Bengt Ljung

Increased noradrenaline release in rat portal vein during sympathetic nerve stimulation due to activation of presynaptic β-adrenoceptors by noradrenaline and adrenaline

With the aim of investigating whether exogenous noradrenaline (NA) and adrenaline (A) can modulate transmitter release via the stimulation of presynaptic beta-adrenoceptors, 3H-release from isolated portal veins was studied after pretreatment with 3H-1-NA, phenoxybenzamine, desipramine and normetanephrine. NA (10 muM) and A (0.05 muM) increased the fractional 3H-release elicited by sympathetic nerve stimulation by 30%. This effect could be blocked by d, 1-propranolol which per se reduced the release by 10%. It is concluded that NA can facilitate its own release via a presynaptic beta-adrenoceptor-mediated positive feed-back mechanism and that adrenaline can stimulate this beta-adrenoceptor-mediated mechanism.

Renal and cardiovascular effects of acute and chronic administration of felodipine to SHR

Renal function and salt and water turnover were studied in SHR during acute and chronic administration of felodipine, which is an efficient antihypertensive vasodilating Ca2+ antagonist. In conscious SHR acute administration of felodipine in hypotensive doses increased renal sympathetic nerve activity but caused renal vasodilation, increases in GFR and a 2-3 fold increase in urinary flow rate and sodium excretion. The fraction of filtered sodium excreted (FENa) was approximately doubled. The diuretic and natriuretic effects of felodipine are therefore suggested to be due to a direct inhibitory action on the renal tubular cells, resulting in reduced sodium reabsorption. Nifedipine also induced diuresis and natriuresis in this system, while minoxidil reduced water and sodium excretion. Throughout 6 months of felodipine treatment, the mean arterial pressure (MAP), remained 25-20 per cent reduced. Felodipine in combination with metoprolol reduced MAP 25-30 per cent and also caused regression of left ventricular hypertrophy, while felodipine alone prevented its further progression. Also during chronic administration, felodipine induced diuresis but had no effect on plasma volume and on sodium or potassium excretion in SHR. It is concluded that in SHR felodipine induces diuresis; on acute treatment this is secondary to reduced tubular sodium reabsorption, although during chronic treatment the sodium loss is compensated for while the diuresis remains. Thus, the cardiovascular and renal effects of Ca2+ antagonists like felodipine differ substantially from those of other potent antihypertensive vasodilators e.g. minoxidil.

Vibration-Induced Inhibition of Vascular Smooth Muscle Contraction

Vascular smooth muscle is known to be exposed to an oscillating strain under physiological and patho-physiological conditions as well as in different occupational and environmental situations. The effect of vibrations of smooth muscle seems to be largly unknown. In the present experiments on isolated preparations of the rat portal vein and the rabbit thoracic aorta, imposed sinusoidal changes in length were found to cause prompt reduction in active force, the extent of which was dependent on amplitude (1-10% of tissue length, peak to peak, i.e. approximately plus or minus 50-500 mum) and frequency of vibration (1-400 Hz) as well as on the prevailing level of active and passive forces. Vibration caused only small and inconsistant reductions of passive force of vascular smooth muscle. The results are in accordance with the hypothesis that vibrations exert a direct action on the contractile process by causing an increased rate of detachment of actin-myosin cross-links. It is suggested that, in vivo, vibrations may affect the diameter of conduit arteries locally in the case of turbulent blood flow as seen in post-stenotic dilation and arterio-venous anastomosis. Possibly, even the normal pulse pressure oscillations may sometimes tend to inhibit the smooth muscle activity in such arteries and thereby influence their diameters.

Postnatal ontogenic development of the adrenergic innervation pattern in the rat portal vein

SummaryThe postnatal development of the adrenergic innervation pattern in the rat portal vein has been studied with the histochemical fluorescence method of Hillarp and Falck.Stretch preparations and transverse freeze-dried sections of intact portal veins were studied from rats during the first 5 weeks of life and from adult rats. Orientation of undifferentiated smooth muscle cells into two layers was observed at 4 days of age. Dominance of the thick outer longitudinal muscle layer was apparent at two weeks of age. A terminal adrenergic nerve plexus with some varicosities was restricted outside the media at the end of the first week. Ingrowth of penetrating non-terminal adrenergic nerve fibers through the longitudinal muscle layer occurred during the second week of age when the main terminal nerve plexus was developing between the two muscle layers. After 3 weeks of age the adult pattern of a two-dimensional adrenergic plexus between the muscle was established. In the adult rat pharmacological treatment with nialamide and noradrenaline revealed the thin, penetrating non-terminal adrenergic nerve fibers in the longitudinal muscle layer which were poorly visible otherwise.The present observations strongly indicate that the main adrenergic plexus between the two muscle layers emanates directly from the outer axonal plexus. These findings are discussed regarding possible trophic interactions between ingrowing sympathetic adrenergic vasomotor nerves and maturing vascular smooth muscle.

Innervation Pattern and Neurogenic Response of Rabbit Veins

The adrenergic neuroeffector mechanism has been assessed in 14 different veins of the rabbit chosen to represent vessels of different, function and regional location. The pattern, distribution and den

vascular Versus Myocardial Selectivity of Calcium Antagonists Studied by Concentration-time-effect Relations

The vascular versus myocardial selectivity of three structurally different calcium antagonists, felodipine, diltiazem, and verapamil, was studied in vitro. The model used was an isolated portal vein preparation and a paced (3 Hz) papillary muscle of the left ventricle of the rat, examined in the same organ bath. In previous experiments with the same tissues, used for screening and eventual selection of felodipine, it was found that the selectivity factors ranged as follows: felodipine much greater than nifedipine greater than diltiazem greater than verapamil = La3+. Since the effect of organic calcium antagonists is slow in onset, the present experiments were designed to determine the inhibitory potencies and the selectivity factor at equilibrium. This was possible by a computer-assisted collection of contractile force measurements and subsequent analysis of the results. In each experiment, one concentration only of one of the three calcium antagonists was given. The time-effect relation was determined for both tissues. After all experiments with a particular drug, when several concentrations had been administered, the hyperbolic concentration-effect relation was determined at various times of exposure. The ensuing pIC50 values, as related to time, for the vascular and the myocardial preparations, described by monoexponential curves and the corresponding potency values (pIC50), could be determined at equilibrium (t = infinity). It was concluded that the vascular over myocardial inhibitory selectivity was marked for felodipine (103), low for diltiazem (8.9), and none for verapamil (0.92).

Effects of phenoxybenzamine on transmitter release and effector response in the isolated portal vein

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Vascular Selectivity of Felodipine: Experimental Pharmacology

This article presents an overview of experimental studies that illustrate the vascular vs. myocardial selectivity of felodipine. The aim of our project was to develop a calcium antagonist that would selectively inhibit the activity of the myogenically active smooth muscle of the arterial resistance vessels without causing negative inotropic effects. In vitro, selectivity was tested as the concentration ratio at 50% inhibition of the peak force of paced papillary muscle and of the spontaneous myogenic activity of rat portal vein. The latter preparation has consistently been used as an in vitro model of myogenically active vascular (arterial) smooth muscle. It was found that dihydropyridines display different quantitative structure-activity relationships with regard to vascular and myocardial effects. Felodipine was the first compound synthetized that showed 100-fold vascular selectivity. In the same test system, Ca2+ chelators, La3+, and verapamil lacked selectivity. The high vascular selectivity of felodipine has been verified in vivo in various hemodynamic experiments. Thus, felodipine lowers arterial blood pressure due to reduced peripheral resistance without altering cardiac contractility. This is the case in various animal models and applies over a wide range of plasma concentrations whether autonomic nervous control is blocked or not. In contrast, nonselective compounds such as verapamil attenuate myocardial contractility in parallel with a reduction in peripheral resistance.

Neuroeffector Function of Isolated Portal Vein from Spontaneously Hypertensive and Wistar-Kyoto Rats: Dependence on External Calcium Concentration

The calcium dependence of the vascular neuroeffector function has been studied in the portal vein of spontaneously hypertensive Okamoto rats (SHR) and Wistar-Kyoto rats (WKY). The noradrenaline (NA) sensitivity of veins of both species, expressed in terms of ED50, was decreased to the same extent in relation to the reduction in Ca2+ ion concentration below 2.5 mM. The responses to individual NA concentrations at subnormal Ca2+ concentrations were better maintained, however, in portal veins from SHR than from WKY, indicating that the excitation contraction coupling mechanism is less dependent on external Ca2+ concentrations in the portal vein from SHR than from WKY. In both strains of rats the spontaneous myogenic activity of the vessel was depressed in low Ca2+ concentrations to a greater extent than responses to nerve stimulation, which, in turn, were more reduced than the excitatory responses to exogenous NA or acetylcholine (ACh). Transmitter release (fractional overflow of 3H-NA/impulse) was less dependent on Ca2+ concentrations than the contractile nerve stimulation response. The persistence of all responses in reduced Ca2+ concentrations was significantly greater in the portal vein of SHR. It is concluded that the phasic, spontaneously active smooth muscle of the rat portal vein is highly dependent on the external calcium concentration and that various induced responses persist to a varying degree in reduced Ca2+ concentrations. It is suggested that this is due to interference with electromechanical coupling as well as myogenic spread of activation. Induced responses of the portal vein from SHR are, in general, less affected by decreased Ca2+ concentrations than the WKY portal vein, indicating an altered vascular smooth muscle excitation-contraction coupling mechanism in spontaneous hypertension. Possibly an increased efficiency of the coupling mechanism may contribute to augment vascular responses in the development of hypertension and promote structural vascular changes.

Norepinephrine Uptake, Smooth Muscle Sensitivity, and Metabolizing Enzyme Activity in Rabbit Veins

Some parameters of the adrenergic neuroeffector mechanism were measured in vitro in the central ear (near the base of the ear), common jugular, pulmonary, brachial, femoral, renal, superficial cervical, cephalic, and small saphenous veins, a branch of the deep circumflex iliac vein, the parietal branch of the internal iliac vein, branches of the anterior mesenteric vein, the inferior vena cava (immediately distal to the left renal vein), and a subcutaneous vein of the back. Although extraneuronal uptake of 3H-norepinephrine was the same in all of the veins except the mesenteric, the neuronal uptake of norepinephrine varied widely. A number of veins, including the femoral and superficial cervical veins, showed no neuronal uptake, and the uptake of others, including the cephalic and mesenteric veins, was greater than that measured in any previously studied vascular tissue. The median effective dose for the contractile effect of norepinephrine on the veins was on the same order of magnitude as that for the aorta and the ear artery. Catechol-O-methyl transferase, but not monoamine oxidase, activity appeared to be related to innervation density. It is concluded that veins show a remarkable variation in the dimensions of their adrenergic parameters, particularly those related to innervation density.