Combination therapy increased glucose production (compared with captopril alone), indicating hepatic insulin resistance. It cannot be assumed that combined preparations with angiotensin converting enzyme inhibitors will ameliorate adverse effects of high doses of thiazide diuretics on insulin action.

Captopril therapy in uncomplicated essential hypertension has no effect on peripheral or hepatic insulin sensitivity.

Background. Two major hypotheses have been proposed to explain catecholamine supersensitivity after myocardial denervation, but neither sufficiently explains certain features of the phenomenon.In addition, a nonsurgical method for long-term myocardial adrenergic denervation is desirable but has not been accomplished or described with respect to catecholamine supersensitivity.Methods and Results. We have accomplished chronic myocardial adrenergic denervation by using 6-hydroxydopamine (6-OHDA). Sixteen weeks after 6-OHDA administration to newborn pigs, we found substantial myocardial adrenergic denervation associated with j-adrenergic receptor (PAR) downregulation. Despite decreased ,8AR number, the dose of isoproterenol yielding 50%o maximal heart rate change (ED50) was decreased, and heart rates during exercise showed increased responsiveness despite decreased circulating catecholamines. Thus, stimulation of fewer receptors yielded an increased response, implying improved signal transduction efficiency. Competitive binding studies with isoproterenol showed an increased proportion of PAR with high-affinity binding in myocardial membranes from 6-OHDA pigs, suggesting that interaction between P3AR and cardiac G, may contribute to improved signal transduction efficiency. However, measures of adenylyl cyclase activity indicated marked reduction in PIAR-dependent and G,-dependent cAMP production in myocardial membranes from denervated animals despite a normal amount of cardiac G, and decreased G;.Conclusions. We have demonstrated that substantial, long-term myocardial adrenergic denervation is possible using 6-OHDA. Denervation supersensitivity in this model does not depend on enhanced cAMP stimulation but rather depends on postreceptor elements in the ,lAR-responsive pathway that may be independent of G,-activated adenylyl cyclase activity. In this model of adrenergic denervation supersensitivity, P-receptors, through GQ, may be linked to an alternative effector that drives heart rate responsiveness. (Circulation 1992;85:666-679 (vomiting, poor appetite) after the initial injection and died within the first 10 days of life; three others died several weeks later, unrelated to toxic effects of 6-OHDA. (Acute toxicity results from norepinephrine released from adrenergic nerves.) 6-OHDA is metabolized rapidly; it has been shown that 24 hours after intravenous injection of [3H]-6-OHDA to rats, no [3H]-amines were found in heart or spleen5; therefore, toxicity related to persistent drug is not likely. All pigs remained with their mother and were weaned at the usual time (8-10 weeks). Five pigs survived and underwent pharmacological and physiological testing at 14-15 weeks and were killed at 16 weeks. These pigs fed vigorously and were developmentally normal.Controls were 10 weight-matched pigs (control, 14±3 kg; 6-OHDA, 13±3 kg; p=NS). Five were killed, and myocardial samples were used for biochemical studies; five underwent identical pharmacological and exercise tests as the experimental group. Experimental and control...

This study was designed to assess G protein function in mononuclear leukocytes (MNL) of patients with congestive heart failure (CHF). MNL membranes were ADP-ribosylated in vitro in the presence of pertussis or cholera toxin. The amount of pertussis toxin substrates did not differ significantly between CHF patients (6,100 ±224 fmol/mg, n =23) and age-matched healthy control subjects (5,812 ±972 fmol/mg protein, n = 19). Among the CHF patients, no differences were observed between those with idiopathic and ischemic CHF. The amount of cholera toxin substrates also did not differ significantly between CHF patients (7,522±1,405 fmol/mg protein, n=11) and control subjects (5,654±707 fmol/mg protein, n=14). Moreover, basal and isoproterenol-and prostaglandin El-stimulated cyclic AMP (cAMP) accumulation in MNL was similar in control subjects and patients. To detect more subtle alterations of the cAMPgenerating system, we incubated anticoagulated blood with 250-400 ng/ml pertussis toxin for 4 hours at 370 C. This treatment completely ADP-ribosylated the MNL pertussis toxin substrates. Incubation with pertussis toxin did not change basal or prostaglandin E1-stimulated cAMP generation in MNL of control subjects, but it significantly enhanced stimulated generation (443 ±44 vs. 643 ±93 pmol/107 cells, p<0.025) in MNL of CHF patients. This enhancement was most pronounced in the most severely ill patients (New York Heart Association class lY) and correlated with plasma norepinephrine levels, another marker of CHF severity (r=0.798, n = 11, p <0.01). Isoproterenol-stimulated cAMP generation, which was much weaker than that produced by prostaglandin E1, was enhanced only in patients in class IV. We conclude that despite apparently unaltered amounts of subunits identifiable by ADP ribosylation with pertussis toxin, MNL of CHF patients appear to have enhanced functional activity (i.e., inhibition of cAMP formation) by these substrates. Thus, incubation of MNL with pertussis toxin reveals a tonic inhibition of cAMP generation in cells of CHF patients. The results suggest that incubation of whole blood with pertussis toxin and subsequent assessment of cAMP accumulation in MNL provide a useful way to examine G protein function in patients with cardiovascular disease. (Circulation 1990;81:1198-1204 I notropic responsiveness is markedly reduced in the hearts of experimental animals and patients suffering from congestive heart failure (CHF). A reduced density of receptors for catecholamines (,3-adrenergic)

Insulin action was not related to insulin pulse frequency in essential hypertension, in contrast to the situation in normal man.