Dopamine receptor agonists in cardiovascular medicine.

The cardiovascular and renal effects of dopamine are mediated through peripheral catecholamine receptors. Knowledge of the receptor type responsible for each of the actions of dopamine leads to its rational use clinically and to understanding the hemodynamic actions of the newer dopamine receptor agonists recently introduced into clinical trials. Several of the newer agonists have profiles of receptor activities that differ from dopamine, and early clinical studies indicate that they will have different therapeutic indications and applications.

Influence of host age and tumor load on the growth and catecholamine content of C-1300 murine neuroblastoma in situ.

The influence of host age and tumor load on survival time, tumor growth parameters and biochemical differentiation, as characterized by tumor catecholamine content, were investigated. A/J mice were implanted with tumor loads of 10(4), 10(5) and 10(6) disaggregated C-1300 murine neuroblastoma (MNB) cells at 1, 7, 14, 21 and 56 days of age. Studies performed in mice between 7 and 56 days of age demonstrated that MNB tumorigenicity, tumor growth rate, host survival and catecholamine content were independent of host age and tumor load whereas, tumor onset time was influenced by both factors. In contrast to older animals, tumor onset time and catecholamine content were decreased and tumor growth rate increased in 1-day-old mice. This difference may be due to the presence of endogenous growth factor(s) that modulate cell proliferation in the immediate post-natal period.

Absence of postsynaptic DA2 dopamine receptors in the dog renal vasculature.

In experiments designed to look for functional postsynaptic DA2 dopamine receptors in the dog renal vasculature, the vascular effects of two selective DA2 receptor agonists, bromocriptine and quinpirole, were studied in pentobarbital-anesthetized dogs. Intra-arterial (i.a.) injections of bromocriptine reduced renal blood flow before and after blockade of alpha-adrenoceptors. I.a. quinpirole produced dose-related increases in renal blood flow which were not altered by blockade of alpha- or beta-adrenoceptors or DA1 dopamine receptors. Neither of the selective DA2 dopamine receptor antagonists, domperidone or YM 09151-2, altered the renal vascular effects of quinpirole, but these were reduced by combined H1 and H2 histamine receptor blockade. The results of these experiments do not support the existence of postsynaptic DA2 dopamine receptors mediating vasodilation in the canine renal vasculature.

Studies on the location of catecholamine receptors in canine sympathetic ganglia.

Receptors mediating catecholamine-induced inhibition were studied in cardiac ganglia of pentobarbital-anesthetized dogs. Using selective agonists and antagonists the presence of three receptor subtypes was verified: alpha 1- and alpha 2-adrenoceptors and dopamine D2 receptors. Activation of alpha 1-adrenoceptors or dopamine D2 receptors reduced the response to preganglionic nerve stimulation but not to direct stimulation of the nicotinic acetylcholine receptors of the principal ganglion cells: response to both types of stimulation were reduced by activation of ganglionic alpha 2-adrenoceptors. These results suggested that two inhibitory systems were present in canine sympathetic ganglia and mediated the effects of exogenous catecholamines. One system involved alpha 1-adrenoceptors and dopamine D2 receptors located proximal to the synapse of the pre- and postganglionic neurons and the other involved alpha 2-adrenoceptors located distal to the intraganglionic synapse.

Inhibitory effects of catecholamines in the paravertebral sympathetic ganglia of the anesthetized dog.

alpha-Adrenoceptor agonists decreased mean arterial pressure when injected into the arterial blood supply of the paraspinal sympathetic ganglia of pentobarbital-anesthetized open-chest dogs. The hypotensive response occurred concomitantly with selective decreases of vascular resistance in the vessels innervated by neurons arising from these ganglia, and both of these responses were blocked by the ganglionic blocking agent, hexamethonium. The hypotensive response to phenylephrine was selectively blocked by terazosin; alpha 1 selective agonist, and antagonist, respectively, while the hypotension produced by intra-arterial clonidine was blocked by rauwolscine; alpha 2 selective agonist and antagonist, respectively. Either terazosin or rauwolscine reduced the hypotension produced by noradrenaline or dopamine. These results demonstrated the presence of both alpha 1- and alpha 2-adrenoceptors in the paraspinal sympathetic ganglia. Activation of either alpha-adrenoceptor subtype inhibited ganglionic transmission.

Dihydrexidine: a new potent peripheral dopamine D1 receptor agonist.

Dihydrexidine (trans-10,11-dihydroxyhexahydrobenzo-[a]phenanthridine) was found to be a full dopamine D1 receptor agonist with a potency five times that of dopamine. Dihydrexidine showed no agonist activity at peripheral dopamine D2 receptors, alpha- or beta-adrenoceptors at the doses which produced near maximal stimulation of dopamine D1 receptors. The chemical structure of dihydrexidine shows that addition of a phenyl ring to a benzo[f]quinoline moiety bestows potent D1 activity upon a structure which had no such activity previously. This observation introduces a new factor in structure-activity considerations for dopamine receptor ligands.

Lack of effect of the opioid antagonist, naltrexone, on the in situ growth of C-1300, N1E-115 and NS206 murine neuroblastoma tumor cell lines.

Attempts have been made to confirm previously reported results which demonstrated that the opioid antagonist, naltrexone, altered the in situ growth of murine neuroblastoma tumors. Adult male A/J mice were injected with tumor cells from three different cell lines of murine neuroblastoma; the spontaneously arising C-1300 line, the adrenergic clonal line N1E-115, and the cholinergic clonal line NS20Y. Naltrexone was administered daily in doses of 0.1, 0.4, or 10.0 mg/kg subcutaneously, to replicate the reported experimental design. In contrast to previous studies, we were unable to demonstrate any effect of naltrexone on in situ growth or other characteristics of tumors produced by the C-1300, N1E-115 or NS20Y murine neuroblastoma cell lines. Ligand binding studies have demonstrated the presence of high levels of opiate binding sites on membranes prepared from the NS20Y clonal cell line and low levels on the membranes of the C1300 tumor line.

Modulation of in situ murine neuroblastoma tumor growth by the adrenergic nervous system: differential response of clonal cell lines to chemical sympathectomy.

The in situ growth characteristics of C-1300, N1E-115 and NS20Y murine neuroblastoma (MNB) tumor cell lines were compared in normal and sympathectomized A/J mice. Adrenergic nerve ablation was produced in neonatal mice by administration of 6-hydroxydopamine (6-OHDA) at a dose of 100 micrograms/gm body weight on post-natal days 4, 6, 8 and 10; controls received equivalent volumes of the vehicle solution (0.9% NaCl/0.1% Ascorbic Acid). All mice were inoculated subcutaneously with 10(6) viable MNB cells four to six weeks after treatment with 6-OHDA or vehicle. The growth rates of tumors produced by the adrenergic MNB cell lines, C-1300 and N1E-115, were significantly lower in sympathectomized mice when compared to control animals. In contrast, tumors induced by the cholinergic MNB cell line, NS20Y, grew at similar rates in both sympathectomized and control mice. All tumors obtained from control and sympathectomized mice regardless of whether they derived from cell lines characterized as cholinergic (NS20Y) or adrenergic (C-1300, N1E-115), contained both norepinephrine and dopamine. Depletion of adrenergic neurotransmitter in A/J mice was induced by administration of reserpine (5-10 micrograms/kg/day) beginning 30 days prior to implantation of the C-1300 MNB cell line and continuing until sacrifice of the animal. The effect of this treatment on organ and tumor catecholamine concentrations was confirmed by high-pressure liquid chromatography. Splenic catecholamine levels in reserpine-treated animals were reduced to 20% of controls as compared to 9% in the neonatally-sympathectomized group. However, there was no discernible effect on C-1300 MNB tumor growth in the reserpine-treated animals. C-1300 MNB tumor concentrations of nor-epinephrine and dopamine were significantly lower in the reserpine-treated animals than in controls. The suppression of tumor growth by adrenergic nerve ablation is selective for specific MNB tumor cell lines. An anatomically intact sympathetic nervous system appears to exert a greater influence than competency of adrenergic neuro-humoral transmission on MNB tumor growth. These data support the hypothesis that modulation of MNB tumor growth by the adrenergic nervous system is not mediated via catecholamines but may be modulated by endogenous growth factor(s).

Studies on the functional role of alpha-adrenoceptors in the cardiac sympathetic ganglia of the dog.

Inhibitory alpha-adrenoceptors were studied in cardiac ganglia of pentobarbital-anesthetized dogs. Blockade of alpha 1- or alpha 2-adrenoceptors augmented preganglionic nerve stimulation induced tachycardia without altering the response to postganglionic nerve stimulation. The effect produced by blockade of ganglionic alpha 1-adrenoceptors with terazosin had different frequency-response characteristics from, was of smaller magnitude than, and was additive with the effect produced by blockade of ganglionic alpha 2-adrenoceptors with rauwolscine. The response to activation of ganglionic nicotinic cholinergic receptors in the absence of electrical stimulation of the preganglionic nerve was not affected by blockade of either alpha 1- or alpha 2-adrenoceptors. The response to nicotinic cholinergic receptor activation during periods of continuous preganglionic nerve stimulation was augmented following blockade of alpha 2-adrenoceptors but unaffected by alpha 1-adrenoceptor blockade. These results suggest that there are two different inhibitory pathways involving alpha-adrenoceptors in mammalian sympathetic ganglia and provide evidence that these inhibitory pathways are operative under the experimental conditions of ganglionic transmission.

Ecallantide: a plasma kallikrein inhibitor for the treatment of acute attacks of hereditary angioedema.

Hereditary angioedema (HAE) is a debilitating, potentially fatal disease characterized by variable and unpredictable acute attacks of swelling affecting the subcutaneous tissue and mucosa. It is an autosomal dominant disorder resulting from a genetic deficiency of functional C1-esterase inhibitor. Available treatments include long-term prophylaxis, short-term prophylaxis and treatment of acute attacks. Ecallantide is a novel, specific and potent inhibitor of plasma kallikrein that was recently approved in the United States for the treatment of acute attacks of HAE in patients aged 16 years and older. In two phase III clinical trials, the subcutaneous administration of 30 mg ecallantide resulted in significantly greater symptom improvement than placebo for acute attacks of HAE. Ecallantide was generally well tolerated throughout the clinical development program. The main safety concern following ecallantide treatment is hypersensitivity reactions, including anaphylaxis. A Risk Evaluation and Management Strategy (REMS) has been implemented to minimize this risk and a long-term observational safety study is currently under way to collect more information about hypersensitivity and immunogenicity. Ecallantide represents a novel treatment option for patients with HAE.

Persistent hypertension after prenatal cocaine exposure.

Multiple blood pressure readings were obtained with time in 12 infants with documented in utero exposure to cocaine. Approximately half had hypertension or high-normal blood pressure with no evidence of renal, cardiovascular, or endocrinologic abnormalities.

Differential effects of 6-hydroxydopamine-induced ablation of peripheral and central adrenergic axons on C-1300 murine neuroblastoma tumor growth and catecholamine concentration in the A/J mouse.

The relationship between 6-hydroxydopamine (6-OHDA)-induced ablation of central and peripheral adrenergic neurons and in situ C-1300 murine neuroblastoma (MNB) tumor growth and catecholamine concentration were investigated. Destruction of central and/or peripheral adrenergic neurons was produced by the intracerebral and/or s.c. administration of 6-OHDA to neonatal A/J mice. Disaggregated MNB cells (1 x 10(6)) were implanted s.c. into each mouse 3 weeks after treatment with 6-OHDA or diluent. Tumor onset time (the time interval between implantation of MNB cells and detection of palpable tumor), tumor weight, tumor weight to body weight ratio, tumor growth rate constant and tissue catecholamine concentrations were determined. Central axotomy caused a significant increase in tumor onset time and decrease in tumor weight when compared to controls. However, neither the tumor weight to body weight ratio or tumor growth rate constant were significantly lowered. In contrast, a reduction in all tumor growth parameters was produced by peripheral axotomy, which differed significantly from centrally axotomized and control animals. The catecholamine concentration of MNB tumors excised from control and 6-OHDA-treated mice 8 days after tumor onset were determined. Norepinephrine and dopamine levels were elevated above controls in MNB tumors obtained from mice that had been either peripherally or peripherally and centrally axotomized; whereas, no change in tumor catecholamine concentrations was noted in centrally axotomized mice. This investigation has demonstrated that ablation of central as well as peripheral adrenergic innervation exerts an inhibitory effect on MNB tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Facilitation of ganglionic transmission by sulpiride: evidence for an inhibitory role of dopamine in the canine sympathetic ganglion.

Effects of the (R) and (S) enantiomers of sulpiride, a potent dopamine (DA) antagonist, on ganglionic transmission were studied in anesthetized dogs. The pre- and postganglionic nerves of cardiac sympathetic ganglia were stimulated electrically, and heart rate was monitored as a measure of ganglionic transmission and sympathetic nerve activity. The heart rate was free from influence of the central nervous system. (R)- And (S)-sulpiride injected i.a. close to the blood supply of the ganglia did not alter basal heart rate, but facilitated ganglionic transmission as demonstrated by an increase in the tachycardia induced by preganglionic nerve stimulation. The (R) enantiomer was 4 times more active than the (S) enantiomer in this respect. Neither enantiomer affected the tachycardia induced by postganglionic nerve stimulation. Norepinephrine and DA injected i.a. caused inhibition of the tachycardia induced by preganglionic nerve stimulation. The inhibitory effect of both catecholamines was antagonized by the sulpiride enantiomers (R)-sulpiride was about 4-fold more potent than (S)-sulpiride in antagonizing DA, whereas (S)-sulpiride was more active against norepinephrine. The sulpiride enantiomers affected neither the tachycardia induced by i.a. administration of acetylcholine nor the bradycardia induced by vagal nerve stimulation. Thus, cholinesterase inhibition and ganglionic stimulation were excluded. These data are, therefore, consistent with the hypothesis that the facilitatory action of the sulpiride enantiomers is related to the antagonism of catecholamines. Positive correlation between the activity of the (R) enantiomer to facilitate ganglionic transmission and to antagonize DA suggests that DA is a physiologically released catecholamine modulating transmission in the cardiac sympathetic ganglia of the dog.

Effects of dopamine, N-N-di-n-propyl dopamine, and (R)- and (S)-sulpiride on guinea pig blood pressure.

Effects of intravenous injections of dopamine (DA) and N-N-di-n-propyl dopamine (DPDA) on mean arterial pressure (MAP) and heart rate (HR) were studied in urethane-anesthetized guinea pigs. DA and DPDA produced dose-related reductions in MAP. DA produced a biphasic change in HR, an initial decrease followed by an increase, while DPDA produced only a decrease in HR. Phentolamine and hexamethonium did not affect the depressor effects of DA, but virtually abolished the depressor effects of DPDA. Thus, DA appears to lower MAP primarily by direct vasodilation; whereas DPDA acts predominantly by inhibiting the sympathetic nervous system. Hexamethonium prevented the bradycardia induced by DA and DPDA, but had no effect on the DA-induced tachycardia. (R)- and (S)-sulpiride produced hypotensive effects of short duration that were due to their weak alpha-adrenergic blocking activity. In addition, the (R) enantiomer produced a secondary pressor effect that was abolished by phentolamine and hexamethonium. (R)-sulpiride potentiated pressor effects of the ganglionic stimulant 1-1-dimethyl-4-phenylpiperazinium iodide (DMPP), suggesting that it facilitated sympathetic nerve activity. This study demonstrates that guinea pig blood pressure can be used to differentiate between the neuronal and vascular origins of hypotension produced by DA agonists. The use of (R)- and (S)-sulpiride for further localizing the actions of DA and DPDA is complicated by their alpha-adrenergic blocking activity and by an apparent facilitatory effect of (R)-sulpiride on sympathetic nerve transmission.

Catecholamine injections in canine paravertebral ganglia produce hypotension by neurogenic vasodilatation.

In the present study the alpha 1 selective agonist phenylephrine (PE), the alpha 2 selective agonist clonidine (CLO) and the non-selective endogenous catecholamine norepinephrine (NE) and dopamine (DA) were injected directly into the blood supply of the paravertebral sympathetic ganglia (PSG) of anesthetized open-chest dogs. Intra-arterial injection of all agonists produced dose-dependent decreases in mean arterial pressure (MAP) and femoral vascular resistance (FVR) but had no effect on heart rate. Their potency order was CLO greater than NE greater than PE greater than DA. Intravenous injections of the medium dose for NE and PE produced significant increases in MAP, while the medium dose of CLO injected iv produced a small decrease in MAP. The ganglionic blocking agent, hexamethonium (10 mg/kg iv) completely eliminated the hypotensive response to all agonists. Intra-arterial administration of the alpha 1 selective antagonist terazosin (0.5 mg) significantly reduced the decrease in MAP produced by the ganglionic actions of PE, but had no significant effect on the response to CLO. In contrast, the alpha 2 selective antagonist rauwolscine (100 micrograms) significantly reduced the decreases in MAP produced by ia CLO, but not that produced by ia PE. However, both antagonists inhibited the hypotensive effect of NE and DA. These findings suggest that both subtypes of alpha-adrenoceptors, alpha 1 and alpha 2, are present in the PSG and that both subtypes are inhibitory since their activation results in reduced transmission of impulses through the ganglia.

Antagonism of prostanoid-induced vascular contraction by 13-azaprostanoic acid (13-APA).

Isometric contractions in vitro of helically cut strips of canine mesenteric arteries (O.D. = 0.6-1 mm) were recorded in the presence of 10 microM indomethacin. PGF2 alpha PGE2, U-46619 (TXA2 mimetic), norepinephrine, 5-hydroxytryptamine, and KCl produced dose-related contractions. The EC50 values of the prostanoids in the control period were: PGF2 alpha, 7.3 +/- 0.7 X 10(-7) M; PGE2, 2.1 +/- 0.2 X 10(-6) M; and U-46619, 4.1 +/- 1.0 X 10(-10) M. Exposure to 13-azaprostanoic acid (13-APA), 5 X 10(-5) M and 2 X 10(-4) M, for 20 min caused parallel and dose-related shifts to the right of the dose-response curves generated by all three prostanoids without affecting the contractile responses to KCl, norepinephrine, or 5-hydroxytryptamine or relaxation induced by PGI2. 13-APA, at the concentrations used, had no agonist activity. Small contractions (10-15%) seen on the addition of 13-APA to the baths were found to be related to the alcohol content of the solvent. Dose ratios (with/without antagonist) at the EC50 level were found to be: in the presence of 5 X 10(-5) M 13-APA PGF2 alpha, 2.7 +/- 0.3; PGE2, 3.5 +/- 0.9; U-46619, 5.2 +/- 0.9; in the presence of 2 X 10(-4) M 13-APA PGF2 alpha, 17.1 +/- 3; PGE2, greater than 50; and U-46619, 23.3 +/- 5.7. Thus, 13-APA is a specific antagonist of these prostanoids with no agonist activity of its own.

Effectiveness of a targeted screening program in identifying infants with positive urine toxicology screening results in a regular neonatal nursery.

We compared the effectiveness in identifying infants with positive results on urine screening for drugs of abuse of a universal screening program and a targeted screening program on the basis of clinical suspicion. A carefully run targeted screening program identified 24.3% of the admissions for toxicology testing and would have found all but two of the infants with positive results.