Patrick T. Horn

Regional variation in the alpha-adrenergic receptors in the canine resistance vessels.

SummaryVasoconstrictor effects of non-selective and relatively selective alpha1- and alpha2-adrenergic agonists (noradrenaline, phenylephrine, methoxamine, clonidine, and alpha-methylnora drenaline) and the inhibition of their vasoconstrictor effects by prazosin or yohimbine were studied in vivo in the renal and femoral vascular beds of pentobarbital anesthetized, beta-adrenergic and ganglion-blocked dogs. Some animals were additionally pretreated with methylphenidate to block uptake of the agonists by the nerves. In the femoral vascular bed the following results were obtained: 1. Clonidine was equipotent with noradrenaline and about 15-fold more potant than phenylephrine in reducing the blood flow. 2. Yohimbi while prazosin had practically no effect on, the induced by clonidine. 3. Vasoconstriction induced by phenylephrine or methoxamine was antagonized by prazosin but not by yohimbine. The results obtained in the renal vascular bed were as follows: 1. Clonidine was about 12-fold weaker than noradrenaline and nearly equipotent with phenylephrine in reducing blood flow. 2. Both yohimbine and prazosin were weak antagonists of the vasoconstriction induced by clonidine and tended to be additive. 3. Prazosin effectively antagonized the effects of phenylephrine or methoxamine. Noradrenaline and alpha-methylnoradrenaline caused vasoconstriction in both beds and their effects were inhibited by both antagonists which tended to be additive in either vascular bed.These results provide further evidence that the vasoconstrictor effects of noradrenaline and other alpha-adrenergic agonists are mediated by both subtypes of alpha-adrenergic receptors in the blood vessels of the dog. Higher potency of clonidine in the femoral bed and its selective inhibition by yohimbine indicate that alpha2 subtype of adrenergic receptors predominate in this bed. Similar considerations in the reverse suggest that alpha1-adrenergic receptors predominate in the renal vascular bed of the dog. Thus, these results show that there is regional variation in the distribution of the subtypes of alpha-adrenergic receptors in the resistance vessels of the dog.

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.

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.

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.

Therapeutic Applications of Drugs Acting on Peripheral Dopamine Receptors

The recent development of dopamine (DA) receptor agonists with different receptor selectivities has confirmed the therapeutic utility of modulations of the peripheral dopaminergic system that were proposed shortly after the description of the cardiovascular effects of DA. In addition to the acute therapy of heart failure, circulatory shock, and renal dysfunction, for which low dose DA has an established role, there is substantial clinical evidence that DA receptor modulation will be a significant advance in the chronic therapy of congestive heart failure and hypertension

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

Isometric contractions in vitro of helically eut strips of canine mesenteric arteries (O.D. = 0.6–1 mm) were recorded in the presence of 10 μM indomethacin. PGF2α 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: PGF2α, 7.3 ± 0.7 × 10−7M; PGE2, 2.1 ± 0.2 × 10−6M; and U-46619, 4.1 ± 1.0 × 10−10M. Exposure to 13-azaprostanoic acid (13-APA), 5 × 10−5M and 2 x 10−4M, for 20 min caused parallel and doserelated shifts to the right of the doseresponse curves generated by ail 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 × 10−5M 13-APA PGF2α, 2.7 ± 0.3; PGE2, 3.5 ± 0.9; U-46619, 5.2 ± 0.9; in the presence of 2 × 10−4M 13-APA PGF2α, 17.1 ± 3; PGE2, >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.

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.

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 α-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 α-adrenergic blocking activity and by an apparent facilitatory effect of C (R)-sulpiride on sympathetic nerve transmission.

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.

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.