Axial stretch modifies contractility of porcine coronary arteries by a protein kinase C-dependent mechanism.

Large coronary arteries undergo marked circumferential and axial deformations due to changes in blood pressure and gross movements of the ventricular wall during systole and diastole. The present study was designed to investigate 1) whether axial stretch of large coronary arteries influences the sensitivity to vasoconstrictors, 2) the mechanisms mediating stretch-dependent changes in vascular sensitivity. Endothelium-denuded cylindrical segments from large porcine coronary arteries were studied under isometric conditions using a balloon-based impedance planimetric technique. In segments subjected to a pressure of 60 mmHg, 20% axial stretch caused a left-ward shift of the concentration-response curves for K+ and 5-hydroxytryptamine (5-HT). Enhancement of vascular sensitivity to 5-HT induced by axial stretch was observed also in maximally K+-depolarized coronary arteries. Protein kinase C inhibition by calphostin C (1 microM) slightly decreased the spontaneous resting tone at 60 mmHg and inhibited the leftward shift of the concentration-response curve for 5-HT elicited by axial stretch. These results suggest that axial stretch of the vessel wall enhances the sensitivity of coronary arteries to vasoconstrictors by a protein kinase C-dependent mechanism.

Studies on concentration-time profiles of nimodipine enantiomers following intravenous and oral administration of nimodipine in patients with subarachnoid hemorrhage.

After i.v. and oral administration of nimodipine the concentration-time profiles of the drug and its enantiomers were studied in seven patients with subarachnoid hemorrhage. Concentrations of nimodipine, (+)-(R)-, and (-)-(S)-nimodipine were analyzed using a new stereoselective high-performance liquid chromatographic method. During the first 3 h after oral administration the concentrations of (+)-(R)- and (-)-(S)-nimodipine were significantly different, the (-)-(S)-enantiomer being found in much lesser concentrations compared to the (+)-(R)-enantiomer. The results indicate that if uptake from the gastrointestinal system is equal for the two enantiomers, then (-)-(S)-nimodipine is metabolized at a much faster rate compared to (+)-(R)-nimodipine after oral administration of the drug in patients with subarachnoid bleeding. After i.v. administration; no significant differences between the concentrations of the (-)-(S) and the (+)-(R) isomers were demonstrated.

Vascular reactivity to nifedipine and Ca(2+) in vitro: the role of preactivation, wall tension and geometry.

The purpose of the study was to investigate the influence of preactivation, wall tension and geometry on the reactivity of porcine coronary arteries to nifedipine and extracellular Ca(2+) in vitro. Porcine large coronary arteries were mounted as ring and cylindrical preparations and studied by wire- and balloon-based techniques. The sensitivity and maximal responses to nifedipine were more pronounced in 25 mM K(+) compared to 10 microM prostaglandin F(2alpha)-contracted preparations. Vascular sensitivity to nifedipine and Ca(2+) was enhanced under isometric compared to isobaric conditions. Under isometric conditions in the presence of 25 mM K(+), coronary rings were more sensitive to nifedipine, but less sensitive to Ca(2+) compared to cylindrical segments. In cylindrical segments, circumferential and axial tension increases augmented the extracellular Ca(2+)-dependent spontaneous resting tone and the sensitivity to extracellular Ca(2+). Coronary rings showed no resting tone at various resting tensions. These results suggest that preactivation, wall tension and vessel geometry are important determinants of Ca(2+)-influxes via nifedipine-sensitive voltage-gated Ca(2+) channels. Furthermore, axial wall tension appears to be a modulator of nifedipine-insensitive transmembrane Ca(2+)-influx that may play a role for the tone and reactivity in large coronary arteries.

Responses to potential vasoactive substances of isolated mammary blood vessels from lactating sows.

The purpose of the investigation was to examine the response of the milk vein and the mammary artery to potential vasoactive substances in lactating sows. The response on artery and vein segments from the same sow was measured for the following substances: noradrenaline (NA), serotonin (5-HT), prostaglandin F2alpha (PGF2alpha), prostacyclin (PGI2), histamine (Hi) and potassium (K+). Interestingly, the contractile force in the mammary vein segments expressed per weight unit (mN/mg) was 1.5-2.5 fold larger than in the artery segments when NA, 5-HT and PGF2alpha were used, but similar for K+, Hi and PGI2. In vein segments, the order of sensitivity to the substances expressed by their pD2 values was 5-HT > NA = PGF2alpha > Hi > K+. The present findings suggest that NA, 5-HT, PGF2alpha, PGI2, and Hi are involved in mammary blood flow regulation in the sow, and the mammary venous system may be as important as the mammary arterial system in this regulation.

A new experimental approach in endothelium-dependent pharmacological investigations on isolated porcine coronary arteries mounted for impedance planimetry.

1. The aim of this study was to investigate whether the balloon-based impedance planimetry technique could be a useful tool in endothelium-dependent investigations. 2. Porcine large coronary arteries contracted with prostaglandin F2alpha (PGF2alpha, 10 microM) did not relax to bradykinin (0.1 nM - 0.1 microM), but did relax to sodium nitroprusside (SNP, 10 microM). However, after eversion of the segments, bradykinin induced relaxations with pD2 values and maximal responses of 8.78+/-0.09 and 75+/-2% (n=6), respectively. 3. Incubation with captopril (1 microM) did not reveal a relaxation to bradykinin in the normal vessel configuration and had no influence on the concentration-relaxation relationship in everted segments. 4. Lowering the luminal pressure in contracted segments from 131+/-5 mmHg (isometric, n=5) to 60 mmHg (isobaric, n=5) did not facilitate the action of bradykinin. 5. Eversion of segments did not influence the concentration-response relationship for K+ (4.7 - 125 mM), PGF2alpha (0.3 - 30 microM), and SNP (30 nM - 30 microM), although the time-courses of responses were faster when the agents were added from the intimal compared to the adventitial side of the preparation. 6. In the same everted segment contracted with PGF2alpha, the concentration-response relationship for bradykinin was not different under isometric and isobaric conditions. 7. These results indicate that, (1) reduced endothelium-dependent relaxations to adventitially administered substances can be ascribed to a diffusion barrier in the vessel wall, while enzymatic degradation, luminal pressure and precontractile responses seem not to play a role, (2) impedance planimetry applied to everted cylindrical segments could be a useful experimental approach in pharmacological studies of endothelium-dependent responses under isobaric and isometric conditions.

The influence of transmural pressure and longitudinal stretch on K+- and Ca2+-induced coronary artery constriction.

UNLABELLED: The aim of the study was to investigate transmural pressure and longitudinal stretch modulation of K+- and Ca2+-induced constriction of porcine conductance coronary arteries. In a pressure myograph set-up, left anterior descendent coronary arteries from 70 to 90 kg pigs were investigated at pressures from 20 to 120 mmHg. Longitudinal extension ratio (lambda = L/L0(-1), where L0 is the in situ length and L the examination length) varied between 0.9 and 1.1. Two protocols were carried out: (1) Outer diameter response to maximal depolarization by K+ 125 mM at 20-120 mmHg and lambda at 0.90-1.10. (2) Concentration-response curves with K+ (4.7-125 mM) and Ca2+ (0.05-4.0 mM) at four combinations of P and lambda (P = 100 mmHg, lambda = 0.9; P = 100 mmHg, lambda = 1.1; P = 40 mmHg, lambda = 0.9; p = 40 mmHg, lambda = 1.1). RESULTS: Endothelial function was preserved. A slight (<5% diameter reduction) basal tone and no myogenic response was found. Protocol 1: the constriction to K+ 125 mM was maximal in a wide pressure range from 40 to 120 mmHg. Despite the fact that K+-induced diameter changes were statistically insignificant between 40 and 120 mmHg, there was a linear trend towards smaller diameter changes in this pressure range (r = -0.54, P < 0.01). Stretch influenced constriction at 20 mmHg because lambda = 0.90 and 0.95 resulted in smaller diameter-reductions than lambda = 1.00-1.10 (P < 0.05 for all). Contrastingly, at 120 mmHg the constriction at lambda = 1.10 was smaller than the responses at lambda = 0.90-1.05 (P < 0.05 for all). Protocol 2: EC50 and EC10 values for K+- and Ca2+ were generally higher (more sensitive) at 40 compared with 100 mmHg. Stretch was of no significant importance for EC50 and EC10 at 40 and 100 mmHg. It is concluded that porcine coronary artery constriction to non-metabolized agonists is maximal at 40 mmHg with a trend towards smaller diameter changes with higher pressures. Longitudinal stretch affects responsiveness at pressure extremes.

A new method for combined isometric and isobaric pharmacodynamic studies on porcine coronary arteries.

1. The principal aim of the present study was to explore the isometric and isobaric capacity of a new intravascular technique, impedance planimetry, in basic pharmacodynamic investigations on porcine isolated epicardial coronary arteries. 2. The balloon-based catheter technique provides simultaneous measurements of luminal cross-sectional area and pressure. Sources of errors that may influence the accuracy of measurements were evaluated in detail. 3. Under isometric conditions, the stretch ratio-tension diagram showed typical developments of resting and active tensions of the smooth muscle when exposed to alternating maximal K+ depolarization and mechanical stretching. The mean (+/- SEM) maximum active tension was 28.43 +/- 1.72 mN/mm, which was reached at a stretch ratio of 1.26 +/- 0.02, corresponding to a resting tension of 10.50 +/- 0.53 mN/mm (n = 7). The concentration-response relationship to K+ at optimal basal tension was characterized by a mean (+/- SEM) pD2 value of 1.67 +/- 0.01 (n = 7). 4. Under isobaric conditions in the pressure range 40-140 mmHg, the method allowed the investigation of active vascular responses to partial K+ depolarization. The maximal active response to 25 mmol/L K+ was found at the transmural pressure of 60 mmHg (n = 7). To obtain full K+ concentration-response curves, a basal tension corresponding to a transmural pressure of 120 mmHg was required. The mean (+/- SEM) pD2 value for the concentration-response relationship to K+ was 1.53 +/- 0.01 (n = 10). 5. The vascular sensitivities to cumulatively added K+ and various agonists, such as acetylcholine, 5-hydroxytryptamine and noradrenaline, obtained from the same vessel segment at the same initial conditions corresponding to 120 mmHg were significantly higher with the isometric than with the isobaric approach. 6. The results of the present study suggest that impedance planimetry could be a useful tool in pharmacological and physiological investigations of medium-sized arteries, both under isometric and isobaric conditions.

Regional differences in the vasorelaxant effects of nicorandil and amlodipine on isolated porcine coronary arteries.

The vasorelaxant effects of nicorandil, a K(+)-channel opener, and amlodipine, a dihydropyridine-type Ca(2+)-channel blocker, were investigated on partially and maximally K(+)-depolarized ring preparations from the porcine left anterior descending coronary artery. By comparing vascular responses in the proximal and distal parts of the epicardial segment, the scope of the study was to evaluate regional differences in the action of nicorandil and amlodipine. Nicorandil (10(-7)-10(-4) M) shifted the K+ concentration-response curves to the right and depressed the maximal contractile responses in a concentration-dependent manner, consistent with K(+)-channel opening and secondary non-K(+)-channel opening mechanisms of action. Nicorandil had a significantly more potent relaxant effect in the proximal compared to the distal arterial rings contracted with 85 mM K+. Pretreatment with methylene blue (10(-5) M) did not significantly influence the regional difference in the action of nicorandil. Amlodipine (10(-9)-10(-6) M) had a significantly more potent and effective inhibitory and relaxant effect than nicorandil under the same conditions. In contrast to nicorandil, the effect of amlodipine was more prominent in the distal compared to the proximal vessel rings. The cumulative addition of extracellular Ca2+ exhibited a more potent contractile response in the distal rather than in the proximal rings. Nicorandil totally and amlodipine partly eliminated the contractile responses to the lowest concentration of Ca2+. The inhibitory effect of amlodipine on the contractile responses to higher Ca2+ concentrations was more pronounced than that of nicorandil. The results show that there are regional differences in the responsiveness of porcine coronary arteries to Ca2+, nicorandil and amlodipine. Our findings indicate that the regional difference in nicorandil-induced vasodilation was caused neither by the K(+)-channel opening nor by the nitrate-like mechanism of action, but could be due to a direct Ca(2+)-influx blocking effect of the drug.

Porcine coronary artery pharmacodynamics in vitro evaluated by a new intravascular technique: relation to axial stretch.

A new intravascular balloon catheter-based technique, impedance planimetry and the wire-mounted isometric tension technique commonly employed to study vessel pharmacodynamics in vitro, were compared. Porcine left anterior descendent coronary artery reactivity to nifedipine was assessed and the influence of 20% axial stretch was investigated. There were no histological differences between segments where the impedance planimetry balloon had been inflated and untouched segments. EC50 values differed significantly between the three procedures applied: The isometric method (n = 7): 2.54 +/- 0.44.10(-9) M; nonstretched arteries by the impedance planimetric method (n = 7): 1.99 +/- 0.40.10(-8) M; arteries 20% axially stretched (n = 7): 2.00 +/- 1.36.10(-7)M (isometric and nonstretched: p < 0.05; isometric and stretched: p < 0.001; nonstretched and stretched: p < 0.05). Maximal relaxant responses to nifedipine were 91.8 +/- 2.1% (isometric method), 105.1 +/- 2.3% (nonstretched), and 104.9 +/- 7.7% (stretched) (ANOVA, p = 0.11). In stretched arteries, the initial 12-min response to an increased dose of nifedipine was more rapid than the response of nonstretched arteries at a concentration of 1.10(-7) M (p = 0.038) and had a nonsignificant tendency toward a more rapid response at other concentrations. Resting tone could not be demonstrated and time control experiments showed no change in the maximal vessel response to potassium with any of the three methods. A new method in the evaluation of artery pharmacodynamics in vitro was presented. The study demonstrated that axial stretching of an artery has impact on the pharmacodynamic reactivity to nifedipine in porcine coronary arteries. Further studies are needed to evaluate the impact of the method on endothelial function.

[Calcium channel blockers (calcium antagonists). Background, effects and use]. / Calciumkanalblokkere (calciumantagonister). Baggrund, virkning og anvendelse.

The calcium ion plays a decisive role in the effect and regulation of several cellular processes. The heart muscle cells, pacemaker and channel systems and vascular smooth muscle are functionally dependent on Ca2+ influx mainly via potential sensitive L (long lasting)-Ca(2+)-channels, which are blocked by Ca(2+)-channel blockers, a group of organic substances binding to specific sites at the Ca2+ channels. The Ca2+ channel blockers are now well established in the treatment of angina pectoris, arterial hypertension, supraventricular arrhythmia and subarachnoidal haemorrhage. On the basis of chemistry and pharmacodynamics the Ca2+ channel blockers are divided into three groups, with verapamil, nifedipine and diltiazem representing 1. generation derivatives and prototypes for groups I, II and III, respectively. All Ca2+ channel blockers act as vasodilators, while group I (verapamil) and to a lesser degree group III (diltiazem) also have antiarrhythmic effects. All Ca(2+)-channel blockers are contraindicated in hypotension. In cases of pronounced bradycardia, sinoatrial and atriventricular block Ca2+ channel blockers with antiarrhythmic effects are contraindicated and must be used with care in combination with beta-blocker treatment and in heart failure. Headache, flushing, reflex tachycardia, nausea, obstipation and ankle oedema are the most important secondary effects. With respect to pharmacodynamics the newly marketed 2. generation derivatives do not differ essentially from the 1. generation derivatives. The clinical potential of the Ca2+ channel blockers is not fully explored and the possibilities for extending their indications are still to be elucidated.

Studies on responses to potassium, noradrenaline, serotonin, histamine and prostaglandin F2 alpha, of isolated pudendal arteries from non-lactating goats.

The effects of potassium (K+), noradrenaline (NA), serotonin (5-HR), histamine (Hi) and prostaglandin F2 alpha (PGF2 alpha) were studied on isolated pudendal arteries from non-lactating goats. K+, NA, 5-HT, Hi and PGF2 alpha had concentration-dependent contractile effects on the arteries. The developed tensions were, in order of potencies, 5-HT > NA > PGF2 alpha > Hi > K+. NA induced a significantly higher maximal contractile force than K+, 5-HT, PGF2 alpha and Hi. Pretreatment with cocaine was without significant effect on the contractile response to NA. The contractile response to Hi was totally eliminated by mepyramine. Ca2+ had a concentration-dependent contractile effect on arteries depolarized by 125 mM K+. The results indicate that NA, 5-HT and PGF2 alpha may play essential roles in the regulation of goat mammary blood flow. The response to K+ is highly dependent on extracellular Ca2+. The contractile response to histamine may be mediated via H1-receptors. The in vitro method used is well suited to study the vascular reactivity in different regions of the mammary vascular bed.

Comparison of in vitro effects of cicletanine, its enantiomers and major metabolite on rat thoracic aorta.

The effects of cicletanine ((+/-)-cic)), its optical isomers (BN-50417,(+)-cic); (BN-50418,(-)-cic) and major metabolite (BN-50699,cic-Met) on active tension were investigated in rat thoracic aortas. (+/-)-cic, (+)-cic, (-)-cic shifted the K(+)-concentration response curve to the right and depressed the maximum contractile response. Cic-Met was devoid of inhibitory effect on K(+)-induced contractions. (-)-Pinacidil had a far more potent inhibitory effect on K(+)-induced contractions than the cicletanine enantiomers and shifted the K(+)-concentration response curve to the right without affecting the maximum contractile response. (+/-)-Cic and nifedipine caused a concentration-related inhibition of Ca(2+)-induced contractions. Nifedipine was far more potent than (+/-)-cic in this respect. The slope of the Schild plot for nifedipine was not different from unity contrary to the significantly different slope for (+/-)-cic. (+/-)-Cic, (+)-cic, (-)-cic and cic-Met (3 x 10(-5) M to 3 x 10(-4) M) caused a concentration-related relaxation of noradrenaline (NA), serotonin (5-HT) and prostaglandin F2 alpha (PGF2 alpha)-induced contractions. In NA-precontracted preparations (-)-cic (10(-4) M-3 x 10(-4) M) had a stronger relaxant effect than (+)-cic. Cic-Met was a weaker antagonist of NA-induced contractions than (+) and (-)-cic. The enantiomers were far less potent relaxing NA-induced contractions than phentolamine. (+)-Cic, (-)-cic and cic-Met had a similar relaxant effect on 5-HT-induced contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Difference between aortic and renal vascular reactivity in cyclosporin A treated rats and the effect of cicletanine.

4 Groups of 2 month-old male Wistar rats were treated with a) cyclosporin A (CyA) 30 mg/kg/day alone, b) CyA plus cicletanine (Cic) 60 mg/kg/day, c) vehicle (vegetable oil) 1 ml/100 g rat/day and d) no treatment for 8 weeks. The reactivity of isolated papillary muscle to isoprenaline and Ca2+ was not altered in any of the treated groups. Endothelium-dependent relaxation induced by acetylcholine was inhibited in aorta ring segments from CyA-treated rats as compared to that of control and CyA + Cic-treated rats. The relaxation induced by acetylcholine in rat aortas was similar in all groups in the presence of 10 microM indomethacin. Noradrenaline sensitivity of aortic segments was not affected by any treatments applied. The Ca(2+)-concentration response curves of aorta segments from CyA-treated and CyA + Cic-treated rats were shifted to the right as compared to control rats. In interlobar renal arteries the endothelium-dependent relaxation induced by acetylcholine was not affected by any form of treatment. In renal arteries 10 microM indomethacin increased the maximal relaxation induced by acetylcholine about 50%. In these vessels noradrenaline sensitivity in CyA and CyA + Cic treated rats was higher than in controls. Cocaine, 3 microM, shifted the noradrenaline concentration response curve to the left about 0.4 log units in all renal vessel groups, thus renal vascular smooth muscle sensitivity to noradrenaline was significantly greater in vessels from rats receiving CyA than in vessels from control rats. Administration of CyA induced only slight renal morphological changes. Cic was without effect on CyA induced morphological abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of thapsigargin and BAY K 8644 on spontaneous mechanical activity in rat portal vein and contractile responses of rat cardiac muscle.

The effect of thapsigargin, 10(-9)-10(-6) M, and Bay K 8644, 10(-9)-10(-7) M, was studied on isolated portal veins and cardiac muscles from rats. In rat portal veins thapsigargin induced a concentration dependent increase in the amplitude of the spontaneous mechanical activity without increasing the frequency of spontaneous activity. Thapsigargin was less effective than Bay K 8644 in increasing the amplitude of the mechanical activity. In contrast to thapsigargin Bay K 8644, 10(-6) M increases the frequency of the mechanical activity. Atropine, 10(-6) M, and phentolamine, 10(-6) M, had no effect on the thapsigargin and Bay K 8644 induced increase in mechanical activity. Nitrendipine, 10(-6) M, totally abolished the mechanical response in preparations stimulated by thapsigargin and Bay K 8644. In rat atrial and papillary muscles Bay K 8644 increases the frequency in right atrium and tension in both atrial and papillary muscles. Thapsigargin was without effect on the frequency and tension in the cardial preparations. In conclusion, thapsigargin increases the amplitude of spontaneous activity in rat portal veins. In contrast to Bay K 8644 thapsigargin was less effective in increasing the amplitude and had no effect on the frequency of spontaneous activity; furthermore, thapsigargin was without effect on cardiac muscles. The results support the view that an endoplasmatic Ca2(+)-pump sensitive to thapsigargin is of importance for spontaneous activity in portal veins while such pump is of minor importance for contractile activity in cardiac muscles.

Stereoselective pharmacodynamic action of (+)-S-12967 and (-)-S-12968, isomers of a new slow acting 1,4-dihydropyridine derivative with calcium channel agonistic and antagonistic effects on rat aorta.

The effects of (+)-S-12967 and (-)-S12968, isomers of a new dihydropyridine (1,4-DHP) derivative [2(7-amino 2,5-dioxaheptyl) 3-ethoxycarbonyl 4-(2,3-dichlorophenyl) 5-methoxycarbonyl 6-methyl 1,4-dihydropyridine] were studied on contractile responses of isolated thoracic aortas from rats and compared to that of nifedipine. The maximal relaxant effect of both isomers was reached in about 2 hr whereas the maximal relaxant effect to nifedipine was obtained within 30 min. The two 1,4-DPH isomers and nifedipine had a far more potent inhibitory effect on potassium (K+) than on noradrenaline (NA) induced contractions. They shifted the K+, Ca2+ and NA-concentration response-curves to the right and depressed the maximal vessel response to these agonists. Nifedipine was about 10 times more potent than the (-)-isomer which again was about 100 times more potent that the (+)-isomer. In contrast to nifedipine (-)-S-12968 and (+)-S-12967 had a dual action on K+ and Ca(2+)-induced contractions as both isomers in low concentrations, 3 x 10(-9)M and 3 x 10(-7)M, respectively, shifted the K(+)-concentration response curves to the left and increased the maximal response. In K(+)-depolarized preparations they increased the response to low Ca(2+)-concentrations without affecting the maximal vessel response at the highest Ca(2+)-concentrations. The result indicates that (+)-S-12967 and (-)-S-12968 possess Ca(2+)-agonistic as well as Ca-antagonistic properties. Compared to nifedipine both isomers are slow acting vasodilators. Their action as regards their potency is stereoselective and the (-)-isomer is more potent than the (+)-isomer.

Effects of pyrroloisoquinoline enantiomers ((+)- and (-)-McN-5652-Z) on behavioral and pharmacological serotonergic mechanisms in rats.

A behavioral syndrome consisting of 5-hydroxytryptamine (5-HT)-dependent behaviors (e.g. forepaw treading, retropulsion and splayed hindlimbs) as well as hyperthermia occurred after bilateral injection of the (6S, 10bR)-(+)-enantiomer of McN-5652-Z into the cerebral ventricles in pargyline-treated rats. Both the behavioral syndrome and hyperthermia produced by (+)-McN-5652-Z were counteracted by parachlorophenylalanine or ketanserin. The (6R, 10bS)-(-)-enantiomer of McN-5652-Z influenced neither behavior nor body temperature. The enantiomers of McN-5652-Z differed also in their ability to inhibit ex vivo binding of paroxetine in rat frontal cortex and hypothalamus, in vitro uptake of 5-HT in rat blood platelets, and 5-HT-induced contraction of rat vascular smooth muscle, with (+)-McN-5652-Z being most active. No difference was observed between the effects of (+)- and (-)-McN-5652-Z on 5-HT metabolism by rat brain monoamine oxidase. Molecular models of N-protonated enantiomers having a cis B,C-ring juncture and a B-ring chair conformation were differentiated using a hypothetical model of the 5-HT uptake area. The findings indicate that the enantiomers of McN-5652-Z are useful tools for studying the stereoselectivity of behavioral and pharmacological effects exerted by serotonergic neurotransmission.

5-Hydroxytryptamine does not release endothelium-derived relaxing factor in rat isolated coronary arteries.

Removal of the endothelium from isolated rat proximal and distal coronary artery segments shifted the 5-HT concentration-response curve to the left without affecting, the maximal contractile response. 5-HT had no relaxing effect in 10(-5) M prostaglandin F2 alpha-precontracted vessels with an intact endothelium in the presence of 10(-5) M ketanserin. The spontaneous myogenic tone increased in both proximal and distal coronary artery segments after the endothelium had been removed. Indomethacin (10(-5) M) reduced the response of the proximal coronary artery segments to 5-HT by 35% but indomethacin had no effect on the 5-HT concentration-response curve of the distal coronary artery segments. Indomethacin relaxed precontracted (40 mM potassium) proximal coronary artery segments independently of the presence of the endothelium, suggesting a non-specific relaxing effect of indomethacin in these arteries. It is concluded that rat coronary artery endothelium is unresponsive to 5-HT because it lacks 5-HT1 receptors. The increased 5-HT sensitivity and spontaneous myogenic tone of endothelium-denuded rat coronary arteries is probably due to the elimination of the relaxing stimulus mediated by spontaneously released endothelium-derived relaxing factor.

[Stereochemistry--an overlooked problem in medical treatment and research]. / Stereokemi--et overset problem i medicinsk behandling og forskning.

On the background of marketing of an increasing number of drug racemates with the subsequent problems for medical treatment and research, a short review is given focusing on the optic isomery and the significance of optic isomeric drugs for medical treatment and research. Different problems, which may arise in relation to the use of drug racemates are mentioned. The racemic problem is elucidated by examination of and reference to existing studies on drug racemates including studies on pharmacodynamic and pharmacokinetic properties of pure (+) and (-)enantiomers. As the receptor systems of the organism and the process of drug metabolization are stereoscelective, the ideal demand to drug racemates should be that they are regarded as two different drugs until investigations have clarified the degree of pharmacodynamic/pharmacokinetic differences between the (+) and (-)enantiomer. Whether the single enantiomer should be preferred to the racemate may be difficult to decide and may require considerable research, but solution of this can, on the other hand, give valuable advances in drug treatment, for instance in form of drugs with more selective and fewer side effects.

Studies on the stereoselective effects of a novel 5-HT2 receptor antagonist on contractile responses of rat aorta.

The effect of the enantiomers of a novel 5-HT2 receptor antagonist, (+/-)-(1R,3S)-1-[2-[4-[3-(p-fluorophenyl)-1-indanyl]-piperazinyl] ethyl]-2-imidazolidinone, was studied on serotonin (5-HT), noradrenaline (NA), potassium (K+), and calcium (Ca2+)-induced contractions in isolated rat thoracic aorta. The enantiomers shifted the 5-HT, NA, K+, and Ca2+ concentration-response curves to the right in a concentration-dependent manner and depressed the maximal contractile responses. The (+)-enantiomer was a far more potent inhibitor of 5-HT-induced contractions than the (-)-enantiomer. The (+)-enantiomer and phentolamine, both at 10(-6) M, had equal inhibitory effects on NA-evoked contractions. The (+)-enantiomer was again more potent inhibiting NA-induced contractions than the (-)-enantiomer. Both enantiomers had an equieffective inhibitory effect on K+ and Ca2(+)-induced contractions. The results show that the 5-HT and alpha-adrenoceptor antagonism of the two enantiomers is stereoselective, the (+)-enantiomer being more potent than the (-)-enantiomer. In contrast the enantiomers had equal, nonstereoselective inhibitory effects on K+ and Ca2(+)-evoked contractions.

Effects of the optical isomers of a novel 5-HT2 antagonist and (-)-Bay K 8644 on spontaneous mechanical activity in rat portal veins.

The effect of the (+)-enantiomer (Ir) and the (-)-enantiomer (Lu) of a novel 5-HT2 antagonist was studied on spontaneous mechanical activity in rat portal veins and compared to that of the Ca-agonist (-)-Bay K 8644. Ir and Lu (10(-8) to 10(-5) M) were found to equally increase the spontaneous mechanical activity in rat portal veins. At high concentrations (10(-4) M) Ir and Lu totally abolished spontaneous activity. The frequency of the spontaneous activity was equally decreased by the two enantiomers. The increase in spontaneous activity induced by Ir and Lu was abolished in Ca-free medium and restored by readdition of Ca. The augmenting effect of the enantiomers on mechanical activity was not influenced by atropine but was totally eliminated by the Ca-antagonist nifedipine. The Ca-agonist (-)-Bay K 8644 was more potent in increasing the amplitude of the mechanical activity than the enantiomers and had a concentration-dependent increasing effect on the frequency of the spontaneous activity. The results indicate that in rat portal veins Ir and Lu have a dual non-stereoselective effect which may include a Ca-agonistic stimulating mechanism of action as well as a pacemaker blocking effect.