Exercise hemodynamics and myocardial metabolism during long-term beta-adrenergic blockade in severe heart failure.

Hemodynamics and myocardial metabolism at rest and during exercise were investigated in 21 patients with heart failure. The patients were evaluated before and after long-term treatment (14 +/- 7 months) with the beta-adrenergic blocking agent metoprolol. Clinical improvement with increased functional capacity occurred during treatment. Maximal work load increased by 25% (104 to 130 W; p less than 0.001). Hemodynamic data showed an increased cardiac index (3.8 to 4.6 liters/min per m2; p less than 0.02) during exercise. Pulmonary capillary wedge pressure decreased at rest (20 to 13 mm Hg; p less than 0.01) and during exercise (32 to 28 mm Hg; p = NS). Stroke volume index (30 to 39 g.m/m2; p less than 0.006) and stroke work index (28 to 46 g.m/m2; p less than 0.006) increased during exercise and long-term metoprolol treatment. The arterial norepinephrine concentration decreased at rest (3.72 to 2.19 nmol/liter; p less than 0.02) but not during exercise (13.2 to 11.1 nmol/liter; p = NS). The arterial-coronary sinus norepinephrine difference suggested a decrease in myocardial spillover during metoprolol treatment (-0.28 to -0.13 nmol/liter; p = NS at rest and -1.13 to -0.27 nmol/liter; p less than 0.05 during exercise). Coronary sinus blood flow was unchanged during treatment. Four patients produced myocardial lactate before the study, but none produced lactate after beta-blockade (p less than 0.05). There was no obvious improvement in a subgroup of patients with ischemic cardiomyopathy. In summary, there were signs of increased myocardial work load without higher metabolic costs after treatment with metoprolol.

Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor in a Swedish hypertensive population.

The Arg16Gly and the Gln27Glu polymorphisms in the gene for the beta2-adrenergic receptor (beta2AR) have been linked to an increased risk for cardiovascular disease. The aim of the present study was to evaluate the significance of these haplotypes for development of myocardial infarction (MI) as well as other cardiovascular phenotypes. In a prospective study cohort (CAPPP), 522 hypertensive patients (174 MI and 348 matched controls) were analysed for the Arg16Gly and the Gln27Glu polymorphisms by dynamic allele-specific hybridisation. The haplotype could successfully be determined in 516 patients. Haplotype was not significantly associated with MI. Systolic blood pressure (SBP) was higher in patients with Arg16Gly+Gln27Gln and lower in patients with Arg16Gly+Gln27Glu as compared with the other haplotypes. Haplotype was not associated with body mass index, diastolic blood pressure, cholesterol, LDL, HDL triglycerides or a diagnosis of diabetes mellitus. The present study found no evidence that haplotype for the two most common polymorphisms in the beta2AR are associated with development of MI in a Swedish hypertensive population, but haplotype may be associated with SBP.

Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project.

OBJECTIVE: The Captopril Prevention Project (CAPPP) evaluated the effects of an ACE inhibitor-based therapeutic regimen on cardiovascular mortality and morbidity in hypertension. One planned subanalysis of the CAPPP was to evaluate the outcome in the diabetic patient group. RESEARCH DESIGN AND METHODS: In the CAPPP, 572 (4.9% of 10,985 hypertensive patients) had diabetes at baseline and were studied according to a prospective, randomized, open, blinded, end point trial design. Patients aged 25-66 years with diastolic blood pressure > or =100 mmHg were included and randomized to receive either captopril or conventional antihypertensive treatment (diuretics and/or beta-blockers). RESULTS: The primary end point, fatal and nonfatal myocardial infarction and stroke as well as other cardiovascular deaths, was markedly lower in the captopril than in the conventional therapy group (relative risk [RR] = 0.59; P = 0.018). Specifically, cardiovascular mortality, defined as fatal stroke and myocardial infarction, sudden death, and other cardiovascular death, tended to be lower in the captopril group (RR = 0.48; P = 0.084), and no difference was observed between the study groups for stroke (RR = 1.02; P = 0.96). Myocardial infarctions were less frequent in the captopril group than in the conventional therapy group (RR = 0.34; P = 0.002). Furthermore, total mortality was lower in the captopril as compared with the conventional therapy group (RR = 0.54; P = 0.034). Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor-based therapy. CONCLUSIONS: Captopril is superior to a diuretic/beta-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients, especially in those with metabolic decompensation.

Vascular alpha-2 adrenoceptor function is decreased in rats with congestive heart failure.

OBJECTIVE: Vascular alpha-2 adrenoceptor function of rats with congestive heart failure (CHF) was characterized in both in vivo and in vitro experiments. METHODS: CHF was induced in Sprague-Dawley rats by coronary artery ligation. Sham-operated rats served as normal controls. Postjunctional alpha-2 adrenergic responsiveness was assessed in vivo using the pithed rat model and in vitro in organ bath. Vascular alpha-2 adrenoceptor density was studied by receptor binding assay. RESULTS: Four to 6 weeks after this surgical procedure, plasma catecholamines were markedly increased in CHF rats. In vivo vascular responses to alpha-2 adrenoceptor agonists BHT933 and clonidine were significantly decreased in CHF rats (P < 0.001). Clonidine elicited dose-dependent responses in endothelium intact mesenteric arteries in both CHF and sham-operated rats. The dose-response curve in CHF was shifted to the right with a pD2 value of 5.5 +/- 0.2 compared with control rats 6.2 +/- 0.2 (P < 0.05). The response to clonidine was selectively blocked by an alpha-2 adrenergic antagonist rauwolscine in both groups. Endothelium denuded arteries showed an enhanced response to clonidine in both CHF and control rats. However, the response to clonidine is still decreased in CHF compared to sham-operated rats (P < 0.05). Alpha-2 adrenoreceptor density, as determined by [3H]yohimbine binding in membrane preparations from mesenteric arteries was decreased in CHF compared to sham-operated rats (Bmax 43 +/- 6 vs. 104 +/- 20 fmol/mg protein, P < 0.05). CONCLUSIONS: Vascular alpha-2 adrenoceptor function is decreased in rats with CHF.

Enhanced acetylcholine and P2Y-receptor stimulated vascular EDHF-dilatation in congestive heart failure.

OBJECTIVE: Congestive heart failure (CHF) is accompanied by impaired peripheral blood flow and endothelial dysfunction with decreased release of nitric oxide (NO). Strong evidence supports the existence of another vasodilatory substance, endothelium derived hyperpolarising factor (EDHF), which has not previously been studied in CHF. METHOD: CHF was induced by left coronary artery ligation resulting in a reproducible myocardial infarction in Sprague Dawley rats. Vasodilatory responses to acetylcholine and extracellular nucleotides (ATP, ADP beta S, ADP and UTP) were examined in cylindrical segments of the mesenteric artery, precontracted with noradrenaline. The combined NO- and EDHF-dilatation (after inhibition of cyclo-oxygenase pathways) was called "total dilatation", as indomethacin had only minor effects in this system. NO-dilatation was studied in segments pretreated with indomethacin and the potassium channel inhibitors charybdotoxin (10(-7.5) M) and apamin (10(-6) M), while EDHF-dilatations were studied in the presence of indomethacin (10(-5) M) and L-NOARG (10(-3.5) M). RESULTS: EDHF-dilatations in CHF were strongly up-regulated for ACh (36% vs. 73%; sham vs. CHF operated rats), ADP beta S (10% vs. 42%), ADP (0% vs. 21%) and UTP (3% vs. 35%). These dilatations were abolished by a combination of charybdotoxin and apamin, confirming that they were mediated by EDHF. The NO-dilatations on the other hand were down-regulated in CHF as compared to sham operated rats for ACh (93% vs. 76%; sham vs. CHF operated rats), ADP beta S (61% vs. 37%). ADP (60% vs. 30%), ATP (49% vs. 34%) and UTP (65% vs. 47%), while a minor decrease was seen in the total dilatation for ACh (87% vs. 75%; sham vs. CHF operated rats), ADP beta S (47% vs. 42%), ADP (59% vs. 39%), ATP (52% vs. 39%) and UTP (59% vs. 44%). CONCLUSION: In this model of non-atherosclerotic CHF there was a minor decrease in the total dilatation and a marked down-regulation of the NO-mediated dilatation, while the EDHF-dilatation was up-regulated. Increased EDHF-activity in CHF may represent a compensatory response to decreased NO-activity to preserve endothelial function and tissue perfusion.

Hypersensitivity of Gi protein mediated muscarinic receptor adenylyl cyclase in chronic ischaemic heart failure in the rat.

OBJECTIVE: The aim was to study the Gi protein mediated muscarinic signalling system in the myocardium of rats with chronic ischaemic heart failure. METHODS: Chronic ischaemic heart failure was induced by myocardial ischaemia (four weeks after coronary artery ligation) in rats. The densities and agonist affinities of muscarinic receptors, and the functional activity and concentration of Gi proteins were studied. RESULTS: In failing hearts, the activity of adenylyl cyclase stimulated by guanyliminodiphosphate (Gpp(NH)p) was decreased by 46%. Stimulated activities of adenylyl cyclase by both sodium fluoride and forskolin, however, remained unchanged. Carbachol depressed forskolin stimulated adenylyl cyclase more in membranes from failing hearts than those from normal hearts. The functional level of Gs protein as measured by a reconstitution assay in sarcolemmal membrane did not differ between the two groups. Furthermore, muscarinic receptors exhibited superhigh and low affinities for agonist in failing hearts whereas those in control hearts displayed only high and low affinities. No significant difference in the peptide equivalent amount of membrane bound Gi protein was found in either group. CONCLUSIONS: The experimental chronic failing heart due to myocardial ischaemia showed a depressed myocardial adenylyl cyclase signalling system. This may be due to the hypersensitivity of the Gi protein mediated muscarinic receptor-adenylyl cyclase system as shown by the increased inhibition of Gpp(NH)p mediated adenylyl cyclase, more potent inhibition of stimulated adenylyl cyclase by carbachol, and the superhigh affinity of the muscarinic receptors for carbachol.

Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure.

OBJECTIVE: NG,NG-dimethylarginine (asymmetric dimethylarginine, ADMA) is an important endogenous substance with potent inhibitory actions on nitric oxide (NO) synthesis. The present study was designed to determine circulating ADMA levels and endothelium-dependent, NO mediated vasodilation in a rat model of congestive heart failure (CHF). METHODS: CHF was induced in rats by coronary artery ligation. Sham-operated rats served as normal controls. Plasma ADMA was determined by high performance liquid chromatography with fluorescence detection. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by the clearance of inulin and p-aminohippuric acid, respectively. Endothelial function of the aorta was assessed in an organ bath. RESULTS: Plasma levels of ADMA in rats with CHF (0.94 +/- 0.05 mumol/l) were significantly increased compared with sham-operated controls (0.75 +/- 0.06 mumol/l, p < 0.05). Plasma levels of ADMA was negatively correlated with GFR (r = -0.65, p < 0.05). Decreased endothelium-dependent relaxation to acetylcholine in the aorta of CHF was completely restored by L-arginine (300 microM) (p < 0.01) while endothelium-independent relaxation to nitroprusside was not altered. ADMA potently inhibited endothelium-dependent relaxation in thoracic aorta of normal and CHF rats. The effect of ADMA was completely antagonized by L-arginine in both groups (p < 0.01). Moreover, L-arginine improved endothelium-dependent relaxation in CHF rats in the presence of ADMA. CONCLUSIONS: An endogenous NO synthesis inhibitor ADMA is increased in the circulation of rats with CHF. The increased plasma levels of ADMA may contribute to the decreased endothelium-dependent relaxation in CHF, which is restored by L-arginine, possibly by competitive antagonism of ADMA.

Congestive heart failure induces downregulation of P2X1-receptors in resistance arteries.

OBJECTIVE: Congestive heart failure (CHF) is accompanied by enhanced peripheral sympathetic nerve activity, increased vascular resistance and impaired peripheral blood flow. Besides noradrenaline and neuropeptide Y, the sympathetic nervous system also releases ATP, which has contractile effects mediated by different subtypes of P2-receptors on the vascular smooth muscle cells. The present study was designed to examine postsynaptic changes of the contractile responses to ATP and other extracellular nucleotides in CHF. METHODS: CHF was induced by left coronary artery ligation resulting in a reproducible myocardial infarction in Sprague-Dawley rats. Contractile responses were examined in cylindrical segments of aorta and the mesenteric artery after endothelium removal. To determine if an altered response was regulated on the transcriptional level, competitive reverse transcription polymerase chain reaction (RT-PCR) was used to estimate the amount of P2X1-receptor mRNA. RESULTS: ATP, which is both a P2X1- and a P2Y-receptor agonist, induced a weaker contraction in the mesenteric artery from CHF as compared to sham operated rats. A decrease in both potency and maximum contraction was shown for the selective P2X1-receptor agonist, alpha beta-MeATP, in the mesenteric artery (pEC50 = 6.04 vs. 5.76, Cmax = 57% vs. 33%, sham vs. CHF operated rats), but not in the aorta. Competitive RT-PCR also revealed decreased P2X1-receptor mRNA levels in CHF operated rats in the mesenteric artery (9106 x 10(3) vs. 714 x 10(3) molecules/microgram, sham vs. CHF operated rats), while it remained unaltered in the aorta. To study the P2Y-receptor induced contractile effects, the P2X1-receptors were first desensitised with alpha beta-MeATP (10(-5) M for 8 min). After P2X1-receptors desensitisation, UTP and UDP induced strong contractions in both the mesenteric artery and in the aorta, while ATP and ADP were much less effective. These contractions were not altered by CHF, indicating that vascular contraction mediated by P2Y-receptors are unaffected by CHF. CONCLUSION: CHF induces downregulation of P2X1-receptor stimulated contraction in the mesenteric artery depending on decreased mRNA synthesis for the receptor, while the P2Y-receptor activity remains unchanged. Downregulation of P2X1-receptors appears to be specific for peripheral resistance arteries. This may represent a compensatory response to enhanced peripheral sympathetic nerve activity and increased vascular resistance in CHF.

The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction.

Several studies have shown that GH can enhance cardiac performance in rats after experimental myocardial infarction and in humans with congestive heart failure. In the present study, the hemodynamic effects of hexarelin (Hex), an analog of GH-releasing peptide-6 and a potent GH secretagogue, were compared with the effects of GH. Four weeks after ligation of the left coronary artery male rats were treated sc twice daily with hexarelin [10 microg/kg x day (Hex10) or 100 microg/kg x day (Hex100)], recombinant human GH (2.5 mg/kg x day), or 0.9% NaCl for 2 weeks. Transthoracic echocardiography was performed before and after the treatment period. GH, but not Hex, increased body weight gain. GH and Hex100 decreased total peripheral resistance (P < 0.05) and increased stroke volume (P < 0.05 and P < 0.01, respectively) and stroke volume index (P = 0.06 and P < 0.01, respectively) vs. NaCl. Cardiac output was increased by GH and Hex100 (P < 0.05), and cardiac index was increased by Hex100 with a borderline significance for GH (P = 0.06). In conclusion, Hex improves cardiac function and decreases peripheral resistance to a similar extent as exogenous GH in rats postmyocardial infarction. The mechanisms of these effects are unclear; they could be mediated by GH or a direct effect of Hex on the cardiovascular system.

Importance of dietary salt in the hemodynamic adjustment to weight reduction in obese hypertensive men.

Twenty-three moderately obese middle-aged men with previously untreated hypertension (World Health Organization classification 1-2) were evaluated to assess the effects on blood pressure (BP) of a diet restricted in energy (fats and carbohydrates) but unrestricted in sodium (Group 1) compared to a diet restricted in energy and sodium (Group 2). The patients were randomly allocated to either of the two groups and were comparable in age, sex, weight, and BP. The same energy- and sodium- restricted diet was given to both groups, but the intake of Group 1 (n = 13) was supplemented with dietary sodium. The average urinary output for Group 1 was 192 +/- 39 mmol/24 hr at baseline and 200 +/- 56 mmol/24 hr during the diet. For Group 2 (n = 10), which remained on the initial diet, urinary sodium excretion changed from 188 +/- 53 mmol/24 hr at baseline to 97 +/- 32 mmol/24 hr (p less than 0.001). Intraarterial BP, cardiac output (CO), plasma volume, circulating norepinephrine (NE), and urinary NE were measured at baseline and at the end of the dieting periods. Before the dietary sodium supplement while on the initial diet, the patients in Group 2 showed a reduction in body weight from 97.3 +/- 10.5 kg to 88.6 +/- 9.9 kg (p less than 0.001). Heart rate (HR) and urinary NE output were significantly reduced in comparison with baseline, but intraarterial BP was unchanged. No change in cardiopulmonary blood volume, CO, or stroke volume (SV) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Reactivity to norepinephrine and effect of sodium on blood pressure during weight loss.

Eighteen moderately obese middle-aged men with untreated mild hypertension were randomized to two groups and placed on a low energy diet regimen for 9 to 11 weeks. In Group I (n = 10) the amount of sodium chloride in the diet maintained the urinary sodium excretion at the predieting level. Mean body mass was reduced by 9.1 +/- 0.7 (SEM) kg. Mean intra-arterial pressure showed no significant change. There were significant decreases in heart rate (p less than 0.05) and urinary norepinephrine excretion (p less than 0.05) but not in plasma concentration of norepinephrine. In Group II (n = 8) energy as well as sodium intake was restricted, with a 95 +/- 22 mmol/24 hour reduction of urinary sodium excretion. Body mass decreased by 9.3 +/- 1.1 kg, and mean arterial pressure decreased by -18.9 to -4.3 mm Hg (95% confidence interval). There were also significant reductions in heart rate (p less than 0.001) and plasma norepinephrine concentrations (p less than 0.01) but not in urinary norepinephrine excretion. The pressor response (mean arterial pressure) to norepinephrine infusion at different dose rates was significantly elevated (p less than 0.05) in Group I during dieting in comparison with baseline. The blood pressure response to norepinephrine during dieting in patients in Group II was not changed from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension optimal treatment (HOT) study: home blood pressure in treated hypertensive subjects.

The Hypertension Optimal Treatment Study is a prospective trial conducted in 26 countries. The aims are to (1) evaluate the relationship between three levels of target office diastolic blood pressure (BP) (< or = 80, < or = 85, or < or = 90 mm Hg) and cardiovascular morbidity and mortality in hypertensive patients and (2) examine the effects on cardiovascular morbidity and mortality of 75 mg aspirin daily versus placebo. A total of 19,193 patients between 50 and 80 years of age had been randomized by the end of April 1994. Treatment was initiated with felodipine 5 mg daily, and additional therapy was given in accordance with a set protocol. The present substudy of 926 patients performed in nine countries aimed to (1) compare home with office BP in a representative subsample of the HOT population after the titration of treatment was completed and (2) clarify whether the separation into the target groups could be expanded into the out-of-office setting. The differences between office and home measurements in diastolic BP of 0.2 mm Hg (SD, 9; 95% confidence interval, -0.36 to 0.81; P=.40) and systolic BP of 0.5 mm Hg (SD, 15; 95% confidence interval, -0.53 to 1.46; P=.21) were not significant. The group differences in home BP were 1.9 mm Hg (< or = 80 versus < or = 85) and 1.2 mm Hg (< or = 85 versus < or = 90) for diastolic BP (F=11.69; ANOVA, P<.0001) and 2.6 and 2.1 mm Hg for systolic BP (F=8.44, P=.0002). Thus, office and home BPs measured with the same semiautomatic device are comparable in treated hypertensive subjects in the HOT Study, and the separation into the target groups based on office readings prevails at home.

Characteristics of 9194 patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint Reduction in Hypertension.

-Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 receptor developed for the treatment of hypertension. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality. Patients with essential hypertension, aged between 55 and 80 years, and ECG-documented left ventricular hypertrophy (LVH) were included. Altogether, 9223 patients in Scandinavia, the United Kingdom, and the United States were randomized from June 1995 through April 1997, and 9194 remain after exclusion of a study center at which irregularities were discovered. This population of hypertensives (mean systolic/diastolic blood pressure, 174.4/97.8 mm Hg) with LVH comprises women (54.1%) and men, mostly retired from active work (mean age, 66.9 years), with a high prevalence of overweight (mean body mass index, 28.0 kg/m2), diabetes mellitus (12.3%), lipid disorders (18.0%), and symptoms or signs of coronary heart disease (15.1%). There were fewer current smokers (<17%) than in the general population, and approximately 7% were nonwhite. Almost 30% of participants had been untreated for at least 6 months when screened for the study. Only 1557 persons who entered the placebo run-in period of 14 days were excluded, predominantly because of sitting blood pressures above or below the predetermined range of 160-200/95-115 mm Hg and ECG-LVH criteria not met. By application of simple 12-lead ECG criteria for LVH (Cornell voltage QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory), hypertensive patients with LVH with an average 5-year coronary heart disease risk of 22.3% according to the Framingham score were identified. This population is now being treated (goal, <140/90 mm Hg) in adherence with the protocol for at least 4 years after final enrollment (ie, through April 2001) and until at least 1040 patients suffer myocardial infarction, stroke, or cardiovascular death.

Guanfacine in essential hypertension: effects during rest and isometric exercise.

The antihypertensive effects of guanfacine (0.5 to 4 mg daily) were investigated for 1 yr in 13 patients with essential hypertension. Blood pressure (BP) and heart rate (HR) response was measured during isometric exercise (handgrip) before starting the therapy, after 1 yr of treatment, and 2 wk after withdrawal. Guanfacine in once-daily dosage reduced BP during rest (supine BP: control, 175 +/- 6/103 +/- 4 mm Hg; 1 yr guanfacine, 161 +/- 5/91 +/- 3 mm Hg). Steady-state plasma concentrations after 1 yr were 4.1 +/- 0.59 ng/ml. Resting plasma norepinephrine (NE) and epinephrine (E) levels were lower during active therapy than 2 wk after withdrawal (guanfacine and control: plasma NE, 0.27 +/- 0.03/0.64 +/- 0.13 ng/ml; plasma E, 0.09 +/- 0.02/0.17 +/- 0.05 ng/ml). The relative reduction of plasma catecholamines (guanfacine and withdrawal) was of the same order during handgrip exercise as during supine rest. During isometric handgrip exercise, BP was lower during guanfacine therapy than before treatment and 2 wk after withdrawal, but the increment in BP during handgrip exercise was not affected by the drug despite the lower BP values on therapy. Our data indicate that the central alpha 2-agonist action of guanfacine reduces sympathoadrenal function equally during rest and isometric exercise.

Plasma concentration--effect relationships for felodipine: a meta analysis.

The plasma concentration versus antihypertensive effect relationship for the calcium antagonist felodipine was investigated in 67 patients with hypertension and 21 healthy subjects by use of the Emax model. No consistent effect of felodipine on blood pressure was observed in the healthy subjects. In patients with hypertension the plasma drug concentration and blood pressure versus time curves mirrored each other, indicating a close relationship between concentration and effect. The maximum effect (Emax) model fitted the diastolic blood pressure data of most patients, but the model was less often applicable in patients with low initial diastolic blood pressure levels. The average Emax values and the plasma felodipine concentration needed to obtain 50% of Emax for the patients with hypertension were 29 mm Hg and 8 nmol/L, respectively. The Emax values increased with increasing initial diastolic blood pressure levels but were similar in patients with high and low plasma felodipine concentrations. Age had negligible influence on the antihypertensive response to felodipine when compensation was made for the plasma concentrations.

Treatment of arterial hypertension with ketanserin in mono- and combination therapy.

We evaluated the long-term antihypertensive effects of ketanserin, a selective serotonin2-receptor blocker with weak adrenergic receptor blocker properties. Ketanserin was given alone, 40 mg o.d. or b.i.d., for 2 years to 12 patients with essential hypertension. Systolic and diastolic blood pressures (BPs) were significantly reduced 14 days after the start of therapy and remained lowered during the 2-year follow-up period. In a larger group of patients who received ketanserin monotherapy for 2 to 3 months, the response to therapy varied considerably between subjects, with an overall response rate (BP less than 165/95 mm Hg) of 60% to 75%. During steady-state conditions, the maximum and minimum ketanserin plasma concentrations varied from threefold to fourfold between subjects and did not correlate with individual reductions in BP, but for each individual there was a positive correlation between BP reduction and ketanserin plasma concentration throughout a study day. In combination with beta-blockers, ketanserin effectively reduced BP in the supine and standing positions. The plasma concentration profile was not altered as much during combination therapy as when ketanserin was given alone. Side effects were few and tolerable. Ketanserin effectively reduces BP both alone and in combination with beta-blockers and may be still another drug useful in the treatment of essential hypertension.

Hemodynamic effects of the use of oral snuff.

The hemodynamic effects during rest and exercise of oral snuff were investigated in an open, placebo-controlled study of nine habitual users of oral snuff. Blood pressure, heart rate, and central hemodynamics were measured noninvasively. Plasma concentrations of nicotine, cotinine, norepinephrine, and epinephrine, as well as neuropeptide Y-like immunoreactivity were measured before and after snuff intake during rest and exercise. Snuff intake induced a significant increase in heart rate and blood pressure and a decrease in stroke volume during rest. Hemodynamic changes were unrelated to nicotine or cotinine concentrations. Resting levels of norepinephrine and neuropeptide Y-like immunoreactivity were similar with or without snuff, whereas epinephrine was slightly increased 30 minutes after snuff intake. The exercise-induced increase in norepinephrine and neuropeptide Y-like immunoreactivity did not differ between the days subjects received snuff and the days they received placebo. In contrast, maximum work load was associated with a slight increase in circulating epinephrine after snuff intake. The findings suggest that snuff intake is associated with significant hemodynamic effects during rest but not during exercise. These effects could not be readily explained by activation of the sympathetic nervous system.

Concentrations of morphine and morphine metabolites in CSF and plasma during continuous subcutaneous morphine administration in cancer pain patients.

Plasma and cerebrospinal fluid (CSF) steady-state concentrations (Css) of morphine (M) and the main metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), were determined by high performance liquid chromatography (HPLC) in 21 cancer patients treated with chronic subcutaneous morphine infusion. There was a moderate, but statistically significant correlation between the daily dose of morphine and the concentrations of morphine, M3G and M6G in CSF. A poorer correlation to concentrations were seen in plasma. The mean +/- SEM CSF/plasma morphine concentration ratio was 0.36 +/- 0.07. In plasma and CSF, the mean steady state concentration of M3G but not M6G substantially exceeded that of morphine where the mean CSF M/M3G/M6G ratio was 1:15:0.5 (molar basis), and the mean plasma ratio was M/M3G/M6G 1:31:3 (molar basis). The mean M3G and M6G concentrations in CSF were approximately 8 and 10% of those found in plasma, but there was a wide interindividual variation. Plasma concentrations of both morphine glucuronides were positively correlated to serum creatinine. Neither pain intensity, evaluated by visual analogue scale (VAS), nor side effects showed any relationship to the CSF M3G concentrations, M3G/M or the M3G/M6G ratios. We conclude that during steady state subcutaneous administration of morphine, there is a large interindividual variation in plasma morphine with poor relationship to the daily administered dose. In CSF this correlation was more evident. Plasma and CSF concentrations of M3G and CSF concentrations of M6G correlated with administered morphine dose. There was an accumulation of both morphine glucuronides in patients with elevated serum creatinine. Measurements of morphine, M3G and M6G in CSF did not show any overt relationship to analgesia or side effects.

Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P.

The hypothesis tested was that inhibition of the L-arginine-nitric oxide (NO) pathway may represent a potential central mechanism of action for acetaminophen (paracetamol). Spinal administration of N-methyl-D-aspartate (NMDA, 0.5 nmol), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, 0.1 nmol) or substance P (SP, 0.5 nmol) to the rat provoked a specific behaviour characterized by biting, scratching and licking (BSL). This behaviour was antagonized by pretreatment with acetaminophen for NMDA and SP but not for AMPA. Further, the antinociceptive effect of acetaminophen was readily reversed by administration of the natural substrate for nitric oxide synthase (NOS), L-arginine, but not by D-arginine. This suggests that the analgesic effect of acetaminophen is related to inhibition of NO generation. Potential mechanisms for this may involve NMDA and SP. Our data suggest that a significant portion of the analgesic effect of acetaminophen, when used clinically, may be related to an interaction with the central nervous system L-arginine-NO pathway.

Renal and hemodynamic effects of isradipine in essential hypertension.

Twenty-three men with essential hypertension participated in a double-blind placebo-controlled study with a crossover design to evaluate the long-term (nine weeks) effects of isradipine on central and renal hemodynamics. Isradipine as monotherapy was titrated from 2.5 to 5 and then to 7.5 mg twice daily. At the end of the crossover periods, cardiac output (dye-dilution) and intraarterial blood pressure were assessed. Compared with placebo, isradipine reduced ambulatory blood pressure from 174/104 to 154/91 (p less than 0.001), whereas the heart rate was unchanged. The reduction of blood pressure was entirely due to a reduction (36 percent; p less than 0.001) of the peripheral resistance. The baroreceptor sensitivity did not change (RR intervals during infusion of phenylephrine) but, with isradipine, the setpoint was shifted to lower blood pressure levels. Renal plasma flow (para-amino hippurate clearance) increased (465 versus 391 ml/minute; p less than 0.05), but glomerular filtration rate ([51Cr]ethylenediaminetetraacetic acid clearance) did not change. Hence, the filtration fraction decreased. With isradipine, there was a post-dose increase in natriuresis (0.45 to 0.34 mmol/minute; p = 0.06). Side effects were mild.