Pharmacodynamic and pharmacokinetic studies on prizidilol and nipradilol (K-351), antihypertensive drugs with combined vasodilator and beta-adrenoceptor blocking actions, in rabbits

Effects of prizidilol and nipradilol (K-351), beta-adrenoceptor antagonists with vasodilator action, on blood pressure and heart rate were studied in normotensive conscious rabbits after i.v. administration. In addition, we investigated relationships between plasma drug concentrations and beta-adrenoceptor blocking activity as estimated by the inhibition of isoproterenol-induced tachycardia and vasodilator activity as assessed by the inhibition of pressor response to angiotensin II (ANG II). Prizidilol (4 mg/kg) produced a significant and sustained fall in blood pressure and a slight increase in heart rate, while hydralazine (2 mg/kg) caused the same degree of hypotension and a marked tachycardia. Nipradilol (1 mg/kg) caused a significant reduction of resting heart rate, but had no significant effect on blood pressure. Propranolol (1 mg/kg) did not affect resting blood pressure and heart rate. Hypertensive response to ANG II was significantly attenuated only by hydralazine. Isoproterenol-induced tachycardia was significantly suppressed by prizidilol, nipradilol and propranolol. Good correlations were observed between beta-adrenoceptor blocking activity and plasma drug concentrations. These data suggest that prizidilol has an advantage over hydralazine to induce less tachycardia, but still may cause a certain degree of increase in heart rate. Nipradilol has a more potent beta-adrenoceptor blocking action than propranolol, while its vasodilator action is not obvious, at least in rabbits. Plasma concentrations of prizidilol and nipradilol are good indicators for beta-adrenoceptor blocking activity, but not for vasodilator activity.     

The effects of bufuralol, a beta-adrenoceptor antagonist with predominant beta 2-adrenoceptor agonistic activity, in the cat and the dog

The effects of bufuralol and its carbinol metabolite have been compared with those of propranolol in the anaesthetised and conscious cat and dog. Bufuralol and its carbinol metabolite are nonselective beta-adrenoceptor antagonists; the former has equivalent potency to propranolol, whereas the latter is six times more potent. In anaesthetised animals both bufuralol and its metabolite exhibited partial agonistic activity, resulting in tachycardia and vasodilation. In conscious cats there was no change in heart rate or slight bradycardia, whereas in dogs both compounds again produced tachycardia. In anaesthetised and conscious cats and conscious dogs, both bufuralol and the metabolite increased abdominal aortic blood flow. There was a reduction in blood pressure in the conscious dog. It is concluded that the partial agonistic activity of bufuralol and its carbinol metabolite is exerted mainly at the beta 2-adrenoceptor, producing vasodilation and reducing peripheral resistance, resulting in a reduction in blood pressure with a long duration of action.     

In vivo evidence that isoproterenol may increase heart rate in the rat by mechanisms in addition to activation of cardiac beta(1)- or beta(2)-adrenoceptors

This study demonstrates that the tachycardia produced by systemic injections of the beta-adrenoceptor agonist, isoproterenol (10 microg/kg, i.v.), in conscious rats were not reduced after injection of the selective beta(1)-adrenoceptor antagonist, atenolol (1 mg/kg, i.v.), or after subsequent injection of the beta(1,2)-adrenoceptor antagonist, propranolol (1 mg/kg, i.v.). The hypotensive responses produced by isoproterenol were slightly diminished by atenolol and markedly diminished by propranolol. The tachycardia produced by catecholamines released for cardiac sympathetic nerve terminals were blocked by atenolol. These results suggest that the hypotensive actions of a 10 microg/kg dose of isoproterenol are mediated by activation of beta(1,2)-adrenoceptors whereas the increases in heart rate may be due to activation of another type of beta-adrenoceptor in cardiac pacemaker cells.     

Observations on the mechanism underlying the differences in exercise and isoprenaline tachycardia after cardioselective and non-selective beta-adrenoceptor antagonists

1 Differences in ability to attenuate isoprenaline tachycardia between the cardioselective beta-adrenoceptor antagonist atenolol and the non-selective drug propranolol, when administered in equivalent anti-exercise tachycardia oral doses, were measured in four normal volunteers. 2 Propranolol at all dose comparisons showed a greater potency in antagonism of isoprenaline tachycardia than atenolol; this ranged from 6 at the lowest doses (40 and 50 mg respectively) to 13 at the highest doses (320 and 400 mg respectively). 3 After doses of each drug which produced equal inhibition of exercise tachycardia, isoprenaline induced a greater increase in heart rate and greater decrease in diastolic blood pressure after pre-treatment with atenolol than after propranolol. 4 The contribution of this isoprenaline induced vasodilatation to the reduced tachycardia response, 1 h after 25 mg oral atenolol, was measured in the same four subjects by correction of the hypotension with an intravenous angiotensin infusion. Reversal by angiotensin of the 17 mm Hg average fall in diastolic blood pressure during the sustained isoprenaline infusion did not reduce the tachycardia. 5 The hypotension that results from isoprenaline stimulation of unblocked vasodilator beta 2-adrenoceptors in normal subjects pre-treated with atenolol appears to make a negligible contribution to the tachycardia response and does not explain the different abilities of cardioselective and non-selective beta-adrenoceptor blocking drugs to antagonise isoprenaline tachycardia. Our results are compatible with the presence of beta 2-adrenoceptors in human atria.     

Regional haemodynamic effects of recombinant murine or human leptin in conscious rats

Regional haemodynamic responses to recombinant murine or human leptin were assessed in conscious, chronically-instrumented, male, Long-Evans rats (350 - 450 g). Human, but not murine, leptin caused a slight hindquarters vasoconstriction, but neither peptide had any effect on mean arterial blood pressure or heart rate. In the presence of the beta(2)-adrenoceptor antagonist, ICI 118551, a hindquarters vasoconstrictor response to human leptin was not seen, and there was a tachycardia, as there was to murine leptin. The nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester, (L-NAME), did not influence the cardiovascular effects of murine or human leptin. The results indicate that the previously reported sympathoexcitatory effects of murine leptin in anaesthetized rats are not manifest as regional haemodynamic changes in conscious rats, and this is not due to beta(2)-adrenoceptor-mediated vasodilator mechanisms opposing any vasoconstrictor responses. Moreover, the ability of L-NAME to unmask a pressor effect of murine leptin in anaesthetized rats may not be apparent in the conscious state.     

Autonomic and antihypertensive activity of oral amosulalol (YM-09538), a combined alpha- and beta-adrenoceptor blocking agent in conscious rats

The autonomic and antihypertensive activities of amosulalol (YM-09538) were studied in conscious rats. Single oral administration of amosulalol antagonized the phenylephrine-induced pressor and isoproterenol-induced positive chronotropic responses with DR10 values of 11.5 and 13.6 mg/kg in pithed rats, respectively, indicating that the compound inhibits both alpha 1- and beta 1-adrenoceptors to almost the same extent in agreement with previously reported results in vitro. Amosulalol was approximately 50 times less potent than prazosin and 12 times more potent than labetalol at alpha 1-adrenoceptors, and it was approximately as effective as labetalol and 2 times more potent than propranolol at beta 1-adrenoceptors. In spontaneously hypertensive rats (SHR), renal hypertensive rats and DOCA/salt hypertensive rats, a single oral administration of amosulalol (3-30 mg/kg) lowered acutely systolic blood pressure with a duration of over 6 hr and was found to be approximately 50 times less potent than prazosin and 3 times more potent than labetalol in lowering blood pressure. Propranolol did not cause such an immediate hypotensive effect. Amosulalol and labetalol did not increase heart rate, whereas prazosin induced a tachycardia in the hypertensive rats. Repeated oral administrations of amosulalol and labetalol (50 mg/kg/day, b.i.d., for 12 weeks) produced not only an antihypertensive effect without evidence of tolerance, but also reductions in plasma renin activity (PRA) and heart rate in SHR with established hypertension. We conclude that alpha-adrenoceptor blockade by amosulalol might account for its antihypertensive activity and that its beta-adrenoceptor blockade might inhibit reflexogenic increases in heart rate and PRA due to the reduction in blood pressure.     

Vanidipinedilol: a vanilloid-based beta-adrenoceptor blocker displaying calcium entry blocking and vasorelaxant activities

Calcium channel and beta-adrenoceptor blockade have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of vanidipinedilol that combine these effects within a single molecule are described here. Intravenous injection of vanidipinedilol (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and bradycardic responses, significantly different from nifedipine-induced (0.5 mg/kg, i.v.) hypotensive and reflex tachycardic effects in pentobarbital-anesthetized Wistar rats. A single oral administration of vanidipinedilol at doses of 10, 25, and 50 mg/kg dose-dependently reduced blood pressure with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat atrium, vanidipinedilol (10(-7), 10(-6), and 10(-5) M) competitively antagonized the (-)isoproterenol-induced positive chronotropic and inotropic effects and inhibited the increase in heart rate induced by Ca2+ (3.0-9.0 mM) in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol and CaCl2 suggested that vanidipinedilol possessed beta-adrenoceptor-blocking and calcium entry-blocking activities. On tracheal strips of reserpinized guinea pig, cumulative doses of vanidipinedilol (10(-10) to 3x10(-6) M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10(-10), 10(-9), 10(-8) M), a beta2-adrenoceptor antagonist, shifted the vanidipinedilol concentration-relaxation curve significantly to a region of higher concentrations. These results implied that vanidipinedilol had a partial beta2-agonist activity. In the isolated thoracic aorta of rat, vanidipinedilol had a potent effect inhibiting high-K+-induced contractions. KCI-induced intracellular calcium changes of blood vessel smooth muscle cell (A7r5 cell lines) determined by laser cytometry also was decreased after administration of vanidipinedilol (10(-8), 10(-7), 10(-6) M). Furthermore, the binding characteristics of vanidipinedilol and various antagonists were evaluated in [3H]CGP-12177 binding to ventricle and lung and [3H]nitrendipine binding to cerebral cortex membranes in rats. The order of potency of beta1- and beta2-adrenoceptor antagonist activity against [3H]CGP-12177 binding was (-)propranolol (pKi, 8.59 for beta1 and 8.09 for beta2) > vanidipinedilol (pKi, 7.09 for beta1 and 6.64 for beta2) > atenolol (pKi, 6.58 for beta1 and 5.12 for beta2). The order of potency of calcium channel antagonist activity against [3H]nitrendipine binding was nifedipine (pKi, 9.36) > vanidipinedilol (pKi, 8.07). The ratio of beta1-adrenergic-blocking/calcium entry-blocking selectivity is 0.1 and indicated that vanidipinedilol revealed more in calcium entry-blocking than in beta-adrenergic-blocking activities. It has been suggested that vanidipinedilol-induced smooth muscle relaxation may involve decreased entry of Ca2+ and partial beta2-agonist activities. In conclusion, vanidipinedilol is a nonselective beta-adrenoceptor antagonist with calcium channel blocking and partial beta2-agonist associated vasorelaxant and tracheal relaxant activities. Particularly, the vasodilator effects of vanidipinedilol are attributed to a synergism of its calcium entry blocking and partial beta2-agonist activities in the blood vessel. A sustained bradycardic effect results from beta-adrenoceptor blocking and calcium entry blocking, which blunts the sympathetic activation-associated reflex tachycardia in the heart.     

Adrenoceptor blocking and cardiovascular effects of the optical isomers of amosulalol (YM-09538), a combined alpha- and beta-adrenoceptor blocking agent, and the corresponding desoxy derivative (YM-11133) in rats

The pharmacological activities of the enantiomers of amosulalol (YM-09538), a combined alpha- and beta-adrenoceptor antagonist, and the corresponding desoxy derivative (YM-11133) were investigated in the cardiovascular system of rats. The optical isomers of amosulalol and YM-11133 antagonized the vasopressor effect of phenylephrine and the positive chronotropic effect of isoproterenol in normotensive pithed rats. Based on DR2 values (micrograms/kg, i.v.) obtained from Schild plots, (+)-amosulalol and YM-11133 (DR2 = 30) were approximately 10 times more potent than (-)-amosulalol (DR2 = 324) in blocking alpha 1-adrenoceptors. For beta 1-adrenoceptors, in contrast, (-)-amosulalol (DR2 = 107) was approximately 60 times more potent than (+)-amosulalol (DR2 = 6460), which was almost equipotent with YM-11133 (DR2 = 3250). The results indicate that the optical isomers of amosulalol interact differently with alpha 1- and beta 1-adrenoceptors. The effects of these phenethylamines on blood pressure and heart rate were studied in urethane-anesthetized rats (i.v.). The rank order of hypotensive potency in anesthetized rats [+)- = desoxy greater than (-)-form) was consistent with the rank order of alpha 1-adrenoceptor antagonism in pithed rats. In contrast, (-)-amosulalol having a more potent beta 1-adrenoceptor antagonist activity than (+)-amosulalol and YM-11133 only produced dose-dependent bradycardia at the hypotensive doses. The results indicate that the vascular alpha 1- and cardiac beta 1-adrenoceptor blocking activities of the optical isomers of amosulalol contribute to their hypotensive and bradycardia, respectively. Thus, the racemate of amosulalol appears to exert an overall activity reflecting the activities of the individual isomers.     

Pharmacodynamic profile of the selective beta 1-adrenoceptor antagonist bisoprolol

The pharmacodynamic activity of (+/-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2- propranol- hemifumarate (bisoprolol, EMD 33 512) has been investigated under in vitro and in vivo conditions. Bisoprolol was found to be an effective beta-adrenoceptor antagonist, the pA2 values determined against isoprenaline in guinea pig atria and tracheal muscle being 7.45 and 6.41, respectively. Thus, the selectivity ratio of bisoprolol in favour of beta 1-adrenoceptors is 11. Inhibition of the isoprenaline-induced tachycardia in guinea pigs indicated a long duration of action for bisoprolol. The compound was devoid of intrinsic sympathomimetic activity as shown by the lack of effect on heart rate in anaesthetized and reserpine pretreated rats. Studies in rabbits and guinea pigs revealed a local anaesthetic activity of bisoprolol at high concentrations. Bisoprolol protected the hearts of anaesthetized dogs against the sequelae of intermittent coronary occlusions, as judged by the reduction of the ST-segment elevation in the epicardial ECG. Bisoprolol exerted a blood pressure lowering effect in conscious renal hypertensive dogs after oral administration of 30 micrograms/kg. There was no indication of any action on the CNS in monkeys following an oral dose of up to 8 mg/kg.     

Responses of cerebral circulation produced by adrenoceptor agonists and antagonists in rats

The effects of intravenous administration of adrenoceptor agonists and antagonists on relative cerebral blood flow, cerebral perfusion pressure, intracranial pressure, mean arterial blood pressure and heart rate were assessed in rats under urethane anesthesia. Administration of phenylephrine (a preferential alpha 1-adrenoceptor agonist), adrenaline (a mixed alpha/beta-adrenoceptor agonist), noradrenaline (a mixed alpha/beta-adrenoceptor agonist) raised mean arterial pressure, cerebral perfusion pressure, cerebral blood flow and intracranial pressure, but lowered heart rate. On the other hand, administration of isoproterenol (a beta-adrenoceptor agonist), phentolamine (an alpha-adrenoceptor antagonist) or propranolol (a beta-adrenoceptor antagonist) lowered mean arterial pressure, cerebral perfusion pressure or cerebral blood flow. In addition, phentolamine raised both intracranial pressure and heart rate, whereas propranolol lowered both intracranial pressure and heart rate. However, isoproterenol produced a decrease in heart rate, without affecting intracranial pressure. There was no significant difference between the groups of animals for PCO2, PO2 or pH throughout the studies. The results suggest that adrenoceptor agonists or antagonists act through breakthrough of autoregulation, with acute hypertension or hypotension, to enhance or to reduce cerebral blood flow in rats.     

Cardiovascular effects of apamin and BRL 34915 in rats and rabbits.

1. The cardiovascular effects of apamin, a selective blocker of certain calcium-activated potassium channels, and BRL 34915, a vasodilator thought to act by opening of potassium channels, have been investigated in vivo in rats and rabbits. 2. In anaesthetized normotensive rats, apamin (0.05 and 0.15 mg kg-1, i.v.) potentiated angiotensin II pressor responses but did not modify baseline blood pressure or heart rate. 3. Apamin (0.15 mg kg-1, i.v.) was without cardiovascular effects in rabbits. 4. BRL 34915 (0.1 and 0.3 mg kg-1, i.v.) lowered blood pressure in rats dose-dependently and caused reflex tachycardia. The heart rate increase was abolished by prior administration of the beta-adrenoceptor blocker bopindolol (0.1 mg kg-1, i.v.). 5. In anaesthetized rabbits, regional blood flow measurements (with radioactive tracer microspheres) showed that BRL 34915 (3 to 30 micrograms kg-1, i.v.) caused marked vasodilatation in the stomach, with increases in flow also to the heart and small intestine. Brain blood flow also tended to increase. Blood flow to the kidneys was reduced by BRL 34915, whereas flow to skeletal muscle was unchanged. 6. Apamin pretreatment did not modify the blood pressure lowering activity of BRL 34915 in rats. The site at which BRL 34915 acts to cause vasodilatation in vivo thus appears to be apamin-insensitive.     

STUDIES ON THE VASODILATOR ACTIONS OF BUCINDOLOL IN THE RAT

Experiments were performed in anaesthetized rats to investigate the vasodilator actions of the beta-adrenoceptor antagonist bucindolol. Bucindolol (3 mg/kg) lowered blood pressure significantly in rats pretreated with (i) prazosin (0.4 mg/kg) (ii) prazosin (0.4 mg/kg) plus propranolol (0.5 mg/kg) or (iii) labetalol (0.5 mg/kg). Thus, a portion of the hypotensive effect of bucindolol was independent of effects on alpha- or beta-adrenoceptors. This was attributed to direct vasodilatation. In reserpinized anaesthetized rats bucindolol increased heart rate and thus had an intrinsic sympathomimetic action (ISA). The ISA was equipotent with that of isoprenaline at the 0.25 nmol/kg dose level, but declined with increasing bucindolol doses, probably due to the onset of beta-adrenoceptor blockade. An isolated perfused rat tail arteries constricted by perfusing with a high-K+ Krebs solution, bucindolol (10(-5) mol/l, 10(-4) mol/l) caused a significant reduction in perfusion pressure indicative of vasodilatation. Since the perfusate contained 10(-6) mol/l propranolol, the vasodilatation was not due to beta-adrenoceptor stimulation. These results are consistent with a direct vasodilator action of bucindolol. We suggest bucindolol lowers blood pressure by a complex mechanism involving beta-adrenoceptor blockade, alpha-adrenoceptor blockade, vasodilatation and perhaps beta 2-adrenoceptor stimulation.     

Effects of dilevalol (R,R-labetalol) compared with nifedipine on heart rate, blood pressure and muscle blood flow at rest and on exercise in hypertensive patients.

1. Dilevalol (R,R-labetalol) is a non-selective beta-adrenoceptor antagonist with beta 2-adrenoceptor agonist activity. Its effects after 1 month's administration on heart rate, blood pressure and muscle blood flow were studied in a double-blind crossover comparison with nifedipine in 16 hypertensive patients. 2. Dilevalol and nifedipine were similarly effective in lowering systolic and diastolic blood pressure at rest, but dilevalol limited the rise in systolic blood pressure induced by exercise more than nifedipine (rise of 27 vs 53 mm Hg respectively, P < 0.01). 3. Dilevalol decreased resting heart rate compared with nifedipine (73 vs 92 beats min-1 respectively, P < 0.01). Dilevalol limited the exercise induced rise in heart rate more than nifedipine (36 vs 48 beats min-1 respectively, P < 0.01). 4. Muscle blood flow (measured by strain gauge plethysmography) was not affected by either dilevalol or nifedipine at rest. After exercise, dilevalol caused an increase in excess blood flow compared with placebo (10.8 vs 5.1 ml min-1 dl-1 respectively, P < 0.01). The difference between dilevalol and nifedipine did not reach statistical significance (10.8 vs 6.5 ml min-1 dl-1 respectively, P > 0.05). 5. On blood pressure and heart rate, dilevalol demonstrated beta-adrenoceptor blocker activity at rest and on exercise. On muscle blood flow, dilevalol appeared to have no effect at rest, but may have acted as a beta-adrenoceptor blocker rather than as a beta 2-adrenoceptor agonist during exercise.     

Acute effect of indenolol on systemic arterial pressure and heart rate in the rat

The acute effects of single intravenous or oral doses of indenolol, as compared to that of propranolol and pindolol, on systemic blood pressure and heart rate were investigated in the rat. In reserpinized anaesthetized rats propranolol neither affected diastolic blood pressure nor heart rate and pindolol produced a dose-related tachycardia with moderate hypotensive effect. After indenolol the fall in diastolic blood pressure was concomitant with a very low increase in heart rate. Both effects were prevented by propranolol. In conscious SHRs the acute hypotensive effect of oral indenolol and pindolol was associated with marked bradycardia and moderate tachycardia respectively, while the decrease in heart rate following propranolol was concomitant to a slight increase in blood pressure. The possibility that the acute haemodynamic changes observed in rats after indenolol may be due to intrinsic sympathomimetic activity predominant at beta 2-vascular adrenergic receptor level is discussed.     

CGP12177-induced haemodynamic and vascular effects in normotensive and hypertensive rats

CGP12177 is a non-conventional partial agonist, known to have cardiostimulating and vasorelaxant properties related to its agonist action on the low affinity state of the beta(1)-adrenoceptor (beta(1LA)-adrenoceptor). In normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), CGP12177-induced vasorelaxant effects were analysed in hindquarter vessels to assess modifications in hind limb vascular resistance, and in femoral artery rings. The global haemodynamic effects induced by CGP12177 were also investigated using telemetry in conscious animals. In hindquarters vasculature precontracted with 5-hydroxytryptamine, CGP12177 (0.16 to 475 microg) produced a similar dose-dependent decrease in hindquarters perfusion pressure in both strains. Vasorelaxation was not modified by nadolol, a beta(1) and beta(2)-adrenoreceptor antagonist, nor by L748337, a beta(3)-adrenoceptor antagonist, but was concentration dependently inhibited by bupranolol, a beta(1LA)-adrenoceptor antagonist at high concentrations. In femoral artery rings from WKY rats and SHR, CGP12177 produced a concentration-dependent relaxation, which was unaffected by nitric oxide synthases inhibition but was significantly reduced in the presence of bupranolol. With double cardiac autonomic blockade (atropine plus atenolol) in conscious WKY rats and SHR, CGP12177 greatly increased heart rate with minor changes in mean arterial pressure in both strains. Conversely, in the absence of double cardiac autonomic blockade, the amplitude of CGP12177-induced heart rate increase was less pronounced and had an hypotensive effect. The reduction in tachycardia and the hypotension were significantly greater in SHR compared to WKY rats. In conclusion, in both strains, CGP12177 produced vasodilating effects in hindquarter vessels and femoral arteries that can be attributed to a beta(1LA)-adrenoceptor stimulation. In conscious WKY rats and SHR, CGP12177-induced cardiostimulation and hypotension were not significantly different after baroreflex blockade, but were decreased and increased respectively, in the presence of baroreflex activity.     

Contribution of spinal dopamine receptors to the hypotensive action of bromocriptine in rats.

Bromocriptine, a dopamine (DA) receptor agonist, has been reported to have hypotensive effects in anesthetized and conscious normotensive rats but its mechanism of action is still not fully understood. Therefore, we studied the changes in mean arterial blood pressure (MAP) and heart rate (HR) elicited by an intravenous (i.v.) administration of bromocriptine (150 micrograms/kg), in either pentobarbital-anesthetized or conscious normotensive rats, pretreated with either i.v. (0.3 mg/kg) or intrathecal (i.t.) (93 nmol) domperidone, a DA receptor antagonist that does not cross the blood-brain barrier. In these preparations, i.v. administration of bromocriptine elicited dose-dependent decreases in MAP and rises in HR. The hypotensive effect was antagonized partially by i.t. and fully by i.v. domperidone. However, the latter compound did not modify the tachycardia, which could be blocked by propranolol (0.5 mg/kg i.v.). In rats pretreated with the latter beta-adrenoceptor antagonist, bromocriptine produced only a decrease in blood pressure that was inhibited by i.v. and i.t. domperidone. These results suggest that, in anesthetized and conscious normotensive rats, the hypotension induced by systemic administration of bromocriptine is fully mediated by DA2 dopamine receptors, which are located partly within the spinal cord and partly in the peripheral circulation.     

Effect of CGP 17/582, a selective beta-adrenoceptor antagonist, on the haemodynamic and hypokalaemic response to adrenaline.

1. CGP 17/582B is a new beta-adrenoceptor antagonist which on experimental studies appears to combine selective beta 1-adrenoceptor blockade with partial agonist activity (ISA). Assessing beta-adrenoceptor selectivity and the degree of partial agonist activity in vivo can be difficult. 2. In a double-blind placebo controlled crossover study we have compared the effect of oral pretreatment for 7 days with CGP (100 mg twice daily), with propranolol (non-selective beta-adrenoceptor blocker with no ISA) and metoprolol (selective beta-adrenoceptor blocker with no ISA) on resting heart rate and heart rate response to submaximal exercise on a bicycle ergometer to assess the degree of beta-adrenoceptor blockade and also the changes in blood pressure, heart rate and potassium during the intravenous infusion of (-)-adrenaline to determine the degree of beta 2-adrenoceptor blockade. 3. Subjects underwent submaximal exercise testing on the second and fifth day of each treatment period and on the seventh day received a 2 h infusion of (-)-adrenaline (0.06 microgram kg-1 min-1). Heart rate, blood pressure, plasma potassium and catecholamines were measured throughout the study period. 4. All three active treatments significantly reduced exercise induced tachycardia. The (-)-adrenaline infusion significantly reduced plasma noradrenaline levels following propranolol and metoprolol and to a lesser extent with placebo but were unaltered on CGP. Baseline heart rate was unaltered by CGP but was significantly reduced by metoprolol and propranolol. Adrenaline significantly reduced plasma potassium levels following placebo and CGP pretreatment but plasma potassium was unaltered by adrenaline with metoprolol and propranolol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECT OF ACUTE ADMINISTRATION OF PRAZOSIN ON BLOOD PRESSURE, HEART RATE AND PLASMA RENIN LEVEL IN THE CONSCIOUS NORMOTENSIVE RAT

This study investigated whether the specific alpha-antagonist, prazosin, stimulated basal plasma renin levels and heart rate. Furthermore the beta-adrenergic nervous system was also investigated to ascertain whether it was involved in this effect. Prazosin (0.1 or 1 mg/kg) was injected subcutaneously (s.c.) to conscious normotensive rats, either alone or in combination with the beta-adrenoceptor antagonist, DL-propranolol (1 or 3 mg/kg). Rats bore chronically implanted dorsal aorta cannula for measurement of blood pressure and heart rate and blood sampling for renin determinations. Acute administration of prazosin (1 mg/kg, s.c.) produced a fall in mean arterial pressure accompanied by renin release and tachycardia. A tenfold lower dose of prazosin did not alter blood pressure or heart rate but did stimulate renin release. Acute administration of DL-propranolol, (1 or 3 mg/kg, s.c.) produced falls in blood pressure and heart rate but did not affect plasma renin level. Combinations of prazosin with propranolol gave falls in blood pressure similar to those predicted on the basis of a simple addition of the effects of the two drugs given separately. Prazosin-induced tachycardia and renin release were attenuated by propranolol. It appears that prazosin produces renin release and tachycardia via stimulation of the beta-adrenergic adrenoceptor.     

An assessment of the partial agonist activity of Ro 31-1118, flusoxolol and pindolol in man.

1. The effects of single oral doses of three beta-adrenoceptor partial agonists (Ro 31-1118, flusoxolol and pindolol), two beta-adrenoceptor antagonists (propranolol and atenolol), two beta-adrenoceptor agonists (salbutamol and prenalterol) and placebo on sleeping heart rate, quality of sleep, supine heart rate, exercise heart rate, blood pressure, forearm blood flow and finger tremor were studied in eight healthy male volunteers. 2. Sleeping heart rate was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol and decreased by propranolol and atenolol. 3. None of the drugs studied affected quality of sleep. 4. Supine heart rate was increased by flusoxolol, prenalterol and salbutamol, unaffected by Ro 31-1118 and pindolol and reduced by propranolol and atenolol. 5. Exercise heart rate was reduced by both beta-adrenoceptor antagonists and the three partial agonists and unaffected by salbutamol and prenalterol. 6. Systolic blood pressure was increased by Ro 31-1118, flusoxolol, salbutamol and prenalterol, unaffected by pindolol and reduced by propranolol and atenolol. Diastolic blood pressure was reduced by salbutamol and prenalterol. 7. Forearm blood flow was increased by Ro 31-1118, salbutamol and prenalterol, unchanged by pindolol and flusoxolol and decreased by atenolol and propranolol. 8. Finger tremor was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol, and prenalterol. 9. beta-adrenoceptor partial agonists have different effects on the cardiovascular system and finger tremor to beta-adrenoceptor antagonists. 10. While Ro 31-1118 and flusoxolol are antagonists mainly at the beta 1-adrenoceptor they have agonist activity at both beta 1- and beta 2 adrenoceptors. 11. While pindolol is a non-selective antagonist its agonist activity is mainly at the beta 2-adrenoceptor.     

Effect of urethane on hydralazine-induced tachycardia in rats.

1. In conscious normotensive rats, hydralazine (5-10 mg kg-1 p.o.) produced a dose-related fall in systolic blood pressure, accompanied by a pronounced increase in heart rate. 2. The tachycardia induced by hydralazine (10 mg kg-1 p.o.) in conscious normotensive rats was strongly inhibited after anaesthesia with urethane (1.26 g kg-1 i.p.). 3. In anaesthetized normotensive rats, hydralazine (1 mg kg-1 i.v.) caused a fall in mean blood pressure, accompanied by irregular effects on the heart rate that consisted in a combination of initial tachycardia followed by bradycardia. 4. In pithed rats, hydralazine (1 mg kg-1 i.v.) did not affect mean arterial blood pressure but produced a significant decrease in heart rate. 5. In rat isolated atria, hydralazine (2 mM) produced a positive inotropic/negative chronotropic effect. 6. These results suggest that urethane inhibits the cardiovascular reflex that causes the tachycardia induced by hydralazine in conscious normotensive rats. For this reason, in anaesthetized normotensive rats appear the direct effect of the drug on the heart.