Tissue-specific determinants of anisotropic conduction velocity in canine atrial and ventricular myocardium.

Electrical conduction is very rapid and highly anisotropic in atrial fiber bundles, such as the crista terminalis. In contrast to left ventricular myocardium in which the ratio of longitudinal to transverse conduction velocities is approximately 3, propagation velocity in the crista terminalis is approximately 10 times greater in the longitudinal than in the transverse direction. To elucidate potential determinants of these distinct conduction properties, we characterized structural and molecular features of intercellular coupling in the crista terminalis and left ventricular myocardium of the canine heart. Analysis of the number and spatial orientation of myocyte interconnections at gap junctions revealed that a typical left ventricular myocyte was connected to 11.3 +/- 2.2 other myocytes. Approximately equal numbers of connections occurred between ventricular myocytes juxtaposed in side-to-side and end-to-end orientation. In contrast, a typical myocyte of the crista terminalis was connected to only 6.4 +/- 1.7 other cells (P < .05), but nearly 80% of these connections occurred between cells oriented in an end-to-end configuration. In comparison with the ventricular pattern, this spatial distribution of connections would limit intercellular current transfer between laterally apposed cells and thereby enhance anisotropy of conduction velocity in the longitudinal and transverse directions. Ultrastructural analysis showed that crista terminalis myocytes were connected by numerous small gap junctions that occurred in relatively simple, straight intercalated disks. Northern blot analysis showed approximately equivalent amounts of mRNAs encoding the gap junction channel proteins connexin43 and connexin45 but approximately four times more connexin40 mRNA in crista terminalis than in the left ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneous transmural distribution of beta-adrenergic receptor subtypes in failing human hearts.

BACKGROUND: Downregulation of myocardial beta-adrenergic receptor density does not occur in a spatially uniform distribution in patients with congestive heart failure. Rather, it results primarily from loss of receptors in the subendocardium. In patients with dilated cardiomyopathy, beta 1-receptors have been found to be downregulated selectively. These observations suggest that considerable transmural heterogeneity in the distribution of beta-adrenergic receptor subtypes exists in the failing human heart. The present study was designed to test this hypothesis. METHODS AND RESULTS: We used quantitative autoradiography of radioligand binding sites to measure the distribution of beta-adrenergic receptor subtypes in transmural sections of left ventricular myocardium obtained from cardiac transplant patients with ischemic (n = 13) and idiopathic dilated (n = 12) cardiomyopathy and from 4 subjects with no history of cognitive heart failure. Analysis of radioligand binding isotherms revealed a significant reduction in total beta-adrenergic receptor density in hearts of patients with ischemic and idiopathic cardiomyopathy (20.3 +/- 1.9 and 18.2 +/- 2.0 fmol/mg protein, respectively, versus 40.0 +/- 11.4 in control subjects; P < .01 for both). Loss of the beta 1-subtype accounted for 86% of the total reduction in beta-receptor density in failing hearts. Despite the significant decreases in overall tissue receptor content, the densities of total beta-receptors and beta-receptor subtypes in subepicardial myocytes were equivalent in failing and control hearts. However, in contrast to control hearts, in which the transmural distribution of total and beta 1-receptors was uniform (endocardial: epicardial receptor density ratios, 0.97 +/- 0.14 and 1.0 +/- 0.2, respectively), hearts of patients with ischemic and idiopathic dilated cardiomyopathy had significantly lower total beta-receptor and beta 1-receptor densities in the subendocardium (ratios, 0.66 +/- 0.06 and 0.46 +/- 0.09 for total and beta 1-receptors, respectively, in ischemic cardiomyopathy and 0.60 +/- 0.08 and 0.52 +/- 0.11 in dilated cardiomyopathy; P < .001 for all values compared with a ratio of 1). Thus, beta 1: beta 2 receptor density ratios were markedly decreased in the subendocardium of ischemic and idiopathic dilated left ventricles compared with control hearts. CONCLUSIONS: A significant transmural gradient in the density of myocardial beta 1-adrenergic receptors exists in the hearts of patients with ischemic and dilated cardiomyopathy, resulting in a markedly altered beta 1: beta 2 receptor density ratio in the subendocardium.

Skeletal muscle beta-adrenoceptor distribution and responses to isoproterenol in hyperthyroidism.

To determine whether hyperthyroidism selectively increases beta-adrenergic receptor density in vessels or fibers of human skeletal muscle, we characterized beta-receptor distribution autoradiographically in muscle biopsies of 18 subjects aged 26 +/- 1 yr before and after daily administration of 100 micrograms 3,5,3'-triiodothyronine (T3) for 2 wk. To establish whether vascular and metabolic responses to beta-adrenergic stimulation are concomitantly altered, we quantified calf blood flow and plasma concentrations of glucose, lactate, glycerol, free fatty acids (FFA), insulin, and C-peptide during graded-dose isoproterenol infusion in eight of these individuals. Differences in beta-adrenergic receptor density among muscle fiber types and vascular components were highly significant (type I greater than type IIa greater than type IIb muscle fibers, P less than 0.001; and type I muscle fibers greater than resistance arterioles, P less than 0.05). Hyperthyroidism increased beta-adrenergic receptor density in all types of muscle fibers (+31-50%; P less than 0.01) but not in resistance arterioles. There was no change in calf blood flow or plasma glucose, glycerol, FFA, insulin, or C-peptide responses to isoproterenol. A rise in lactate during stages 3 and 4 of isoproterenol infusion (P less than 0.01) was observed before but not after T3 administration. Thus hyperthyroidism increases beta-adrenergic receptor density in fibers but not vessels of human skeletal muscle without increasing either metabolic or vascular responses to selective beta-adrenergic stimulation.

Autoradiographic delineation of skeletal muscle alpha 1-adrenergic receptor distribution.

We used light microscopic autoradiography to quantify the distribution of alpha 1-adrenergic receptors in vessels and muscle fibers of slow-twitch (type I), fast-twitch (types IIa and IIb), and mixed fiber muscles of the rat hindquarter. Frozen cross sections of soleus, vastus lateralis, and gastrocnemius muscles were incubated under equilibrium binding conditions with 10-200 pM [3H]prazosin with or without 10(-5) M phentolamine. Because of the low concentration of bound radioligand, specific binding could not be detected with scintillation spectrometry in whole tissue sections scraped from slides. However, quantitative autoradiographic analysis after extended intervals of emulsion exposure revealed a low but significant level of specific binding in muscle fibers. No difference in alpha 1-receptor density was observed among types I, IIa, and IIb fibers. Small blood vessels had a much greater alpha 1-receptor density than muscle fibers. Resistance arterioles (20-100 microns diam) and small arteries (100-500 microns diam) contained 5.8 +/- 0.9 and 31.6 +/- 7.6 (+/- SE) times more binding sites per unit section area, respectively, than did surrounding muscle fibers (both P less than 0.001). Ratios of specific grain densities in fibers and blood vessels did not vary with radioligand concentration, indicating that observed grain densities reflected differences in receptor concentration rather than radioligand affinity by fiber and vessel receptors. The densities of vascular alpha 1-receptors did not vary in slow- and fast-twitch muscles, but resistance arterioles were six and eight times more numerous in soleus than in gastrocnemius and vastus muscles, respectively (both P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)