Regulation of K+ and Ca2+ channels in experimental cardiac failure

Abstract

To examine the status of ATP-sensitive K+ (K+ATP) channels and 1,4-dihydropyridine-sensitive Ca2+ (Ca2+DHP) channels during experimental cardiac failure, we have measured the radioligand binding properties of [3H]glyburide and [3H]PN 200 110, respectively, in tissue homogenates from the rat cardiac left ventricle, right ventricle, and brain 4 wk after myocardial infarction induced by left coronary artery ligation. The maximal values (Bmax) for [3H]glyburide and [3H]PN 200 110 binding were reduced by 39 and 40%, respectively, in the left ventricle, and these reductions showed a good correlation with the right ventricle-to-body weight ratio in heart-failure rats. The ligand binding affinities were not altered. In the hypertrophied right ventricle, Bmax values for both the ligands were not significantly different when data were normalized to DNA content or right ventricle weights but showed an apparent reduction when normalized to unit protein or tissue weight. Moderate reductions in channel densities were observed also in whole brain homogenates from heart failure rats. Assessment of muscarinic receptors, beta-adrenoceptors and alpha 1-adrenoceptors by [3H]quinuclidinyl benzilate, [3H]dihydroalprenolol, and [3H]prazosin showed reductions in left ventricular muscarinic and beta-adrenoceptor densities but not in alpha 1-adrenoceptor densities, consistent with earlier observations. It is suggested that these changes may in part contribute to the pathology of cardiac failure.

Impaired beta-adrenergic response and decreased L-type calcium current of hypertrophied left ventricular myocytes in postinfarction heart failure

“…In contrast to most studies, in which I Ca(L) density is evaluated in a small number of cells, in the present investigation, by analyzing a larger number of cells, we confirmed that I Ca(L) density is indeed reduced ( Figure 1A) in postinfarction myocytes, in agreement with the reduction in DHP binding sites described in homogenates from infarcted rats (14,17,18).…”

“…On the other hand, dihydropyridine (DHP)-binding sites have always been shown to be reduced (14,17,18), even in a study in which I Ca(L) density was found to be maintained (14). The peak amplitude of [Ca 2+ ] i transients has been shown to be reduced (3,11,19) or maintained (5,20).…”

“…Also, the increase in the peak amplitude of [Ca 2+ ] i transients induced by ß-adrenergic stimulation has been shown to be attenuated (5) or augmented (22) in postinfarction myocytes. Binding experiments showed even more diverse results, i.e., maintained (22)(23)(24)(25), reduced (6,8,18) or increased (26) ß-adrenergic receptor density.…”

On Becoming a Pharmacologist: Channeling David Triggle

“…4) and how chronic and intermittent therapy with nitroglycerin affected responsiveness, as measured by receptor density and vascular reactivity responses [28,29]. The ability to conduct such collaborative work aimed at addressing clinically relevant questions was an excellent learning experience, which proved immensely valuable as I subsequently entered the pharmaceutical industry.…”

Physiologic and emerging pathophysiologic role of cardiac calcium channels

“…For example, a significant decrease in cardiac [~H]I,4-dihydropyridine binding sites has been reported in this rat model. Gopalakrishnan and coworkers [36] reported a 40% decrease in the density of [3H]PN200-110 binding sites in the myocardium of rats 4 weeks following ligation of the coronary artery. The decrease in L-type voltage-sensitive calcium channel density reported by these investigators was not specific to the left ventricle, since this study also reported decreases in [3H]PN200-110 binding sites in the brains from these animals.…”