Tissue response selectivity of calcium antagonists is not due to heterogeneity of [3H]-nitrendipine binding sites.

[3H]-nitrendipine binding data and isolated tissue response for five calcium antagonists were evaluated in rabbit myocardium and aorta. The [3H]-nitrendipine binding site was qualitatively identical in myocardium and aorta, as the [3H]-nitrendipine KD, KIS for nicardipine and nifedipine and interactions with verapamil, D600 and diltiazem were not different in aortic and cardiac membranes prepared by similar means. In contrast, the inhibition of the Ca2+-induced contractile response in right ventricular myocardium and aortic ring segments indicated a greater than 10,000 fold selectivity of nicardipine for antagonism of vascular responses. This resulted in a different order of potency for calcium antagonist interaction with the [3H]-nitrendipine binding site in cardiac membranes (nicardipine greater than nifedipine greater than D600 greater than verapamil greater than diltiazem) as compared to antagonism of myocardial tissue response (D600 greater than verapamil greater than or equal to nifedipine greater than nicardipine greater than or equal to diltiazem). In heart the difference between the potency of nicardipine in binding experiments and tissue response approached 4 orders of magnitude. We conclude that tissue response selectivity of calcium antagonists is not explained by heterogeneity of [3H]-nitrendipine binding sites.

Endomyocardial biopsy.

Endomyocardial biopsy is an accepted, useful invasive tool for the analysis of human endomyocardium at the cellular and subcellular levels. It is applicable in the evaluation of specific diseases including cardiac allograft rejection, myocarditis, anthracycline cardiotoxicity, and infiltrative cardiomyopathies. The procedure can be performed in a cardiac catheterization room on an outpatient basis. The technique is quite safe when performed by trained cardiologists. Left ventricular biopsies are also safe but require systemic heparinization to prevent thromboembolization. The clinical indications for performing an endomyocardial biopsy include routine followup and suspected rejection of cardiac allograft, suspected myocarditis, monitoring or diagnosis of suspected anthracycline cardiotoxicity, and suspected secondary cardiomyopathies. Left ventricular endomyocardial biopsy is indicated for diseases that predominantly involve the left side of the heart, including left heart irradiation, cardiac fibroelastosis in infants, endomyocardial fibrosis, and scleroderma heart disease, and when right ventricular biopsy is unsuccessful. Endomyocardial biopsy is increasingly being used for research in the areas of tissue biochemistry, primary and valvular cardiomyopathies, immunology, beta receptor enzymology, drug interactions, and myocardial fibrosis. Endomyocardial biopsy has not been shown to be clinically useful in the evaluation of primary, dilated, hypertrophic, or alcoholic cardiomyopathies. These disease processes all lack pathognomomic microscopic abnormalities, and subclassification has neither been successful nor therapeutically useful. In addition, this technique is limited in diagnosing any cardiac abnormality that is not diffuse, inasmuch as only a few samples of the endomyocardial layer are obtained for evaluation. Therefore, a negative biopsy result is not 100 percent specific in excluding certain diseases. A further limitation of this technique is the need for an experienced cardiac pathologist who is well versed in interpretation of biopsy specimens. Finally, there should be a sufficiently large case load to train and to maintain skilled practitioners so that the procedure can be performed with little risk. The role of endomyocardial biopsy will continue to expand as research continues to find more uses for the technique and as more clinicians become skilled in its use.

Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response.

We developed methods for identifying beta-adrenergic receptors in human right ventricular endomyocardial biopsy tissue with the radioligand (-)[125I]iodocyanopindolol (ICYP). Specific ICYP binding in a crude, high-yield membrane preparation derived from endomyocardial biopsy tissue was high (specificity greater than 90%), of high affinity (KD around 20 pM), saturable and stereospecific for the (-) vs the (+) isomer of isoproterenol. Subjects with mild-moderate and severe biventricular dysfunction had respective decreases in beta-adrenergic receptor density of 38.2% and 57.7% when normalization methods were averaged, with no significant differences in ICYP dissociation constant. A subgroup of subjects was subdivided by left ventricular ejection fraction (LVEF) into those with mild cardiac dysfunction (LVEF less than 0.50 greater than 0.40) and severe heart failure (LVEF less than 0.20) and given graded sequential infusions of dobutamine and calcium gluconate. Those with severe cardiac dysfunction had marked impairment of the dobutamine dP/dt and stroke work index response, whereas these responses to calcium did not differ in the two groups. These data indicate that in the intact human heart endomyocardial biopsy may be used for direct analysis of beta-adrenergic receptors, heart failure-associated myocardial beta-adrenergic down-regulation begins with mild-moderate ventricular dysfunction, reduction in myocardial beta-receptor density is related to degree of heart failure, and beta-receptor down-regulation is associated with pharmacologically specific impairment of the beta-agonist-mediated contractile response.