PubMed Health⌕ Search

Biomedical subjects

J M Ambrose

Publications and source records attributed to J M Ambrose.

6 recordsLinked to original sources
PubMed1985

Effects of the calcium antagonists perhexiline and cinnarizine on vascular and cardiac contractile protein function.

The weakly basic, lipophilic Ca++ antagonists perhexiline and cinnarizine have been compared with the calmodulin inhibitor W-7 and the cardiotonics Vardax and APP-201-533 for the ability to modulate Ca++-dependent contractile protein interactions directly, as well as Ca++-calmodulin-mediated myosin light chain phosphorylation, in arterial actomyosin or cardiac myofibrils. Both perhexiline and cinnarizine inhibited arterial myosin P-light chain phosphorylation and superprecipitation of arterial actomyosin over the concentration range of 10 to 200 microM. Concomitant inhibition of arterial superprecipitation and phosphorylation by perhexiline (IC50 = 33 microM) and cinnarizine (IC50 = 60 microM) was similar to W-7 (IC50 = 35 microM), and was characterized by a rightward shift in the pCa superprecipitation and pCa-light chain phosphorylation relationships, depressed maximum activity and attenuation by 2 microM exogenous calmodulin. However, whereas inhibition of superprecipitation and P-light chain phosphorylation by W-7 was equal at different Mg++ concentrations, relatively greater inhibition with perhexiline and less inhibition with cinnarizine was apparent as the free Mg++ concentration was lowered. In cardiac myofibrils prepared from both bovine and canine ventricles, perhexiline stimulated Mg-adenosine triphosphatase (ATPase) activity and cinnarizine was without effect, whereas W-7 significantly depressed ATPase activity. Perhexiline was 10-fold more potent and 3-fold more efficacious than either Vardax or APP-201-533 in canine cardiac myofibrils. Whereas APP-201-533 increased Ca++ sensitivity and maximum ATPase activity (Vmax), perhexiline increased Ca++ sensitivity, but not Vmax, and W-7 depressed both parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed1984

Effects of felodipine, nitrendipine and W-7 on arterial myosin phosphorylation, actin-myosin interactions and contraction.

The relative effects of felodipine, a dihydropyridine with purported calmodulin antagonistic properties, have been compared with the calmodulin inhibitor, W-7, for inhibition of Ca2+-dependent force development and direct inhibition of Ca2+-calmodulin mediated arterial myosin light chain phosphorylation and actin-myosin interactions. Felodipine (IC50 3 X 10(-9) M) was approximately 30 000 X more potent than W-7 (IC50 10(-4) M) and equipotent with another dihydropyridine, nitrendipine, in inhibiting isometric force development in K+-depolarized aortic smooth muscle strips. In contrast, W-7 (IC50 4 X 10(-5) M) was approximately 5 X more potent than felodipine (IC50 2 X 10(-4) M) in inhibiting Ca2+-dependent myosin light chain phosphorylation or superprecipitation of arterial actomyosin. Concentration-related inhibition of both parameters by W-7 was tightly coupled to concomitant inhibition of force development in intact smooth muscle. In contrast, inhibition of myosin light chain phosphorylation and superprecipitation by felodipine was only apparent at concentrations greater than or equal to 10(-5) M while maximal inhibition of force development occurred at a concentration as low as 10(-7) M. Inhibition of contractility by W-7 was minimal in paced rabbit atria, whereas inhibition by felodipine was similar to that seen with nitrendipine. These results suggest that the pharmacologically-relevant mechanism of Ca2+ antagonism in smooth muscle by felodipine is similar to nitrendipine (blockade of the Ca2+ entry channel) and does not involve direct inhibition of Ca2+-calmodulin stimulated myosin light chain phosphorylation and subsequent actin-myosin interactions.

Actins↗
PubMed1984

Effects of calcium antagonists and vasodilators on arterial myosin phosphorylation and actin-myosin interactions.

The mechanism of action of many direct-acting vascular smooth muscle relaxant agents is undefined. Moreover, an additional intracellular locus of action for some Ca++ entry blockers has been proposed. We have examined the potential for direct action by some of these agents at the level of smooth muscle contractile proteins by quantitating changes in Ca++-dependent superprecipitation of native arterial actomyosin. Moreover, inasmuch as previous research has linked phosphorylation of the 20,000 dalton myosin light chain to Ca++-dependent regulation of contraction, effects on myosin phosphorylation also were quantitated. Whereas the standard calmodulin antagonist W-7 inhibited both parameters by approximately 50% at 10(-4) M, diazoxide, hydralazine, 3-isobutyl-1-methylxanthine, papaverine, propranolol, nifedipine, nitrendipine, sodium nitroprusside and verapamil did not significantly inhibit either parameter at equimolar concentrations. Cyclandelate significantly delayed the onset of superprecipitation, but did not affect the extent of superprecipitation or myosin phosphorylation. The Ca++ antagonists felodipine and diltiazem inhibited superprecipitation by approximately 25%. However, unlike W-7, or felodipine, diltiazem did not concomitantly inhibit myosin phosphorylation. Inhibition of superprecipitation by diltiazem was apparent at a concentration of 10(-6) M, was manifest by a rightward shift in the pCa relationship and could be attenuated by exogenous calmodulin. These results show that most vasodilators do not have direct effects on smooth muscle contractile protein function. However, diltiazem may inhibit Ca++-dependent arterial actin-myosin interactions by a mechanism which is independent of regulation of myosin light chain phosphorylation.

Actins↗