The effect of dopamine on renal blood flow in man

Summary 1. The effect of dopamine on renal blood flow as measured directly by an indicator dilution technique has been studied in eleven hypertensive patients. — 2. Dopamine (1 and 2 µg/kg body wt/min) caused a mean increase of 77.1% and 121.6% respectively in renal blood flow. This was four to five times greater than the corresponding change produced in cardiac output (+16.8% and +37% respectively over control values). — Neither propranolol (2 studies) nor phentolamine (1 study) blocked these changes in renal blood flow. — 4. Dopamine 2 µg/kg body wt/min caused a mean increase in sodium excretion from 0.269±0.246 mequiv/min to 0.942±0.429 mequiv/min in 4 hypertensive subjects. There was also an increase in glomerular filtration rate, measured by inulin clearance, from 95.2±13.8 ml/min to 124.7±13.4 ml/min and in effective renal blood flow measured by PAH clearance from 490.2±170.8ml/min to 673.0±256.2 ml/min.     

The effect of felodipine on forearm haemodynamics and the myogenic response of the forearm resistance vessels in normal man.

The effect of felodipine 10 mg oral solution or placebo on peripheral haemodynamics and the response of the forearm resistance vessels to venous occlusion was studied in seven normotensive individuals. Felodipine produced a significant fall in diastolic blood pressure (DBP max = -15 mm Hg), a rise in heart rate (heart rate max = +15 beats min-1) (both P less than 0.01), and an overall fall in calculated forearm vascular resistance (calculated forearm vascular resistance max = -19.6 units, P less than 0.001). Felodipine had no significant effect on the vasodilator response, but limited the vasoconstrictor response following venous occlusion. These observations suggest that felodipine is a potent vasodilator and interferes with the myogenic response of vascular smooth muscle of the forearm resistance vessels.     

The effect of captopril on the superior mesenteric artery and portal venous blood flow in normal man.

1. Measurements of superior mesenteric artery and portal venous blood flow were made non-invasively along with systemic and other regional (cardiac index, forearm and cutaneous blood flow) vascular responses to acute ingestion of the ACE inhibitor captopril (50 mg) or placebo (50 mg vitamin C), in 12 healthy subjects while supine and during head-up tilt. 2. After captopril, superior mesenteric artery and portal blood flow rose markedly with a reduction in superior mesenteric artery vascular resistance. Supine blood pressure was unchanged but cardiac index and forearm blood flow rose; during head-up tilt, blood pressure fell in some subjects. 3. There was a rise in levels of plasma renin activity and a fall in levels of plasma angiotensin II after captopril. After placebo, there were no significant changes in splanchnic blood flow, systemic or other regional responses and in biochemical measurements, while supine. 4. Our studies indicate that captopril is a potent dilator of the splanchnic vascular bed and suggest that this action may contribute to its therapeutic effects. The studies indicate a role for angiotensin II in the control of this large vascular bed although other agents (bradykinin, prostacyclin) may contribute.     

Methods for assessment of the effect of drugs on cerebral blood flow in man.

The cerebral circulation is not an unimportant vascular bed but it is difficult one to investigate. Methodological difficulties are the main reasons for the paucity of clinical pharmacology studies to date. Of the methods currently available those of the McHenry (1964) and Wyper et al. (1976) appear to be the most useful to the clinical investigator. Increasing use of multiple detectors even with inhalation techniques may give evidence of regional drug effects upon the cerebral circulation. Improvements in methodology in the last few years, particularly the development of atraumatic methods are likely to act as an important spur to research in this field.     

The effect of the endothelin ET(A) receptor antagonist CI-1020 on hypoxic pulmonary vasoconstriction.

The mechanism of Hypoxic Pulmonary Vasoconstriction is unknown. The role of endothelin-1 in hypoxic pulmonary vasoconstriction was studied in precontracted small and large pulmonary arteries using the endothelin ETA receptor antagonist sodium-2-benzol [1,3]dioxol-5-yl-4-(4-methoxyphenyl)-4-oxo-3-(3,4,5-trimethoxy-ben zyl)-but-2-enoate (CI-1020). Small rat pulmonary arteries exhibit a mixed endothelin ETA receptor and endothelin ETB2 receptor population whereas large rat pulmonary arteries contain only endothelin ETA receptors. CI-1020 inhibited endothelin-1 in small vessels via endothelin ETA receptor blockade (1 and 10 microM) and at high concentrations via endothelin ETA receptor and endothelin ETB2 receptor blockade (100 microM). CI-1020 (0.01, 0.1 and 1 microM) inhibited endothelin-1 in large vessels via endothelin ETA receptor blockade alone. CI-1020 (1, 10 and 100 microM) significantly reduced hypoxic pulmonary vasoconstriction in small vessels, by -9.8+/-1.4, -9.2+/-2.3 and -8.0+/-1.7% 80 mM K+, respectively, compared to +2.5+/-4.2% with vehicle (P < 0.05). CI-1020 (0.01, 0.1 and 1 microM) had no significant effect upon hypoxic pulmonary vasoconstriction in large vessels. In small, but not large, pulmonary arteries hypoxic pulmonary vasoconstriction is due in part to the action of endothelin-1 at the endothelin ETA receptor.     

The effects of oral acebutolol and propranolol on forearm blood flow in hypertensive patients.

1 Nine hypertensive patients received by mouth daily doses of 400 mg of acebutolol and then, after a 2 week washout period, 80 mg of propranolol for 2 week periods in an open study. 2 Both treatments caused equivalent cardiac blockade as assessed by reduction in exercise tachycardia. 3 Both treatments lowered blood pressure, although this effect on pressure was better maintained in the case of acebutolol. 4 Forearm blood flow, at rest, was significantly reduced at 2 h after dosing with propranolol, but not after acebutolol. 5 This difference between the two drugs is probably due to the cardioselectivity of orally administered acebutolol in man.     

Alpha 1-and alpha 2-adrenoceptor mediated vasoconstriction in the forearm of normotensive and hypertensive subjects

alpha 1- And alpha 2-adrenoceptor mediated vasoconstriction were studied in 13 patients with essential hypertension and 13 age-matched normotensive controls. This was done by comparing the changes in forearm blood flow induced by intra-arterial infusion of the selective alpha 1- and alpha 2-adrenoceptor agonists methoxamine and B-HT 933, the catecholamines adrenaline and noradrenaline, and the selective alpha 2-adrenoceptor antagonist yohimbine in both study groups. The catecholamines were infused in the presence of propranolol in order to prevent beta-adrenergic effects. Forearm blood flow was measured by plethysmography. All agonists produced a dose-dependent vasoconstriction which was more pronounced in the hypertensive patients, although the difference was significant only for the infusion of the catecholamines and for the combined effects of methoxamine and B-HT 933. No preference was found for either the alpha 1- or alpha 2-adrenoceptor mediated vasoconstriction in the greater response of the hypertensive patients. These results could well be explained by structural vascular changes, secondary to the elevated blood pressure. No evidence was found for increased alpha 2-adrenoceptor mediated basal vascular tone in patients with essential hypertension, since yohimbine tended to induce a greater vasodilatation in the normotensive subjects.     

The effects of flosequinan on regional blood flow in normal man.

1. The effects of 100 mg and 200 mg flosequinan on limb, hepatic and renal blood flow were investigated in 14 healthy male volunteers in a placebo controlled double-blind randomised three-way crossover study. 2. Heart rate, blood pressure, forearm blood flow and venous capacitance measured by volume plethysmography, were recorded sequentially over 4 h, after oral dosing. 3. Apparent hepatic and renal blood flows were estimated 2 h post-dose by indocyanine green dye clearance and clearance of 125-iodohippuran respectively. 4. Flosequinan produced dose-dependent reductions in resting diastolic blood pressure, accompanied by a rise in heart rate. 5. Forearm blood flow increased to a maximum 4 h after 200 mg and this was accompanied by a fall in forearm vascular resistance. 6. Hepatic blood flow increased, compared with placebo, after 200 mg flosequinan, accompanied by a fall in hepatic vascular resistance. Renal blood flow remained unchanged but renal vascular resistance fell significantly, compared with placebo, following both doses of the drug. 7. In normal man blood flow to the limb, hepatic and renal vascular beds is preserved despite dose-dependent reductions in blood pressure following single doses of flosequinan.     

Effect of oxpentifylline on blood viscosity and cerebral blood flow in man.

The effects of intravenous oxpentifylline on blood viscosity and cerebral blood flow were studied in eight patients with cerebrovascular disease using a double-blind placebo controlled design. A single dose of 200 mg oxpentifylline in 10 ml saline was given by intravenous injection over 10 min and compared with 10 ml saline alone. Whole blood and plasma viscosity were measured in a Contraves LS 30 coaxial viscometer at shear rates of 0.7 and 94.5 s-1. Cerebral blood flow was measured by the non-invasive intravenous xenon133 clearance method. The measurements were made before and then 30 min after the start of the injection of drug or saline alone. Oxpentifylline was found to have no significant effect on blood viscosity or cerebral blood flow.     

The effect of a single oral dose of ethanol on hepatic blood flow in man

Summary The magnitude and time course of changes in hepatic blood flow following oral ingestion of a single (0.6 g/kg) dose of ethanol was studied using the model compound indocyanine green (ICG).Hepatic blood flow was not significantly different at 40, 90, 150 and 210 minutes following ethanol as compared to baseline values measured 20 and 70 min prior to alcohol ingestion.These results suggest that ethanol, at concentrations commonly associated with social drinking, has minimal effects on liver blood flow and would be expected to contribute little to changes in either the bioavailability or clearance of drugs highly extracted by the liver.     

C-peptide has no effect on forearm blood flow during local hyperinsulinaemia in healthy humans

BACKGROUND: C-peptide increases forearm blood flow (FBF) in patients with Type 1 diabetes, probably by interaction with insulin, but not in healthy subjects. It is unclear if the vasodilating effect is sealed at normal fasting insulin concentrations. METHODS: The effects of C-peptide alone and during local hyperinsulinaemia were studied in healthy young men. Subjects received intra-arterial insulin at 6 pmol min-1 (low dose) or placebo for 60 min with subsequent coinfusion of C-peptide at increasing doses of 2-60 pmol min-1 in a double-blind crossover study (n = 8). In control experiments insulin at 30 pmol min-1 (high dose) was coinfused with C-peptide (n = 3). FBF was measured by strain-gauge plethysmography. RESULTS: Placebo had no effect on FBF (mean percentage change from baseline at 50 min -3.1%, 95% confidence interval [CI]-14.9, + 8.7). Insulin infusion slightly enhanced FBF by + 10.2% (95% CI -6.8, + 27.2; low dose) and + 17.6% (95% CI -38.8, + 74.0; high dose), respectively. The mean individual difference of the change in FBF between low-dose insulin and placebo was + 13.3% (95% CI -6.0, + 32.7; P = NS). Infusion of C-peptide increased local C-peptide concentrations from 1.8 +/- 0.1 ng ml-1 to 6.1 +/- 2.8 ng ml-1, but had no effect on FBF during placebo or hyperinsulinaemia (mean difference vs low dose insulin -16.0%, 95% CI -38.9, + 6.9). CONCLUSION: The vasodilating effect of C-peptide seen in Type 1 diabetes is not detectable during fasting or hyperinsulinaemia in the forearm vasculature of healthy subjects. This suggests saturation of its vasodilating potency at insulin concentrations within the normal or in the supraphysiological range.     

Lack of tolerance in forearm blood vessels in man to glyceryl trinitrate.

1. Nitrate tolerance is a clinical problem. The cause is not known but it has been suggested that tolerance to organic nitrates occurs within the blood vessels to reduce sensitivity to the drug. We have determined the sensitivity of human forearm resistance vessels and veins to glyceryl trinitrate (GTN) at the beginning and end of a 7 day period of GTN administration in healthy volunteers using a clinically relevant dose of transdermal drug. 2. Eight healthy volunteers completed the study which entailed measurement of change in forearm venous compliance and change in forearm blood flow following intraarterial infusions of two doses of glyceryl trinitrate (0.5 and 2.0 micrograms min-1) before, after 2 h and after 7 days of transdermal GTN administration using one 10 mg patch each 24 h. 3. Changes in venous compliance and blood flow were measured by venous occlusion plethysmography using a basal infusion of noradrenaline (1 microgram min-1) to increase venous tone. 4. Noradrenaline produced the expected decrease in forearm blood flow and venous compliance. The effect of locally infused GTN on venous compliance and forearm blood flow was similar on the three study days. In particular there was no significant difference in the response to GTN following 7 days transdermal administration compared with that after 2 h. 5. We conclude from this study that local vascular tolerance to GTN is unlikely to explain the clinical problem of nitrate tolerance, and that other mechanisms such as neurohumoral activation may be important.