Paul M. Vanhoutte

Selectivity of calcium antagonism and serotonin antagonism with respect to venous and arterial tissues

There are marked differences in responsiveness to naturally occurring vasoactive substances1-4 between isolated blood vessels of different anatomical origin and in particular between arteries and veins. This discussion will deal with two major aspects where arterial and venous smooth muscle differ in their sensitivity to vasoactive agents; their sensitivity to inhibitors of calcium-influx (Ca2+ antagonists) on the one hand and their reactivity to serotonin (5-hydroxytryptamine) and serotonin antagonists, on the other.

Effect of the Ca2+ antagonist lidoflazine on normoxic and anoxic contractions of canine coronary arterial smooth muscle

Anoxia augments contractions of isolated canine coronary arteries to 5-hydroxytryptamine and norepinephrine. Lidoflazine inhibits normoxic contractions to both monoamines and the further increases in tension seen with anoxia in rings exposed to 5-hydroxytryptamine; further increases in tension caused by anoxia in presence of norepinephrine were not affected by lidoflazine. These experiments demonstrate that anoxia can cause constriction of large coronary arteries and that lidoflazine depresses both anoxic and normoxic contractions of coronary smooth muscle.

Effect of age and spontaneous hypertension on the tachyphylaxis to 5-hydroxytryptamine and angiotensin II in the isolated rat kidney.

SUMMARY The isolated and perfused kidney of tbe mature spontaneously hypertensive rat (SHR) exhibits an increased vascular reactivity and a delayed tachyphylaxis to 5-hydroxytryptamine, when compared to weight-matched normotensive animals. To evaluate the influence of the duration of the hypertensive state on these differences, the vascular reactivity to 5-hydroxytryptamine was determined in isolated kidneys from agematched normotensive and spontaneously hypertensive rats of 3.5, 6 and 12 months of age. Responses to increasing doses of 5-hydroxytryptamine were compared. At all ages the responses to the agonist were greater in the SHR than in the control rats. In the normotensire rats, the sensitivity to the monoamlne decreased, while the maximal response increased with aging. The vascular reactivity to increasing doses of 5-hydroxytryptamine was not altered by aging in the SHR. There was a significant correlation between the maximal vasoconstrictor response to 5-hydroxytryptamine in the isolated kidneys and the systolic arterial blood pressure (SBP) of the donor rats. Maximal constrictor responses to 5-hydroxytryptamine were repeated at given intervals. Tbe degree of tachyphylaxis was decreased in hypertensive rats compared with normotensive rats at 3.5, and 6 months of age. Tacnyphylaxis to 5-hydroxytryptamine was depressed by aging in both normotensive and hypertensive rats. By contrast, tachyphylaxis to angiotensin II (AH) was not effected by either age or hypertension. There was no cross-tachyphylaxls between 5-hydroxytryptamine and AH. Lowering the Cal+- concentration of the perfusate did not affect tachyphylaxis to either 5-hydroxytryptamine or AH. The present experiments indicate that the delayed tachyphylaxis to 5-hydroxytryptamine in the kidneys of SHR is due to a specific alteration of the vascular smooth muscle cells, which may be the consequence of premature aging.

Cocaine-induced release of noradrenaline in rat tail artery

consistently lower than their arterial counterparts, the estimated amount eliminated will then be smaller and result in a larger estimated amount of drug remaining in the body. This will be the case even at the attainment of the steady state as shown in Fig. la. As a result, estimated V,, values from venous data are higher than from arterial data. The dotted lines in Fig. la , would be obtained if the infusion continued to the steady state. From a physiological point of view, the driving force for drug distribution and elimination lies mainly in the arterial blood (Chiou 1981, 1982a; Chiou & Lam 1982: Chiou et al 1981), hence the use of arterial plasma data is more appropriate to describe the disposition kinetics of drugs. The results of the present study have demonstrated the uptake and release of procainamide by the leg (assumed to be a non-eliminating tissue) during infusion and postinfusion periods, respectively. V,, determination from arterial plasma, therefore, better reflects the true apparent distribution volume of procainamide in these rabbits. The inclusion of an additional non-eliminating tissue from a venous sampling site simply increases this volume term by a factor of 1.5. Similar magnitudes of difference due to the use of arterial or venous plasma data in the determination of the V,, of propranolol in dogs and rabbits have also been recently reported (Lam & Chiou 1981). In the light of the potential effect of the A-V difference on the determination of V,, and the difficulty and risk involved in sampling the systemic arterial blood, new equations employing venous plasma and urinary excretion data have been recently proposed for V,, determination (Chiou & Lam 1981; Chiou 1982a). In other words, the determination of V,, using these new equations is theoretically independent of the source of blood or plasnta employed. Finally, the observed A-V differences are not unique in this study; they have been reported for many compounds in animal and human (Chiou et al1981; Orskov & Christensen 1969; Slot 1965; Tucker & Mather 1979). Their implications in the determination and in the physiological significance of the apparent volume of distribution at the pseudodistribution equilibrium (Chiou 1981), and the total body clearance (Chiou 1982b) have been recently discussed.

Effect of removal and substitution of potassium ions on the adrenergic and cholinergic reactivity in canine femoral artery

Canine femoral arteries responded to acetylcholine with relaxations; these were abolished in potassium free solution, restored by potassium or rubidium but not by cesium or amonium. Potassium and rubidium were equipotent in inducing ouabain-sensitive relaxation, while amonium and cesium were less potent. The results (1) confirm that sodium-potassium exchanges are indirectly involved in cholinergic relaxation of arterial smooth muscle and (2) suggest that membrane hyperpolarisation resulting from increased electrogenic sodium transport does not affect the inhibitory response to the cholinergic transmitter.

LOCAL CONTROL OF VENOUS FUNCTION

Publisher Summary nAlterations in venous diameter affect hemodynamics both at the local and the general level. Locally, the degree of opening of the veins is one of the factors determining the ratio between pre- and post-capillary resistance and, thus, the movements of fluid to the tissues. From the general hemodynamic point of view, changes in venous diameter help adjust the total capacity of the cardiovascular system and, thus, the return of blood to the right heart; in the skin, they contribute mainly to thermoregulatory adjustments. The diameter of each vein is at each moment the resultant of the distending pressure within it (passive changes) and of the degree of activity of the smooth muscle cells in its wall (active changes). Venous smooth muscle cells possess the morphological characteristics of contractile tissues; they contain sarcoplasmic reticulum, mitochrondria, and contractile proteins. The trigger for contraction is the change in membrane permeability that is associated with changes in membrane potential.

Physiopathology and Pharmacotherapy of Occlusive Arterial Disorders

When the metabolic demands of the tissues exceed the ability of the cardiovascular system to provide them with enough blood, the resulting tissue ischemia may endanger its function. In cardiac and skeletal muscle, the accumulation of anaerobic metabolites causes stimulation of pain receptors, which then cause the symptoms of angina pectoris and intermittent claudication, respectively. These symptoms are nonpathognomonic, and they may have a nonvascular origin, such as severe anemia, prolonged isometric exercise, or hypoxemia.