G. Franchi

Kinins and intracranial hemorrhages.

* Department of Medicine, Division of Clinical Pharmacology, University of Florence, Florence, Italy. Presented at The Tenth Annual Meeting of the International College of Angiology, Geneva, Switzerland, July 23 to 28, 1968. This research was financed partly by the National Research Council, Rome, Italy. The pathogenesis of some of the phenomena which follow apoplexy and subarachnoid hemorrhage, even today, has not been convincingly interpreted. It is logical that under these conditions one should not look for the mechanism of these phenomena only in large, asphyctic processes, either edematous or destructive, but also in the action of the biologic substances which may be activated and concentrated in nervous tissue and in the cerebrospinal fluid (CSF) after intracranial bleeding. Recent advances in biochemistry and pharmacology give evidence that vari-

Prekallikrein and Kallikrein Inhibitor in Plasma of Patients Affected by Recent Myocardial Infarction

Different causes may carry to the shock. The shock credibly has a pathological substrate, that is a damage of the microvessels, particularly capillaries and venules, vasa vasorum included; the sufference of the microvessels concerns mainly the endothelial and basal membrane. Pathogenetically the basic mechanism of the shock is the capillary damage by hypoxia. Hypoxia, in order to establish a capillary damage, must be calibrated in intensity and duration; differently hypoxia, if too important and acute, provokes death following an acute brain damage; if instead too slight, hypoxia does not damage sufficiently the microvessels.

Human 5-hydroxytryptamine venomotor receptors

Abstract The venoconstriction test (VCT) is a method for exploring the monoamine venomotor receptors in man: it is a painless, innocuous technique, able to give the maximum information with the minimum trouble, according to the requirements of the clinical pharmacological tests. The VCT records the local venospasm when very small amounts of 5-HT, noradrenaline or epinephrine are administered through a needle inserted orthodromically into the vein. The VCT is a suitable technique for an acceptable pharmacological evaluation of the vascular reactivity to 5-HT in man. The threshold effect, even if different from subject to subject, is quite constant in the same subject; the threshold doses of 5-HT in the majority of adult men and women, range between 100 and 500 ng. The inhibiting activity of anti-serotonin drugs such as LSD-25, BOL-148, methysergide, nicergoline, BC-105, cyproheptadine, and MY-25 is evaluated in man in quite a satisfying way. An unexpected result was the enhancement of 5-HT and noradrenaline reactivity by treatment with monoamine oxidase inhibitors. Supersensitivity to 5-HT but not to noradrenaline has been observed following administration of parachlorophenylalanine, a specific 5-HT depletor. Skin reaction, capillary permeability, blood pressure and blood flow are used to test the vascular activity of 5-hydroxytryptamine ( Fontanini et al. 1958 ; Scherbel and Harrison, 1958 ; Halpern et al. 1960 ): however, these parameters, when applied in human pharmacology, are quite unsuitable because of technical difficulties, scarce sensitivity and reproductivity. Human veins are very sensitive to the spasmogenic action of 5-HT ( Magalini et al. 1956 ). However the venous tone is quite difficult to measure because of the influence of the autonomous nervous system and of the humoral agents ( Duggan et al. 1953 ; Sharpey-Schafer and Ginsburg, 1962 ; Sharpey-Schafer, 1963 ). few years ago a technique was arranged to test the sensitivity of the 5-HT venomotor receptors in man ( Sicuteri et al. 1964 ). This technique (venoconstriction test: VCT) is based upon the high responsiveness to 5-HT of the vein. The method is highly sensitive, being able to detect the activity of fractions of micrograms of 5-HT; it is practically painless and innocuous, in view of the exiguity of the doses; and the results are quite constant and reproductive. VCT has been used successfully to test agonists, antagonists and correlated drugs on the monoamine (5-HT and catecholamines) venomotor receptors: in the present paper we have collected the most significant information on the human pharmacology of the 5-HT venomotor reactivity, reported fragmentarily in short communications ( Sicuteri et al., 1964a , Sicuteri et al., 1965 , Sicuteri et al., 1966 ).

Some Physiological and Pathological Roles of Kininogen and Kinins

Some biological substances may be called “vasoneuroactive” since their target organs are the blood vessels and the nervous system (Sicuteri, 1965b). This is an arbitrary way to group these substances but useful for handling the pathogenetic problems of some important syndromes characterized by local circulatory disorders and nervous reactions, such as neuropsychic troubles and pain.

Impaired 5-Hydroxytryptamine Tachyphylaxis in Migraine

Tachyphylaxis (TPX) to the spasmogenic activity of 5HT can be demonstrated in vivo in the superficial hand dorsal veins in man by the computerized venotest. The 5HT-TPX is reverted by previous local naloxone administration. Tachyphylaxis to 5HT is usually absent in the migraineur. The restored 5HT spasmogenic effect by naloxone suggests the possibility of local opioid apparatus participation in TPX to 5HT.

COAGULATION CHANGES DURING MIGRAINE.

Biologically active substances regulating caliber and permeability of the capillary vessels are probably important in the pathogenesis of migraine.1-3 Substances like serotonin, histamine and bradykinin have three biologically active characteristics common to all other similar compounds : they all (1) dilate the capillaries, increasing their permeability; (2) have a remarkable painful effect; and (3) induce changes in the function of the nervous system, particularly in the behavior.

Painful vein overdistension in migraine patients: no relationship with serotoninergic parameters

Overdistension of the hand-forearm veins after a period of ischaemia-induced stasis causes local pain in a high percentage of migraineurs, but never in healthy subjects. To investigate the mechanism of such pain, we compared 5-hydroxytryptamine (5HT) whole blood levels and hand vein 5HT reactivity of migraine subjects who did experience pain during venous overdistension to those who did not. No differences were found in whole blood 5HT levels or in the venoconstrictor activity of 5HT between subjects experiencing pain and those who did not. No correlation was found between whole blood 5HT levels and the degree of 5HT-induced venoconstriction. Our results suggest that, if platelets are considered as a model of central antinociceptive 5HT neurons, pain appearance is not due to reduced 5HT at a central level and, therefore, to increased perception of peripheral nociceptive stimuli. Moreover, the similar 5HT venoconstrictive effect (indirect marker of venous tone and, therefore, of venous distensibility) seems to indicate that a mechanical factor is not involved in pain appearance during the HAVD test.

Plasmatic Kininogen in Acute Hepatitis and in Liver Cirrhosis

The first researches on the kininogen level in plasma indicated that the probable site of synthesis of this precursor was the liver (Diniz et al., 1961; Diniz and Carvalho, 1963). This observation was based upon the fact that, being the liver the main site of the protein synthesis, it was natural to beleive that also the polypeptide sequence of kininogen was realized in this organ. We still lack, however, of direct evidences of this situation in man; as regards to the animal, Bryan et al. (1971) were able to prove in the rat that the synthesis of kininogen occurs in the liver. However, in man we still lack of evident proofs. Diniz et al. (1961, 1963) noticed that in serious damage of the hepatic functions, namely cirrhosis, the plasmatic kininogen resulted to be depressed.

Adrenergic Receptors and Kinins

Epinephrine, as it is known, exhibits a diphasic effect on the blood pressure. In hypertensive patients, if small amounts of epinephrine are used, the hypotension is more evident than hypertension (Greppi 1932, Goldenberger et al. 1948). The effect of nor-adrenaline is simply monophasic. The first phase by epinephrine, namely slight hypertension, is due to the alpha-receptor stimulation; second phase, namely hypotension, is due to a beta-receptor stimulation (Alhquist 1948).

Role of kinins in the mechanism of the sterile carditis from myocardial infarction

platelets are refractory to aggregation by AA in vitro (CHIGNARD and VARGAFTIG [1]). In this species a moderate thrombocytopenia accompanies the hypotensive effects of AA (0.3-1 mg/kg). The thrombocytopenia and hypotension induced by AA are increased 2-fold by ADP. Linoleie acid, which is not a PG precursor, induces a comparable thrombocytopenia, but fails to induce hypotension. Moreover, although AA induced hypotension is inhibited by aspirin (10 mg/kg), the accompanying thrombocytopenia is not affected by the drug. The effects of AA in dogs are thus not fully PG-synthetase dependent. Cat platelets aggregate in vitro in the presence of AA. In this species, AA (0.3 mg/kg) induces hypotension and moderate thrombocytopenia. 5HT is a powerful platelet aggregating substance in cats, in vivo (20-40 #g/kg)and in vitro. Cyproheptadine (1 mg/kg) suppressed the effects of 5HT, but failed to interfere with those of AA, which were totally inhibited by aspirin. AA was a powerful hypotensive agent in rabbits (active dose: 50-100 /tg/kg); at these doses no thrombocytopenia was observed. Finally, hypotension, bronchoconstriction and thrombocytopenia were induced by AA (0.1-0.3 mg/kg) in guinea-pigs, all of them being inhibited by aspirin. Platelet depletion failed to prevent the effects of AA in all tested species, whereas bronchoconstricfion elicited by ADP or by ATP was suppressed under these conditions (LEFORT and VARGAFTIG, 1975 [10]). We conclude that the hypotensive effects of AA are plateletindependent, since they occur after platelet depletion. With the exception of the dog, AA induces systemic effects when transformed by the action of the aspirin-sensitive PG synthetase. Guinea-pigs are the best-known species for studies of AA-induced PG synthetase-dependent effects in vivo, since in this species bronchoconstriction and hypotension are accompanied by intense and reversible thrombocytopenia, which is inhibited by aspirin.