Decline in beta adrenergic receptor-mediated vascular relaxation with aging in man

Beta adrenergic relaxation of vascular smooth muscle, mediated by cyclic AMP, is blunted with age in a variety of experimental animals. The applicability of these observations to man is uncertain. The dorsal hand vein technique provides an excellent method to examine the direct effects of aging on vascular responsiveness. Thirty-nine healthy male volunteers over the age range of 19 to 79 were studied. No differences in vascular responsiveness to phenylephrine, an alpha adrenergic agonist, were found for either the ED50 (dose producing 50% vasoconstriction) or Emax (maximum vasoconstriction attained). In marked contrast, vascular relaxation induced by isoproterenol, a beta adrenergic agonist, was significantly different in both the ED50 (dose producing 50% of maximum relaxation from a preconstricted state) and Emax (maximum relaxation attained). ED50 +/- S.E.M. for the youngest and oldest deciles were 8.9 +/- 2.3 and 60 +/- 17.0 ng/min, respectively (P less than .05); Emax +/- S.E.M. were 96.7 +/- 3.3 and 37.7 +/- 8.7%, respectively (P less than .001). Nitroglycerin, a smooth muscle relaxant whose effects are not mediated through the cyclic AMP system, was also used to examine the specificity of this blunted response to isoproterenol. Almost complete relaxation was achieved with the infusion of nitroglycerin in the older group. These results suggest that aging is associated with a specific decrease in beta adrenoreceptor-mediated vascular relaxation.     

Impaired endothelial-dependent forearm vascular relaxation in black Americans

BACKGROUND: Hypertension is a major cause of morbidity and mortality in the general population and has an even more significant impact on the black community in particular. Explaining the interethnic differences has been difficult. Differences in endothelial function may provide some insight into the causes of the increased incidence of hypertension in the black population versus their white cohorts. METHODS: In this study 16 black subjects and 12 white subjects received brachial artery infusions of acetylcholine (12.5, 25, and 50 microg/min) and angiotensin II (3.82, 9.55, and 19.10 ng/min). Measurement of forearm vascular resistance by venous occlusion plethysmography was conducted. RESULTS: The dose of acetylcholine at 50% maximal observed response (EC50) for black subjects was 10.6+/-2.39 microg/min and 3.3+/-0.44 microg/min in the white subjects (mean +/- SEM; P < .05). Sodium nitroprusside infusions at 1 and 2 microg/min did not cause a significant difference in response between the 2 groups. After angiotensin II was infused, forearm vascular resistance Emax was 3.42+/-0.78 mm Hg/100 mL tissue volume/min for black subjects and 3.16+/-0.99 mm Hg/100 mL tissue volume/min for white subjects. CONCLUSION: This study shows impaired endothelial-dependent forearm vascular relaxation as measured by decreased acetylcholine response in black subjects. This impairment in endothelial function may contribute to the increased incidence of hypertension in black subjects compared with white subjects. Mechanisms for this finding warrant further investigation.     

Responsiveness of superficial hand veins to phenylephrine in essential hypertension. Alpha adrenergic blockade during prazosin therapy.

Patients with essential hypertension show an increase in vascular resistance. It is unclear whether this is caused by structural changes in the arterial wall or by hyperresponsiveness of vascular smooth muscle to endogenous alpha adrenergic agonists. Using the dorsal hand vein compliance technique we compared the changes in diameter of superficial veins in response to phenylephrine, an alpha 1 adrenergic receptor agonist, and to nitroglycerin, a venorelaxant, in patients with essential hypertension and in normotensive subjects. The dose of phenylephrine that produced 50% of maximal venoconstriction (ED50) in the hypertensive subjects was 257 ng/min (geometric mean; log mean +/- SD was 2.41 +/- 0.54). In the control subjects the ED50 was 269 ng/min (geometric mean; log mean was 2.43 +/- 0.43). Maximal response (Emax) for phenylephrine was 84 +/- 13% in the hypertensive subjects and 90 +/- 6% in the control subjects. Differences in the group means of the ED50 (P = 0.92) or the Emax (P = 0.27) were not significant. There were no significant differences in the ED50 (P = 0.54) or the Emax (P = 0.08) for nitroglycerin between the two groups. These results show no evidence for a generalized change in alpha adrenergic responsiveness in hypertension and support the concept that increased blood pressure responses to alpha adrenergic stimulation in hypertensives are due to structural and geometric changes in the arterial wall rather than to an increased responsiveness of postsynaptic alpha adrenergic receptors. The phenylephrine studies were repeated in seven hypertensive patients during treatment with prazosin, an alpha 1 adrenergic antagonist. The mean dose ratio of the shift in phenylephrine ED50 (ED50 during prazosin therapy/ED50 before prazosin therapy) was 6.1. This indicates that small doses of prazosin (1-2 mg) cause significant in vivo shifts in the dose-response relationship of alpha adrenergic agonists. The dorsal hand vein compliance technique is useful in detecting systemic effects of alpha adrenergic antagonists.     

Plasma levels and effects of metoprolol on blood pressure, adrenergic beta receptor blockade, and plasma renin activity in essential hypertension.

The effects of metoprolol, a selective beta adrenergic receptor antagonist, on blood pressure, beta receptor blockade (antagoinst of isoproterenol and exercise tachycardia), and plasma renin activity (PRA) have been compared with those of placebo in 16 patients with essential hypertension. The dose of metroprolol was 25 mg three times daily for 1 wk and thereafter 100 mg three times daily for 5 wk. The mean decrease in blood pressure during treatment with metoprolol was 24 +/- 3.8 (SEM)/10 +/- 2.1 mm Hg in the lying position and 23 +/- 4.4/9 +/- 3.1 mm Hg after 1 min in the standing position. At a dose of 2.9 to 5.4 mg/kg, steady-state plasma concentrations of metoprolol varied 17-fold (from 20 to 341 ng/ml) between patients and correlated with the interindividual variability in isoproterenol antagonism (r = 0.58, p less than 0.05) and decrease in exercise tachycardia (r = 0.65, p less than 0.01). By contrast, neither of these variables correlated with the dose of metoprolol in mg/kg. Metoprolol decreased PRA by 67 +/- 1.9 and 71 +/- 1.2% in the lying and standing positions, respectively. The decrease in the mean arterial blood pressure in the lying position was significantly correlated to the PRA during the placebo period (r = 0.61, p less than 0.05) but not to the plasma steady-state levels of metoprolol, the degree of beta receptor blockade, and the decrease in PRA.     

Evidence for cardiac beta 2-adrenoceptors in man

We compared the effects of single doses of 50 mg atenolol (cardioselective), 40 mg propranolol (nonselective), and placebo on both exercise- and isoproterenol-induced tachycardia in two experiments involving nine normal subjects. Maximal exercise heart rate was reduced from 187 +/- 4(SEM) after placebo to 146 +/- 7 bpm after atenolol and 138 +/- 6 bpm after propranolol, but there were no differences between the drugs. The effects on isoproterenol tachycardia were determined before and after atropine (0.04 mg/kg IV). Isoproterenol sensitivity was determined as the intravenous dose that increased heart rate by 25 bpm (CD25) and this was increased from 1.8 +/- 0.3 micrograms after placebo to 38.9 +/- 8.3 micrograms after propranolol and 8.3 +/- 1.7 micrograms after atenolol. The difference in the effects of the two was significant. After atropine the CD25 was unchanged after placebo (2.3 +/- 0.3 micrograms) and atenolol (7.7 +/- 1.3 micrograms); it was reduced after propranolol (24.8 +/- 5.0 micrograms), but remained different from atenolol. This change with propranolol sensitivity was calculated as the apparent Ka, this was unchanged by atropine (11.7 +/- 2.1 and 10.1 +/- 2.5 ml/ng). These data are consistent with the hypothesis that exercise-induced tachycardia results largely from beta 1-receptor activation that is blocked by both cardioselective and nonselective drugs, whereas isoproterenol activates both beta 1- and beta 2-receptors so that after cardioselective blockade there remains a beta 2-component that can be blocked with a nonselective drug. While there appear to be beta 2-receptors in the human heart, their physiologic or pathologic roles remain to be defined.     

Effect of hydrocortisone on phenylephrine--mean arterial pressure dose-response relationship in septic shock

BACKGROUND: Septic shock is characterized by decreased responsiveness to catecholamines. Because endogenous steroids are known to play a role in the modulation of vasomotor tone, the purpose of our study was to investigate the phenylephrine-mean arterial pressure dose-response relationship in patients with septic shock and the effect of a physiological dose of hydrocortisone on it. METHODS: Twelve patients meeting usual criteria for septic shock and 12 age-matched control subjects were investigated before and 1 hour after receiving 50 mg intravenous hydrocortisone. Sixteen incremental doses of phenylephrine (microg/kg/min) were infused, and the effects on mean arterial pressure (mm Hg) were recorded. A sigmoid model, E = E0 + [Emax x Dgamma/(ED50gamma + Dgamma)], was fitted to individual data. In this model, E is the predicted effect and D is the dose of phenylephrine infused. E0 represents the basal value of effect (ie, the value of mean arterial pressure without drug), Emax is the maximum theoretical effect, ED50 is the dose of phenylephrine for which an effect of 50% of Emax is observed, and gamma is the Hill coefficient which accounts for the sigmoidicity of the curve. RESULTS: As compared with in control subjects, in patients, E0 was decreased before (58 +/- 8 versus 73 +/- 7 mm Hg) and after (64 +/- 12 versus 82 +/- 10 mm Hg) administration of hydrocortisone (P = .0001 for group), Emax was reduced before (39 +/- 17 versus 84 +/- 18 mm Hg) and after (77 +/- 26 versus 106 +/- 21 mm Hg) administration of hydrocortisone (P = .0001 for group), ED50 was not modified, and gamma was increased before (3.5 +/- 1.8 versus 1.3 +/- 0.3) and after (1.9 +/- 1.1 versus 1.3 +/- 0.3) administration of hydrocortisone (P = .0010 for group). Hydrocortisone similarly increased E0 in both groups (P = .0003 for sequence, P = .2883 for interaction), increased more Emax in patients than in control subjects (P < .0001 for sequence; P = .0280 for interaction), did not change ED50, and decreased y in patients but not in control subjects (P = .0025 for sequence, P = .0025 for interaction). CONCLUSIONS: In patients with septic shock, the Emax of phenylephrine is decreased, whereas its ED50 is not modified, both before and after administration of hydrocortisone. A physiological dose of hydrocortisone tends to normalize the relationship.     

Racial differences in propranolol pharmacokinetics.

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.     

Forearm beta adrenergic receptor-mediated vasodilation is impaired, without alteration of forearm norepinephrine spillover, in borderline hypertension.

Impaired beta adrenoceptor-mediated vasodilation associated with enhanced sympathetic activity has been reported in established hypertension. We examined whether altered beta adrenoceptor-mediated vasodilation occurs early in the disease process, when structural vascular changes are likely to be less marked, by measurement of forearm blood flow by strain gauge plethysmography after the intraarterial administration of increasing doses of a beta receptor agonist, isoproterenol, in eight subjects with borderline hypertension (BHT) and 13 normotensive (NT) controls. To determine the role of sympathetic activation in the regulation of responsiveness, we measured local sympathetic activity in the forearm by a radioisotope dilution technique. Vasodilation in response to isoproterenol, measured either as changes in forearm blood flow or forearm vascular resistance, was impaired in the BHT group so that flow at the highest dose of isoproterenol (400 ng/min) increased less (15.2 +/- 1.5 ml/100 ml per min) than in the NT group (24.4 +/- 2.4 ml/100 ml per minute) (P < 0.001). Although, systemic norepinephrine spillover was significantly greater in BHT, the difference in blood flow response to isoproterenol was not accounted for by increased local sympathetic activity since forearm norepinephrine spillover at baseline (BHT 1.0 +/- 0.4 ng/min vs. NT 0.64 +/- 0.13 ng/min) and after the administration of isoproterenol 60 ng/min (BHT 5.2 +/- 1.4 ng/min vs. NT 6.0 +/- 1.5 ng/min) and 400 ng/min (BHT 13.5 +/- 2.9 ng/min vs. NT 16.5 +/- 2.7 ng/min) did not differ between the two groups. We therefore conclude that vasodilation in response to isoproterenol is impaired in subjects with BHT and that this impairment is not explained by locally increased basal, or stimulated, sympathetic activity.     

In vivo modeling of the pharmacodynamic interaction between benzodiazepines which differ in intrinsic efficacy.

The pharmacokinetic and pharmacodynamic interactions between the benzodiazepine agonist midazolam, on one hand, and the partial agonist bretazenil and inverse agonist Ro 19-4603, on the other, were characterized in vivo in rats using effect parameters derived from quantitative EEG analysis. Male Wistar-derived rats received an i.v. infusion of 3 mg/kg bretazenil or 3 mg/kg Ro 19-4603 in 5 min during a steady-state infusion of midazolam at a rate of 2.8 mg/kg/hr. EEG signals were continuously measured and quantified by aperiodic EEG analysis and the change in amplitudes in the 11.5 to 30 Hz (beta) frequency band was used as measure of drug effect on the central nervous system. Frequent arterial blood samples were taken to determine the pharmacokinetics of the drugs. Both bretazenil and Ro 19-4603 did not influence the steady-state plasma concentrations of midazolam, but markedly antagonized the midazolam-induced increase in EEG effect measure to the extent of their own intrinsic maximal effects. The changes in EEG effect as a function of drug concentrations were described by a competitive interaction model, allowing the estimation of the pharmacodynamic parameters (means +/- S.E.) of the partial agonist, Emax = 15 +/- 5 microV/sec and EC50 = 19 +/- 5 ng/ml, and inverse agonist, Emax = -5.8 +/- 1.6 microV/sec and EC50 = 7.8 +/- 2.5 ng/ml. Similar values of the pharmacodynamic parameters were obtained after a single i.v. administration of these drugs, which provides evidence for the validity of the proposed interaction model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Equal Efficacy and Improved Tolerability with 50 mg Controlled-Release Metoprolol Compared with 100 mg Conventional Metoprolol in Hypertensive Patients

The clinical efficacy and tolerability of 50 mg of a new controlled-release formulation of metoprolol (metoprolol CR) was compared with that of a double dose (100 mg) of conventional immediate-release metoprolol tablets in 64 hypertensives in a randomized, double-blind, crossover study. At the end of a 6-week placebo run-in period and after each of two 8-week active treatment periods, 3-min bicycle exercise tests were performed at 25, 1.3, and 5 h after dose intake. Twenty-five hours after dose the mean supine SBP/DBP on metoprolol CR 50 mg was 147/95 mm Hg and on conventional metoprolol 100 mg 148/94 mm Hg, respectively. The percentage of responders (DBP less-than-or-equal 90 mm Hg or reduction in DBP greater-than-or-equal 10 mm Hg) was 45% on both regimens. At 25 h after dose, exercise heart rate was lower on 50 mg metoprolol CR (136 versus 140 beats min(minus sign1); p < 0.001) than on 100 mg conventional metoprolol, whereas the opposite was found at 1.3 h (131 versus 107 beats min(minus sign1); p < 0.001) and at 5 h (131 versus 113 beats min(minus sign1); p < 0.001). In agreement with the more even plasma metoprolol concentration and exercise heart rate, the patients perceived less fatigue during exercise on 50 mg metoprolol CR at 1.3 h after dose, the approximate time of maximum plasma concentration for 100 mg conventional metoprolol. The total number of adverse events recorded on metoprolol CR 50 mg and conventional metoprolol 100 mg were 62 and 103, respectively (p < 0.01). Thus, this study has demonstrated that the new controlled-release formulation of metoprolol has made it possible to halve the dose of metoprolol and yet achieve the same blood pressure control as well as greater beta(1)-blockade at the end of 24-h dosing intervals. Corresponding to lower peak plasma metoprolol concentrations, perceived fatigue and overall tolerability was improved on metoprolol CR 50 mg compared to conventional metoprolol 100 mg.     

Effects of antihistamines and local anesthetics on excess tachycardia in conscious dogs

Atropine produces cardioacceleration in conscious dogs partly by reversing the pre-existing parasympathetic cardioinhibition and partly by inducing "excess tachycardia" (ET). Because ET occurs independently of adrenergic mechanisms, the present study sought to determine whether ET is generated by a positive chronotropic action of endogenous histamine on pacemaker cell H1 receptors. ET was antagonized in conscious dogs by the H1-receptor antagonists pyrilamine, diphenhydramine, chlorpheniramine and promethazine (1-5 mg/kg i.v.), but not the H2-receptor antagonist cimetidine (2-10 mg/kg i.v.). Pyrilamine (0.1 mg/kg i.v.), but not cimetidine (4 mg/kg i.v.), also eliminated a histamine tachycardia (31 +/- 4.1 beats/min) produced by injecting histamine (22 +/- 14.2 micrograms) into the sinus node artery after pharmacological autonomic blockade. The 30-fold greater dose of pyrilamine required to antagonize ET than histamine tachycardia suggests a nonantihistaminic, and possibly a local anesthetic mechanism of action on ET. Indeed, lidocaine, procaine, propranolol and pyrilamine antagonized ET in doses corresponding to the known relative local anesthetic potencies of these agents. The same doses of pyrilamine, lidocaine and procaine had significantly less effects on a comparable beta adrenergic tachycardia produced by intravenous isoproterenol infusion (0.1-0.5 micrograms/kg/min i.v.) after hexamethonium (10 mg/kg i.v.). The results indicate that H1-receptor blockers antagonize ET because of their local anesthetic effects and not their antihistaminic properties. The results also suggest that the ionic pacemaker mechanisms generating ET and beta adrenergic tachycardia are different.     

Effect of intravenous infusion of adrenaline on the cardiovascular responses to distal body subatmospheric pressure in man

1. On two separate occasions, at least 1 week apart, seven young healthy male subjects received intravenous infusions of either adrenaline [0.27 nmol (50 ng) min-1 kg-1] or saline (154 mmol/l NaCl), plus ascorbic acid (5.68 mmol/l), over 30 min. 2. On each occasion, the subjects were exposed to distal body subatmospheric pressure (DBSP), 0 to 50 mmHg (0 to 6.65 kPa) in 10 mmHg (1.33 kPa) steps, before infusion, during the final 15 min of the infusion, and at 15 min and 30 min after the cessation of the infusion. 3. Venous adrenaline concentrations of 2.85 +/- 0.22 nmol/l were achieved during the adrenaline infusion, compared with 0.49 +/- 0.07 nmol/l during the saline infusion (P less than 0.001). At 15 min and at 30 min after cessation of the adrenaline infusion, venous adrenaline concentrations had fallen to levels similar to those achieved after the cessation of the saline infusion. 4. Heart rate rose significantly from 58 +/- 4 beats/min to 67 +/- 4 beats/min during the adrenaline infusion (P less than 0.05), but there was no further significant change in response to 50 mmHg (6.65 kPa) DBSP. At 30 min after the cessation of the adrenaline infusion, heart rate rose from 60 +/- 4 beats/min to 78 +/- 7 beats/min in response to 50 mmHg DBSP. This increase was significantly greater than that observed before the adrenaline infusion [58 +/- 4 beats/min to 69 +/- 7 beats/min during 50 mmHg (6.65 kPa) DBSP; P less than 0.01].(ABSTRACT TRUNCATED AT 250 WORDS)     

Isoproterenol induced cardiovascular hypersensitiviy in nonpheochromocytoma patients with paroxysmal hyperadrenergic symptoms

The objective of this study was to determine whether graded isoproterenol infusion test identifies a specific hypersensitivity response of the LV diastolic relaxation properties in nonpheochromocytoma patients with paroxysmal symptoms of hyperadrenergic surges. We hypothesized that patients with hyperadrenergic surges, not due to pheochromocytoma, have hypersensitivity of cardiac beta-adrenergic receptor responses to exogenous catecholamines, resulting in enhancement of LV relaxation. We assessed the physiological beta 1 and beta 2 receptor responsiveness to graded isoproterenol infusion (0.01, 0.02, 0.03 and 0.04 microgram/kg per min) in 32 patients presented with hyperadrenergic surges not due to pheochromocytoma. Two major observations were made. First, systemic hemodynamic evaluation using 99m Technetium first pass method revealed hyperkinetic state only in 21 patients (20 females and 1 male; aged 31 +/- 9 years); the other 11 patients were without hyperkinetic circulatory state (10 females and 1 male; aged 41 +/- 9 years). At baseline, plasma catecholamines were not significantly different between the two groups. The baseline corrected LV peak filling and ejection rates (cPFR and cPER) were significantly higher in hyperkinetic group (cPFR: 10 +/- 2 vs 8 +/- 2 x 10(-2) Hz/ms, P = 0.03; cPER: 11 +/- 2 vs 8 +/- 1 x 10(-2) Hz/ms, P = 0.002) and their baseline HR was faster (85 +/- 16 vs 70 +/- 9 beats/min, P = 0.006). Second, the cardiac and vascular responses to isoproterenol infusion were compared between these two groups. During the graded isoproterenol infusion, the response of HR, systolic, and diastolic BP were not significantly different between the two groups at all doses of isoproterenol, but cPFR and cPER had a more marked response to the lowest dose of 0.01 mg/kg per min in the hyperkinetic group. Thus, the graded isoproterenol infusion test can differentiate between two groups of nonpheochromocytoma patients presenting with paroxysmal symptoms of hyperadrenergic surges. Only patients with baseline hyperkinetic hemodynamic profile had accentuated cardiac hyperresponsiveness to a low dose of isoproterenol. We concluded that cPFR and cPER is a more sensitive index to assess the response to isoproterenol, because of metabolic determinants affecting the rate of change in LV volume.     

Pharmacokinetic-pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjects

Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK-PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 micro g/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK-PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0--> infinity and Cmax (normalised to the dose 1 micro g/kg), t1/2alpha and t1/2beta. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL.min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53). An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 micro g/kg (P < 10-4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively.     

Lidocaine elimination: effects of metoprolol and of propranolol

The effects of administration of metoprolol and propranolol on lidocaine elimination were studied in six healthy young men who did not smoke. Each received three single intravenous doses of lidocaine (2.5 to 3.0 mg/kg injected over 10 min): one alone, one after 1 day pretreatment with propranolol (40 mg orally every 6 hr), and one after 1 day pretreatment with metoprolol (50 mg orally every 6 hr). Lidocaine clearance was 0.88 +/- 0.28 l X hr-1 X kg-1 before beta blockade, 0.61 +/- 0.20 l X hr-1 X kg-1 during metoprolol dosing, and 0.47 +/- 0.16 l X hr-1 X kg-1 during propranolol dosing. There was no correlation between the change in lidocaine elimination and the steady-state concentrations of metoprolol or propranolol, nor between the change in lidocaine clearance and the change in resting heart rate produced by either beta blocker. Metoprolol and propranolol reduce lidocaine elimination significantly.     

A pharmacokinetic-pharmacodynamic model of heart rate during cocaine administration in humans

We developed a pharmacokinetic-pharmacodynamic model of the heart rate response to cocaine consisting of the sum of the baseline heart rate, a chronotropic drug effect, and a conditioned heart rate response. The conditioned response was modeled as having a monoexponential decline. Cocaine's chronotropic effect was modeled as obeying a maximum (Emax) drug-effect relationship without tachyphylaxis. The model was tested by fitting the kinetic and heart rate data from an earlier study. The data from five subjects in that study were well fit by the model: mean Emax, 64 beats/min, and mean drug concentration producing 50% of Emax, 838 ng cocaine/ml. The data from the other three subjects in that study were fit well, employing a linear rather than an Emax drug effect relationship: mean effect coefficient, 0.035 beats/min/ng cocaine/ml. The findings emphasize the importance of conditioning in the responses to psychoactive drugs.     

The Adrenal Receptor for Angiotensin II is Altered in Essential Hypertension

To determine the mechanism underlying altered adrenal responsiveness in patients with essential hypertension, the renin-angiotensin-aldosterone axis was assessed in normotensive and hypertensive subjects using three pharmacological probes: SQ 20881, a converting enzyme inhibitor; saralasin, a competitive angiotensin antagonist with prominent agonist properties; and angiotensin itself. All subjects were studied while supine and in balance on a 10 meq Na/100 meq K intake. The decrement in plasma aldosterone with SQ 20881 in 26 hypertensive subjects (15+/-3 ng/dl) was normal (13+/-4 ng/dl), suggesting that the altered adrenal responsiveness in hypertensives is not because of a change in a postreceptor event or in the relative contribution of angiotensin to the control of aldosterone secretion.Saralasin at a dose (0.1 mug/kg per min) that reduced aldosterone levels in all normals produced a normal aldosterone decrement (14+/-3 ng/dl) in 19 patients with renovascular hypertension (12+/-4 ng/dl). The same dose, however, had no net effect on plasma aldosterone levels in 70 patients with normal or high renin essential hypertension (-1+/-1 ng/dl) despite identical metabolic balance and control renin and angiotensin levels. The altered response could be explained by an agonist effect, aldosterone rising in 45 of the essential hypertensives. There were no significant differences between normal and abnormal responders in pre- and postcortisol, -potassium, -renin and -angiotensin concentrations.Angiotensin was infused (0.1-3 ng/kg per min) in 15 patients with normal renin essential hypertension, previously studied with saralasin. A probit transformation defined the dose required to induce a 50% increase in aldosterone (ED50). In the patients in whom aldosterone rose with saralasin, the dose required to induce a 50% increase was significantly greater (P < 0.001) than in those in whom aldosterone fell normally (1.02+/-0.06 [SD] vs. 0.38+/-0.07 ng/kg per min). Vascular responses were similar in the various groups. We conclude that altered adrenal responsiveness to angiotensin in some essential hypertensive patients is secondary to a change in the interaction of angiotensin with its adrenal receptor.     

Ethnic differences in cyclic AMP accumulation: effect on alpha 2, beta 2, and prostanoid receptor responses

Platelet alpha 2- and lymphocyte beta 2-adrenergic receptor density and responsiveness and platelet responses to prostaglandin E2 (PGE2) were measured in black subjects and white subjects. Mean (+/- SEM) alpha-receptor density was greater in white subjects (248 +/- 29 versus 392 +/- 31 fmol/mg protein; p less than 0.005), whereas beta-receptor densities were similar (black subjects, 19.2 +/- 2.2 fmol/mg protein; white subjects, 15.2 +/- 1.4 fmol/mg protein). Basal platelet cyclic AMP levels (black subjects, 7.8 +/- 1.1 pmol/mg protein; white subjects, 14.5 +/- 2.4 pmol/mg protein; p less than 0.05) and PGE2-induced increases in platelet cyclic AMP levels were higher in white subjects (black subjects, 47.1 +/- 3.3 pmol/mg protein; white subjects, 65.5 +/- 3.4 pmol/mg protein; p less than 0.001). Basal lymphocyte cyclic AMP levels (black subjects, 1.2 +/- 0.3 pmol/10(6) cells; white subjects, 2.8 +/- 0.6 pmol/10(6) cells; p less than 0.05) and mean isoproterenol-induced cyclic AMP increases were also higher in white subjects (black subjects, 6.2 +/- 0.6 pmol/10(6) cells; white subjects, 8.5 +/- 0.8 pmol/10(6) cells; p less than 0.05). Responses to isoproterenol as fold stimulation of basal were not significantly higher in black subjects (8.51 +/- 0.97 versus 6.16 +/- 0.86 fold-stimulation of basal). Platelet responses to PGE2 as fold stimulation of basal (black subjects, 7.9% +/- 0.7%; white subjects, 8% +/- 1.3%) and alpha 2-receptor-mediated inhibition of PGE2 responses by UK-14304 (black subjects, 38.2% +/- 1.7%; white subjects, 40.6% +/- 2.3%) were also similar in the two groups.     

Plasma famotidine concentration versus intragastric pH in patients with upper gastrointestinal bleeding and in healthy subjects

To study the concentration-response relationship of famotidine, we serially monitored intragastric pH and measured plasma drug concentrations simultaneously after an intravenous injection of this H2-receptor antagonist (0.1 mg/kg) in eight patients with upper gastrointestinal bleeding and in six healthy subjects. By applying the sigmoidal Emax model the mean (+/- SD) plasma famotidine concentrations associated with an intragastric pH of 4.0 in patients and healthy subjects were estimated to be 17.7 +/- 10.7 and 24.8 +/- 10.3 ng/ml, respectively (not significantly different). No significant differences were observed in the mean pharmacokinetic parameters between the two study groups. Multiple regression analysis revealed that not only a pharmacokinetic factor (i.e., elimination t1/2) but also a pharmacodynamic (or sensitivity) factor (i.e., a drug concentration associated with an intragastric pH of 4.0) contributed significantly (p less than 0.01) to the overall variability in the duration of antisecretory effect in our study subjects, with standardized partial regression coefficients of 0.54 and -0.63, respectively. Based on these data, we predict that around-the-clock control of a fasting intragastric pH above 4.0 can be attained by a continuous infusion of famotidine at rates ranging from 6 to 25 mg/day (mean +/- SD, 11 +/- 7 mg/day) in a 70 kg patient whose pharmacokinetic and pharmacodynamic characteristics are similar to those of our patients.     

In vivo characterization of the pharmacodynamic interaction of a benzodiazepine agonist and antagonist: midazolam and flumazenil.

The pharmacokinetic and pharmacodynamic interaction between the benzodiazepine agonist midazolam and antagonist flumazenil was quantified in vivo in rats, using effect parameters derived from aperiodic EEG analysis. The benzodiazepine-induced increase in amplitudes in the 11.5 to 30 Hz (beta) frequency band of the EEG was used as effect measure. A competitive interaction model was derived that could describe and predict the time course of EEG effect after administration of several combinations of midazolam and flumazenil. Two approaches to derive the interaction model were evaluated. In a first experiment, rats received 10 or 20 mg/kg midazolam i.v. in 15 min during a steady-state infusion of flumazenil at a rate of 0, 0.25, 0.5 or 1 mg/kg/hr. The EEG was continuously measured and frequent blood samples were taken to determine the pharmacokinetics of the drugs. Flumazenil did not influence the pharmacokinetics of midazolam, but a significant reduction in the clearance of flumazenil was observed in the presence of midazolam. Flumazenil did not possess any intrinsic efficacy with regard to the EEG effect measure. With increasing flumazenil concentrations, a parallel shift in the concentration-EEG effect relationship of midazolam was observed, confirming the competitive nature of the interaction. An agonist-antagonist interaction model was used to quantify the interaction, yielding the pharmacodynamic parameters of midazolam [(mean +/- S.E.): Emax = 80 +/- 5 microV/sec, EC50 = 35 +/- 3 ng/ml and N = 1.1 +/- 0.2] and flumazenil: EC50 = 24 +/- 2 ng/ml and N = 1.6 +/- 0.1. In a second experiment, rats received 5 mg/kg flumazenil or placebo i.v. in 10 min during a steadystate infusion of midazolam.(ABSTRACT TRUNCATED AT 250 WORDS)