Positive Inotropic Responses of the Sodium Channel Modulator BDF 9148 in Diseased Rat Myocardium

1999

Clin Exp Pharma Physio

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.

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of BDF 9148 on the Action Potentials and Contractions of Left Ventricles From Normo‐ and Hypertensive Rats

Nand

1999

Clin Exp Pharma Physio

“…Hypertension causes hypertrophy of the heart and blood vessels (Diez 1992), and this hypertrophy may change the effects of drugs on these tissues (cardiac; Boyden and Jeck 1995: vascular;Kuriyama et al 1995). The positive inotropic effects of BDF 9148 are maintained in the presence of cardiac hypertrophy (Hoey, Nankervis and Brown 1995;Doggrell andNand 1995: Schwinger et al 1996). The effects of drugs on the cardiovascular system can also be altered by age.…”

Section: Introductionmentioning

confidence: 99%

The relaxing effect of BDF 9148 on the KCl-contracted aorta isolated from normo- and hyper-tensive rats

Naunyn-Schmiedeberg's Arch Pharmacol

Liang

1998

BDF 9148, a positive cardiac inotrope, relaxes the rat isolated portal vein and the KCl-contracted rat aorta. The aims of our study were to determine the mechanism of action of BDF 9148, and to ascertain whether the relaxing effect of BDF 9148 was maintained in the presence of the hypertrophy associated with hypertension, by investigating the effects of BDF 9148 on the contractility and electrophysiology of aortae of Wistar Kyoto normo-tensive rats (WKY) and Spontaneously Hypertensive Rats (SHRs). High concentrations of veratridine contracted the quiescent rat aorta. BDF 9148 had no effect on the quiescent, but relaxed the KCl-contracted WKY and SHR aorta by a tetrodotoxin insensitive mechanism, and these relaxations decreased with age but were not greatly altered by hypertrophy. The verapamil relaxations of the KCl-contracted aorta were not altered by age or hypertrophy. The ability of KCl to depolarise the aorta was reversed by verapamil, but not by BDF 9148. On the contracted rat aorta, the relaxant responses to acetylcholine were abolished by removal of the endothelium but potentiated by IBMX (10[-6] M), and the responses to isoprenaline were inhibited by propranolol (10[-6] M) but potentiated by forskolin (10[-7] M). The relaxation responses of the KCl-contracted aorta to BDF 9148 were not altered by removal of the endothelium, or by propranolol, forskolin and IBMX. In summary, the effects of verapamil and BDF 9148 on the aorta are different, and thus it is unlikely that the relaxant responses to BDF 9148 on the aorta are due to calcium channel blocking activity. The mechanism of the relaxant effect of BDF 9148 on the aorta remains unknown, but we have shown the response is endothelium-independent, and not mediated by sodium channel opening, hyperpolarization, beta-adrenoceptors, or by stimulating adenylate cyclase or guanylate cyclase.

Affinity Constants and β-Adrenoceptor Reserves for Isoprenaline on Cardiac Tissue from Normotensive and Hypzrtensive Rats

Journal of Pharmacy and Pharmacology

Petcu

Barnett

1998

To determine whether there are differences in cardiac beta-adrenoceptor responsiveness, isoprenaline affinity constants and fractional beta-adrenoceptor occupancy-response relationships for isoprenaline in the early stages of established hypertension, we studied the effects of bromoacetylalprenololmenthane (BAAM) and ([3,5-diamino-6-chloro-N-(1[N-beta-(2-hydroxyl-3-alpha-naphthoxypropy lamino)ethylcarbamoyl]-1-methylethyl)-pyrazine-2-carboxamide (ICI 147 798), slowly reversible beta-adrenoceptor antagonists, on the isoprenaline responses of the left ventricular papillary muscle and the left and right atria of 6-month-old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The papillary muscles, but not the right and left atria, of the SHR were less responsive to isoprenaline than those of the WKY. The isoprenaline pD2 values (the negative logarithms of the molar concentrations of agonist producing 50% of the maximum response) were 7.72 and 8.00 on the SHR and WKY papillary muscles, respectively. On the WKY papillary muscle the isoprenaline KA values were 2-3 x 10(-6) M, which is as expected for isoprenaline at beta1 or beta2-adrenoceptors. Isoprenaline had 100-fold greater affinity on the WKY and SHR left atria than on the papillary muscles; the isoprenaline KA values were 2-4 x 10(-8) M. On the WKY papillary muscle and left atrium, isoprenaline had to occupy 3-4% of the beta-adrenoceptors to produce a 50% maximum response; on the WKY papillary muscle and left atrium isoprenaline had to occupy 25-35% and 55%, respectively, of the beta-adrenoceptors to produce a 90% maximum response. The SHR papillary muscles and left atrium had smaller beta-adrenoceptor reserves for isoprenaline than did the WKY tissues. We were unable to obtain isoprenaline KA values on the WKY right atrium. The isoprenaline KA value on the SHR right atrium was 1-4 x 10(-8) M. Because the isoprenaline KA values for the left and right atria are markedly different from those previously reported for isoprenaline at beta1 or beta2-adrenoceptors, we suggest that atypical beta-adrenoceptors might be present on the atria of WKY and SHR. We have also demonstrated a lower beta-adrenoceptor reserve on SHR papillary muscle and atria in the early stages of established hypertension.