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Calcium antagonists [130], blocking calcium entry into cells, have a well-known relaxant effect on vascular smooth muscle. However, this does not mean that they produce a uniform vasodilation in all vascular beds [5, 27, 28]. It is generally considered that calcium antagonists are more potent in coronary and cerebral vessels than in peripheral vessels [27]. The reasons for such a preferential action have not been elucidated. A selective action on cerebral and coronary vessels may contribute to a beneficial effect of these drugs in several cerebral and cardiac disorders, and particularly in the syndromes of cerebral and coronary vasospasm where the use of calcium antagonists has been rewarding.

Irrespective of their mechanism of action, which so far has not been clarified, calcium channel blockers (CCBs) have a documented prophylactic effect on classical and common migraine, as well as on cluster headache. The drugs may reduce migraine prodromes, the frequency of migraine attacks, and also decrease the severity and possibly the duration of these attacks. Notably, their optimum effect is often seen after more than 2 months of treatment. Side effects seem to be few and mild. Whether or not there are differences in therapeutic efficacy between different CCBs is presently unclear. As comparisons with other alternatives of treatment are sparse, the place of CCBs in migraine therapy remains to be established.

Smooth muscle preparations of the urethra, bladder, and ureter were obtained from patients undergoing operations for various urological disorders. The urethral preparations were contracted by noradrenaline (0.1-3 microgram . ml-1), prostaglandin F2alpha (1-10 microgram . ml-1), and potassium (127 mM), the bladder preparations by carbacholine (0.004-1 microgram . ml-1), prostaglandin F2alpha (1-10 microgram . ml-1), potassium (127 mM), and barium chloride (3 mM), and the ureter preparations by potassium (127 mM), and barium chloride (3 mM). Irrespective of the mode of activation, pretreatment with nifedipine (0.1 microgram . ml-1) for 10 min. reduced the responses. Nifedipine also relaxed preparations contracted by the contractile agents used. In 19 female patients, aged 20 to 73 years, undergoing investigation because of urgency and/or urge incontinence, simultaneous urethrocystometry at rest was performed before and after oral administration of 20 to 40 mg nifedipine. Bladder capacity and residual urine were also determined. Nifedipine did not affect the pressures within the bladder and urethra, nor did it increase the bladder capacity. However, after nifedipine intake there was a statistically significant increase in residual urine. The results suggest that nifedipine can inhibit contractile activity induced by drugs with different modes of action; the drug does not affect the tone in bladder and urethra.

Isolated submucosal (lamina propria) preparations from the female rabbit urethra exhibited both contractant and relaxant properties. The nerve-mediated contraction to electrical field stimulation was adrenergic in nature, and both this response and the contraction induced by exogenous application of noradrenaline were blocked to a greater extent by α 2 than by α 1 -adrenoceptor blocking agents. Vasoactive intestinal polypeptide was found to be a potent inhibitor of the noradrenaline-mediated contraction. Neuropeptide Y induced contraction of the preparation, but also inhibited the nerve-mediated contractant response. In noradrenaline-contracted preparations, electrical field stimulation induced a non-adrenergic, non-cholinergic relaxation. The maximum relaxant response was significantly greater when the preparations were contracted by clonidine than by noradrenaline. Abundant smooth muscle cells with no obvious connection to vessel walls were found in the submucosa, but to what extent the contractant and relaxant responses can be ascribed to vascular or non-vascular smooth muscle is not settled. The results indicate a non-uniform distribution of the peripheral nervous control within the wall of the female rabbit urethra. The demonstrated contractant and relaxant properties of the submucosal tissue might be of importance for urethral function.

The blood flow in the human nasal mucosa is controlled by the functional state of the resistance vessels. This blood flow was studied by means of the 133Xe washout method. Using topical application of drugs that stimulate or block adrenoceptors, including clinical doses of nasal decongestants, we classified the adrenoceptors of the resistance vessels in the mucosa. The results suggest that stimulation of α2-adrenoceptors causes a reduction of nasal mucosal blood flow; stimulation of α1- and β2-adrenoceptors seems to have no significant effects. Drugs that selectively stimulate α2-adrenoceptors, as well as those with preference for α1-adrenoceptors, cause nasal decongestion. To avoid the negative effects of a nasal mucosal blood flow reduction, it is suggested that a nasal decongestant with an α1-adrenoceptor stimulating effect should be preferable to a drug acting mainly on α2-adrenoceptors, provided that the decongestive effects are equal.

The effects of removal of extracellular calcium and of the calcium channel blockers nifedipine, verapamil and diltiazem were studied on contractions induced by electrical field stimulation and high K + -solution in isolated preparations of the human vas deferens. Electrically induced contractions were blocked by tetrodotoxin and α-adrenoceptor blockade. They were abolished in calcium-deficient medium, and suppressed by the calcium channel blockers in the order of potency nifedipine> verapamil> diltiazem. The maximum blocking effect of nifedipine was approximately 40%. All the blockers practically abolished K + -induced contractions. It is concluded that even if the contractile response of the human vas deferens to electrical stimulation is dependent on extracellular calcium, calcium channel blockers seem to have only a limited effect on this contraction and their capability of impairing the function of the vas deferens in patients is questioned. ( J. Urol., 138: 654–658, 1987 )

Enprofylline (3-propylxanthine), a novel bronchodilating xanthine derivative that seems to lack adenosine antagonistic potency was given intravenously to eight recumbent healthy male volunteers in the doses 0.5, 1 and 1.5 mg/kg body-weight and to six of them also orally in the doses 2, 4 and 6 mg/kg. Mean enprofylline plasma levels ranged between 1.6 and 4.4 mg/1 (8.2-22.2 mumol/1) after intravenous, and between 1.9 and 5.5 mg/1 (9.8-27.9 mumol/1) after oral administration. Enprofylline was rapidly and completely absorbed and had an elimination half-life of approximately 2 hrs. About 90% of the dose given by either route was recovered as unchanged drug in the urine. A slight but significant increase in heart rate was seen at peak plasma levels after each of the highest intravenous and oral doses. At these dose levels the heart rate response to orthostatic tests was significantly increased by enprofylline. Adverse reactions were mild and short-lasting and occurred most frequently after the two highest intravenous and oral doses. Headache and nausea were noted in 5 of the 24 intravenous experiments and in 9 of the 17 times that enprofylline was given orally. In conclusion, the circulatory effects of enprofylline were small and the adverse reactions mild. Further clinical studies with enprofylline seem warranted.

Contractant and relaxant effects of prostaglandins (PG) F2 alpha, E1 and E2, prostacyclin (PGI2), the thromboxane A2 agonist U46619 and the prostaglandin endoperoxide analogue U44069 were investigated in isolated preparations of the human corpus cavernosum, corpus spongiosum and cavernous artery. In corpus cavernosum and corpus spongiosum preparations, PGF2 alpha produced concentration-dependent contractions showing rhythmic variations in tension. The contractions were effectively relaxed by carbachol and vasoactive intestinal polypeptide. U46619, U44069 and PGI2 also contracted corpus cavernosum and corpus spongiosum strips at resting tension, U46619 being the most potent drug. PGE1 and PGE2, but not PGI2 relaxed corpus cavernosum and corpus spongiosum preparations contracted by noradrenaline (NA) and PGF2 alpha. PGE1 was the more effective agent; high concentrations of PGE2 produced contraction. In cavernous artery segments, PGF2 alpha produced concentration-dependent contractions. No oscillations in tension were observed; carbachol had no relaxant action, but VIP effectively relaxed the vessels. U46619 and U44069, but not PGI2 had contractant effects on cavernous artery segments at resting tension. PGE1 and PGI2, but not PGE2 relaxed NA contracted vessel preparations; all agents (PGE2 less effectively) relaxed PGF2 alpha contracted vessel segments. It is concluded that cavernous artery and erectile tissue proper (corpus cavernosum and corpus spongiosum) differ importantly in their reaction to various prostanoids. It cannot be excluded that products of the arachidonate cascade can be involved in the control of penile tumescence and erection.

Organ blood flow, as estimated by the radioactive labelled microsphere technique, was studied in rats before and after intracaval administration of the calcium antagonist nifedipine. Intra-uterine and arterial blood pressures were registered simultaneously. Two groups of animals were investigated, one non-treated and one treated with oestradiol. After administration of nifedipine, an increase in the blood flow to the brain, the heart and the kidneys was seen in both groups of animals. However, in the uterus, blood flow was markedly increased in non-treated, but not so in oestradiol-treated animals. The arterial blood pressure and intra-uterine pressure were almost unaffected. The results suggest that nifedipine can markedly increase blood flow to the uterus of non-oestrogen-treated rats with only minor effects on intra-uterine and arterial blood pressures.

The possible calcium antagonistic action of the anti-anginal drug terodiline was investigated by two experimental techniques. In isolated preparations of rabbit aorta and pregnant human uterus exposed to a calcium-free medium and then depolarized by potassium, terodiline in concentrations of 4.5--36 microM inhibited contractions produced by cumulative addition of calcium to the extracellular medium. This effect of terodiline could be reversed by high concentrations of calcium. Within the same concentration range, terodiline also reduced potassium-induced 45Ca influx in isolated aorta without affecting calcium efflux. It is suggested that terodiline, which structurally has similarities to prenylamine and fendiline, like these drugs can be classified as a calcium antagonist.

The influence of extracellular Ca2+ and nifedipine on contractile responses to 10 microM noradrenaline (NA) was investigated in isolated rat and cat middle cerebral (RCA, CCA) and mesenteric (RMA, CMA) arteries. In the CCA (containing predominantly alpha 2-adrenoceptors), the NA-induced contractions developed considerably more slowly than in the RCA, RMA (containing mainly alpha 1-adrenoceptors) and CMA (sensitive to both alpha 1- and alpha 2-adrenoceptor selective antagonists). The tonic component of the NA-induced contraction in the four types of artery was substantially suppressed after only short periods in Ca2+-free solution. In each type of artery, excluding the CCA, the contractile response to 124 mM K+ was more sensitive to Ca2+ deprivation than that to NA. This suggests that NA, besides mobilizing extracellular Ca2+, can also release Ca2+ from an intracellular pool in the RCA, RMA and CMA, but not in the CCA. Thus, alpha 1-adrenoceptor-mediated contractions in the RCA and RMA seem to depend on both Ca2+ influx and intracellular Ca2+ release, whereas alpha 2-adrenoceptor-mediated contractile responses in the CCA appear to rely almost entirely on Ca2+ influx. Both the maximum response and the tonic component of the NA-induced contraction were significantly more sensitive to nifedipine in the CCA than in the RCA. In comparison with the NA-induced contractions in these arteries, those in the RMA and CMA were relatively resistant to nifedipine. In the CCA exposed to NA in Ca2+-free medium, nifedipine almost abolished the contraction induced by re-addition of Ca2+, whereas in the other types of artery, Ca2+ re-application evoked a significant contraction also in the presence of the drug. The differential effects of nifedipine presumably reflect differences between the arteries, not only in the relative contribution of Ca2+ influx and intracellular Ca2+ release to the contractile activation, but also in the nifedipine sensitivity of the Ca2+ entry pathways utilized by NA. It is concluded that the mechanisms through which NA induces contraction seem to be related both to the subtype of alpha-adrenoceptor stimulated by NA and to the type of vessel studied.

The effects of prostaglandin F2alpha (PGF2alpha 2.8 X 10(-7) --2.8 X 10(-5) M) on isolated segments of human peripheral arteries and veins were investigated. In both types of vessel, PGF2alpha had a concentration-dependent contracting effect. The contraction developed more slowly and had a longer relaxation time after washing than responses induced by noradrenaline or potassium. In the veins, the maximum response to the prostaglandin was 128 +/- 3.6% of that to potassium (P less than 0.01); in the arteries, the maximum amplitudes of PGF2alpha and potassium induced contractions were of similar magnitude. The arterial preparations were less responsive to PGF2alpha than to noradrenaline. On a molar basis, noradrenaline was approximately 10 times more potent than PGF2alpha. Veins, maximally contracted by noradrenaline or potassium, increased their tension further on addition of PGF2alpha. Similarly, preparations maximally contracted by PGF2alpha also showed a further increase in tension after addition of noradrenaline or potassium. The PGF2alpha induced contractions were not affected by alpha-adrenoceptor blockade (phentolamine, prazosin). The calcium antagonists verapamil and nifedipine relaxed preparations contracted by PGF2alpha, and reduced the responses in a concentration-dependent way when added 15 min. before the prostaglandin. Immersion for 30 min. in a calcium-free medium, reduced the PGF2alpha induced response in both arteries and veins. In the veins, but not in the arteries, the responses to potassium and noradrenaline were more reduced than that to PGF2alpha (P less than 0.01). Contractions induced by all agents were further depressed by verapamil and nifedipine after exposing the preparations to the calcium-free medium. It is suggested that PGF2alpha induces contraction both by enhancing the transmembrane flow of calcium, and by facilitating release of calcium from intracellular stores.

The alpha-adrenoceptor-mediated contractile effects of noradrenaline (alpha 1 + alpha 2), phenylephrine (alpha 1) and clonidine (alpha 2) on human saphenous veins were investigated in vivo and in vitro. By infusion (0.3 ml min-1) of the drugs (increasing concentrations in the infused solution) into distended (40 mmHg) saphenous veins in six healthy subjects, local vasoconstriction was induced, measured by a photo-electric device. The drugs induced dose-dependent contractions in all subjects, and dose-response curves were constructed. These were compared with concentration-response curves based on in-vitro results. Macroscopically normal saphenous veins, taken at saphenousectomies, were used, and the preparations were contracted isometrically in organ baths by the agonists. From the curves obtained in vivo and in vitro, the relative potencies of phenylephrine and clonidine (in relation to noradrenaline) were calculated and compared. The relative potencies of phenylephrine in vivo (76%) and in vitro (82%) did not differ significantly. However, the relative potency of clonidine was significantly (P less than 0.05) lower in vivo (90%) than in vitro (99%). Thus, it is concluded that there are differences between the results obtained in vivo and in vitro, stressing the importance of comparative in vivo-in vitro studies.

The effects of the tertiary amine atropine and its structural analogues homatropine and scopolamine, as well as the quarternary amine emeprone, were evaluated on noradrenaline (NA)-induced contractions of isolated female rabbit urethral ring preparations. In addition, the abilities of these antimuscarinics to inhibit 3H-dihydro-alpha-ergocryptine (3H-DHE) binding to alpha-adrenoceptors were studied on a crude membrane preparation from the female rabbit bladder base and urethra. Atropine and homatropine depressed the NA-induced contractions in a concentration-dependent way, whereas this was not seen with scopolamine. Emeprone 10(-5) and 10(-4) M augmented the contractions, an effect possibly attributable to a NA-uptake blocking effect. All antimuscarinics displaced specific 3H-DHE binding, the order of potency being atropine greater than homatropine greater than emeprone greater than scopolamine. In general a good correlation was seen between the binding and mechanical activity studies for atropine, homatropine and scopolamine, while this was not found for emeprone. It is concluded that alpha-adrenoceptor blockade by atropine can be observed at concentrations exceeding 10(-7) M. Scopolamine, showing alpha-adrenoceptor blocking properties only in high concentrations, may be used as an alternative for blockade of muscarinic cholinoceptors.

Isolated preparations of the thoracic aorta from spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR) were contracted by noradrenaline (NA) 1.8 X 10(-5)M, and potassium (K+) 127 mM, after 30 min. pretreatment in a Ca++-free medium. In both SHR and NWR aortae, the contractions were markedly reduced; no significant differences were found between the two types of vessels in Ca++-free medium. On addition of Ca++, the contractions were restored to a significantly greater extent in the NWR than in the SHR aortae. In the presence of nifedipine 7.2 X 10(-9)M, the response to Ca++ was significantly more reduced in the SHR than in the NWR preparations. Relaxation of NA and K+ contracted preparations was induced by wash-out of the contractile agents, by addition of nifedipine 2.9 X 10(-8)M, and by introduction of a Ca++-free medium. After wash-out of NA, relaxation was slower in SHR than in NWR vessels. Relaxation induced by nifedipine and Ca++-free medium was more complete in SHR than in NWR preparations. After wash-out of K+, relaxation was more rapid in NWR than in SHR aortae. Nifedipine and Ca++-free medium induced relaxation was more complete in SHR than in NWR preparations. The results suggest that in the SHR aortae contraction induced by NA and K+ is more dependent on extracellular Ca++ than is the response in the NWR preparations; the SHR vessels are also more sensitive to the relaxing effects of nifedipine.

A survey is given on the vascular and neuronal effects of calcium antagonists under physiological and pathological conditions. Special emphasis is put on vasospasm caused by subarachnoid haemorrhage and on postischaemic cerebral hypoperfusion following different forms of cerebral ischaemia, and on the attempts to influence these phenomena pharmacologically.

Influx of calcium from the extracellular medium seems to be important for spontaneous as well as agonist-induced contractile activity in urinary tract smooth muscle. To a various extent this calcium influx occurs through pathways which can be blocked by calcium channel blockers. These drugs effectively suppress spontaneous ureteral activity in vitro. Whether they affect ureteral motility in vivo or whether they can counteract ureteral spasm associated with ureteral stones have not been established. Calcium channel blockers partially block electrically as well as agonist-induced detrusor contractions. Some of these drugs abolish even atropine-resistant contractile responses induced by electrical stimulation in detrusor muscle. Drugs with combined antimuscarinic and calcium channel blocking effect therefore have an attractive effect profile. Experiences with calcium channel blockers in the treatment of patients with 'unstable bladder' are limited, but results obtained with terodiline seem promising. Even if calcium channel blockers reduce agonist-induced contraction in isolated urethral muscle, their clinical effect on urethral function seems to be small. The effects of calcium blockers on urinary tract smooth muscle may be clinically useful and deserve further study.

The effect of the calcium antagonist, nifedipine, on menstrual pain was investigated in 40 women with severe, primary dysmenorrhoea and 36 of them were observed over 3 consecutive menstrual cycles. Twenty-six patients experienced good pain relief, 10 moderate relief and 4 reported no benefit. The frequency of symptoms associated with menstrual pain was not reduced. Fifteen women regularly suffering from migraine during the menstrual period reported increased headache after intake of the drug. Due to this side effect four of these patients did not continue treatment for more than one cycle. All patients had transient facial flushing occurring 15--30 min after drug intake; this was well tolerated. An increase in pulse rate was also invariably found. However, only 5 patients complained of palpitations. Twenty-five of the 36 women completing the three-month trial wanted to continue nifedipine therapy regularly. It is concluded that calcium antagonists like nifedipine can be used for treatment of severe primary dysmenorrhoea, and that further evaluations of these drugs are indicated.

The effects of the calcium channel blockers (CCBs) verapamil, nifedipine and diltiazem on contractile activation of isolated human penile erectile tissues were investigated. Specimens of the corpus spongiosum (CS) and corpora cavernosa (CC) were obtained from men with a history of normal penile erection undergoing cystourethrectomy because of bladder malignancy. Preparations were mounted in organ baths and isometric tension was recorded. Deprivation of extracellular calcium abolished electrically induced contractions in both CS and CC preparations within 15 min.; norepinephrine (NE)-induced contractions were reduced by 90% (CS) and 83% (CC) after 30 min. All the CCBs reduced electrically induced contractions concentration-dependently, nifedipine being the most potent agent. Contractions induced by exogenous NE were depressed by about 50%, whereas high K+ (124 mM) induced responses were abolished. It is concluded that contraction in penile erectile tissues is mediated mainly by neuronally released NE stimulating postjunctional alpha-adrenoceptors. The contraction is highly dependent on extracellular calcium and can partly be inhibited by CCBs. It cannot be excluded that some CCBs injected intracavernosally may be useful for diagnosis and even treatment of erectile dysfunction. However, calcium channel blockade may not be as effective as a therapeutic principle as blockade of alpha-adrenoceptors.

A short review is given of some of the adverse reactions to prostaglandin synthetase inhibitors. Broadly, these side-effects can be divided into those common to the whole group, and those more or less characteristic of the individual drugs. Among the former, symptoms from the gastrointestinal tract and from the central nervous system are the most conspicuous. Skin reactions, bronchospasm, and serious blood dyscrasias have been reported for several of these drugs and the list of more rare side-effects is long. It is concluded that drugs like phenylbutazone and oxyphenbutazone should not be used for treatment of dysmenorrhea because of the risks of serious adverse reactions. However, even if among the newly introduced compounds none can be said to be free from risks, some seem to have an acceptable ratio between therapeutic efficacy and side-effects.

✓ Cat cortical arterioles were exposed in vivo to cerebrospinal fluid (CSF) from four patients with subarachnoid hemorrhage (SAH) due to a ruptured intracranial aneurysm. Pial arteriolar caliber was measured by the television image-splitting technique. There was a consistent vasoconstrictive response to CSF. This effect could be ascribed neither to the pH of the CSF nor to the potassium concentration. The vasoconstriction, which was more pronounced with decreasing arteriolar caliber, could be resolved by the perivascular application of nifedipine.

Terodiline, a drug with anticholinergic and calcium antagonistic properties, effectively relaxed carbachol-contracted, isolated human bladder preparations. In the concentrations used, terodiline displaced to the right the concentration-response curve obtained on cumulative addition of carbachol. The maximum response was slightly reduced only at the highest terodiline concentration used (5μM), suggesting a mainly competitive antimuscarinic effect. Nine patients, aged 12–78 years, suffering from urge urinary incontinence were investigated by simultaneous urethro-cystometry before and after treatment with terodiline 12.5 mg twice or three times daily for 10 days. The patients reported subjective improvement with almost no side effects. Objectively, the number of uninhibited bladder contractions and the amplitude of the contractions decreased. The bladder capacity was almost doubled. There were no marked effects on bladder and urethral pressures at rest, and only two of the investigated patients had slight residual urine after treatment. The results suggest that terodiline is a promising alternative to existing drugs for inhibition of undesired detrusor activity.

The effects of racemic terodiline on isolated detrusor preparations from rabbit and man were compared with those of its (+)- and (-)-isomers, and with those of its main metabolite, parahydroxy-terodiline. Concentration-response (c-r) relations for carbachol and frequency-response relations for electrical stimulation were determined before and after addition of drugs. In preparations from both rabbit and man, all the drugs tested concentration-dependently shifted the c-r curve for carbachol to the right. (+)-Terodiline was more potent than (+/-)-terodiline, whereas (-)-terodiline and parahydroxy-terodiline were less potent. All drugs in concentrations greater than 10(-6) M had a non-competitive effect, depressing the maximum of the carbachol contraction. All drugs had a depressant effect on electrically evoked contractions. (+)-Terodiline was as effective (rabbit) or more effective (man) than (+/-)-terodiline, whereas (-)-terodiline and parahydroxy-terodiline were less effective. It is concluded that (+)-terodiline contributes to a main part of the detrusor effects of the racemate, and that part of this action is anticholinergic. Parahydroxy-terodiline had a profile of action similar to that of (+/-) terodiline, but its potency was low. Since it is present in plasma in low concentrations, its contribution to the clinical effects of terodiline is probably small. (+)-Terodiline may have a therapeutic potential.

Tinidazole was administered to healthy volunteers and serum concentrations were measured following single oral and intravenous doses and after repeated dosage at different dose levels. The elimination half-time was 12-13 h. Pharmacokinetics did not change with dose, route of administration or repeated dosage. The bioavailability of single oral doses ranged between 88 and 129% with a mean of 99%. Serum concentration curves tended to have double peaks or plateaus at about 4-6 h. 74% of the intravenous dose was eliminated from serum at 24 h, but only 19% was recovered in the urine, suggesting alternative ways of elimination. Excretion in the bile and a subsequent enterohepatic circulation may explain the variations in bioavailability and the shape of the serum concentration curves.

Human myometrial visceral and vascular preparations and placental chorionic and stem villous vessels were dissected from myometrial and placental specimens obtained at term Caesarean section and after vaginal delivery. Vascular ring preparations and myometrial strips were mounted in organ bath and isometric tension recorded. Only myometrial preparations developed spontaneous contractile activity, which was effectively blocked by the calcium channel blocker nitrendipine (NTD) 10(-7) M. Pretreatment with calcium-depleted medium for 30 min. almost abolished myometrial responses to high K+ (124 mmol), oxytocin (OX) and prostaglandin F2 alpha (PGF2 alpha). Vascular responses to high K+ (124 mmol) were also nearly abolished by such treatment. However, noradrenaline (NA), vasopressin (VP) and PGF2 alpha in myometrial arteries and PGF2 alpha in chorionic vessels and stem villous arteries induced significant, but reduced contractions after calcium depletion. In all vascular preparations, exposed to calcium-depleted medium, NTD (10(-8) M) almost abolished contractions induced by calcium (0.1-4.0 mM) in the presence of K+ (124 mmol) and depressed responses to calcium in the presence of the other agonists tested. NTD (10(-10)-10(-7) M) depressed myometrial contractions induced by K+, OX and PGF2 alpha more effective than vascular responses to K+, NA, VP and PGF2 alpha in the myometrial arteries and K+ and PGF2 alpha in the placental arteries. It is concluded that activation of contraction in vessels from the human utero-placental unit implies multiple cellular sources of calcium, while in myometrial smooth muscle, influx of superficially bound calcium may be an important initial step in contractile activation. Treatment with calcium channel blockers during late human pregnancy might involve relaxation of the myometrium together with vasodilatation of the myometrial and foetal placental vascular beds.

Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1-4 mg/l, i.e. in the assumed "therapeutic interval" according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean +/- SEM) were 32.5 +/- 8.7, 13.3 +/- 2.5, and 157 +/- 23 min.

The influence of muscarinic receptor stimulation (carbachol) and blockade (scopolamine) on the release of 3H~labelled noradrenaline from adrenergic neurons was investigated in isolated detrusor preparations from rabbit, cat and man. A significant influence on the release of 3H from adrenergic nerve terminals was found in the three species with a concentration-dependent decrease and increase induced by carbachol and scopolamine, respectively. Using the α2-adrenoceptor stimulating and blocking agents clonidine and rauwolscine in rabbit and human detrusor preparations, the presence of prejunctionally located inhibitory α2-adrenoceptors could also be demonstrated. The findings indicate the possibility of a functionally important interaction between cholinergic and adrenergic nerves in the urinary bladder mediated via inhibitory muscarinic receptors on adrenergic nerve terminals.

Milrinone, a new, nonglycosidic inotropic agent with peripheral vasodilating properties, was given as a single oral 5 mg dose to 7 healthy subjects, 7 patients with moderate renal impairment (CRI I, creatinine clearance 30-63 ml/min) and 7 patients with severe renal impairment had hypertension. The mean urinary recovery of milrinone was 82% in healthy subjects, the renal clearance was 288 ml/min and the plasma half-life (t1/2) was 0.94 h. In CRI the mean plasma t1/2 was prolonged (CRI I 1.78 h, CRI II 3.24 h). There was a significant linear relationship between creatinine clearance and the elimination rate constant, and between creatinine clearance and the renal clearance of milrinone. During the study day there was a tendency to a decrease in supine BP from 1 to 6-8 h after dosing, with the maximal decrease at 2-3 h (healthy subjects 118/71----107/56, CRI 159/95----136/79 mmHg). The same degree of change was seen in standing BP. A slight rise in standing HR was seen from 2-6 h after dosing. Changes in BP and HR are difficult to evaluate since the study was not placebo-controlled. The plasma elimination rate of milrinone was decreased in CRI and dose adjustment may be necessary. Placebo-controlled studies of milrinone in hypertensive patients would be required to validate its possible antihypertensive effect.

In animal experiments, esophageal smooth muscle, including the lower esophageal sphincter (LES) has been shown to be dependent on extracellular calcium both for tone and agonist induced contractions. Calcium channel blockers (CCB) suppress contractile activity, and block both resting and stimulated calcium influx. In normal man as well as in patients with hypercontractility disorders of the esophagus, such as achalasia and diffuse esophageal spasm, CCBs have been shown to reduce LES pressure and esophageal contractions, and also to cause symptomatic improvement. Controlled clinical trials on their effectiveness are lacking, but the therapeutic principle seems promising.

Isometric tension was recorded in ring preparations of human peripherial arteries and veins contracted by potassium (127 mM) and noradrenaline (1.8 × 10-5 M). In the veins, nifedipine had a marked relaxing effect on contractions induced by both agents, and also reduced the contractile amplitude when added prior to stimulation. The inhibiting effect of nifedipine was more marked on the potassium than on the noradrenaline-evoked responses. This was in contrast to verapamil, which inhibited the noradrenaline-induced contractions significantly more, than those produced by potassium. After immersion of the vein preparations in calcium-free medium for 30 min., the potassium contracture decreased to 26±2.0% (mean ± S.E.M.) of the response in normal Krebs solution, and the noradrenaline-evoked response to 7.1±0.8%. The responses to both agents were completely restored when the calcium concentration was increased from 0 to 4 mM. Nifedipine (1.5 × 10-7 M) depressed the potassium contracture in calcium-free solution to 7.3±1.6%, and the noradrenaline response to 5.5±1.6%; on addition of calcium, the response elicited by potassium increased to 16±1.7%, and that by noradrenaline to 56±8.6%. Compared with its actions on the veins, the effect of nifedipine on the arterial preparations was less pronounced. In the arteries, too, the inhibiting effect of nifedipine was significantly more pronounced on the potassium than on the noradrenaline-induced contraction. Immersion for 30 min. in calcium-free medium reduced the response to potassium to 61±6.0% and that to noradrenaline to 68±5.6% of the control in normal Krebs. Nifedipine (2.9 × 10-7 M) further reduced the potassium contraction to 20±4.0%; the response to noradrenaline was unaffected, being 74±6.4% of the control.

Branched false tendons, strands, of the cat heart were investigated to test a hypothesis that the myofibrils in Purkinje fibres act as supports for the fibres by diminishing and distributing mechanical stress. If the cells belonging to the conducting system in the intraventricular network of strands are subject to mechanical stress during dilatation of the ventricles, the tension developed will be spread along the different directions of the strands. At the branchings of strands, mechanical stress from different directions will meet. The Purkinje fibres and their myofibrils were observed to run parallel with the directions of the calculated component tension forces. Purkinje fibres were connected by intercalated discs, and also by fine filamentous material interlinking the basement membranes of the fibres. The material appeared similar to that found in myotendinous junctions. Leptofibrils were interspersed at the places where the shearing stresses were calculated to be most extensive. Taken together, our results strongly suggests that the myofibrils and the leptofibrils in Purkinje fibres are supportive structures.

1. 1. Contractions of isolated human pial arteries, induced either by exposition to hemorrhagic cerebrospinal fluid (CSF) from patients with subarachnoid hemorrhage and cerebral vasospasm or by exposition to noradrenaline, were markedly augmented after preincubation of the vessel segments with the cyclooxygenase inhibitor indomethacin, while serotonin-induced contractions were unaffected. 2. 2. Prostacyclin relaxed human pial arteries contracted by either PGF 2α , noradrenaline, serotonin or hemorrhagic CSF. The same though less marked effects were obtained with 6-keto-PGE 1 . 3. 3. The results support the contention that an intact vascular prostacyclin synthesis is important for the maintenance of a normal cerebrovascular tone, and that disturbances of the prostaglandin metabolism may be a prerequisite for the development of arterial spasm after aneurysmal subarachnoid hemorrhage. Tentatively, 4. 4. a prostacyclin deficiency may be involved in the pathogenesis of delayed cerebral vasospasm after subarachnoid hemorrhage.

By means of anterior rhinomanometry, the decongestant effect of topically applied phenylpropanolamine (PPA) was evaluated in 40 patients with nasal obstruction. A dose-response relation was obtained for 0.5, 2.5 and 5.0% PPA solution, with the maximum effect (40% decongestion) found with the 2.5% solution. The decongestant effect was comparable to that induced by physical exercise (50% decongestion). It is concluded that PPA nose-drops are effective and offer an attractive alternative to some of the commonly used nasal decongestants.

Enprofylline, a xanthine-derivative shown experimentally to lack universal adenosine receptor antagonism, has been examined in patients with partly reversible, chronic, obstructive lung disease. Significant bronchodilation was produced by enprofylline 2 mg/kg, giving a peak plasma concentration of 3.0 +/- 0.6 microgram/ml (mean +/- SD). A dose of 2 + 4 mg/kg dilated the bronchi at least to the same extent as theophylline 9.2 +/- 0.9 mg/kg (plasma level 18.5 +/- 4.7 micrograms/ml). Neither at the low nor at the high dosage (2 +/- 4 mg/kg), giving plasma concentrations of 8.5 +/- 1.4 microgram/ml, did enprofylline produce theophylline-like CNS effects, such as restlessness and tremor, but it did exhibit some of the innocuous side effects expected with xanthine derivatives, such as epigastric discomfort and headache. The comparison with theophylline was limited because different dosage forms had to be used (solution an tablets), which for example, resulted in different absorption rates. Nevertheless, the present findings indicate enprofylline to be potent bronchodilator in patients with obstructive lung disease, suggesting that adenosine-receptor antagonism is not involved in the bronchodilator effects of xanthines.

The kinetics of the antibacterial actions of cephalexin and cephaloridin against a strain of Escherichia coli and a strain of Staphylococcus aureus were studied by a flow microcalorimeter. The heat production was related to the number of viable organisms (CFU ml-1), the pH, the optical density of the culture medium (OD540), and the morphology of the antibiotic-exposed bacteria. No heat effects could be registered when the number of CFU was below 10(4) ml-1. The addition of cephalexin, 2.5 microgram ml-1 (5 x MIC), to cultures of S. aureus caused a decrease in the heat production which was only roughly correlated with the number of CFU ml-1. This was also the case when 9.0 microgram ml-1 (2 x MIC) of this drug were added to cultures of E. coli. Two to three hours after the drugs had been added, no heat effects could be registered for the following 6--8 hours, after which an increase in the heat production again occurred. The MIC and MBC of the organisms isolated during this late heat increase were 8--40 times higher than those of the parent test organisms. A direct relation between drug concentration and response, i.e. heat effects produced, was found when increasing concentrations of cephalexin, i.e. 1.0 up to 50 micrograms ml-1 (2--100 x MIC) were added in the logarithmic growth phase to cultures of S. aureus. In ampoule calorimetric experiments, E. coli was cultured in a non-aerated, sealed growth vessel in the presence of cephalexin or cephaloridin in concentrations corresponding to 1/2 x MIC. The thermograms did not differ in shape, although the heat effects occurred somewhat later in the culture containing cephaloridin.

The effects of a new calcium antagonist, isradipine (PN 200-110) on postpartum uterine activity and the maternal cardiovascular system were investigated. Uterine activity was recorded by a microtip transducer catheter inserted transcervically within 45 min of normal vaginal delivery. 0.5 mg of isradipine was given as a bolus injection during 5 min to 7 women with spontaneous uterine activity and 1 mg was given during a 15-min period to another 8 women with oxytocin-stimulated uterine activity. Matched controls with similar pre-injection activity (+/- 5%) but not given the drug were selected for comparison. The effects of the drug in 3 women (given 1 mg of isradipine) were compared with those in matched controls and in women given 0.25 mg of terbutalin i.v. as a bolus injection. Isradipine had a marked inhibitory effect on both spontaneous and oxytocin-stimulated uterine activity. The inhibitory effect of 1 mg of isradipine seemed comparable to that of 0.25 mg of terbutalin. The inhibition occurred within 1-2 min after the injection and was sustained throughout the study period (2 h). A transient reduction of the systolic (mean maximum decrease 10-15%) and diastolic blood pressure (mean maximum decrease 15-20%) was seen, particularly during the injection period. Hypotension (systolic blood pressure less than 80 mmHg) was not recorded. A moderate increase in pulse rate (mean maximum increase 22-27%) was seen in all cases. The results show that isradipine given as a bolus injection can inhibit early postpartum uterine activity, with minimal side effects.

Digoxin had contractant effects on isolated, human mesenteric arteries and veins. Veins were more sensitive to this action of the glycoside than arteries. The contractions were not affected by phentolamine or by washing with a digoxin-free solution. However, they were abolished by the calcium antagonist nifedipine, and by washing with a calcium-free medium. In the presence of digoxin, the maximum response to noradrenaline (1.8 x 10(-5) M) increased markedly in both arteries and veins, and the concentration-response curve for the amine was displaced to the left. Immersion of vein preparations in calcium-free solution for 30 min. abolished the digoxin contracture; an increase in extracellular calcium restored the response. Changes in extracellular potassium concentration caused changes in tension in tension of the mesenteric veins similar to those previously demonstrated in peripheral veins--both in the presence and in the absence of digoxin. It is concluded that digoxin contracts mesenteric vessels by a direct action on the muscle cells, and potentiates the contractant effects of noradrenaline. These effects are dependent on the availability of extracellular calcium. Mesenteric vascular reactions caused by changes in extracellular potassium are influenced by digoxin.

Electrical field stimulation of ring preparations of the epididymal (Ve) and prostatic (Vp) parts of the human isolated vas deferens produced contractions with similar frequency-dependence and appearance. The contractions of Ve, but not of Vp preparations were abolished by tetrodotoxin (10(-6)M). Noradrenaline (NA), phenylephrine, and methoxamine, but not clonidine induced repetitive, phasic contractions in both Ve and Vp preparations, and increased the amplitude of electrically induced responses. Clonidine concentration-dependently decreased electrically induced contractions in Ve preparations, but had no significant effects in Vp preparations. Phentolamine and prazosin abolished electrically induced contractions in Ve but not in Vp preparations. In Ve rings the contractions were increased by rauwolscine; no such effect was observed in Vp preparations. Isoprenaline, propranolol, acetylcholine and carbachol had no effects in the Ve or Vp preparations. Scopolamine and atropine reduced electrically induced responses. Clonidine decreased and rauwolscine increased the electrically induced release of 3H in both Ve and Vp preparations pre-loaded with 3H-NA. Phenylephrine, prazosin, isoprenaline, propranolol, carbachol and scopolamine had minor or no effects on the 3H release. Radioligand receptor binding experiments using 3H-prazosin and 3H-rauwolscine as ligands revealed similar densities of alpha 1- and alpha 2-adrenoreceptors in the human vas deferens. There seemed to be no differences in their distribution between the epididymal, middle and prostatic part of the organ. It is concluded that the neurotransmission in the human vas deferens is noradrenergic and mediated via alpha 1-adrenoreceptors. The prazosin and tetrodotoxin resistant part of the electrically induced contraction in Vp preparations may be caused by direct smooth muscle stimulation.

Topical anti-inflammatory (cutaneous "vasoconstriction") and systemic glucocorticoid (depression of plasma cortisol and changes in differential WBC count) potencies of the two glucocorticoids budesonide and beclomethasone dipropionate (BDP) were compared in human volunteers. After topical application, budesonide was 2-3 times more potent than BDP in inducing "vasoconstriction". After oral administration, on the other hand, budesonide was 2-4 times less potent than BDP in depressing plasma cortisol and changing the total or differential WBC. After inhalation, too, significant differences in favour of budesonide were noted, but the divergence between the drugs was less pronounced. The improved relationship between the topical and systemic glucocorticoid effects of budesonide makes it a promising alternative for aerosol treatment in asthma.

The hypothesis has been examined that adenosine is involved in the diuretic and free fatty acid (FFA) - releasing action of xanthines. The effects of theophylline (T), a potent adenosine antagonist, were compared with those of enprofylline (3-propyl xanthine, E), which exerts negligible antagonism of adenosine. Eight healthy male volunteers were given E 1.5 mg/kg, T 5.0 mg/kg or placebo 0.9% saline (P) intravenously in a double-blind, randomized, cross-over investigation. Blood samples were analyzed for E, T, catecholamines (CA: adrenaline, noradrenaline and dopamine), FFA, renin, glucose, glucagon and insulin, and urine was collected at 2-h intervals. T (plasma concentration 53 +/- 8 mumol/l) but not E (11 +/- 2 mumol/l) caused an increase in FFA from 0.42 to 0.86 mmol/l after 90 min. Without affecting the urinary excretion of potassium, T doubled natriuresis and the urine volume as compared to E and P. Neither T nor E had any effect on plasma CA, or on any other of the metabolic parameters studied. E, but not T, produced a small but statistically significant decrease in diastolic blood pressure (5 mmHg) and an increase in heart rate (3 beats/min). It is suggested that the difference between E and T in terms of stimulation of FFA-release and natriuresis may be related to their different ability to antagonize adenosine.