Ectopic activity in the rat pulmonary vein can arise from simultaneous activation of alpha1- and beta1-adrenoceptors.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is the most common electrical cardiac disorder in clinical practice. The major trigger for AF is focal ectopic activity of unknown origin in sleeves of cardiac muscle that extend into the pulmonary veins. We examined the role of noradrenaline in the genesis of ectopic activity in the pulmonary vein. EXPERIMENTAL APPROACH: Mechanical activity of strips of pulmonary vein isolated from male Wistar rats was recorded via an isometric tension meter. Twitch contractions of cardiac myocytes were evoked by electrical field stimulation in a tissue bath through which flowed Krebs-Heinseleit solution warmed to 36-37 degrees C and gassed with 95% O(2) 5% CO(2). KEY RESULTS: The superfusion of noradrenaline induced ectopic contractions in 71 of 76 different isolated pulmonary veins. Ectopic contractions in the pulmonary vein were not associated with electrically evoked twitch contractions. The effect of noradrenaline on the pulmonary vein could be replicated by the simultaneous, but not separate, application of the alpha adrenoceptor agonist phenylephrine and the beta adrenoceptor agonist isoprenaline. The use of selective agonists and antagonists for adrenoceptor subtypes showed that ectopic activity in the pulmonary vein arose from the simultaneous stimulation of alpha(1) and beta(1) adrenoceptors. The application of noradrenaline to isolated strips of left atrium did not induce ectopic contractions (n=10). conclusions: These findings suggest an origin for ectopic activity in the pulmonary vein that requires activation of both alpha and beta adrenoceptors. They also open new perspectives towards our understanding of the triggering of AF.

Role of EDHF in the vasodilatory effect of loop diuretics in guinea-pig mesenteric resistance arteries.

1. Relaxing effect of loop diuretics, piretanide and furosemide in comparison with acetylcholine (ACh) was investigated in guinea-pig isolated mesenteric resistance arteries. 2. Concentration-response curves to ACh (0.001 - 10 microM) and diuretics (0.0001 - 1 microM) were constructed in noradrenaline (10 - 30 microM)-precontracted arteries incubated either in normal physiological salt solution (PSS) or in 30 mM KCl PSS (K-PSS). 3. In PSS, maximal relaxations (R(max)) and pD(2) to ACh were 87+/-2% and 7.1+/-0.1 (n=10). L-N(G)-nitro-arginine methyl ester (L-NAME, 100 microM) reduced R(max) by 20% (P<0.01, n=7) and pD(2) by 10% (P<0.01). In contrast, indomethacin (10 microM) increased R(max) by 19% (P<0.01, n=8) and pD(2) by 10% (P<0.05). Combination of L-NAME+indomethacin reversed the effect observed with either of these inhibitors used alone. In K-PSS, R(max) was attenuated by 40% (P<0.001, n=6) compared to PSS. L-NAME reduced R(max) by 65% (P<0.01, n=5) and increased pD(2) by 15 fold. L-NAME+indomethacin suppressed the resistant relaxation. 4. In PSS+L-NAME+indomethacin, inhibitors of small (SK(Ca); apamin, 0.1 microM) and large (BK(Ca); iberiotoxin and charybdotoxin, 0.1 microM) conductance Ca(2+)-sensitive K(-)-channels used alone had little effect on the ACh-response. Combination of apamin+iberiotoxin reduced R(max) by 40% (P<0.05, n=7) while apamin+charybdotoxin fully abolished the resistant relaxation. 5. In PSS, piretanide and furosemide induced relaxation with R(max): 89+/-3% vs 84+/-5% and pD(2): 8.5+/-0.1 vs 7.7+/-0.2 (P<0.01) for piretanide (n=11) and furosemide (n=10), respectively. Endothelial abrasion suppressed relaxation to diuretics. L-NAME and indomethacin used alone or in combination did not significantly modify the response to diuretics. 6. In K-PSS, piretanide-induced relaxation was abolished whereas that to furosemide was reduced by 70% (P<0.001, n=9) compared to PSS and was suppressed by L-NAME+indomethacin. In PSS+L-NAME+indomethacin, apamin slightly reduced relaxation to diuretics whereas charybdotoxin or iberiotoxin abolished the response. 7. These results indicate that ACh-evoked relaxation is mediated by both NO/PGl(2)-dependent and -independent mechanisms. The EDHF-dependent component relies on activation of Ca(2+)-activated K(+) channels, is sensitive to a combination of apamin+charybdotoxin and to a smaller degree to a combination of apamin+iberiotoxin. Loop diuretic-induced relaxation is endothelium-dependent, appears to be mediated by NO, PGl(2) and EDHF for furosemide and EDHF only for piretanide. For the two diuretics, opening of BK(Ca) channels may be involved in the relaxation.

Role of nitric oxide and endothelium in the flow-induced dilation of rat coronary arteries under two preconstriction conditions.

1. Pressure-induced tone and flow-induced dilations were studied in a rat perfused epicardial coronary artery mounted in an arteriograph. Spontaneous tone was assessed in arteries submitted either to 60 or 90 mmHg intraluminal pressure either under control conditions, after incubation with NG-nitro-L-arginine methyl ester (L-NAME; 100 mumol/L) or after endothelial denudation. Flow-induced dilation was quantified under these conditions in preparations either submitted to 60 mmHg and preconstricted with 10 mumol/L 5-hydroxytryptamine (5-HT) or exhibiting spontaneous tone at 90 mmHg. 2. Spontaneous tone was greater at 90 mmHg compared with tone obtained at 60 mmHg (21 +/- 2 vs 10 +/- 2% reduction of the fully dilated diameter after sodium nitroprusside incubation, respectively). Incubation with L-NAME or removal of the endothelium significantly increased spontaneous tone at both pressures compared with control. 3. In arteries submitted to 60 mmHg and preconstricted with 10 mumol/L 5-HT, flow (0-800 microL/min) induced a continuous dilation (maximal value 63 +/- 4%). As a function of flow, shear stress first increased and then plateaued at values of approximately 76 +/- 6 dyn/cm2. After L-NAME incubation or endothelial denudation, the flow-induced dilation was reduced to the same extent and was obtained for higher values of shear stress (172 +/- 14 and 150 +/- 14 dyn/cm2, respectively). 4. In arteries exhibiting spontaneous tone, starting flow led, first, to a constriction followed by a dilation up to 76 +/- 4% of the initial tone. Incubation with L-NAME greatly altered flow-induced dilation. Endothelium removal further reduced the dilation obtained for very high values of shear stress (up to 300 dyn/cm2). 5. The present study shows that different patterns of vasodilation induced by flow can be observed, depending on the initial vasoconstrictor stimulus. In 5-HT-preconstricted arteries, flow-induced dilation appears to be fully dependent on the synthesis and release of nitric oxide. In arteries with spontaneous tone, a vasoconstrictor substance could be released for low values of flow. Nitric oxide is mainly, but not exclusively, responsible for the vasodilation. For both experimental conditions, removal of the endothelium greatly reduced the response, but a dilation was still observed.

Trandolapril treatment at low dose improves mechanical and functional properties in perfused coronary arteries of spontaneously hypertensive rat.

The ex-vivo effects of a 1-month treatment period with trandolapril at a low dose (0.3 mg/kg/day) were assessed on the mechanical and functional alterations observed in SHR coronary arteries. The in-vitro intrinsic elastic properties of the wall in treated SHR coronary arteries were determined in comparison to those of SHR rats. In preconstricted preparations, agonist- and flow-induced dilatations were investigated in arteries of both groups. Arterial segments were cannulated at both ends using an arteriograph system. Internal diameter and wall thickness were continuously monitored while intraluminal pressure and flow were controlled. Wall thickness was reduced in arteries of treated rats compared to those in control SHR (mm): 52 +/- 2 vs. 41 +/- 2, P < 0.001, respectively. Arterial stiffness, expressed by the incremental elastic modulus-stress relationship, was significantly lower in arteries of treated compared to control SHRs. In preconstricted preparations, dilatations induced by bradykinin were significantly greater in treated SHR compared to control SHR arteries whereas dilatations induced by acetylcholine were slightly but not significantly increased. On the other hand, starting flow at the plateau of 5-HT-induced constriction led to dilatations which were not significantly different in the treated compared to the control group. The maximal dilatation induced by flow in arteries of treated rats was obtained for the same value of shear stress compared to that determined in preparations of control SHRs: (dyn/cm2) 63 +/- 3 vs. 61 +/- 2, respectively, NS. These results show that together with hypertrophy, the abnormal mechanical properties observed in the coronary arterial wall of SHR were improved by a low dose of trandolapril treatment. However, differential effects of trandolapril treatment were observed on agonist and flow-induced dilatations. Although flow-induced dilatation seemed to remain unaffected, acetylcholine-induced dilatation was slightly improved and bradykinin-induced dilatation was markedly increased by trandolapril treatment.

Pressor and bradycardic effects of tacrine and other acetylcholinesterase inhibitors in the rat.

The cardiovascular effects of three different acetylcholinesterase inhibitors: physostigmine, tacrine and rivastigmine injected by intravenous (i.v.) route were compared in freely moving Wistar rats. The three drugs significantly increased both systolic and diastolic blood pressure and decreased heart rate. Compared to physostigmine, a 20-fold higher dose of tacrine and a 40-fold higher dose of rivastigmine was necessary to induce a comparable pressor effect. Tacrine was chosen as a model to study the mechanisms underlying the cardiovascular effects of i.v. cholinesterase inhibitors. Atropine totally abolished while methylatropine did not affect tacrine pressor effects. Conversely, both drugs abolished tacrine-induced bradycardia. The alpha1-adrenoceptor antagonist prazosin or the vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2, Arg8] vasopressin partially but significantly reduced tacrine pressor effect and mostly abolished it when administered concomitantly. The tacrine pressor response was inhibited in a dose-dependent manner by the i.c.v. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 1.45 microg), the muscarinic M1 receptor antagonist pirenzepine (ID50 = 4.33 microg), the muscarinic M2 receptor antagonist methoctramine (ID50 = 1.39 microg) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50 = 31.19 microg). Central injection of such muscarinic receptor antagonists did not affect tacrine-induced bradycardia. Our results show that acetylcholinesterase inhibitors induce significant cardiovascular effects with a pressor response mediated mainly by the stimulation of central muscarinic M2 receptors inducing a secondary increase in sympathetic outflow and vasopressin release. Conversely, acetylcholinesterase inhibitor-induced bradycardia appears to be mediated by peripheral muscarinic mechanisms.

The elastic modulus of conductance coronary arteries from spontaneously hypertensive rats is increased.

OBJECTIVE: To assess the alterations of morphological and functional properties of conductance coronary and mesenteric resistance arteries in spontaneously hypertensive rats (SHR). DESIGN: The in-vitro intrinsic elastic properties of the wall material in SHR coronary arteries were determined in comparison with those of Wistar-Kyoto (WKY) rats. Mesenteric resistance arteries from rats of both strains were also studied. METHODS: Arterial segments were cannulated at both ends using an arteriograph system and subjected to pressure increments with simultaneous measurements of the wall thickness and internal diameter. The strain, stress and incremental elastic modulus (Einc) were calculated from diameter-pressure curves. RESULTS: Over the full range of pressures tested (10-160 mmHg), the internal diameters of SHR coronary arteries were not significantly different from those of WKY rat arteries, whereas we observed that SHR mesenteric resistance arteries had a significantly smaller diameter. The stress-strain curve for coronary arteries was shifted significantly to the left-hand side for the SHR group indicating more stress per unit strain, whereas the opposite was found for mesenteric resistance arteries. When Einc was determined under isobaric conditions, we found no difference between SHR and WKY rat coronary arteries, whereas this parameter was decreased significantly for SHR mesenteric resistance arteries. When Einc was estimated at the respective operating pressures, it was 1.7- to 2.8-fold greater for SHR than it was for WKY rat mesenteric resistance and coronary arteries. Moreover, the total collagen area: lumen area ratio was significantly greater for the SHR than it was for the WKY rat coronary artery wall, but this ratio was similar for mesenteric preparations from the two strains. CONCLUSION: These results show that, at a given stress or operating pressure level, the material of SHR coronary artery wall is characterized by an increase in Einc, whereas there is no increase in Einc for in mesenteric resistance arteries. This functional alteration is accompanied by an increase in the relative proportion of collagen, a component with a high elastic modulus, in the wall. In contrast, we found no change in elastic modulus and in the relative proportion of collagen for the SHR mesenteric resistance arteries. Furthermore, the present results support the hypothesis that alterations in distensibility differ among the components of the SHR vasculature.

Components of flow-induced dilation in rat perfused coronary artery.

This study was undertaken to determine the endothelial factors involved in the flow-induced dilation of a rat perfused coronary artery. Segments of the right interventricular coronary artery were taken from 10-15-week-old male Wistar rats. Vessels were mounted in an arteriograph where internal diameter was continuously monitored while intraluminal pressure was controlled. Vessels were preconstricted with serotonin (10 mumol/L), and the dilation induced by flow (0-800 microliters/min) was quantified. This dilator effect was measured in control conditions, after incubation with L-NAME (100 mumol/L), with indomethacin (100 mumol/L), and after mechanical destruction of the endothelium (-E). Dilations were expressed as percentage of the serotonin-induced constriction, and wall shear stress tau due to the physical forces exerted on the wall of the vessel was calculated and expressed in dyn/cm2. In control conditions, raising the flow up to 800 microliters/min led to an increase in dilation (maximal dilation 63% +/- 4%) and in shear stress (maximal shear stress 76 +/- 4 dyn/cm2). With indomethacin, maximal dilation was 69% +/- 4% and maximal shear stress was 81 +/- 6 dyn/cm2. With L-NAME or after destruction of endothelium, dilation was greatly reduced (39% +/- 3% and 40% +/- 2%, respectively) whereas shear stress values were greatly increased (173 +/- 14 and 150 +/- 13 dyn/cm2, respectively). These results confirm the viability of this model for the study of flow-dependent dilation. This dilation seems to be greatly dependent on NO release. In contrast, results do not favor a significant involvement of prostanoid vasodilating substance. Without endothelium, a dilation was still observed and showed the persistence of an endothelium-independent component of flow-induced dilation in this preparation that remains to be determined.

Effects of nitric oxide and sodium nitroprusside on the intrinsic elastic properties of pressurized rat coronary artery.

The study was designed to assess the influence of either nitric oxide (NO) or sodium nitroprusside and the absence of endothelium on the intrinsic elastic properties of coronary arteries from WKY rats. For this purpose, segments of the right interventricular coronary were mounted in an arteriograph where wall thickness and internal diameter were continuously monitored while intraluminal pressure was controlled in the absence of flow. To study the passive properties, pressure-diameter relationships were determined by measuring the corresponding internal diameter for each stepwise increase in intraluminal pressure. Thus, wall stress, strain and incremental elastic modulus (Einc) were assessed in the following experimental conditions: control, incubation with nitro-L-arginine methyl ester (L-NAME, 100 microM) or L-NAME + L-arginine (L-arg, 100 microM), incubation with sodium nitroprusside (SNP, 100 microM), endothelium removal (CHAPS). The Einc-stress relationship was not significantly different in the different experimental conditions, but values of Einc plotted as function of strain were significantly decreased after L-NAME incubation and partly reversed after L-arg addition. The same effect was observed after endothelium destruction but to a lesser extent. After SNP incubation, values of Einc were significantly decreased for small values of strain and increased for high values of this parameter. These results show that NO synthase inhibition induced, for a given strain, a decrease of elastic modulus in coronary arteries. It can be speculated that functional antagonism exerted by NO against spontaneous contractile tone was reduced. Thus, the smooth muscle cells were in a greater state of activation and probably more strongly involved in the intrinsic elastic properties of this preparation. However, an unexplained effect of NO on wall stiffness cannot be excluded. Conversely, SNP increased the initial diameter and induced an initial decrease in stiffness followed by a subsequent increase. After endothelium destruction, stiffness was significantly decreased compared to control conditions. It can be concluded that NO modulates the intrinsic elastic properties of the coronary arteries through smooth muscle cell relaxation. Furthermore, results with SNP support the hypothesis that the lower the state of activation of the smooth muscle cells, the higher the elastic modulus of the arterial wall in this coronary artery preparation.

[Effects of short-term treatment with trandolapril on vasodilatator responses mediated by receptors or on blood flow in the coronary arteries in SHR]. / Effets d'un traitement court par le trandolapril sur les réponses vasodilatatrices médiées par des récepteurs ou le débit au niveau d'artères coronaires chez le SHR.

The aim of the study was to assess the effects of a one-month treatment period with the ACE inhibitor trandolapril (0.3 mg/kg/day) on the endothelial reactivity in epicardial right coronary arteries (CA) of 26-30 week-old SHRs. For this purpose, segments of CA were mounted in an arteriograph where wall thickness and internal diameter (ID) were continuously monitored while intraluminal pressure (IP) was controlled. In the absence of flow and under an IP of 30 mmHg, IDs were not significantly different in control compared to those of treated SHR arteries (microns, 250 +/- 8 vs 240 +/- 7). In preconstricted preparations (5HT, 10 microns extraluminally) C/E curves were constructed by adding acetylcholine (AC, 0.01-10 microM) or bradykinin (BK, 0.01-10 microM) in the bath. On the other hand, the effect of a stepwise increase in intraluminal flow (50-450 microliters/min; IP = 30 mmHg) of perfusion solution was observed. The effects of subsequent additions of sodium nitroprusside (SNP) were assessed. Maximal relaxations were expressed as percent of maximal contractions. Results were as follows: [table: see text] These results show that the endothelium-dependent relaxation induced by AC and BK were significantly increased in coronary arteries of treated compared to control SHRs whereas the flow-induced relaxation seemed to remain unaffected in our experimental conditions. From these data, it can be concluded that a short period of ACE inhibition in SHRs is able to improve the endothelium-dependent vasodilation induced by agonists in the coronary arterial bed.

Impaired endothelial relaxations induced by agonists and flow in spontaneously hypertensive rat compared to Wistar-Kyoto rat perfused coronary arteries.

The study was designed to compare the effects of agonists and flow on endothelial reactivity in perfused coronary arteries of spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. To this end, coronary arteries were cannulated at both ends using an arteriograph system. In the absence of flow and under an intraluminal pressure of 30 mm Hg, SHR arteries had larger internal diameters compared to those of WKY rats (275 +/- 10 vs. 239 +/- 7 microns, p < 0.01). In preparations preconstricted with serotonin HT, concentration-effect curves were constructed by adding acetylcholine or bradykinin in the bath. On the other hand, the effect of a stepwise increase in intraluminal flow (50-450 microliters/min) of physiological salt solution was observed. Agonist-induced dilations were significantly smaller in arteries of SHRs compared to those of WKY rats. Starting flow at the plateau of constriction led to dilations that were also weaker in SHR compared to WKY vessels: 27 +/- 6 vs. 61 +/- 3, p < 0.001, when expressed as percentage of maximal initial constrictions. The maximal dilation induced by flow in SHR arteries was obtained for a greater value of shear stress compared to that determined in WKY preparations: 81 +/- 6 vs. 60 +/- 4 dyn/cm2, p < 0.01. After endothelium destruction, flow-induced dilation was totally abolished in SHR arteries but only reduced in those of WKY rats. Subsequent additions of sodium nitroprusside induced complete dilations in vessels from both strains. The same protocol was performed in arteries submitted to a perfusion pressure of 90 mm Hg. In these conditions, impairments of agonist- and flow-induced dilations were also evidenced in SHR arteries. These results show that both the endothelium-dependent dilation induced by acetylcholine or bradykinin and the flow-induced dilation are impaired in coronary arteries of SHRs compared to WKY rats. These alterations appear to be due to a deterioration of endothelial cell function in the presence of a normal reactivity of the smooth muscle cells.

Endothelial and smooth muscle properties of coronary and mesenteric resistance arteries in spontaneously hypertensive rats compared to WKY rats.

To investigate if the functional alterations observed in resistance arteries of spontaneously hypertensive rats (SHRs) were also present at the coronary level, in vitro experiments were performed in mesenteric resistance arteries (MRA) and in right (RIC) and left interventricular coronary (LIC) arteries taken from 15-25-week-old SHR and age-matched Wistar Kyoto rats WKYs. Using a passive extension protocol, internal diameters corresponding to 100 mmHg intraluminal pressure (D100) were determined and vessels were set up to a normalized internal diameter (0.9 D100). SHR mesenteric resistance arteries had a significantly smaller diameter compared to WKY arteries, whereas both types of SHR coronary arteries had a greater diameter compared to those of WKY rats. In arteries in the absence of contracting agonist, nitro-L-arginine (NOLA, 100 microM) induced a progressive rise in basal tone, which could be reversed by subsequent addition of L-arginine (100 microM) but not D-arginine (100 microM). When expressed as percent of maximal contractions induced by agonists (noradrenaline, NA [10 microM] in MRA; serotonin, 5-HT [10 microM], in RIC and LIC), these contractions were significantly stronger in WKY compared to SHR coronary and mesenteric resistance arteries. In NA-precontracted MRA and 5HT-precontracted coronary arteries in the presence of indomethacin (10 microM), the magnitude of acetylcholine-induced maximal relaxations (expressed as percent of maximal contractions induced by agonists) was greater in WKY compared to SHR arteries. After a 30-min incubation period, NOLA (100 microM) completely inhibited relaxations induced by acetylcholine (0.01-10 microM) in all types of precontracted arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of endothelium-derived NO in the basal tone and in the vasodilator responses to muscarinic agonists in the rat isolated mesenteric arterial bed.

To investigate the involvement of nitric oxide (NO) derived from endothelial cells in the control of vascular tone in the rat mesenteric vascular bed, the effects of different procedures known to interfere with the NO-cyclic GMP pathway were evaluated both on the basal tone and on the vasodilatory responses to four muscarinic agonists. To this aim, rat isolated mesenteric vascular beds were perfused at constant pressure. Water infusion significantly increased the resting perfusion pressure whereas L-NOARG, L-NAME and methylene blue were devoid of effect. In noradrenaline-preconstricted vascular bed, the perfusion pressure was significantly increased after water or L-NAME infusion. The vasodilator response induced by subsequent addition of acetylcholine in bolus was not significantly modified by pre-treatment with indomethacin but was significantly reduced by water infusion. Responses to acetylcholine and to three other muscarinic agonists--carbachol, oxotremorine or McNeil A 343--were assessed. Incubation with L-NAME did not modify the initial peak falls of the agonists except for McNeil A 343, whereas it significantly reduced the area under the pressure trace for all the substances. The latter effect was reversed after a subsequent incubation with L-Arginine. Finally, L-NAME strongly and significantly increased the drop in perfusion pressure and the area under the pressure trace following bolus of glyceryl trinitrate. These results suggest that in the mesenteric arterial bed of the rat, which can be considered as a resistant arteries preparation, basal tone appears to be controlled by a factor other than NO. Moreover, the vasodilator responses of muscarinic agonists are affected by L-NAME in their second late sustained phase only, which probably relies on a de novo synthesis of endothelium derived-NO. Finally, endothelium derived-NO exerts inhibitory effects both on the sensitivity of the vascular smooth muscle to glyceryl trinitrate and on the magnitude of its contraction in the presence of noradrenaline, two types of effects which are sensitive to L-NAME.

Effects of trandolapril on vascular morphology and function during the established phase of systemic hypertension in the spontaneously hypertensive rat.

The aim of this study was to determine the morphologic and functional vascular changes occurring following 4 weeks of treatment with the angiotensin-converting enzyme inhibitor trandolapril in the spontaneously hypertensive rat (SHR) in the established phase of hypertension. At the dosage used, 0.4 mg/kg orally, trandolapril decreased blood pressure of the SHR by 15-18% compared with that of the control animals. Immediately before the end of treatment, the following changes from control values were observed: (1) 9, 11, and 12% reductions for myocardial hypertrophy and the media thickness of the thoracic aorta and femoral arteries, respectively; and (2) an increase in the compliance of the resistance arteries, demonstrated by a shift to the right of the in vitro tension-diameter curves and a significant 22% increase in their normalized internal diameter, while their maximum contractile ability was significantly decreased. Following discontinuation of treatment, blood pressure levels remained significantly lower in the treated versus the control groups for up to 4 weeks after the last administration. At that time measurement of the studied parameters showed: (1) a rapid reversion to control values of the compliance of the resistance vessels; and (2) a slower progression, but in the same direction, in the parameters of cardiac and vascular hypertrophy. Thus, trandolapril, administered for a short period in the adult SHR, was able to reverse the cardiac and vascular morphologic changes present in this model of hypertension. Like the effect on blood pressure, these effects were slowly reversible at the end of treatment, whereas the functional consequences at the resistance artery level seemed to display a more rapid reversibility.

Effects of ryanodine on tension development in rat aorta and mesenteric resistance vessels.

1. The effect of ryanodine on contractile responses dependent either on intracellular Ca2+ release or on extracellular Ca2+ influx were studied in aorta and mesenteric resistance vessels of the rat. 2. In aorta, in the presence of extracellular Ca2+, pretreatment with ryanodine (10(-5)M) did not modify contractile responses to noradrenaline (NA) (10(-6)M) whereas in the absence of Ca2+, pretreatment with ryanodine reduced to about 25% the contractile response to NA (10(-6)M) and totally abolished the transient contraction elicited by caffeine (5 x 10(-2)M). 3. In mesenteric resistance vessels, ryanodine (10(-5)M) had no effects on NA (10(-5)M)-induced tension in the presence of extracellular Ca2+ but totally abolished contractile responses to caffeine (10(-2)M) in the absence of Ca2+. 4. In K+ -depolarized mesenteric resistance vessels, pretreatment with ryanodine (10(-5)M) significantly enhanced contractile responses to Ca2+ concentrations higher than 10(-4)M and 10(-3)M for arteries depolarized with 30 mM and 40 mM K+ respectively. Concentrations of either diltiazem (6 x 10(-7)M) or nifedipine (10(-8)M) that abolished contractile responses to Ca2+ in depolarized arteries (K+, 40 mM) did not totally inhibit the enhancement of Ca2+ -induced contractions obtained in the presence of ryanodine. 5. Ryanodine did not modify the Ca2+ concentration-effect relationships in mesenteric resistance vessels exposed to NA or arginine vasopressin. 6. These data are consistent with the hypothesis that ryanodine induces a release of Ca2+ from intracellular stores, resulting in a subsequent reduction of the amplitude of contractions dependent upon intracellular Ca2+ liberation. Furthermore, the ability of sarcoplasmic reticulum to buffer rises in cytoplasmic Ca2+ may be reduced in the presence of ryanodine, thereby accounting for the potentiation of contractile responses to Ca2+ in K+-depolarized mesenteric resistance vessels.

Bronchospasmolytic effects of RU 42173.

The bronchodilator properties of RU 42173, a new beta-adrenergic stimulant with an original structure, as a cyclic analogue of an arylethanolamine, have been evaluated on different in vitro and in vivo models and compared with those of salbutamol and isoprenaline. RU 42173 equipotently inhibited histamine-, acetylcholine-, and KCl-induced contractions in isolated guinea pig trachea or small bronchus and in isolated human bronchus. When administered to guinea pigs by the IV or aerosol route, RU 42173 dose-dependently inhibited bronchospasm induced by histamine, acetylcholine, and methacholine. It also inhibited PAF-induced bronchoconstriction and PAF-induced hyperreactivity to histamine. Moreover, RU 42173 had a rapid onset and prolonged duration of action. The potency of RU 42173 was similar to that of salbutamol.

Compared effects of calcium entry blockers on calcium-induced tension in rat isolated cerebral and peripheral resistance vessels.

The effects of the calcium entry blockers verapamil (V), diltiazem (D), nifedipine (NF) and nicardipine (NC) have been studied on calcium concentration-effect curves elicited in depolarized (K+, 40 mmol/l) and in serotonin-exposed (6 mumol/l) rat middle cerebral arteries (RMCA) in order to compare the relative potencies of the blockers against these two calcium channel activating mechanisms. In control conditions, Ca2+ sensitivity expressed as pD2 and maximal active wall tension (AWT) were not significantly different in depolarized and in 5-HT-exposed vessels: pD2: 3.39 +/- 0.08 vs 3.50 +/- 0.06 and AWT: 0.93 +/- 0.15 mN.mm-1 vs 0.90 +/- 0.16 mN.mm-1 respectively. V, D, NF and NC displaced Ca2+ control curves to the right and depressed the maximum contractile response in the two experimental conditions, which suggests a noncompetitive type of antagonism. All the blockers were more potent inhibitors of Ca2+-induced contractions in depolarized than in serotonin-exposed middle cerebral arteries. The IC50 values (concentration of blockers producing a 50% inhibition of maximal control contractile response) were (nmol/l): V = 20, D = 120, NF = 0.4, NC = 1 and V = 400, D = 10,000, NF = 20, NC = 7 in depolarized and serotonin-exposed arteries respectively. From these IC50 values, the relative order of potency of the CEB's was not the same in the two experimental conditions suggesting that while serotonin and K+ both promote the entry of Ca2+ into vascular smooth muscle cells of RMCA, they either activate a different gating mechanism associated with a single common channel or perhaps distinct channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of calcium entry blockers on Ca2+-induced contraction of depolarized and noradrenaline-exposed rat resistance vessels.

The effects of four calcium entry blockers (CEBs), diltiazem (D), verapamil (V), nifedipine (NF) and nicardipine (NC), were investigated on Ca2+ concentration-effect curves of rat depolarized (K+, 40 mM) or noradrenaline (NA, 3 microM)-exposed mesenteric resistance vessels. Under control conditions, NA-exposed vessels were more sensitive to Ca2+ (pD2: 4.12 +/- 0.11) than depolarized vessels (pD2: 3.16 +/- 0.02, P less than 0.01) whereas the maximal active wall tensions were not significantly different (2.86 +/- 0.11 mN/mm and 2.11 +/- 0.34 mN/mm respectively). In depolarized vessels, D, V, NF and NC induced a concentration-dependent shift to the right and a depression of the maximal effect of the Ca2+ curves, which suggested a non-competitive antagonism. The IC50 (concentration of CEB producing a 50% inhibition of the maximal contractile response from control curve) values were: D: 3 X 10(-7), V: 1.3 X 10(-7), NF: 4.5 X 10(-9), NC: 3 X 10(-9) M. In NA-exposed vessels, the CEBs produced a concentration-dependent shift to the right of the Ca2+ curves before depressing their maximal effect. This suggested that the antagonism was different from that observed in depolarized arteries. In this case, the IC50 values were: D: 4.5 X 10(-7), V: 2 X 10(-7), NF: 9 X 10(-9), NC: 7 X 10(-9) M. Although the gating mechanisms activated in this study were differently affected by CEBs, since there were marked qualitative differences in their antagonistic effects on Ca2+ concentration-effect curves, depolarization and NA promoted the entry of Ca2+ into smooth muscle cells of rat resistance vessels by mechanisms with the same sensitivity to CEBs as expressed by IC50 values.

The guinea-pig isolated bronchus for the in vitro study of small calibre airway reactivity.

Small calibre airway reactivity to different contractile and relaxant agents was tested in vitro using small segments (about 1 mm long and 0.2 mm in internal diameter) of guinea-pig isolated intralobular bronchi. EC50 values of, and maximal contractile responses to contractile agents were as follows (mean +/- s.e.mean, n = 6): acetylcholine 13.6 +/- 2.6 microM and 1140 +/- 80 mg; histamine 5.2 +/- 0.7 microM and 1094 +/- 95 mg; 5-hydroxytryptamine (5-HT) 0.7 +/- 0.1 microM and 595 +/- 61 mg; prostaglandin F2 alpha (PGF2 alpha) 8.8 +/- 1.2 microM and 1100 +/- 88 mg; tetraethylammonium 2.9 +/- 0.3 mM and 1055 +/- 94 mg; KC1 14.6 +/- 0.5 mM and 965 +/- 81 mg. EC50 values of, and maximal relaxant responses to beta-adrenoceptor stimulants on preparations precontracted with acetylcholine (1.4 X 10(-4)M) were: isoprenaline 0.40 +/- 0.5 microM and 782 +/- 65 mg, n = 18; salbutamol 0.19 +/- 0.02 microM and 494 +/- 55 mg, n = 5; terbutaline 0.87 +/- 0.18 microM and 263 +/- 40 mg n = 5; fenoterol 0.06 +/- 0.02 microM and 722 +/- 47 mg, n = 5; adrenaline 0.71 +/- 0.13 microM and 653 +/- 62 mg, n = 5; noradrenaline 10.8 +/- 0.9 microM and 566 +/- 97 mg, n = 5. Differences in the maximal relaxant effects between the beta-adrenoceptor stimulants showed that the preparation utilized is a relevant model for assessment of the intrinsic activity of these drugs. 5 The high ratio (about 180) of the ECm for noradrenaline (beta-adrenoceptor agonist) to that for fenoterol (beta 2-adrenoceptor agonist), and the lack of effect of prenalterol (beta 1-adrenoceptor agonist) suggested that beta 2-adrenoceptors are preferentially involved in the relaxant activity of beta-adrenoceptor stimulants in this preparation.

[Nicardipine: vascular compliance and development of genetic hypertension in the SHR rat]. / Nicardipine: compliance vasculaire et développement de l'hypertension génétique chez le rat SHR.

The potential preventive effects of nicardipine (100 mg/kg q.d., orally, for 6 weeks, starting at the 6th week of age) on genetic hypertension development (GHD) have been investigated in young SHRs. Furthermore, at the end of the treatment period, segments of mesenteric arteries were isolated in order to determine their vascular compliance and reactivity to noradrenaline and the total proteins content and the amount of DNA in the vascular wall. At the end of the treatment period and 20 hours after the last drug administration, nicardipine exhibited no preventive effects against GHD but heart rate was lower in treated than in control animals. Mesenteric vascular compliance was not treatment-affected but the maximal contractile response of the vessels to noradrenaline was slightly decreased. Finally, total proteins and DNA contents of the vascular wall were unchanged. It thus appears that there is a striking parallelism between nicardipine's lack of effects on resistance vessels' compliance and vascular total proteins and DNA contents on the one hand and the drug's inability to oppose GHD in young SHRs on the other.