Alpha adrenoceptor regulation of coronary artery blood flow in normal and stenotic canine coronary arteries

The response of systemic blood pressure, heart rate, lead II ECG and left circumflex (LCX) coronary artery blood flow to left cardiac sympathetic nerve stimulation was measured in pentobarbital-anesthetized, open chest, spinal transected and vagotomized dogs. After beta adrenoceptor blockade, left cardiac sympathetic nerve stimulation produced frequency dependent decreases in LCX blood flow. Selective alpha-2 adrenoceptor blockade with idazoxan produced a greater inhibition of this decrease in LCX blood flow than did selective alpha-1 adrenoceptor blockade with prazosin. In an additional population of dogs which were similarly prepared but were not spinally transectioned or pretreated with a beta adrenoceptor antagonist, left cardiac sympathetic nerve stimulation produced an increase in LCX blood flow in all animals which reached a maximum within 40 sec, and then began to decline slowly. However, after beta adrenoceptor blockade, identical stimulation parameters produced only a decline in LCX blood flow which returned to the level of control resting blood flow by the end of the stimulation period. Both selective alpha-2 adrenoceptor blockade with idazoxan and selective alpha-1 adrenoceptor blockade with prazosin produced an inhibition of the LCX blood flow decrease provoked by left cardiac sympathetic nerve stimulation in dogs pretreated with beta adrenoceptor antagonists. Idazoxan produced a slightly greater inhibition of the LCX blood flow decrease than did prazosin, suggesting a greater role for postjunctional vascular alpha-2 adrenoceptors in LCX blood flow regulation during cardiac sympathetic nerve stimulation. The presence of a severe coronary artery stenosis reduced, but did not inhibit, the increase in LCX blood flow in response to cardiac sympathetic nerve stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effects of the novel inotropic agent, ibopamine, with epinine, dopamine and fenoldopam on renal vascular dopamine receptors in the anesthetized dog

The effect of i.v. administration of the novel, p.o. active inotropic prodrug, ibopamine, on canine renal vascular dopamine DA-1 receptors was determined in the anesthetized dog. These effects were compared with those produced by the active form of ibopamine, epinine, and with the standard DA-1 receptor agonists, dopamine and fenoldopam. After pretreatment of pentobarbital-anesthetized dogs with phenoxybenzamine (10 mg/kg i.v.) and propranolol (2 mg/kg i.v.) to block alpha and beta adrenoceptor-mediated effects, respectively, the renal blood flow responses to i.v. administration of ibopamine, epinine, dopamine and fenoldopam were determined before and after selective blockade of DA-1 receptors by i.v. infusion of SK&F R-83566 (0.5 microgram/kg/min). Under control conditions, ibopamine produced a dose-dependent increase in renal blood flow as a result of renal vasodilation (i.e., decrease in renal vascular resistance), and was approximately 10-fold less potent than epinine in this respect. Epinine elicited qualitatively similar renal hemodynamic changes to ibopamine with the exception of potency. Dopamine was approximately equipotent with epinine as a renal vasodilator, and both compounds were 10-fold less potent than fenoldopam. Concurrent with the renal vasodilation produced by all four compounds, there was a reduction in mean arterial blood pressure and total peripheral vascular resistance. After the administration of SK&F R-83566, the renal vasodilator responses to fenoldopam were antagonized markedly with an approximate 30-fold rightward shift in the log dose-response curve, whereas the renal vasodilator responses to dopamine were abolished completely and converted into small vasoconstrictor responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of leukotriene D4-induced coronary vasoconstriction by leukotriene antagonists in the anesthetized dog

Anesthetized open-chest dogs were instrumented for the measurement of left circumflex coronary artery (LCX) blood flow and aortic blood flow, systemic arterial blood pressure, heart rate, lead II ECG, left ventricular end-diastolic pressure, left ventricular developed pressure and left ventricular positive and negative dP/dt to study the hemodynamic effects of leukotriene D4 (LTD4) and selective LTD4 antagonists on the coronary vasculature. Administration of LTD4 alone into the LCX (0.625-10 micrograms) produced a dose-dependent decrease in LCX blood flow, dP/dt and aortic blood flow and an increase in left ventricular end-diastolic pressure. Systemic arterial blood pressure, left ventricular developed pressure and heart rate were unchanged by LTD4. During i.v. infusions of the LTD4 antagonists, SK&F 102922 or FPL 55712 (1 mg/kg/min), the dose-dependent decreases in LCX flow, dP/dt and aortic blood flow were blocked whereas the increase in left ventricular end-diastolic pressure remained unchanged. The thromboxane A2 antagonist, SK&F 88046 (5 mg/kg + 0.1 mg/kg/min), which has been reported previously to block the coronary blood flow reducing action of LTC4, had no effect on the LCX blood flow responses to intracoronary LTD4. In a separate study, dogs instrumented in a similar manner were given bolus injections of arginine-vasopressin (1 microgram), the thromboxane A2 mimetic, U-46619 (10 micrograms), LTD4 (10 micrograms), angiotensin II (1 microgram) and prostaglandin F2 alpha (100 micrograms) directly into the LCX to provoke coronary vasoconstriction. SK&F 102922 and FPL 55712 selectively blocked the coronary vasoconstriction produced by LTD4, but had no effect on vasoconstriction produced by the other agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the alpha adrenoceptor activity of dopamine, ibopamine and epinine in the pulmonary circulation of the dog

The ability of dopamine, ibopamine and epinine to elicit alpha adrenoceptor-mediated vasoconstriction was studied in the in situ, autoperfused pulmonary circulation of the open-chest anesthetized dog. Animals were pretreated with propranolol to eliminate beta adrenoceptor-mediated relaxation of the pulmonary vasculature. Heparinized blood was withdrawn from the left femoral artery and transferred via a peristaltic pump to the pulmonary arterial branch supplying the left diaphragmatic lobe of the lung. The flow rate of the pump was adjusted so that mean pulmonary perfusion pressure in the lobe was equal to resting diastolic pulmonary artery pressure (10 +/- 1 mm Hg). Under conditions of constant left atrial pressure and pulmonary blood flow, intralobar administration of dopamine, ibopamine and epinine elicited dose-dependent increases in perfusion pressure of the lobe, reflecting increases in pulmonary vascular resistance. Prazosin (100 micrograms/kg i.v.), a selective alpha-1 adrenoceptor antagonist, inhibited the pulmonary vasopressor responses to dopamine, ibopamine and epinine. Rauwolscine (100 micrograms/kg i.v.), a selective alpha-2 adrenoceptor antagonist, inhibited pulmonary pressor responses to dopamine and epinine without altering significantly the pulmonary vasoconstrictor response to ibopamine. These data indicate that dopamine and epinine stimulate both postjunctional vascular alpha-1 and alpha-2 adrenoceptors to elicit pulmonary vasoconstriction in the dog, whereas ibopamine, when injected directly into the pulmonary circulation, stimulates primarily postjunctional vascular alpha-1 adrenoceptors. However, when ibopamine was administered intraduodenally, both prazosin and rauwolscine were found to inhibit the resulting pulmonary vasopressor response. This finding is consistent with the hypothesis that ibopamine is converted to its active metabolite epinine, which stimulates both pulmonary vascular alpha-1 and alpha-2 adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction in the in situ, autoperfused, pulmonary circulation of the anesthetized dog

Alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction was studied in the in situ, autoperfused pulmonary circulation of the open-chest anesthetized dog utilizing selective alpha adrenoceptor agonists and antagonists. Animals were pretreated with propranolol (1 mg/kg i.v.) to eliminate beta adrenoceptor-mediated effects in the pulmonary circulation. Blood was withdrawn from the right femoral artery and transferred, via a peristaltic pump, to the pulmonary arterial branch supplying the left diaphragmatic lobe of the lung. The flow rate of the pump was set so that the perfusion pressure in the lobe was equal to resting diastolic pulmonary artery pressure (10 +/- 1 mm Hg). Under conditions of constant left atrial pressure and pulmonary blood flow, intralobar administration of alpha adrenoceptor agonists elicited increases in perfusion pressure of the lobe, reflecting changes in pulmonary vascular resistance. Intralobar administration of the selective alpha-1 adrenoceptor agonist methoxamine and the selective alpha-2 adrenoceptor agonist B-HT 933 elicited dose-dependent increases in lobar perfusion pressure, as did the nonselective alpha adrenoceptor agonist norepinephrine. Prazosin (100 micrograms/kg i.v.), a selective alpha-1 adrenoceptor antagonist, inhibited pulmonary vasopressor responses to methoxamine and norepinephrine without altering significantly the response to B-HT 933. Rauwolscine (100 micrograms/kg i.v.), a selective alpha-2 adrenoceptor antagonist, inhibited the response to B-HT 933 and norepinephrine with little effect on methoxamine. Intralobar administration of tyramine to evoke the release of endogenous norepinephrine resulted in dose-dependent increases in lobar perfusion pressure. The response to tyramine was inhibited selectively by prazosin with little effect of rauwolscine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of fenoldopam prodrugs with prolonged renal vasodilator activity

Fenoldopam (SK&F 82526) is a short-acting selective dopamine-1 agonist in clinical trials for the treatment of hypertension, congestive heart failure and renal failure. In the present study, we tested various N-ethyl carbamate esters of fenoldopam in the conscious dog instrumented with a femoral arterial Vascular-Access-Port and a renal artery flow probe. Oral administration of SK&F R-82526 at 1 and 3 mumol/kg resulted in transient (30-60 min) dose-dependent increases in plasma fenoldopam levels and renal blood flow. Administration of the 7,8-bis-N-ethyl carbamate ester of R-fenoldopam (SK&F R-106114) and the 4',7,8-tris-N-ethyl carbamate ester of R-fenoldopam (SK&F R-105058) at 1, 3 and 10 mumol/kg p.o. also resulted in dose-dependent increases in plasma fenoldopam levels and renal blood flow; however, both parameters remained elevated for at least 4 hr. Intravenous administration of SK&F R-105058 also resulted in sustained plasma fenoldopam levels and increases in renal blood flow, indicating that slow absorption was not the cause of the sustained effect. The present study indicates that N-ethyl carbamate esters of fenoldopam are fenoldopam prodrugs which result in sustained increases in renal blood flow and plasma fenoldopam levels.     

Alpha adrenoceptor-mediated vasoconstriction in rat hindlimb: innervated alpha-2 adrenoceptors in the saphenous arterial bed

The alpha adrenoceptor subtypes mediating vasoconstriction to exogenous agonists and to spinal sympathetic nerve stimulation have been characterized in the autoperfused (constant flow) femoral (predominantly skeletal musculature) and saphenous (predominantly cutaneous) vascular beds of the pithed rat. Intra-arterial infusion of the alpha-1 adrenoceptor agonist, methoxamine, increased perfusion pressure in both vascular beds over the same range of infusion rates, and the maximum responses were similar. The selective alpha-2 adrenoceptor agonist, B-HT 933, also increased perfusion pressure in both beds, although the maximum response to B-HT 933 in the saphenous bed was approximately twice that observed in the femoral bed. Responses to methoxamine were blocked by the alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg), but not the alpha-2 adrenoceptor antagonist, rauwolscine (1 mg/kg), or by the selective postjunctional alpha-2 adrenoceptor antagonist, SK&F 104078 (1 mg/kg). Conversely, responses to B-HT 933 were blocked by rauwolscine and by SK&F 104078, but not by prazosin. Vasopressor responses to B-HT 933 in both vascular beds of the rat hindlimb also were reduced markedly by the calcium channel blocker, nifedipine (1 mg/kg), whereas responses to methoxamine were relatively resistant to inhibition by nifedipine. In the femoral bed, as in the systemic arterial circulation, responses to sympathetic nerve stimulation were strongly inhibited by prazosin, were potentiated by rauwolscine and were unaffected by SK&F 104078. In contrast, in the saphenous arterial bed, the responses to sympathetic nerve stimulation were inhibited by all three antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective alpha-2 adrenoceptor blockade by SK&F 86466: in vitro characterization of receptor selectivity

SK&F 86466 (6-chloro-N-methyl-2,3,4,5-tetrahydro-1-H-3-benzazepine) is a potent and selective antagonist at alpha-2 adrenoceptors. Prejunctional alpha-2 adrenoceptor antagonism can be demonstrated either by blockade of the alpha-2 adrenoceptor-mediated neuroinhibitory effect of clonidine or B-HT 920 in the guinea-pig atrium [receptor dissociation constant (KB) = 13-17 nM] or by potentiation of nerve-evoked release of [3H]norepinephrine from prelabeled guinea-pig atria, dog splenic artery or rabbit ear artery. Blockade of the postjunctional alpha-2 adrenoceptor was also seen, as demonstrated by a parallel shift to the right of the concentration-response curve for B-HT 920 as a constrictor agent in the dog saphenous vein. The KB for SK&F 86466 in this test system was 42 nM. The affinity of SK&F 86466 for the alpha-1 adrenoceptor is much lower, with a KB of 900 nM against norepinephrine-mediated constriction in the rabbit ear artery, or 1100 nM vs. SK&F 89748-induced constriction in the dog saphenous vein. The alpha-2/alpha-1 adrenoceptor selectivity ratio of SK&F 86466 is comparable to that obtained with agents such as yohimbine, making SK&F 86466 a useful tool for characterization of alpha-2 adrenoceptors and for investigation of their physiological role.     

Clebopride enhances contractility of the guinea pig stomach by blocking peripheral D2 dopamine receptor and alpha-2 adrenoceptor.

The mechanism of action of clebopride on the motility of guinea pig stomach was examined by the receptor binding assay for bovine brain membrane and by measuring gastric contractility and the release of acetylcholine from the stomach. The receptor binding assay revealed that clebopride bound to the D2 dopamine receptor with a high affinity and to the alpha-2 adrenoceptor and 5-HT2 serotonin receptor with relatively lower affinity, and not to D1 dopamine, alpha-1 adrenergic, muscarinic acetylcholine, H1 histamine, or opioid receptor. In strips of the stomach, clebopride at 10(-8) M to 10(-5) M enhanced the electrical transmural stimulation-evoked contraction and the release of acetylcholine. This enhancement was attributed to the blockade of the D2 dopamine receptor and alpha-2 adrenoceptor because: 1) Maximum responses obtained with specific D2 dopamine receptor antagonist, domperidone, and with specific alpha-2 adrenoceptor antagonist, yohimbine, were smaller than that with clebopride, and the sum of the effects of these two specific receptor antagonists is approximately equal to the effect of clebopride. 2) The facilitatory effect of clebopride was partially eliminated by pretreatment of the sample with domperidone or yohimbine, and the facilitatory effect of clebopride was not observed in preparations treated with the combination of domperidone and yohimbine. Clebopride also antagonized the inhibitory effects of dopamine and clonidine on the electrical transmural stimulation-evoked responses. These results indicate that clebopride acts on post ganglionic cholinergic neurons at D2 and alpha-2 receptors in this preparation to enhance enteric nervous system stimulated motility.     

Evidence for heterogeneity between pre- and postjunctional alpha-2 adrenoceptors using 9-substituted 3-benzazepines

A series of alpha adrenoceptor antagonists, including both reference compounds and the novel benzazepine antagonists, SK&F 86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine) and two of its 9-substituted derivatives, SK&F 101253 and SK&F 104078, were tested in vitro for affinity at central and peripheral alpha adrenoceptor subtypes. Peripheral alpha-1 adrenoceptor antagonist potency of these agents, as assessed by the receptor dissociation constant (KB) against norepinephrine-induced contraction in the rabbit aorta, correlated with the Ki value for inhibition of [3H]prazosin binding to central alpha-1 adrenoceptors in rat brain homogenates. Central alpha-2 adrenoceptor affinity, measured as the Ki for inhibition of [3H]rauwolscine binding to rat brain homogenates, correlated well with antagonist activity at peripheral postjunctional alpha-2 adrenoceptors as reflected by the KB against B-HT 920-induced contraction in canine saphenous vein. The 9-substituted benzazepines, SK&F 101253 and SK&F 104078, produce preferential blockade of postjunctional vs. prejunctional alpha-2 adrenoceptors in peripheral models. The high affinity of SK&F 104078 for postjunctional alpha-2 adrenoceptors in the canine saphenous vein was confirmed by its ability to inhibit [3H]rauwolscine binding to postjunctional alpha-2 adrenoceptors in this tissue. The observation that the Ki values for these antagonists against [3H] rauwolscine binding correlate with their KB values at the postjunctional alpha-2 adrenoceptors, rather than those at the prejunctional neuroinhibitory alpha-2 adrenoceptor, suggests a pharmacologic similarity between the postjunctional vascular alpha-2 adrenoceptors and the central [3H]rauwolscine binding site.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antidiarrheal activity of alpha-2 adrenoceptor agonist SK&F 35886

Alpha-2 adrenoceptor agonists exhibit antidiarrheal activity in animal models and in humans. However, hypotensive and sedative side effects seriously limit the use of these agents to treat diarrhea. SK&F 35886 (2,6-dimethyl phenylamino imidazoline) is an alpha-2 adrenoceptor agonist with little central nervous system activity. In Ussing chamber preparations of rabbit ileum, SK&F 35886 produces a concentration-dependent decrease in basal short-circuit current (Isc) (EC50 0.2 microM) that is dependent on the presence of mucosal HCO3. This concentration-response curve is shifted to the right of rauwolscine, increasing the EC50 to 30 microM. Prazosin had no effect on this response. Flux studies indicate that SK&F 35886 increases net Cl absorption and enhances HCO3 absorption without altering net Na flux. After PGE2 stimulation of Isc, SK&F 35886, applied either serosally or mucosally, immediately returns the Isc to base line. This effect is due to a reversal of the PGE2-induced inhibition of Na and Cl absorption. In vivo SK&F 35886 dose-dependently inhibits PGE2-induced enteropooling when given orally (ED50 approximately 31 micrograms/kg). This effect is attenuated significantly by rauwolscine (1.0 micrograms/kg s.c.). In cecectomized rats, SK&F 35886 abolishes PGE2-induced diarrhea within 1 hr after oral administration of the drug. SK&F 35886 (500 micrograms/kg p.o.) did not alter hexobarbital sleep time or elicit piloerection or lethargy, whereas clonidine (37.3 micrograms/kg p.o.) significantly enhanced hexobarbital sleep time. These results illustrate the ability of a peripheral acting alpha-2 agonist to promote absorption and inhibit secretion and diarrhea in the mammalian intestine.     

Comparison of the cardiovascular actions of dopamine and epinine in the dog

The effects of i.v. infusions of 3 and 6 micrograms/kg/min of dopamine (DA) and epinine on heart rate, arterial blood pressure, regional blood flows and vascular resistances in the renal, mesenteric and femoral vascular beds were compared in pentobarbital-anesthetized dogs. At the 3 micrograms/kg/min infusion rate, neither DA nor epinine changed blood pressure, whereas at the higher infusion rate both increased blood pressure by about 20 mm Hg. DA increased renal blood flow significantly at both infusion rates; whereas, epinine did not change renal blood flow. After administration of phenoxybenzamine, both epinine and DA decreased blood pressure; upon adding propranolol, the vasodepressor effect of epinine, but not of DA, was abolished. However, propranolol did not inhibit epinine-mediated vasodilation in the renal or mesenteric vascular beds, but a marked increase in femoral vascular resistance was observed. The addition of (R)-sulpiride, a DA antagonist, abolished DA and epinine-induced vasodilation in the mesenteric and renal vascular beds. Experiments in animals treated with hexamethonium to block ganglion transmission and propranolol to block beta adrenoceptors revealed that both selective alpha-1 (terazosin) and alpha-2 (rauwolscine) adrenoceptor antagonists inhibited the vasopressor response to DA to a greater degree than the responses to epinine. Thus, although DA and epinine possess significant DA1 activity, the consistent increase in renal blood flow observed with DA is not seen with epinine because of the more potent alpha adrenoceptor activity of the latter, which is mediated by both alpha-1 and alpha-2 adrenoceptors.     

Pharmacological, hemodynamic and autonomic nervous system mechanisms responsible for the blood pressure and heart rate lowering effects of pergolide in rats

In conscious spontaneously hypertensive rats, pergolide (50.0 micrograms/kg s.c.) produced a sustained decrease in tail artery pressure which was blocked by haloperidol (1.0 mg/kg s.c.) pretreatment. In anesthetized spontaneously hypertensive rats this effect was accompanied by a fall in total peripheral resistance inasmuch as pergolide did not significantly change cardiac output. In anesthetized normotensive rats, pergolide (30.0 micrograms/kg i.v.) also lowered blood pressure. This effect was not significantly modified by adrenalectomy, methysergide, idazoxan (alpha-2 adrenoceptor antagonist), vagotomy alone or plus ligation of carotid arteries or plus atenolol, but was entirely prevented by domperidone or sulpiride pretreatment and was reverted to a pressor response (due to stimulation of alpha adrenoceptors and 5-hydroxytryptamine receptors) by blockade of ganglionic transmission with chlorisondamine. Pergolide given either i.v. or into the cisterna magna or the lateral cerebral ventricle produced changes in blood pressure of the same magnitude. In intact or adrenalectomized rats, i.v. pergolide significantly lowered plasma norepinephrine concentration. Furthermore, in saline but not sulpiride-pretreated pithed rats, pergolide reduced the pressor responses and the accompanying increases in plasma norepinephrine evoked by electrical stimulation of the spinal cord. However, pergolide failed to modify the vascular reactivity to several pressor agents and lacked beta-2 and DA-1 dopamine receptor agonist properties. These results indicate that the decrease in blood pressure produced by pergolide can be accounted for by an inhibition of sympathetic tone resulting from stimulation of peripheral neuronal dopamine receptors. A possible central contribution remains to be substantiated. The pronounced bradycardia produced by pergolide (30.0 micrograms/kg i.v.) in anesthetized intact rats was partly reduced by vagotomy, methylatropine, domperidone, sulpiride, idazoxan, phentolamine or atenolol. The effects of pergolide in vagotomized rats were further diminished by domperidone but they were blocked by the combination of phentolamine or idazoxan plus domperidone. In rats pretreated with atenolol or in rats with the cervical section of spinal cord and the low level of heart rate increased with an isoprenaline infusion, the decrease in heart rate produced by pergolide was abolished by domperidone, methylatropine or idazoxan. In pithed rats, pergolide changed neither the base-line heart rate nor the tachycardia to exogenous norepinephrine nor the bradycardia evoked by carbachol or electrical stimulation of the peripheral cervical vagus.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of fenoldopam on regional vascular resistance in conscious spontaneously hypertensive rats

The effects of fenoldopam, a selective dopamine-1 agonist, on regional blood flow and vascular resistance were examined in conscious unrestrained spontaneously hypertensive rats (SHR). Rats were instrumented chronically with pulsed Doppler flow probes to allow measurement of renal, mesenteric and hindquarters blood flow. Maximal changes in mean arterial pressure, heart rate and regional blood flow were recorded after i.v. administration of fenoldopam (1-1000 micrograms/kg). Fenoldopam produced a dose-dependent reduction in arterial pressure and increased heart rate in the conscious SHR. Significant increases in mesenteric (maximal = 69 +/- 10%) and renal (maximal = 42 +/- 4%) blood flows were observed at all doses of fenoldopam. In the hindquarters, vascular resistance was increased after low doses of fenoldopam (1-30 micrograms/kg), but decreased with higher doses (100-1000 micrograms/kg). After ganglionic blockade, hindquarter vasodilation was observed with fenoldopam at low (10 micrograms/kg) and high (500 micrograms/kg) doses. Pretreatment with metoclopramide (20 mg/kg) or SCH 23390 (30 micrograms/kg), a new selective dopamine-1 antagonist, significantly attenuated the vasodilator responses to fenoldopam in all three vascular beds. Pretreatment with propranolol failed to alter the vascular effects of fenoldopam, but reduced the tachycardia markedly. This study indicates that fenoldopam decreased regional vascular resistance in the renal, mesenteric and hindquarters vascular beds of the conscious SHR with the mesenteric vascular bed demonstrating the greatest reactivity. The vasodilation induced by fenoldopam in these vascular beds appeared to be due to stimulation of vascular dopamine-1 receptors.     

Differential effects of nifedipine, nicorandil and nitroglycerin on the pressor responses elicited by selective alpha-1 and alpha-adrenoceptor agonists in conscious dogs

The influence of vasodilators with varying mechanisms of action on pressor responses mediated by alpha-1 and alpha-2 adrenoceptors was investigated in chronically instrumented, conscious dogs. After ganglionic, cholinergic and beta adrenergic blockade, equipressor doses of phenylephrine (0.6 microgram/kg i.v.), a selective alpha-1 adrenoceptor agonist, and B-HT 933 (20 micrograms/kg i.v.) a selective alpha-2 adrenoceptor agonist, were administered before and in the presence of infusions of nifedipine (0.25-2.0 micrograms/kg/min), nicorandil (4.0-32.0 micrograms/kg/min) or nitroglycerin (1.0-8.0 micrograms/kg/min). Nifedipine produced a dose-related attenuation of the increase in mean arterial pressure after bolus administration of phenylephrine (from 26 +/- 1 to 7 +/- 1 mm Hg) and B-HT 933 (from 29 +/- 2 to 5 +/- 1 mm Hg). Nicorandil did not affect phenylephrine-mediated pressor responses but significantly attenuated those to B-HT 933 (28 +/- 2 to 10 +/- 1 mm Hg). In contrast, nitroglycerin had no effect on either phenylephrine or B-HT 933-mediated responses. In additional experiments after autonomic nervous system blockade, multiple doses of phenylephrine (0.6, 1.25 and 2.5 micrograms/kg i.v.) and B-HT 933 (10, 20 and 40 micrograms/kg i.v.) were administered before and after i.v. infusions of nifedipine (1.0 microgram/kg/min) or nicorandil (16.0 micrograms/kg/min). Nifedipine significantly decreased the pressor responses to all doses of phenylephrine and B-HT 933. In contrast, the attenuation from control of alpha-2-mediated increases in arterial pressure by nicorandil was partially overcome at higher doses (40 micrograms/kg) of B-HT 933.(ABSTRACT TRUNCATED AT 250 WORDS)     

Additional evidence for functional subclassification of alpha-2 adrenoceptors based on a new selective antagonist, SK&F 104856.

SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4-methyl-thieno[4,3,2ef][3] benzazepine) shows a similar selectivity profile to the previously reported alpha adrenoceptor antagonist, SK&F 104078 (6-chloro-9-[(3-methyl-2-butenyl)oxy]-3-methyl-1H-2,3,4,5-tetrahydro-3- benzazepine), having the ability to block alpha-1 and postjunctional alpha-2 adrenoceptors, although having little or no activity at most prejunctional alpha-2 adrenoceptors. SK&F 104856 is more potent than SK&F 104078, and lacks the 5-hydroxytryptamine receptor antagonist activity associated with the earlier compound. The postjunctional vs. prejunctional selectivity of SK&F 104856 at alpha-2 adrenoceptors in the same tissue preparation was demonstrated in both canine and human saphenous vein. Concentrations substantially higher than those required to block postjunctional alpha-2 adrenoceptor-agonist induced vasoconstriction had no effect on the ability of norepinephrine, acting on prejunctional alpha-2 adrenoceptors, to inhibit stimulation evoked transmitter overflow in the human tissue, and only a small effect in the canine vein. As observed with SK&F 104078, SK&F 104856 has some prejunctional alpha-2 adrenoceptor antagonist activity in the rat vas deferens, although the receptor dissociation constant is nearly 50-fold higher than that at the postjunctional alpha-2 adrenoceptor in the canine saphenous vein. The results obtained with SK&F 104856 provide additional evidence to support the premise that alpha-2 adrenoceptors can be functionally differentiated. Because SK&F 104856 can selectively antagonize certain alpha-2 adrenoceptor-mediated responses, this agent may be a useful tool to evaluate the functional roles of the multiple alpha-2 adrenoceptor subtypes that have been identified in biochemical and molecular studies.     

Role of receptor reserve in the inhibition of alpha-1 adrenoceptor-mediated pressor responses by calcium antagonists in the pithed rat

The effect of the calcium channel antagonists nifedipine and FR 34235 on the vasopressor response to alpha-1 adrenoceptor stimulation in the pithed normotensive rat was investigated. The maximal pressor response elicited by the full alpha-1 adrenoceptor agonist SK&F l-89748 was slightly but significantly reduced by 1-mg/kg doses of nifedipine (21 +/- 2%) and FR 34235 (34 +/- 4%). In comparison, the maximal pressor response to alpha-1 adrenoceptor stimulation by the partial alpha-1 agonist SK&F 88444 was markedly inhibited by nifedipine (51 +/- 1%) and FR 34235 (65 +/- 3%). Partial inactivation of the postsynaptic alpha-1 adrenoceptors with phenoxybenzamine (0.1 mg/kg) resulted in a maximal increase in diastolic pressure to alpha-1 adrenoceptor activation by SK&F l-89748 less than that induced by SK&F 88444. After phenoxybenzamine treatment, nifedipine and FR 34235 produced even greater reductions in the maximal vasopressor response to alpha-1 adrenoceptor stimulation by SK&F l-89748 (77 +/- 8 and 85 +/- 1%, respectively). Moreover, an inverse linear correlation (r = 1.00) was observed between the sensitivity of the maximal vasopressor response to nifedipine and FR 34235 and the magnitude of the maximal pressor response. The data suggest that the sensitivity of the alpha-1 adrenoceptor-mediated pressor response to inhibition by calcium antagonists in the pithed rat is inversely related to the magnitude of the pressor response, and they are consistent with the notion that the presence of "spare" alpha-1 adrenoceptors may determine the sensitivity of the pressor response to calcium antagonists.     

Mechanisms mediating the positive inotropic and chronotropic changes induced by dopexamine in the anesthetized dog

Mechanisms contributing to the increments in heart rate (HR) and cardiac contractile force (CCF) produced by dopexamine (DPX) were studied in anesthetized dogs. Intravenous infusions of DPX (4.0 micrograms/kg/min) produced increments in HR, CCF and renal blood flow and decrements in mean arterial pressure (MAP). The sequential administration of atenolol (0.5 mg/kg i.v.) administered at a dose selective for beta-1 adrenoceptors, propranolol (2.5 mg/kg i.v.) and the DA1 dopamine receptor antagonist, SCH 23390 (10 micrograms/kg i.v.) blocked the DPX-induced changes in HR, CCF, MAP and renal blood flow, respectively. After ganglionic blockade, the increments in HR and CCF produced by DPX (4.0 and 16.0 micrograms/kg i.v.) were reduced 90 and 76%, respectively, with little or no change in its hypotensive effect. In separate dogs, administration of the beta-2 adrenoceptor agonist salbutamol (0.55 microgram/kg i.v.) produced a comparable decrement in MAP but smaller increments in HR and CCF than produced by DPX (16.0 micrograms/kg i.v.). DPX (64 micrograms/kg i.v.) also produced greater increments in HR during cardioaccelerator nerve stimulation (1 Hz, 0.5 msec, supramaximal voltage) than before nerve stimulation. Therefore, we tested the effect of DPX (1.0, 4.0 and 8.0 micrograms/kg/min i.v.) on the increments in HR, CCF and MAP produced by norepinephrine (0.25 microgram/kg i.v.) and the indirect acting sympathomimetic amine, tyramine (60 micrograms/kg i.v.). DPX potentiated the increments in HR, CCF and MAP produced by norepinephrine and suppressed those produced by tyramine. Thus, the positive inotropic and chronotropic effects of DPX in the intact dog are due primarily to baroreceptor-mediated stimulation and inhibition of neuronal uptake of norepinephrine.     

Regional perfusion in hearts with acute coronary artery occlusion and subsequent β2- and α1-adrenergic blockade

Summary. Blockade of cardiac adrenoceptor subtypes, coronary or myocardial, might elicit compensatory interaction from remaining unblocked subtypes. An attempt to explore this interplay was made by studying regional myocardial blood flow alterations associated with β₂-adrenergic blockade followed by β₁-adrenergic blockade in anaesthetized cats with acute coronary occlusion. In order to maintain constant needs for perfusion, atrial pacing was established and the aortic blood pressure was kept constant. In myocardium remote from the ischaemic region, β₂-adrenergic blockade produced higher endocardial blood flow whereas no flow changes were observed close to the ischaemic region. With subsequent β₁-adrenergic blockade, blood flow increased endocardially in non-ischaemic regions, but remained unchanged in epicardial tissue. Control experiments without coronary ligation revealed no increase in left ventricular oxygen consumption during the experiments and support the theory that the observed blood flow increase in the coronary ligation group, following drug interventions, was not caused by increased cardiac work. This study indicates that combined β₂- and α₁-adrenergic blockade alters the balance between receptor subtypes. Unopposed β₁-mediated vasodilation is the most likely candidate to explain why endocardial flow was increased.     

Evaluation of the alpha and beta adrenoceptor-mediated activities of the novel, orally active inotropic agent, ibopamine, in the cardiovascular system of the pithed rat: comparison with epinine and dopamine

The alpha and beta adrenoceptor-mediated effects of the novel, orally active inotropic prodrug, ibopamine, have been studied in the pithed rat and compared with those effects mediated by dopamine and the active form of ibopamine, epinine. All three agents produced alpha adrenoceptor-mediated pressor responses in pithed rats, and the vasopressor effects of ibopamine and epinine, but not dopamine, were potentiated by beta adrenoceptor blockade with propranolol (3 mg/kg i.v.). Catecholamine depletion with reserpine (5 mg/kg i.p.) did not affect the vasoconstrictor response elicited by any of these agents, indicating a direct effect in the vasculature. Epinine was 10 times more potent than ibopamine or dopamine. The pressor response to all three agents was antagonized by the alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.) and the alpha-2 adrenoceptor antagonist, rauwolscine (0.5 mg/kg i.v.), suggesting the involvement of both alpha adrenoceptor subtypes in the vasopressor responses elicited by these compounds. After complete blockade of alpha adrenoceptors using a combination of phenoxybenzamine (3 mg/kg i.v.), prazosin (0.1 mg/kg i.v.) and rauwolscine (1 mg/kg i.v.), higher doses of ibopamine, epinine and dopamine produced a propranolol-sensitive, beta-1 adrenoceptor-mediated positive chronotropic response that was significantly reduced in reserpine-pretreated rats, indicating a significant indirect component in the activity of these compounds at the level of the myocardium. Epinine and dopamine were equipotent and were 10 times more potent than ibopamine as directly acting beta-1 adrenoceptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)