In a study with healthy volunteers (6 monozygotic and 4 dizygotic twin pairs) we followed up diazepam serum levels and psychotropic effects of diazepam after single-dose administration. We found that pharmacokinetic properties of diazepam as well as its influence on memory and performance are probably not under genetic control. On the other hand, genetic factors seem to contribute to effects of diazepam on affectivity.
Summary— The effects of verapamil (120 mg orally) and a placebo on arterial pressure, heart rate, PR interval, arterial flows and diameters of the brachial and carotid arteries (pulsed Doppler technique), forearm vascular resistance, and venous diameter and compliance (cutaneous microstrain gauge and plethysmography) have been compared over a 10‐hr period in six healthy volunteers during a double‐blind and cross‐over study. Verapamil reduced diastolic blood pressure by approximately 10 mm Hg, did not affect heart rate and increased PR interval by approximately 15%. Verapamil significantly increased brachial and carotid arterial blood flows by 56% (P<0.01) and 16% (P<0.05), respectively, but the diameters of these vessels were not significantly modified (+ 7 and + 4%, respectively, NS). Forearm vascular resistance decreased by 40% (P<0.01), indicating that verapamil preferentially dilates small arteries. All these effects peaked at 2 h after drug intake and lasted for 6 h. Verapamil increased hand dorsal vein diameter and flow by 95% (P<0.05) and 80% (P<0.05), respectively, from 2 to 4 h after drug intake but venous compliance, assessed by the venous diameter/venous flow ratio, was not significantly modified (from 0.71 to 0.69, NS), thus indicating that veins are not directly affected by this drug.
The properties of some tricyclic and non-tricyclic antidepressants on antagonist histamine H1 and muscarinic acetylcholine receptors have been evaluated on guinea-pig ileum. They act like competitive antagonists on histamine H1 receptors. Some of them show a competitive antagonism and others a non-competitive antagonism on muscarinic acetylcholine receptors. A few of them are very potent antagonists on histamine H1 and/or muscarinic acetylcholine receptors, while others, especially the non-tricyclic antidepressants, have a small potency. All antidepressants have a higher histamine H1 activity than muscarinic acetylcholine activity. These results cannot explain the therapeutic effect of these drugs, but they can account for some side effects and drug interactions.
The renal and iliac vascular effects of dopamine were compared in pentobarbital anaesthetized rats. Local vascular resistances were calculated from simultaneous measurement of blood pressure, renal and iliac blood flow. Without pretreatment, dopamine increased renal and iliac vascular resistance. After pretreatment with prazosin, dopamine decreased the renal vascular resistance while the iliac vascular resistance was still increased. After a combination of yohimbine and prazosin pretreatment, dopamine lowered both the renal and iliac vascular resistance by 30%. These responses were not modified by the beta-adrenoceptor antagonist, sotalol, or by pretreating the rats with reserpine. The renal but not the iliac vascular response to dopamine was abolished by (+)-butaclamol, a stereoselective dopamine receptor antagonist, and by SCH 23390, the DA1-selective dopamine receptor antagonist. The decrease in iliac vascular resistance was not modified by indomethacin or the non-selective 5-HT receptor antagonist, metitepin. These results show that after blockade of alpha1 and alpha2-adrenoceptors, dopamine induces iliac vasodilation by a postsynaptic mechanism independent of an interaction with beta-adrenoceptors, dopamine or serotonin receptors. They also confirm in the rat in vivo the existence of renal vasodilation mediated by DA1 dopamine receptors.
Cats and rats anaesthetized with pentobarbital were used to study the central cardiovascular effects of the clonidine displacing substance (CDS). The potential influence of centrally applied CDS on the cardiovascular effects of clonidine was also investigated in both species. CDS is a brain substance which is not a catecholamine (CA) and which displaces completely the binding of tritiated clonidine to brain membranes. It was observed that direct application of CDS unilaterally to the nucleus reticularis lateralis (NRL), a privileged site of action for clonidine in the cat, increases markedly the mean arterial pressure (MAP) and does not affect the heart rate (HR). CDS also causes hypertension when infused into the left vertebral artery in the cat. When MAP reverted to baseline, the hypotensive effect of clonidine given by the same route is significantly prevented. In rats, the intracisternal administration of CDS increased MAP without affecting HR. Here also, the CDS pretreatment antagonized the hypotensive effect of i.v. clonidine as compared with control animals. It is concluded that CDS is an endogenous non-catecholamine ligand for receptors involved in the hypotensive effect of clonidine. This substance interferes with clonidine on these receptors. It is a candidate as a neuromodulator or a neurotransmitter involved in the blood pressure regulation at least in the NRL region.
The effects of selective inhibitions of both cyclo-oxygenase and lipoxygenase pathways were studied in the isolated, perfused and ventilated guinea-pig lungs. Leukotriene D4 (0.3 nmol) induced a significant bronchoconstriction. This effect was significantly inhibited by IPL 55712 (a SRS-A antagonist) and by Imidazole or Dazoxiben (specific thromboxane synthetase inhibitors), but aspirin and indomethacin were without significant effect on this broncho-constriction. Our results suggest that the principal component of leukotriene D4 induced bronchoconstriction in guinea-pig lungs is primary.
