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Kidney-pancreas (KP) transplantation has been shown to improve left ventricular (LV) geometry and function 6-24 months after the procedure, yet whether these improvements are sustained in long-term survivors has not been demonstrated. This study examined whether early improvements in LV geometry and function were sustained 3-5 years after KP transplantation. Left ventricular function and geometry were prospectively evaluated prior to, and at 1, 2, and 3-5 years posttransplant using two-dimensional, M-mode, echocardiography with Doppler interrogation in the parasternal and apical views. The sample included 21 KP and a comparison group of 12 diabetic kidney-alone (KA) recipients. Long-term (3-5 years) data were obtained for KP recipients only. Although KA recipients had a longer duration of dialysis and worse diastolic function pretransplant, the groups were similar on other baseline measures. KA recipients experienced minimal improvements while KP recipients had significant improvements in cardiac function and geometry, both in terms of mean values and the percentage of KP recipients who experienced normalization posttransplant (p < 0.05). KP recipient improvements were also sustained at 3-5 years posttransplant on three of five measures, with 75% of long-term KP recipients achieving normal LV mass posttransplant compared with 31% pretransplant. Data indicate that significant impairments in cardiac geometry and function occur in diabetic KA and KP recipients. Though both groups experienced early improvements posttransplant, KP recipients achieved more dramatic and clinically significant improvements at 1, 2, and 3-5 years posttransplant. Additional studies are needed to examine the relevance of these findings with regard to the cardiac morbidity and mortality of these patients.

The heart has a three-dimensional extracellular fibrillar collagen scaffolding that normally serves a variety of functions important to tissue integrity and efficiency of muscular systolic pump and diastolic suction pump function (see article by Kovács). An adverse accumulation of extracellular matrix structural protein compromises tissue stiffness and adversely affects myocardial viscoelasticity, this leads to ventricular diastolic and systolic dysfunction. Hormonal factors, such as chronic, inappropriate (relative to dietary salt intake and intravascular volume) elevations in circulating angiotensin II and aldosterone, are accompanied by fibrosis of right and left sides of the heart. Hemodynamic factors regulate cardiac myocyte work and their adaptive hypertrophic growth. The relative contributions of hormonal and hemodynamic factors in regulating growth of muscular and nonmuscular compartments must form the basis for the selection of pharmacologic intervention that will optimize the management of symptomatic heart failure that accompanies hypertensive heart disease and ischemic cardiomyopathy. Cardioprotective strategies that prevent alteration of normal cardiac tissue structure by fibrosis and appearance of abnormal ventricular stiffness (viscoelasticity) are based on negating the generation of these hormones or interfering with their receptor-ligand binding. A regression of established cardiac fibrosis and improvement in abnormal ventricular stiffness is feasible. Experimental and clinical findings with lisinopril in hypertensive heart disease, where cardiac fibrosis and abnormal ventricular stiffness are present, indicate that such cardioreparation should be a targeted objective of pharmacologic intervention. Systematic analysis of this approach using a controlled clinical trial format is warranted. In recognizing the importance of viscoelastic elements in regulating the mechanical behavior of cardiac tissue, and in turn systolic and diastolic ventricular function, a broader tissue compartment based paradigm (ECM versus myocyte) for the management of heart failure emerges.

We conducted an open-label study to determine the impact of cytochrome P-4502D6 (CYP2D6) on propranolol pharmacokinetics and response in 12 healthy men with CYP2D6 extensive metabolizer (EM) phenotype and 3 healthy men with CYP2D6 poor metabolizer (PM) phenotype. Subjects received R,S-propranolol hydrochloride 80 mg every 8 hours for 16 doses. After the sixteenth dose, blood and urine samples were collected for 24 hours, and serum propranolol and urine metabolite concentrations were determined by chiral high-performance liquid chromatography. Heart rate response to treadmill exercise was measured serially over 24 hours. Apparent oral clearance of propranolol and partial metabolic clearance values of propranolol to 4-hydroxypropranolol (HOP), propranolol glucuronide, and naphloxylactic acid (NLA) were estimated. Apparent oral clearance and elimination half-life of propranolol were not different between EMs and PMs. Partial metabolic clearance of propranolol to HOP was significantly higher and to NLA was significantly lower in EMs than in PMs. No differences in percentage reductions in exercise heart rate were observed between EMs and PMs. The CYP2D6 PM phenotype has no effect on propranolol blood concentrations and does not alter response to propranolol. Our data also suggest that CYP2D6 mediates approximately 65% and 70% of S- and R-propranolol's 4-hydroxylation, respectively.

1. Racial differences in propranolol enantiomer kinetics following oral dosing were previously documented in our laboratory. The purpose of this study was to more completely describe propranolol kinetics in black and white subjects with the goal of gaining a better understanding of the mechanism(s) responsible for racial differences in oral propranolol kinetics. 2. Twelve white and 13 black healthy males were included in the study. Poor metabolizers of dextromethorphan and mephenytoin were excluded. Subjects took oral propranolol 80 mg every 8 h for 16 doses and received an intravenous dose of radiolabelled propranolol with the 16th dose. Serum and urine samples were collected for 24 h after the 16th dose. Serum concentrations of R- and S-propranolol and urine concentrations of its three primary metabolites were determined by h.p.l.c. 3. Apparent oral clearances of R- and S-propranolol were higher (P < 0.05) in blacks than whites (R-propranolol: 5036 +/- 4175 ml min-1 vs 2854 +/- 879 ml min-1; S-propranolol 3255 +/- 1723 ml min-1 vs 2125 +/- 510 ml min-1; blacks vs whites). 4. R- and S-propranolol clearances were higher in blacks than whites (R-propranolol 1069 +/- 316 ml min-1 vs 841 +/- 161 ml min-1; S-propranolol 947 +/- 271 ml min-1 vs 771 +/- 142 ml min-1; blacks vs whites, P < 0.05). 5. There were trends (P > 0.05 < 0.10) toward higher side chain oxidation, 4-hydroxylation and R-propranolol glucuronidation in blacks compared with whites. Ethnic differences in the enantiomeric ratios of partial metabolic clearance values were not observed. 6. We conclude the higher propranolol oral clearances in black subjects are explained by blacks having slightly higher hepatic metabolism via all three of its major metabolic pathways. Higher propranolol clearances among black subjects were also observed and we conclude this finding is explained largely by the higher hepatic metabolism, but also by slightly higher liver blood flow among black subjects.

Objective: The objective of this study was to determine whether metabolism via cytochrome P4502D6 (CYP2D6) was higher in Black subjects than White subjects., Methods: Ten Black and 10 White healthy male volunteers who were phenotyped CYP2D6 extensive metabolizer phenotypes participated in this randomized, cross-over study in which metoprolol was used as a model CYP2D6 substrate. In both study phases, subjects received oral rac-metoprolol tartrate (200 mg); during one phase, subjects also took quinidine sulfate (100 mg) daily beginning 3 days before the dose of metoprolol. Plasma samples were collected for 12 and 24 hr after the dose in the metoprolol and metoprolol plus quinidine phases, respectively. Metoprolol enantiomer concentrations were determined by chiral HPLC with fluorescence detection., Results: S-metoprolol areas under the concentration vs. time curves during the metoprolol phase were 879 +/- 600 ng/ml*hr in White subjects vs. 984 +/- 653 ng/ml*hr in Black subjects. During inhibition of CYP2D6-mediated metabolism with quinidine, S-metoprolol areas under the concentration vs. time curves were 2515 +/- 749 and 2719 +/- 742 in White and Black subjects, respectively. Metoprolol elimination half-lives in both groups were approximately doubled by quinidine. Mean S-metoprolol/R-metoprolol ratios were 1.39 in both racial groups during the metoprolol phase, and during the metoprolol plus quinidine phase were 0.89 and 1.03 in White subjects and Black subjects, respectively (p < 0.05, Blacks vs. Whites). The percentage of metoprolol metabolism inhibited by quinidine was similar between Blacks and Whites (e.g., 66 +/- 15% and 64 +/- 25% of S-metoprolol apparent oral clearance in Blacks and Whites, respectively)., Conclusions: We conclude that there are no differences between Black subjects and White subjects in metabolism via CYP2D6. There were also no racial differences in the contribution of CYP2D6 to overall metoprolol metabolism. The results of this study suggest that drugs are primarily metabolized by CYP2D6 will not exhibit racial differences in their disposition.

Objective: Dose-response studies in patients with hypertension have shown that black subjects are less responsive to beta-blocker therapy than white subjects, whereas studies in healthy volunteers suggest marginal or no racial differences in response. No concentration-response studies have been conducted in black subjects and white subjects. The purpose of this study was to characterize beta-blocker pharmacodynamics in healthy black and white men., Methods: Thirteen black and 13 white healthy men took 80 mg oral propranolol three times daily, for a total of 16 doses. Heart rate response to treadmill exercise was measured at various times over 24 hours. Serum propranolol samples were collected during the same 24-hour time period and were measured by chiral HPLC. The sigmoid maximal effect (Emax), Emax, and linear models were fitted to percentage reductions in exercise heart rate and S-propranolol concentrations., Results: Black subjects had significantly lower values for serum concentration producing one-half the maximal effect (EC50) and unbound EC50 than white subjects (EC50: 10.2 ng/ml (4.4 to 28.0 ng/ml) versus 24.4 ng/ml (14.3 to 64.1 ng/ml), blacks versus whites; unbound EC50: 1.29 ng/ml (0.686 to 4.91 ng/ml) versus 2.77 ng/ml (1.70 to 8.11 ng/ml), blacks versus whites). There was no statistical difference in Emax (33.3% [22.2% to 39.7%] versus 38.3% [30.7% to 45.1%], blacks versus whites)., Conclusions: Healthy black men were more sensitive to beta-blockade than healthy white men. The results of this study in healthy volunteers suggest that the racial differences in response observed in patients with hypertension are related to hypertensive pathophysiology rather than normal physiology.

Noninvasive M mode echocardiography with Doppler recording was prospectively performed on type I diabetic recipients of pancreas-kidney (n = 20), pancreas-after-kidney (n = 2), and kidney-alone (n = 11) allografts to determine whether the return of euglycemia by pancreas transplantation in the uremic diabetic person was associated with improved cardiac function. Each patient was studied preoperatively and at 6 and 12 months posttransplant. Echocardiographic parameters which were compared included measures of systolic function (shortening fraction), diastolic function (early/active peak velocity ratio, early/active integral ratio), and left ventricular geometric parameters (interventricular septal thickness, posterior wall thickness, left ventricular mass). The only statistically significant improvement observed for kidney-alone recipients was an increased shortening fraction from baseline (24.91%) to 6 months (32.13%, P < or = 0.0188). In contrast, the pancreas group demonstrated sustained improvement in all outcomes with measures at 12 months consistently showing a significant improvement from baseline which was also significantly better than that reported for the kidney-alone group. This study showed stabilization of cardiac function by echocardiography for diabetic kidney-alone recipients, whereas significant improvement in function occurred for pancreas-kidney recipients. The improvement in cardiac function for pancreas recipients was seen at 6 months with continued improvement evident at 12 months.

Previous studies have suggested that racial differences may exist in beta-adrenoceptor-mediated responsiveness. However, no clear conclusions can be drawn based on these studies because of the confounding effect of the parasympathetic nervous system on responses to isoproterenol bolus doses. In this study, we blocked the effects of the parasympathetic nervous system with atropine, to determine whether racial differences exist in sensitivity to beta-adrenoreceptor stimulation and blockade. Sixteen healthy black and white men participated in the study. Atropine was administered before all studies to induce parasympathetic blockade. Isoproterenol sensitivity studies and treadmill exercise were then performed in the with and without beta-adrenoceptor blockade by propranolol. Responses measured included heart rate (HR), blood pressure (BP), and tremor. The average isoproterenol dose producing a 25-beat/min increase in HR was more than twofold higher in blacks than in whites (3.4 +/- 1.2 vs. 1.6 +/- 0.4 micrograms, respectively, p < 0.05). There were no racial differences in response to beta-adrenoreceptor blockade. Our results showed that during parasympathetic blockade blacks were less sensitive to the chronotropic effects of isoproterenol than whites. We conclude that these response differences are due to greater beta-adrenoceptor sensitivity in whites than in blacks.

Racial differences in the antihypertensive response to propranolol are well documented. This study was conducted to determine whether differences between black subjects and white subjects in propranolol enantiomer pharmacokinetics and protein binding exist that may contribute to the response differences. Twenty-six healthy men (13 black and 13 white subjects) took 80 mg propranolol orally three times daily for 16 doses. Serum samples were collected for 12 hours after the last dose for analysis by chiral HPLC. Protein binding was determined by equilibrium dialysis. Area under the serum concentration-time curve (AUC) for both propranolol enantiomers was lower in black subjects than in white subjects (e.g., l-propranolol AUC: 292 +/- 100 versus 394 +/- 121 ng.hr/ml, p less than 0.05) and apparent oral clearance was higher in black subjects than in white subjects (e.g., l-propranolol apparent oral clearance: 27.6 +/- 8.2 versus 20.6 +/- 7.0 ml/min/kg, p less than 0.05). Fraction unbound and unbound AUC were not statistically different between black subjects and white subjects for either enantiomer, although the lack of statistical significance may have been attributable to the small sample size. In summary, racial differences in unbound l-propranolol concentration probably do not explain the clinically observed differences in response to propranolol. However, the racial differences in apparent oral clearance suggest there may be racial differences in hepatic metabolism of propranolol.

Relapsing polychondritis is purported to be an autoimmune disease characterized by inflammation of cartilaginous structures including the nose, ears, glottis, trachea, and mainstem bronchi. Arthropathy, aortopathy, scleritis, conjunctivitis, iritis, vertigo, otitis media, glomerulonephritis, and skin lesions are common manifestations. We have recently cared for an elderly nonsmoker with a history of abdominal aortic aneurysm repair and recurrent bouts of painful ear swelling who presented with a pulmonary infiltrate and pulmonary function studies suggestive of small airways disease. Subsequent transbronchial biopsy revealed no pathogens but was associated with excessive bleeding, perhaps suggestive of a vasculitic process in the lung. The pulmonary infiltrate cleared over a 2-month interval with the use of corticosteroids. Unusual in this otherwise classical case of relapsing polychondritis was that the pulmonary infiltrate and small airways disease were the prominent pulmonary manifestations and no tracheobronchial abnormalities were visualized.

The elderly are reported to be less sensitive to the beta-blocking effects of propranolol. However, age-related changes in the stereoselective pharmacokinetics or protein binding of propranolol enantiomers could have confounded the results of previous studies because only 1-propranolol contributes significantly to the beta-blocking effects of the racemate. To avoid these confounding variables, we studied 10 young (mean 28 years) and 10 elderly (mean 64 years) subjects, and determined the cardiac beta-receptor sensitivity in terms of unbound, active 1-propranolol. The doses of isoproterenol required to increase heart rate (HR) by 25 beats/min were determined before and during a continuous infusion of propranolol. The serum concentration of 1-propranolol was determined by enantioselective high-performance liquid chromatography (HPLC), and the unbound fraction was determined by equilibrium dialysis. The apparent in vivo receptor dissociation constant for unbound 1-propranolol increased from 0.066 +/- 0.047 ng/ml in the young to 0.218 +/- 0.264 ng/ml in the older group (p less than 0.05). The unbound fraction was decreased in the older subjects (0.141 +/- 0.023 vs. 0.121 +/- 0.025, p less than 0.05) because of an increase in alpha 1-acid glycoprotein concentration (55 +/- 11 mg/dl vs. 72 +/- 19 mg/dl, p less than 0.05). Advancing age was associated with a decreased sensitivity to isoproterenol (rs = 0.76, p less than 0.05) and to unbound 1-propranolol (rs = 0.45, p less than 0.05). We conclude that the older subjects have (a) decreased sensitivity to the beta-blocking effects of 1-propranolol and to the agonist effects of isoproterenol, and (b) a lower unbound fraction of 1-propranolol.

Previous studies of the effects of age on the disposition of propranolol have produced variable results. We evaluated the stereoselective disposition and protein binding of propranolol enantiomers in 10 young (mean age, 28 years) and 10 older (mean age, 64 years) healthy subjects. After receiving racemic propranolol orally for 6 days, the oral clearances of d-propranolol and l-propranolol were lower by 13% and 17% in the older group compared to the young group, but these differences were not statistically significant. The older subjects had higher alpha 1-acid glycoprotein concentrations (p less than 0.05) and lower unbound fractions of l-propranolol (p less than 0.05). After protein binding was accounted for, the unbound oral clearance of each enantiomer was similar in both groups. l-Propranolol was more highly protein bound than d-propranolol (p less than 0.05) in both young and older subjects. The unbound oral clearance d/l ratio was not different from unity in either group, indicating that the stereoselective differences in oral clearance were largely attributable to the stereoselective differences in protein binding.

CI-930, a new type III phosphodiesterase inhibitor, was evaluated for treatment of refractory congestive heart failure. The hemodynamic, pharmacokinetic and clinical response to the drug was determined in 10 patients. At the peak plasma concentration after intravenous CI-930, cardiac index increased from 2.0 to 2.7 liters/min/m2 (p less than 0.002), pulmonary artery wedge pressure decreased from 26 to 17 mm Hg (p less than 0.001) and systemic vascular resistance decreased from 1,999 to 1,471 dynes cm-5 (p less than 0.05). Heart rate and blood pressure did not change significantly. Similar changes were observed with oral CI-930. Peak CI-930 plasma concentration occurred 1.2 +/- 0.8 hours after oral administration. Beneficial hemodynamic effects were sustained 12 to 18 hours after the oral dose. The sustained hemodynamic effects observed after oral administration appear to be related to an active metabolite of CI-930 that has prolonged duration of action and slow washout. The drug was well tolerated and has potential for treatment of congestive heart failure.

The employment of rapid freezing of fresh tissue for electron microscopic studies of nervous tissue is receiving increasing attention. We report here on the design of a specimen carrier for use with freezing machines. This apparatus permits electrical stimulation and recording of responses closely comparable to those obtained in ordinary in vitro conditions. The essential features of this apparatus are that it employs miniature suction electrodes for stimulation and recording, a detachable well for mounting the specimen in Ringer's solution and a detachable cap for maintaining the specimen in a physiologic state suitable for freezing. This specimen carrier was designed for sympathetic ganglia but could be used with other types of neural tissue for correlative electrophysiological and morphological or biochemical studies.

Hemodynamic response after intravenous and oral administration of a new phosphodiesterase inhibitor, CI-914, was studied in 13 patients with severe congestive heart failure. Comparable significant increases in cardiac index of 26% (p less than 0.01) and 19% (p less than 0.02) after intravenous and oral administration were observed. Systemic vascular resistance, right atrial and pulmonary artery wedge pressure decreased significantly after intravenous drug administration. Although similar changes occurred after oral administration, they were not statistically significant. Peak CI-914 plasma concentration occurred 2.3 +/- 2.2 hours after oral drug administration and exhibited measurable hemodynamic effects for up to 10 to 12 hours. Seven of the 13 patients received long-term oral CI-914 for as long as 12 weeks and exhibited an improvement in New York Heart Association functional class and exercise capacity. Five patients died with progressive heart failure, 1 patient died suddenly and 1 died of sepsis. The drug was well tolerated and appears to have potential as a cardiotonic agent.

Acute and chronic hemodynamic effects at rest and during exercise of a new dihydropyridine calcium antagonist, nicardipine hydrochloride, were studied in 10 patients with chronic heart failure. Acute intravenous administration of nicardipine resulted in a significant decrease in arterial blood pressure, systemic vascular resistance, and pulmonary capillary wedge pressure. There was a significant increase in cardiac index, stroke volume index, and the left ventricular stroke work index. Cardiac index measured at peak exercise increased significantly when compared with the cardiac index obtained at peak exercise before the infusion. After 9 days of continuous therapy with nicardipine, 30 mg three times a day, a significant decrease in arterial blood pressure and systemic vascular resistance and a significant increase in the cardiac index, stroke volume index, and left ventricular stroke work index at rest were observed in response to a single oral dose of 30 mg nicardipine. Data at peak exercise were also obtained before and 2 hours after the oral administration of nicardipine. With this comparison there was a significant increase in cardiac index, stroke work index, and exercise duration. It is concluded that in this group of patients with severe chronic heart failure, nicardipine enhanced myocardial performance during rest and exercise and this enhancement is sustained after 9 days of oral therapy.