P. van Brummelen

Regional vascular effects of serotonin and ketanserin in young, healthy subjects.

The local hemodynamic effects of serotonin (5-hydroxytryptamine; 5-HT) and the selective 5-HT2 antagonist ketanserin were investigated in the forearm of 20 healthy volunteers. Single doses of 5-HT (0.1-80 ng/kg/min) and ketanserin (5-125 ng/kg/min) were administered intra-arterially. The relative alpha 1-adrenergic receptor and 5-HT2 blocking potencies of ketanserin were investigated using intra-arterial infusions of cumulative doses of methoxamine (0.1, 0.3, and 0.5 microgram/kg/min), tyramine (0.25, 0.50, and 1.25 microgram/kg/min), and 5-HT (10, 30, and 80 ng/kg/min) together with a low dose (5 ng/kg/min) and a high dose (50 ng/kg/min) of ketanserin. Forearm blood flow was measured by venous occlusion plethysmography. Heart rate and intra-arterial blood pressure were recorded semicontinuously. Intra-arterial infusion of 5-HT induced an initial transient vasodilatation, followed by a steady vasodilatation for the low doses of 5-HT (0.1-10 ng/kg/min; p less than 0.05). A steady vasoconstriction was only obtained at the highest dose of 5-HT. Ketanserin induced a dose-dependent increase in forearm blood flow from 15 ng/kg/min (p less than 0.05) onward. The vasodilatation induced by 5-HT (1 ng/kg/min) was significantly enhanced by ketanserin (125 ng/kg/min; p less than 0.05), whereas the vasoconstriction elicited by 5-HT (80 ng/kg/min) was reversed by ketanserin (50 ng/kg/min; p less than 0.05), thus confirming that 5-HT2 receptors were stimulated by 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Nisoldipine: Kinetics and effects on blood pressure and heart rate in patients with liver cirrhosis after intravenous and oral administration

SummaryThe pharmacokinetics and effects on blood pressure and heart rate of nisoldipine were studied in 8 patients with cirrhosis and in 8 age-matched healthy controls. On separate occasions each subject received nisoldipine by i.v. infusion (0.37 mg in 40 min) and as a tablet (5 mg for patients and 20 mg for control subjects).After i.v. nisoldipine, the elimination half-life was 9.7 h in control subjects and 16.6 h in the cirrhotics. The volume of distribution was 4.1 l/kg and 6.4 l/kg and the total systemic clearance was 847 ml/min and 494 ml/min, respectively. On oral nisoldipine, systemic availability was fourfold higher in patients with cirrhosis: 14.7% versus 3.7%.After i.v. administration of nisoldipine there was a brief decrease in systolic and diastolic blood pressure in both groups, whereas the heart rate increased. After 4 h a second effect peak appeared in the control subjects. After oral nisoldipine similar effect-time profiles were found, but effects lasted longer than after i.v. administration.Comparison of the maximal total plasma concentration of nisoldipine and the maximal effect in the two groups revealed that sensitivity to nisoldipine was not different in patients with cirrhosis.A reduction in the dose of nisoldipine is recommended when cirrhotics require oral nisoldipine in therapeutic practice.

Influence of hydrochlorothiazide on the plasma levels of triglycerides, total cholesterol and HDL-cholesterol in patients with essential hypertension

The influence of hydrochlorothiazide (HCT) treatment on the plasma levels of triglycerides, total cholesterol and high density lipoprotein cholesterol (HDL-cholesterol) was studied in 10 patients with essential hypertension. After a placebo period of 4 weeks, 50 mg HCT twice daily was given for a period of 9 months, followed by a second placebo period of 4 weeks. Triglycerides, total cholesterol and HDL-cholesterol were determined at the end of both placebo periods and after 1, 3, 6 and 9 months of HCT. For the whole group, there were no significant changes in triglycerides or HDL-cholesterol, whereas total cholesterol significantly increased during HCT. In 6 patients, plasma triglycerides were higher during HCT as compared to both placebo periods. In only 4 patients did HDL-cholesterol increase during HCT. Changes in triglycerides, total cholesterol and HDL-cholesterol were not related and no correlation was found with changes in blood pressure, body weight or serum potassium. In conclusion, this study confirms a possible adverse effect of diuretic treatment on plasma lipids, which should be considered when determining therapeutic regimens for hypertension.

Pharmacokinetics and hemodynamic effects of long-term nisoldipine treatment in hypertensive patients.

In six patients with essential hypertension, the pharmacokinetics of nisoldipine were investigated before, during, and after 4 weeks of treatment. On day 1, nisoldipine was infused intravenously (i.v. 2 mg in 2 h); on day 2, oral nisoldipine treatment (10-mg tablets twice daily) was started for 4 weeks. During this period, patients came to the hospital six times, on which occasions blood samples were taken for the determination of trough and peak concentrations of nisoldipine. After 4-week treatment, the infusion experiment was repeated. In the first infusion experiment, systemic clearance was 1.02 +/- 0.23 L/min (mean +/- SD), terminal half-life (t1/2) was 15.4 +/- 6.7 h, and volume of distribution was 5.9 +/- 1.8 L/kg. After 4 weeks, these parameters had not changed significantly. Nisoldipine lowered blood pressure (BP) in all patients, whereas forearm blood flow and heart rate (HR) increased. Neither were the hemodynamic changes different after the oral treatment period, although basal BP was lower than before oral treatment. No accumulation of nisoldipine occurred during the 4-weeks treatment period.

Effects of a new long-acting beta-blocker bopindolol (LT 31-200) on blood pressure, plasma catecholamines, renin and cholesterol in patients with arterial hypertension

SummaryBopindolol (LT 31-200), a new, long-acting, non-selective beta-blocker, was given as monotherapy to 13 patients, 12 with essential hypertension and 1 with renovascular hypertension. After a placebo period of 4–6 weeks, bopindolol was given once daily, starting with 1 mg and subsequently increasing at two-weekly intervals to 2 and 4 mg once daily until a diastolic blood pressure⩽90 mmHg was achieved. The effective dose was continued for 12 weeks. In 10 patients plasma levels of renin, noradrenaline, adrenaline and cholesterol were measured during placebo and after 3 months of therapy. Blood pressure and heart rate were lowered significantly during bopindolol treatment. The mean effective dose was 2.2 mg per day. In 10/13 patients a diastolic blood pressure⩽90 mmHg was achieved. Side effects were minimal. Changes in plasma noradrenaline and adrenaline were small and not significant, but renin and cholesterol were significantly reduced. Thus, LT 31-200 is an effective and well tolerated beta-blocker when given in a once daily dosage.

Arterial and venous effects of serotonin in the forearm of healthy subjects are not age-related

The influence of age on the regional arterial and venous effects of serotonin (5-HT) was investigated in 13 young (aged 22–31 years) and seven older (aged 50–69 years) healthy volunteers. Single-dose infusions of 5-HT (1, 10, and 80 ng/kg/min) and of the 5-HT2 receptoi antagonist ritanserin (50, 150, and 500 ng/kg/min) were administered into the brachial artery. Subsequently, the relative arterial and venous effects of the highest dose of 5-HT were investigated. Forearm blood flow (FBF) and maximum venous outflow (MVO) were measured by venous occlusion plethysmography. Heart rate (HR) and intraarterial (i.a.) blood pressure were recorded semicon tinuously. In both age groups, 5-HT induced an initia transient arterial dilation, followed by a persistent increase in FBF for the doses of 1 and 10 ng/kg/min and a relative small decrease in FBF for the highest dose. of both age groups, the highest dose of 5-HT induced a similar large reduction in MVO (p < 0.05 for both). The reduction in MVO was attenuated by ritanserin (500 ng/kg/ min, p < 0.05 for both groups). In the younger subjects, this dose of ritanserin also unmasked an arterial dilator effect of the highest dose of 5-HT (p < 0.05). The single infusions of ritanserin did not influence FBF significantly in either study group. No significant differences were observed between the age groups. These results show that in the forearm of healthy subjects arterial and venous vascular responses to 5-HT were not age-related. In the arterial vascular bed, 5-HT acted predominantly as a vasodilator; at high doses, mainly venous vasoconstriction was observed. That ritanserin did not significantly influence FBF in either age group provides evidence that 5-HT2 receptors are not involved in maintenance of basal vascular tone in the vascular bed investigated.

Effects of 5-hydroxytryptamine on Capillary and Arteriovenous Anastomotic Blood Flow in the Human Hand and Forearm and in the Pig Hind Leg

The effects of intraarterially infused serotonin (5-HT) on capillary and arteriovenous anastomotic (AVA) blood flow were investigated in the hand and forearm of 19 healthy volunteers, and in the hind leg of six anesthetized pigs using radioactive microspheres with a diameter of 15 μm. The 5-HT2-receptor antagonist ketanserin was used in an attempt to identify the receptors involved. None of the drugs in the doses used induced systemic hemodynamic effects. Low doses of 5-HT significantly increased forearm blood flow with a maximum response at the dose of 1 ng/kg/min (68 ± 14%, p < 0.05), whereas only at the highest dose of 80ng/kg/min was a net decrease in forearm blood flow measured ( - 28 ± 6%. p < 0.05). Conversely, finger blood flow was not influenced by the lower doses of 5-HT, whereas a major reduction was observed at the highest dose ( - 90 ± 3%). Ketanserin increased both total forearm blood flow and AVA blood flow. The drug blunted the constrictor response to 5-HT in the forearm but only slightly attenuated this response in the finger. The percentage AVA blood flow in the human hand and forearm was not influenced by an infusion of 5-HT at 80 ng/kg/min alone. However, after pretreatment with ketanserin, which itself increased the AVA component, this dose of 5-HT significantly reduced AVA flow. In the pig, total femoral blood flow was not influenced by 5-HT, but AVA blood flow was significantly reduced and capillary skin blood flow increased. It is concluded that in both humans and pigs intraarterially infused 5-HT decreases AVA blood flow but that this effect is seemingly not mediated by 5-HT2 receptors but, as previously reported in the porcine carotid circulation, may involve 5-HT1-like receptors. The fact that low doses of 5-HT did not induce a net vasodilation in the finger is attributed to the relative absence of skeletal muscles and abundance of AVAs in the finger.

Pharmacokinetics and Haemodynamic Effects of Nisoldipine in Patients with Liver Cirrhosis

In eight patients with liver cirrhosis and in eight control subjects the pharmacokinetics and haemodynamic effects of nisoldipine were studied. In a randomised crossover study design the participants received nisoldipine by intravenous infusion (0.37 mg in 40 min) and as a tablet (5 mg for the patients; 20 mg for control subjects). Heart rate and blood pressure were measured serially. Blood samples were taken regularly for determination of nisoldipine concentration. After intravenous nisoldipine, plasma half-life was 9.7 ± 5.4 h in the control subjects and 16.6 ± 4.6 h in the liver patients (P <0.02). Volume of distribution was 4.1 ± 2.1 liter/kg and 6.4 ± 2.3 liter/kg (NS) respectively, and systemic clearance was 0.85 ± 0.31 liter/min and 0.49 ± 0.12 liter/ min, respectively (P <0.01). On oral nisoldipine systemic availability was much higher in the patient group (14.7 ± 10.1% vs 3.7 ± 2.1% (P <0.01)).

Influence of calcium entry blockade on α1 - and α2-adrenoceptor mediated vasoconstriction in the forearm of hypertensive patients

SummaryThe influence of treatment with the calcium entry blockers PY 108-068 (PY) and PN 200-110 (PN) on α1- and α2-adrenoceptor mediated vasoconstriction has been investigated in the forearms of hypertensive patients. Changes in forearm vascular resistance (FVR) in response to the intra-arterial infusion of drugs were determined at the end of a placebo period and after 2–4 weeks of treatment with PY or PN. The drugs used were the selective agonists methoxamine (α1) and B-HT 933 (α2). During placebo, basal FVR was dose-dependently increased by methoxamine and B-HT 933. Basal blood pressure was lowered during PN but not during PY. Treatment with the calcium entry blockers did not influence the effect of methoxamine, but the vasoconstriction induced by B-HT933 was attenuated by both of the calcium entry blockers. These results confirm the findings in animal studies that calcium entry blockers preferentially inhibit the α2-adrenoceptor mediated vasoconstriction induced by selective agonists.

Blunting of Exercise‐Induced Tachycardia and Renin Release 24 Hours After a Single Dose of Sotalol

Sotalol significantly reduces resting and exercise-stimulated heart rate and plasma renin activity 2 hours and to a lesser degree also 24 hours after oral administration of a single 200-mg dose in healthy volunteers. Because of this 24-hour beta-adrenoceptor blocking effect, sotalol should be suitable for once-daily dosing in clinical practice.