Biomedical subjects

S A Doggrell

Publications and source records attributed to S A Doggrell.

At least 55 records · Page 3Linked to original sources

PubMed1997

Effects of veratridine on the action potentials and contractility of right and left ventricles from normo- and hypertensive rats.

1. We have studied the effects of prolonging the opening of sodium channels with veratridine on the action potentials (AP) and contractility of isolated right and left ventricles of Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). It was examined whether the effects of veratridine were altered in the SHR right ventricle in the absence of hypertrophy. The main aim of the present study was to test the hypothesis that the effects of veratridine were altered in the SHR left ventricle in the presence of hypertrophy. 2. The tail-cuff pressures of 14- and 22-week-old, but not 5-week-old, SHR were greater than those of the WKY rat. At 14 weeks of age of SHR left, but not right, ventricle had developed hypertension-associated hypertrophy. 3. The AP and contractions and the ability of veratridine to prolong the AP and act as a positive inotrope were similar in the right ventricles from 22-week-old WKY rats and SHR. The effects of veratridine and the AP and contractions of left ventricles of 5-, 14- and 22-week-old WKY rats and of 5- and 14-week-old SHR were also similar. 4. The AP of the left ventricles of 22-week-old SHR were prolonged by 3 ms at the action potential duration (APD)50 and APD90 levels. The contractions to cardiac stimulation and the maximum combined force responses to cardiac stimulation and isoprenaline were reduced in the left ventricles of 22-week-old SHR compared with WKY rats and younger SHR. 5. The effectiveness of veratridine in prolonging the AP and augmenting the contractions to cardiac stimulation was reduced in the hypertrophied left ventricle of 22-week-old, but not 14-week-old, SHR. 6. In summary, the response to prolonging the opening of sodium channels with veratridine is not altered in the SHR right ventricle. However, in left ventricles of the hypertrophied 22-week-old, but not 14-week-old, SHR the effects of veratridine are reduced and this demonstrates that the response to prolonging the opening of sodium channels is changed in persistent hypertension-associated hypertrophy.

Action Potentials↗

PubMed1996

Effects of potassium channel blockers on the action potentials and contractility of the rat right ventricle.

1. The effects of several potassium channel blockers on the action potentials and contractile force of the electrically driven rat right ventricle have been determined. 2. Glibenclamide, which blocks the ATP-sensitive potassium channels, had no effect on the ventricular action potentials or contractile force responses. 3. 4-Aminopyridine, which blocks the Na(+)-activated potassium channels in ventricles, at 0.3-3 mM increased the amplitude and prolonged the action potentials, and also augmented the force responses to cardiac stimulation and to isoprenaline. 4. Clofilium, a selective blocker of the delayed outward rectifying potassium channel, at 0.1 and 0.3 microM prolonged the action potentials. At 0.1 microM, clofilium augmented the cardiac stimulation responses and, at 0.3 microM, clofilium augmented the maximal responses to isoprenaline. At 1 and 3 microM, clofilium had a lesser ability to prolong action potentials and did not alter force responses. 5. Procaine blocks the Na(+)-activated and the delayed outward rectifying potassium channels and, at higher concentrations, sodium channels. Procaine, at 30 microM, prolonged the action potentials and augmented the force responses to isoprenaline, presumably by blocking potassium channels. Procaine, at 1 mM, had no effect on action potentials but reduced the maximal force responses to isoprenaline, probably by blocking sodium channels. 6. Tetraethylammonium blocks the inward rectifying and delayed outward rectifying potassium channels. Tetraethylammonium, at 1 and 3 mM, prolonged the action potentials and augmented all of the force responses; these effects are likely to be predominantly due to blocking the outward rectifying potassium channel. Thus, in the presence of procaine, the effects of tetraethylammonium are predominantly due to the additional blockade of the inward rectifying potassium channel and there were no effects. 7. None of the potassium channel blockers at any of the concentrations tested had arrhythmogenic effects alone or in the presence of isoprenaline. 8. In summary, this study has shown that blockade of the Na(+)-activated and the delayed outward rectifying, but not the ATP-sensitive or inward rectifying, potassium channel is associated with prolongation of the action potentials, augments the contractile force responses, and is not arrhythmogenic on the rat right ventricle. New drugs that block the Na(+)-activated or delayed outward rectifying potassium channel may have potential as positive inotropes in the treatment of heart failure.

4-Aminopyridine↗

PubMed1996

Veratridine augments and BDF 9148 attenuates the spontaneous contractile force of the rat portal vein.

Veratridine and BDF 9148 both increase the force of myocardial contraction but their effects on the contractility of vascular smooth muscle are largely unknown. We have examined the effects of the drugs on the contractile force of the rat portal vein. The force responses of the rat portal vein were not altered by tetrodotoxin (< or = 30 microM) but were augmented by Bay K 8644 (10 nM-10 microM), and attenuated by nifedipine (10 nM-10 micro M). Veratridine slightly reduced the force of spontaneous contractions at concentrations of 0.1-1 microM, then augmented the force at concentrations up to 100 microM. The reduction was prevented by 30 nM tetrodotoxin; a higher concentration of 3 microM prevented the effect of veratridine. Pretreatment with nifedipine at 30 nM reduced the maximum augmentation observed with veratridine. BDF 9148 (0.3-300 microM) attenuated the force and this attenuation was increased in the presence of tetrodotoxin at 3 microM but reversed to an augmentation in the presence of Bay K 8644 at 10 microM. The augmentation produced by BDF 9148 in the presence of Bay K 8644 was reduced by tetrodotoxin at 30 nM. These results suggest that veratridine predominantly opens sodium channels which in turn open voltage-dependent calcium channels to augment the force responses of the rat portal vein, but attenuate force in the presence of sodium-channel blockade with tetrodotoxin. BDF 9148 predominantly closes calcium channels to attenuate the force of the rat portal vein but in the presence of maximum calcium-channel opening with Bay K 8644 augments force probably by opening sodium channels.

Animals↗

PubMed1995

The effects of veratridine and BDF 9148 on the action potentials and contractility of the rat right ventricle.

1. The effects of veratridine, BDF 9148 and lignocaine on the action potentials and contractile force of the electrically-driven rat right ventricle have been determined. 2. Veratridine at 10(-7)-10(-6) M and BDF 9148 at 10(-7)-10(-5) M had no effect on the threshold potential or amplitude but prolonged the ventricular action potentials. 3. In contractility studies, veratridine at 10(-7)-10(-6) M augmented the cardiac stimulation responses and the augmenting effects with 3 x 10(-7) and 10(-6) M were greater at 2 than 4 Hz. In the presence of veratridine at 3 x 10(-6) M, the ventricle would not pace. 4. BDF 9148 at 10(-7)-10(-5) M augmented the cardiac stimulation responses and the augmenting effects with 10(-7) and 3 x 10(-7) M were greater at 2 than 4 Hz and the effect was maximal at 3 x 10(-7) M and submaximal at 10(-5) M. The effects of BDF 9148 at 10(-5) were not readily reversible. 5. Lignocaine at 10(-4) M had no effect on the ventricular action potential duration but decreased the threshold potential and amplitude and also reduced the cardiac stimulation force responses. In the presence of lignocaine, the augmenting effects of veratridine and BDF 9148 on ventricular force were reduced. 6. In summary this study has shown that BDF 9148 prolongs the action potential and augments the contractile force responses of the rat right ventricle by a lignocaine-sensitive mechanism. BDF 9148 or similar drugs may have potential as positive inotropes in the treatment of heart failure.

Action Potentials↗

PubMed1995

Loss of maximum attenuation and receptor reserve for isoprenaline at the beta 2-adrenoceptors of the portal veins of hypertensive rats.

OBJECTIVE: To test the hypothesis that vascular beta 2-adrenoceptor hyporesponsiveness in spontaneously hypertensive rats (SHR) is not induced by increased blood pressure or venous hypertrophy. DESIGN: We compared the attenuating effects or isoprenaline, sodium nitroprusside and verapamilon the portal veins from Wistar-Kyoto (WKY) rats and SHR. studied the effects of slowly reversible beta-adrenoceptor antagonists, bromoacetylalprenololmenthane (BAAM) and ICI 147798, on the isoprenaline responses in order to determine the affinity and fractional beta 2-adrenoceptor occupancy-response relationships for isoprenaline. RESULTS: The SHR portal veins did not develop hypertrophy. There was a small reduction in the sensitivity to isoprenaline and a marked reduction in the maximum attenuation of hypertension caused by isoprenaline. The sensitivity and efficacy of sodium nitroprusside and verapamil were not altered by hypertension. BAAM and ICI 147798 inhibited the isoprenaline responses and reduced the maximum attenuation to isoprenaline. In the WKY rat portal vein the dissociation constant (KA) values for isoprenaline were independent of BAAM concentration, and was 1.78 +/- 0.32 x 10(-7) mol/l. Similar isoprenaline KA values were obtained from the ICI 147798 data and in the SHR portal vein. In the WKY rat portal vein, from the BAAM data, it was calculated that isoprenaline produced 50, 95 and 100% maximum responses by occupying 6 +/- 1, 20 +/- 3 and 43 +/- 5% (n = 21) of the available beta 2-adrenoceptors, respectively. Similar occupancy-response relationships were obtained in the WKY rat portal vein from the ICI 147798 data. At each level of isoprenaline response the receptor reserve was significantly smaller in the SHR than it was in the WKY rat portal vein. Thus, from the BAAM data, isoprenaline produced 50, 95 and 100% maximum responses by occupying 14 +/- 3, 33 +/- 6 and 58 +/- 7% (n = 15) of the available SHR portal vein beta 2-adrenoceptors, respectively. CONCLUSIONS: The SHR portal vein displays a selective beta 2-adrenoceptor hyporesponsiveness in the absence of a raised blood pressure or hypertrophy. This beta 2-adrenoceptor-associated hyporesponsiveness consisted of a marked loss of maximum attenuation in response to isoprenaline and of beta 2-adrenoceptor reserve for isoprenaline responses.

Adrenergic beta-Agonists↗

PubMed1995

Comparison of the attenuating effects of four beta-adrenoceptor agonists on rat isolated uterus and aorta.

1. The ability of four beta-adrenoceptor agonists to attenuate oxytocin (0.2, 2 and 20 nmol/L) or KCl (20, 40 and 80 mmol/L)-induced contractions of the uterus (n = 5-8 for each agonist) and the KCl (18 mmol/L)-induced contractions of the aorta (n = 9 for each agonist) from rats, pretreated with oestradiol has been compared. 2. Isoprenaline, salbutamol, terbutaline and procaterol (0.1-10 mumol/L) attenuated the contractions of the uterus and the aorta. All four agonists had similar attenuating potencies on the uterus. 3. Procaterol caused the same maximal attenuation (33%) on the aorta as the other beta-adrenoceptor agonists and is thus acting as a full beta 2-adrenoceptor agonist under these experimental conditions. Isoprenaline and procaterol were much more potent than salbutamol and terbutaline in attenuating the aorta responses. 4. This study showed that isoprenaline and procaterol were potent attenuants on both the uterus and aorta whereas salbutamol and terbutaline were potent uterine but only modest aorta attenuants. This preliminary study indicates that the responsiveness of uterine and vascular tissue to certain beta 2-adrenoceptors differs.

Adrenergic beta-Agonists↗

PubMed1995

Increase in affinity and loss of 5-hydroxytryptamine2A-receptor reserve for 5-hydroxytryptamine on the aorta of spontaneously hypertensive rats.

1. The aim of this study was to determine whether the KA value and fractional occupancy-response relationship for 5-hydroxytryptamine (5-HT) at 5-HT2A-receptors were altered in a rat model of genetic hypertension. Thus, the effects of phenoxybenzamine, an irreversible blocker at 5-HT2A-receptors, on the responses of the aorta from spontaneously hypertensive rats (SHRs) and normotensive rats to 5-HT have been examined. The two strains of normotensive rats used were Wistar Kyoto (WKY) rats and Wistar rats bred in Auckland (WA rats). 2. The sensitivity to 5-HT was increased in aortae from hypertensive rats. The pD2 values for 5-HT during the first challenge were 5.54 +/- 0.08 (14), 5.43 +/- 0.05 (12) and 6.08 +/- 0.04 (12) on the aorta of WKY rats, WA rats, and SHRs, respectively. 3. The affinity for 5-HT was increased in hypertension. Phenoxybenzamine at 2 x 10(-8)M for 30 min caused nonparallel rightward shifts of 5-HT response curves and the KA values were 16.8 x 10(-6)M, 45.6 x 10(-6)M and 4.4 x 10(-6)M on the WKY rat, WA rat, and SHR aorta, respectively. 4. There was a loss of receptor reserve for 5-HT in aortae from hypertensive rats. On the WKY and WA rat aortae, 5-HT caused 50 and 95% maximal responses by occupying 10-20 and 45-60%, whereas on the SHR aorta 5-HT produced 50 and 95% maximal responses by occupying 20-30 and 75-85% of the available 5-HT2A receptors, respectively. 5. The sensitivity to phenylephrine was not altered in hypertension. The mean pD2 values for phenylephrine were 7.14 +/- 0.05 (22) and 7.11 +/- 0.06 (22) on the WKY rat and SHR aorta, respectively. 6. These results show that there is a selective increase in sensitivity to 5-HT on the aorta in a rat model of genetic hypertension. There is also an increase in affinity for 5-HT at the 5-HT2A-receptors and a loss of 5-HT2A-receptor reserve for 5-HT responses on the aorta of SHRs.

Animals↗

PubMed1995

The effects of racemic, (+)- and (-)-pinacidil on the membrane potential of the rat aorta.

The endothelium-intact and -denuded rat aorta is hyperpolarized by racemic and (-)-pinacidil, probably by opening ATP-dependent potassium channels. (+)-Pinacidil caused depolarization of the endothelium-intact and -denuded rat aorta. The depolarization induced by 20 mAM KCl in the endothelium-intact rat aorta was reversed by racemic and (-)-, but not by (+)-pinacidil. On the endothelium-intact rat aorta, isoprenaline produced hyperpolarization and ICI 118551 (erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylamino butan-2-ol) had no effect alone but prevented isoprenaline from causing hyperpolarization. The hyperpolarization induced by isoprenaline was reversed by racemic and (+)-, but not by (-)-pinacidil. Glibenclamide depolarized the endothelium-intact rat aorta and prevented the hyperpolarizing action of racemic pinacidil and (-)-pinacidil. (+)-Pinacidil prevented the hyperpolarizing action of (-)-pinacidil. Glibenclamide is probably preventing the hyperpolarization associated with opening of the ATP-dependent potassium channel by blocking this channel. Several mechanisms may underlie the depolarizing action of (+)-pinacidil, including blocking of ATP-dependent potassium channels.

Animals↗

PubMed1994

Characterization of the contractile responses to noradrenaline and adrenaline of aorta from normotensive and hypertensive rats.

1. The effects of phenoxybenzamine treatment on the contractile responses of the aorta from WKY and SH rats to noradrenaline and adrenaline have been determined. 2. There was no change in sensitivity of the aorta to noradrenaline or adrenaline with hypertension. 3. Phenoxybenzamine treatment caused nonparallel rightward shifts of the concentration-response curves to the lower concentrations of noradrenaline and adrenaline. 4. The KA value for noradrenaline on the WKY rat aorta was 4.15 x 10(-8) M and noradrenaline produced a 95% maximum response by occupying 95% of the available alpha 1-adrenoceptors. These parameters were significantly different on the SH rat aorta; thus the KA value for noradrenaline was 76.40 x 10(-8) M and noradrenaline produced a 95% maximum response by occupying 63% of the alpha 1-adrenoceptors. 5. The KA value for adrenaline on the WKY rat aorta was 5.03 x 10(-8) M and adrenaline produced a 95% maximum response by occupying 95% of the available alpha 1-adrenoceptors. These adrenaline parameters were not significantly different on the SH rat aorta. 6. In summary this study has demonstrated that although the sensitivities of the rat aorta to noradrenaline and adrenaline do not alter, there is a change in the KA and receptor reserve for noradrenaline, but not adrenaline in hypertension.

Animals↗

PubMed1994

The effects of racemic cromakalim, BRL 38226 and levcromakalim on the membrane potential of the rat aorta and of BRL 38226 on the contractile activity of the rat aorta and portal vein.

The effects of racemic cromakalim and the (+)-3R,4S and (-)-3S,4R isomers, BRL 38226 and levcromakalim respectively, on the membrane potential of the rat aorta have been determined. In addition, preliminary studies of the effects of BRL 38226 on the contractility of the rat aorta and portal vein have been made. The rat aorta is hyperpolarized by racemic cromakalim at 10 microM and by levcromakalim at 1 microM, but is depolarized by BRL 38226 at 1 microM. In the presence of depolarization with 20 microM KCl, racemic cromakalim and levcromakalim, but not BRL 38226, reversed the depolarization of the rat aorta. In the presence of hyperpolarization with isoprenaline at 1 microM or in a CaCl2-free Krebs solution, racemic cromakalim and BRL 38226, but not levcromakalim reversed the hyperpolarization. Glibenclamide at 0.3 and 1 microM depolarized the rat aorta. Pretreatment with glibenclamide at 1 microM prevented the hyperpolarizing action of racemic cromakalim but did not alter the depolarizing action of BRL 38226. Pretreatment with BRL 38226 at 10 microM also prevented the hyperpolarizing action of racemic cromakalim. Contractility studies demonstrated that BRL 38226 and glibenclamide have no effect on the resting tone of the rat aorta in normal Krebs solution. However in a CaCl2-free Krebs solution, BRL 38226 and glibenclamide, 0.1-100 microM, caused small contractions. BRL 38226 and glibenclamide increased the spontaneous contractile activity of the rat portal vein in normal Krebs solution. The present study illustrates that levcromakalim opens the ATP-dependent potassium channels of the rat aorta to cause hyperpolarization. BRL 38226 and glibenclamide produce depolarization and contraction of the rat aorta and increase the contractile activity of the rat portal vein, possibly by blocking the ATP-dependent potassium channels.

Animals↗

PubMed1994

Functional beta-adrenoceptors in the left atrium of normotensive and hypertensive rats.

1. The aim of the study was to characterize the functional beta 1-and beta 2-adrenoceptors of the rat left atrium and to investigate how these functional beta-adrenoceptor responses were altered in hypertension. The contractile responses of the left atrium from Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats to isoprenaline, T-0509 and procaterol were characterized. Subsequently, the effects of selective beta 1-(bisoprolol) and beta 2 (ICI 118,551)-adrenoceptor antagonists were investigated on these responses. 2. The maximal combined contractile responses of the rat left atrium to cardiac stimulation and CaCl2, isoprenaline, T-0509 or procaterol were not altered by hypertension. 3. The sensitivities to CaCl2 (pD2 on WKY left atrium = 2.99), isoprenaline (8.82) and T-0509 (8.84) were not altered by hypertension. There was an increase in sensitivity to procaterol from a pD2 value of 7.21 to 7.61 in the left atrium of the SH rat. 4. The basal tension induced by cardiac stimulation alone was inhibited by bisoprolol at > or = 10(-8) M and by ICI 118,551 at > or = 10(-7) M and this inhibitory effect is probably due to membrane stabilizing activity. 5. The pKB values for bisoprolol against isoprenaline, T-0509 and procaterol on the WKY were 8.43, 8.68 and 8.18, respectively, and were not different from SH rat left atrium. 6. The pKB value for ICI 118,551 against isoprenaline was increased from 7.06 on the WKY to 7.44 on the SH rat left atrium. The pKB values for ICI 118,551 against T-0509 and procaterol on the WKY were 7.18 and 8.14, respectively and were not significantly different from the SH rat left atrium values. 7. These results suggest that: (a) procaterol stimulates the beta 1-, in addition to, the beta 2-adrenoceptors of the rat left atrium; (b) functional beta 1-adrenoceptors are not altered in hypertension, and (c) there is probably an increase in the affinity of procaterol and isoprenaline for the beta 2-adrenoceptors which underlies the small increase in the functional beta 2-adrenoceptor response in hypertension.

Animals↗

PubMed1993

The effects of (+/-)-, (+)-, and (-)-atenolol, sotalol, and amosulalol on the rat left atria and portal vein.

The effects of (+/-)-, (+)-, and (-)-atenolol, sotalol, and amosulalol alone on the rat left atria and portal vein and on the respective beta 1- and beta 2-adrenoceptor-mediated responses to isoprenaline have been determined. (+/-)-Atenolol at 10(-6) M had no effect whereas high concentrations of (+/-)- and (-)-sotalol, 10(-5)-10(-4) M, and (+/-)-, and (-)-amosulalol depressed the response of the rat left atria to cardiac stimulation which indicates membrane stabilizing activity. None of the drugs tested had any effect alone on the rat portal vein. The order of potency as antagonists was (+/-)-amosulalol > (+/-)-atenolol > (+/-)-sotalol at beta 1-adrenoceptors and (+/-)-amosulalol > (+/-)-sotalol > (+/-)-atenolol at beta 2-adrenoceptors. (+/-)-Atenolol and (+/-)-amosulalol are beta 1-selective whereas (+/-)-sotalol is beta 2-selective. For each of the racemic beta-blockers, the beta 1- and beta 2-adrenoceptor blocking activity was predominantly due to the (-)-enantiomer.

Adrenergic beta-Antagonists↗

PubMed1993

Alprenolol and bromoacetylalprenololmenthane are competitive slowly reversible antagonists at the beta 1-adrenoceptors of rat left atria.

We studied the effects of alprenolol and bromoacetylalprenololmenthane (BAAM) on rat left atria. Alprenolol and BAAM at 10(-7), 3 x 10(-7), and 10(-6) M inhibited the cardiac stimulation response slightly, which is indicative of membrane-stabilizing activity independent of beta-adrenoceptor blockade. This membrane-stabilizing activity was readily reversible. Alprenolol and BAAM also caused surmountable antagonism of isoprenaline responses, and this beta 1-adrenoceptor antagonism was slowly reversible. Inhibition of the isoprenaline responses with alprenolol and BAAM at 10(-6) M was at equilibrium after 60 min, which is indicative of reversible antagonism. We conclude that alprenolol and BAAM are competitive slowly reversible beta 1-adrenoceptor antagonists on rat left atria.

Adrenergic beta-Antagonists↗

PubMed1993

Negative inotropic effect of pinacidil on the rat left atria.

Cromakalim at 50 microM and pinacidil at 0.1-10 microM had no effect, but pinacidil at 0.1 mM had a negative inotropic effect on the rat electrically-driven left atria without altering the positive inotropic responses to isoprenaline or phenylephrine alone. Glibenclamide had no effect but 4-aminopyridine, procaine (30 microM) and tetraethylammonium (3 mM) augmented the cardiac stimulation response. The ability of pinacidil to attenuate the cardiac stimulation response was not altered by glibenclamide, 4-aminopyridine or procaine but was prevented by pretreatment with tetraethylammonium. Thus, on the rat left atria, pinacidil has a negative inotropic effect which is unrelated to the opening of ATP-sensitive potassium channels, but may be due to opening the inward rectifying potassium channels.

Animals↗

PubMed1992

Characterization of the antagonism with metoprolol, ICI 147,798, pindolol, mepindolol and bopindolol on the responses of the rat left atria to isoprenaline.

The aim of the study was to determine whether the antagonism with pindolol, mepindolol and bopindolol at the beta 1-adrenoceptor of the rat left atria, a tissue with plenty of spare beta 1-adrenoceptors for isoprenaline maximum responses, was readily reversible or not. The effects of these drugs were compared to those of metoprolol, a readily reversible, and of ICI 147,798, an irreversible beta-adrenoceptor antagonist. Metoprolol at 10(-7) and 10(-6) M, ICI 147,798, pindolol, bopindolol (all at 10(-8) and 10(-7) M) and mepindolol at 10(-9) and 10(-8) M inhibited the cardiac stimulation responses to a small extent, which is indicative of membrane stabilizing activity, and also caused surmountable antagonism of isoprenaline responses. The inhibitory effects on the isoprenaline responses of metoprolol and pindolol were readily reversible, that of mepindolol was slowly reversible and those of ICI 147,798 and bopindolol were not reversed in 3 h. The inhibitory effects on isoprenaline responses of metoprolol at 10(-6) M, pindolol and bopindolol at 10(-7) M and mepindolol at 10(-8) M were at equilibrium, which is indicative of reversible, whereas the inhibitory effects of ICI 147,798 were increased, which is indicative of irreversible antagonism, when the beta-blocker treatment time was increased from 1 to 2 h. We conclude that the antagonism with pindolol at the beta 1-adrenoceptors of the rat left atria is readily reversible, that of mepindolol is slowly reversible and that of bopindolol is very slowly reversible.

Adrenergic beta-Antagonists↗

PubMed1992

An analysis of the inhibitory effects of prazosin on the phenylephrine response curves of the rat aorta.

On the endothelium-intact rat aorta some studies have shown prazosin to cause nonparallel rightward shifts of alpha 1-adrenoceptor agonist response curves. The aim of the present study was to analyze the inhibitory effect of prazosin on the phenylephrine responses of the endothelium-intact and endothelium-denuded rat aorta. Firstly I used phenoxybenzamine treatment to characterize the phenylephrine responses. The KA values for phenylephrine were 0.13-0.18 microM and 0.07-0.16 microM in the endothelium-intact and endothelium-denuded rat aorta, respectively. In order to produce maximal responses of the endothelium-intact or--denuded preparation, phenylephrine had to occupy 95-99% of the alpha 1-adrenoceptors. Secondly I compared the inhibitory effects of phentolamine and prazosin on the endothelium-intact rat aorta. Phentolamine at 0.1 and 1 microM caused parallel rightward shifts of phenylephrine response curves with no effect on phenylephrine maximal responses (phentolamine pA2 = 7.9). The inhibitory effects of phentolamine were readily reversible. Prazosin at 0.1-10 nM caused nonparallel rightward shifts of the phenylephrine response curves with a depression of the maximal response. These inhibitory effects of prazosin were either irreversible or only very slowly reversible in drug-free solution and slowly reversible in the presence of phentolamine. Ninety min was required for the inhibitory effect of prazosin to reach equilibrium whereas phentolamine was at equilibrium after 45 min. Finally I have characterized the inhibitory actions of prazosin on the endothelium-denuded rat aorta. Prazosin caused parallel rightward shifts of phenylephrine response curves with no effect on phenylephrine maximal responses. The inhibitory effects of prazosin were at equilibrium after 45 min and were readily reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Effects of potassium channel openers and calcium channel blockers on the force responses of the electrically driven rat right ventricle strip.

1. The effects of potassium channel openers (cromakalim and pinacidil) and of calcium channel blockers (verapamil, diltiazem and flunarizine) on the contractile responses of the rat right ventricle have been determined. 2. On the electrically driven rat right ventricle cromakalim at 3 x 10(-7), 10(-6), 3 x 10(-6) M and 10(-5) M, and pinacidil at 10(-6), 10(-5) and 3 x 10(-5) M had no effect on the force responses to cardiac stimulation or to isoprenaline. 3. Pinacidil at 10(-4) M in a vehicle of 0.7% ethanol reduced the force responses to cardiac stimulation. This inhibitory effect was solely due to the ethanol. Pinacidil in 5 x 10(-4) M HCl (which had no effect alone) potentiated some of the responses to isoprenaline. 4. Verapamil, greater than or equal to 10(-6) M, diltiazem, greater than or equal to 10(-5) M, and flunarizine, greater than or equal to 10(-6) M, reduced the force responses to cardiac stimulation and to isoprenaline. 5. The present study has shown that calcium channel blockers, but not potassium channel openers, have inhibitory effects on the rat right ventricle.

Animals↗

PubMed1992

Further analysis of the inhibitory effects of dihydroergotamine, cyproheptadine and ketanserin on the responses of the rat aorta to 5-hydroxytryptamine.

1. The aim of the present study was to analyse the inhibitory effects of dihydroergotamine, cyproheptadine and ketanserin on the rat aorta contractile responses to 5-HT. Initially phenoxybenzamine treatment was used to determine whether spare receptors exist at the maximum responses to 5-HT. Then the reversibility of the inhibitory effects of phentolamine, dihydroergotamine, cyproheptadine and ketanserin against the fast and slow response of the rat aorta to 5-HT were determined. 2. Phenoxybenzamine caused non-parallel rightward shifts of the 5-HT concentration-response curves with reduced maximal responses. The KA values for 5-HT to produce fast and slow responses were 2-5 x 10(-5) M. These KA values are much higher than those previously reported for 5-HT at 5-HT2-receptors and suggest that the 5-HT2-receptor of the rat aorta is 'atypical'. The rat aorta has spare 5-HT-receptors for the maximal fast and slow responses to 5-HT. 3. Phentolamine, dihydroergotamine, cyproheptadine and ketanserin inhibited the fast and slow responses to 5-HT. Phentolamine and ketanserin and the higher concentrations of dihydroergotamine and cyproheptadine tested had greater inhibitory effects on the fast than slow 5-HT responses possibly because the fast 5-HT response did not always reach equilibrium in the presence of antagonists. 4. The inhibitory effects on 5-HT responses of phentolamine at 10(-6)-10(-5) M were readily reversible, those of cyproheptadine at 10(-9)-10(-8) M and ketanserin at 10(-8) M were slowly reversible and those of dihydroergotamine at 10(-9)-10(-8) M were irreversible by washing in drug-free Krebs. 5. The inhibitory effects of phentolamine and ketanserin were not altered by increasing the treatment time whereas some of the effects of cyproheptadine and the effects of dihydroergotamine on responses to 5-HT were increased by prolonging the contact time with the antagonist from 75 to 150 min. 6. The present study shows that at the rat aorta 5-HT2-receptor, phentolamine is a competitive readily reversible, cyproheptadine and ketanserin are competitive slowly reversible and dihydroergotamine is a competitive irreversible antagonist.

Animals↗