R. S. Reneman

Platelet-vessel wall interactions: Implication of 5-hydroxytryptamine. A review

The evidence for an impact of platelet-derived 5-hydroxytryptamine (5-HT) on local tissue perfusion is reviewed. By interacting with 5-HT2 serotonergic receptors, 5-HT, directly or through amplification, activates platelets, endothelial and vascular smooth muscle cells producing platelet aggregation, vascular permeability increase and large vessel constriction. Pharmacodissection in experimental animals with selective serotonergic 5-HT2 receptor antagonists, e.g. ketanserin, shows that 5-HT largely contributes to the platelet-mediated increase in vascular permeability, to platelet-vessel wall interaction during hemostasis, to cardiopulmonary dysfunction provoked by thromboembolism and to the platelet-mediated inhibition of peripheral collateral circulation. Clinical results obtained with ketanserin further substantiate an involvement of platelet-derived 5-HT in the pathogenesis of impaired tissue perfusion in some cardiovascular conditions.

The cerebral blood distribution in dogs and cats. An anatomical and functional study

On the basis of corrosion preparations and of microsphere studies, the following characteristics of the canine and feline cerebral circulation were observed. (1) In cats, a greater part of the vertebral arterial blood goes to the brain and it is more specifically restricted to the ponto-medullary and cerebellar structures. These structures received approximately 3 times more microspheres in cats than in dogs. (2) In dogs, an important amount of vertebral blood goes to the neck muscles, and the intracranial vertebral blood supply is spread over a greater area of the brain, including the thalamo-hypothalamic and posterior cortical zone. (3) In cats the thalamo-hypothalamic area receives a greater amount of blood via the common carotid artery than in dogs. (4) In both animal species, the vascular connections between the left and right side of the brain are more extensive in the vertebral than in the carotid bed. However, for either vascular bed, a more important left to right transmission was found in the dog.

The l-enantiomer of nebivolol potentiates the blood pressure lowering effect of the d-enantiomer

In this study the effect of l-nebivolol on the blood pressure lowering action of d-nebivolol was investigated after intraperitoneal administration of the drugs to spontaneously hypertensive rats. Doses of l-nebivolol which did not affect blood pressure when given alone potentiated the decrease in systolic and diastolic blood pressure induced by 1.25 mg.kg-1 d-nebivolol. The potentiating effect of l-nebivolol was seen at doses higher than 0.16 mg.kg-1. At 1.25 mg.kg-1 d-nebivolol significantly reduced the heart rate, an effect which was not potentiated by l-nebivolol in doses up to 1.25 mg.kg-1. Higher doses of l-nebivolol (2.5 and 5.0 mg.kg-1) in combination with 1.25 mg.kg-1 d-nebivolol not only lowered the blood pressure further, but also significantly reduced the heart rate; thus at these doses the enantiomers together exerted more pronounced beta 1-adrenoceptor blocking properties. This is probably disadvantageous, because d,l-nebivolol has been shown to decrease arterial blood pressure in hypertensive patients and animals before it reaches its maximal beta 1-adrenoceptor blocking effect. Therefore, the racemic mixture of 50% d-nebivolol and 50% l-nebivolol seems to contain the two compounds in near optimal proportions for an antihypertensive effect.

Platelet-mediated vascular permeability in the rat: A predominant role for 5-hydroxytryptamine

The intradermal injection in rat skin of washed, thrombin-activated platelets produces an increase in vascular permeability, the intensity of which increments with the platelet concentration. Pretreatment of the recipient animals with serotonergic antagonists, including the specific 5-HT2 receptor blocker ketanserin, potently inhibits the platelet-mediated and the 5-HT-induced vascular defect. Amine depletion of platelets or skin tissues with reserpine reduces the response to platelets. Platelet prostanoid and lipoxygenase derivatives play no major role in the vascular response to platelet. The permeability increase induced by exogenous 5-HT and by activated platelets is reduced by alpha 1-adrenergic stimulation with noradrenaline or phenylephrine and by beta 2-stimulation with terbutaline or isoprenaline, and is potentiated by adenosine; this points to a modulation of permeability by blood flow changes and to a direct beta-adrenergic effect at the endothelial cell membrane. This study demonstrates a predominant role for 5-HT in the platelet-mediated vascular permeability increase in a sensitive species like the rat.

Specific α-adrenoceptor blocking effect of droperidol on isolated smooth muscles

Abstract The present study was conducted so as to obtain more insight into the controversies concerning the α-adrenoceptor blocking properties of droperidol, a short-acting neuroleptic agent used in neuroleptanalgesia. The effect of droperidol on the vasoconstriction induced by norepinephrine, sympathetic nerve stimulation, histamine and potassium ions was studied on isolated, perfused ear arteries; its effect on norepinephrine-induced contraction was studied on isolated aorta, spleen and vas deferens. In addition, the onset and duration of action of droperidol was studied. Low doses of droperidol inhibit the vasoconstriction induced by norepinephrine and sympathetic nerve stimulation in the ear artery of the rabbit (3.3 × 10 −9 M and 1.3 × 10 −8 M respectively). At similar low doses, droperidol inhibits norepinephrine-induced contractions in the other tissues studied and has a potency comparable to that of phentolamine; its action is rapid in onset and of short duration. High doses of droperidol (10 −6 M) also inhibit the vasoconstriction of the ear artery induced by histamine and by potassium ions. These findings indicate that at low doses, droperidol has specific and competitive α-adrenoceptor blocking effects.

Cardiac and hemodynamic effects of intravenous R80122, a new phosphodiesterase III inhibitor, in a canine model of myocardial ischemia and heart failure.

Summary: The cardiac and hemodynamic effects of R80122, a new specific phosphodiesterase III inhibitor, were studied in a closed-chest canine model of acute global left ventricular ischemia complicated by heart failure. The results obtained were compared with those obtained with milrinone. Intravenous infusion of the compounds (0.005 mg/kg/min for both) was started when stable heart failure had developed and was continued for 50 min followed by a washout period of 60 min. Both R80122 and milrinone improved the function of the acutely failing heart, as indicated by the increase in the values of the variables related to left ventricular function, but differences existed. The most striking differences were the normalization of the left ventricular external mechanical efficiency with R80122, but not with milrinone, and the maintenance of aortic blood pressure during infusion of R80122, which decreased during infusion of milrinone. Milrinone tends to induce ventricular tachycardia more frequently than R80122. It can be concluded that R80122 and milrinone improve the function of the acutely failing heart, but that the changes induced by R80122 are better balanced, i.e., enhancement of external mechanical efficiency with maintenance of aortic blood pressure.