectively. The augmentation of force with azimilide was similar on 12- and 22-month-old WKY rats and 12-month-old SHRs but reduced on the 22-month-old SHR left ventricle. Azimilide, 3 x 10(-6) and 10(-5) M, augmented the force responses of the 22-month-old SHR left ventricle by 40 and 50%, respectively. As azimilide is a vasodilator and positive inotrope in the rat, and the positive inotropic effect is present in heart failure, azimilide should undergo further testing as a positive inotrope for the treatment of heart failure.

Effects of clofilium on cardiovascular tissues from normo- and hypertensive rats.

1. The overall aim was to test whether clofilium has some potential as a positive inotrope for heart failure. We used Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs) and studied the effects of clofilium on isolated blood vessels, left ventricular action potentials and left ventricular contractility. 2. Clofilium at < or = 10(-6) M had no effect on WKY portal vein contractions and at < or = 3 x 10(-4) M had no effect on WKY or SHR quiescent mesenteric and intralobar pulmonary arteries. 3. Clofilium at 10(7) - 10(-5) M prolonged the WKY left ventricular action potentials and with 10(-6) and 10(-5)M this included after-depolarizations. 4. Clofilium at < or = 3 x 10(-5) M augmented the peak force, prolonged the contractions and did not cause arrhythmias in the absence and presence of isoprenaline on left ventricle strips from 12-month-old WKY. 5. The 12-month-old SHR has hypertrophy of the left ventricle with reduced peak force and prolongation of relaxation. The effects of clofilium on 12-month-old SHR left ventricle contractility were similar to those in the age-matched WKY. 6 In summary, clofilium has positive inotropic effects on the rat left ventricle that are maintained in hypertrophy. Clofilium does not have effects on blood vessels that would be detrimental in heart failure. Clofilium prolongs the rat left ventricle action potential and causes after-depolarizations. The pro-arrhythmic potential of clofilium, however, makes it unlikely that it could be used as a positive inotrope in the treatment of heart failure.

Effects of tetraethylammonium, 4-aminopyridine and bretylium on cardiovascular tissues from normo- and hypertensive rats.

Our objective was to test whether potassium-channel blockade is a potential positive inotropic mechanism for heart failure. Thus we studied the effects of tetraethylammonium, 4-aminopyridine and bretylium on left ventricular action potentials, left ventricular contractility in the absence and presence of hypertrophy, and on isolated blood vessels from Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs). Tetraethylammonium at 10(-3)-10(-2) M, 4-aminopyridine at 10(-4)-10(-3) M and bretylium at 10(-6)-10(-4) M prolonged the action potentials of the WKY left ventricular strip. Similar concentrations of tetraethylammonium, 4-aminopyridine and bretylium augmented the peak force, prolonged the contractions, and did not cause arrhythmias in the absence or presence of isoprenaline on left ventricular strips from 12-month-old WKY. The 12-month-old SHR has hypertrophy of the left ventricle with reduced contractility and prolongation of relaxation. The effects of tetraethylammonium and bretylium were similar on WKY and SHR, whereas the effects of 4-aminopyridine were reduced on SHR left ventricular contractility, which suggests that the function of the transient outward-blocking potassium channel may be impaired in hypertrophy. Bretylium at < or = 10(-4) M had no effect on the portal vein, intralobar or mesenteric arteries. Tetraethylammonium and 4-aminopyridine at > or = 10(-5) M increased the duration or amplitude, or both, of the portal vein contractions. Tetraethylammonium at > or = 10(-2) M and 4-aminopyridine at > or = 3 x 10(-4) M contracted the mesenteric artery, and 4-aminopyridine also contracted the intralobar pulmonary artery. In summary, we have demonstrated that the action potential prolonging effects of potassium-channel blockade is associated with a positive inotropic effect on the rat left ventricle. The non-specific blockers, tetraethylammonium and 4-aminopyridine, do not have potential as positive inotropes in heart failure because of their widespread effects, including vasoconstriction. The potential of bretylium and some of the newer selective potassium-channel blockers as positive inotropes requires further evaluation.

The effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles from normo- and hypertensive rats.

The objective was to test the hypothesis that the effects of the sodium channel blockers lignocaine and tetrodotoxin are modified in the presence of hypertension-induced hypertrophy. We describe the effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles isolated from 6-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The upstroke velocity, amplitude, and overshoot of the action potential were reduced; action potentials were prolonged; and the contractions were reduced on the hypertrophied left ventricles of the SHRs. Lignocaine and tetrodotoxin reduced the upstroke velocity, amplitude, and overshoot and prolonged the left ventricular action potentials. These effects of lignocaine and tetrodotoxin on the SHR were less than those on the WKY left ventricle, possibly because the action potential was already modified by hypertrophy. Lignocaine also reduced the left ventricular contractions and the concentrations producing this reduction were lower for the hypertrophied than those for the normal left ventricle. Tetrodotoxin at 3 x 10(-6)-10(-5) M caused similar attenuation of the WKY and SHR left ventricle contractions. Our study shows that the effects of lignocaine on contraction are enhanced in the hypertrophied left ventricle of the SHR, which suggests that the binding is increased or the access of lignocaine to the receptor is enhanced in hypertrophy. In contrast, the effects of tetrodotoxin on contractions are similar, and thus the binding or access of tetrodotoxin to the receptor is not altered in the hypertrophied left ventricle of the SHR.

Effects of BDF 9148 on the action potentials and contractions of left ventricles from normo- and hypertensive rats.

1. The aim of the present study was to test the hypothesis that responses to BDF 9148, which prolongs the opening of sodium channels, are reduced in the spontaneously hypertensive rat (SHR) left ventricle in the presence of hypertrophy and failure. 2. We studied the effects of BDF 9148 on the action potentials and contractions of left ventricles from 5-week-old prehypertensive, 14-week-old hypertensive, 6- and 12-month-old hypertension-associated hypertrophy and 18-month-old hypertension-induced heart failure SHR and age-matched Wistar-Kyoto normotensive (WKY) rats. 3. Action potentials and left ventricular contractions did not alter in the early stages of hypertension (14-week-old SHR). The diastolic membrane potential did not change with hypertension-associated hypertrophy, but there was a reduction in amplitude and a prolongation of action potentials in the left ventricles of 6-18-month-old SHR. Cardiac stimulation responses and maximum contractions to 10(-6) mol/L isoprenaline were reduced at 6 months, whereas the maximum contractions to 10(-2) mol/L CaCl2 were only reduced in left ventricles of 18-month-old SHR. 4. At concentrations ranging from 10(-7) to 3 x 10(-6) mol/L, BDF 9148 increased the amplitude and prolonged the duration of action potentials and augmented the force in WKY rat left ventricles. The augmenting effects of BDF 9148 at 3 x 10(-6) mol/L were smaller than at 10(-6) mol/L, possibly because the high concentration of BDF 9148 was also blocking calcium channels. Similar effects were observed with BDF 9148 in the early stages of hypertension (14-week-old SHR). 5. In the presence of persistent hypertension-associated hypertrophy of the SHR left ventricle at > or = 6 months, the effects of BDF 9148 on action potentials and contractions were significantly reduced to a small extent. This impairment of the response to BDF 9148 may reflect the reduced contractility of the SHR left ventricle and/or it may indicate that the response to the opening of sodium channels is altered from 6 months of age. 6. In summary, most of the response of BDF 9148 is maintained in the presence of hypertrophy and failure. Thus, BDF 9148 may have some potential for the treatment of heart failure.

Effects of veratridine on the action potentials and contractility of right and left ventricles from normo- and hypertensive rats.

1. We have studied the effects of prolonging the opening of sodium channels with veratridine on the action potentials (AP) and contractility of isolated right and left ventricles of Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). It was examined whether the effects of veratridine were altered in the SHR right ventricle in the absence of hypertrophy. The main aim of the present study was to test the hypothesis that the effects of veratridine were altered in the SHR left ventricle in the presence of hypertrophy. 2. The tail-cuff pressures of 14- and 22-week-old, but not 5-week-old, SHR were greater than those of the WKY rat. At 14 weeks of age of SHR left, but not right, ventricle had developed hypertension-associated hypertrophy. 3. The AP and contractions and the ability of veratridine to prolong the AP and act as a positive inotrope were similar in the right ventricles from 22-week-old WKY rats and SHR. The effects of veratridine and the AP and contractions of left ventricles of 5-, 14- and 22-week-old WKY rats and of 5- and 14-week-old SHR were also similar. 4. The AP of the left ventricles of 22-week-old SHR were prolonged by 3 ms at the action potential duration (APD)50 and APD90 levels. The contractions to cardiac stimulation and the maximum combined force responses to cardiac stimulation and isoprenaline were reduced in the left ventricles of 22-week-old SHR compared with WKY rats and younger SHR. 5. The effectiveness of veratridine in prolonging the AP and augmenting the contractions to cardiac stimulation was reduced in the hypertrophied left ventricle of 22-week-old, but not 14-week-old, SHR. 6. In summary, the response to prolonging the opening of sodium channels with veratridine is not altered in the SHR right ventricle. However, in left ventricles of the hypertrophied 22-week-old, but not 14-week-old, SHR the effects of veratridine are reduced and this demonstrates that the response to prolonging the opening of sodium channels is changed in persistent hypertension-associated hypertrophy.