The current endothelin receptor classification: time for reconsideration?

The possible involvement of endothelins in a variety of diseases has attracted the attention of many pharmacologists in search of a novel therapeutic approach. The rapid development of endothelin research has resulted in the molecular characterization and pharmacological recognition of ETA and ETB receptors, and in the development of compounds selective for these receptors. However, the characterization of receptors in various assays has shown that a number of effects are mediated by receptors that do not fit the present criteria for ETA or ETB receptors. In this article, Willem Bax and Pramod Saxena address endothelin receptors in general, and atypical receptors in particular.

5-HT(1)-like receptor agonists and the pathophysiology of migraine.

Recently, AG-25086 and GR-43175 have been reported to be highly effective in aborting acute migraine attacks. These compounds seem selectively to stimulate a sub-population of 5-HT(1)-like receptors to inhibit noradrenaline release from certain sympathetic neurovascular terminals, to contract dog saphenous vein and dog, monkey and human basilar arteries, and to decrease the arteriovenous anastomotic component of carotid blood flow in the cat. GR-43175 neither has any antinociceptive effect nor crosses the blood-brain barrier. Pramod Saxena and Michel Ferrari review the clinical effectiveness of these 5-HT(1)-like receptor agonists and their selective pharmacology, both of which strongly suggest that excessive dilatation in the extracerebral cranial (scalp and/or dural) vasculature is an integral part of the pathophysiology of migraine.

5-Hydroxytryptamine: a chameleon in the heart.

5-HT has profound effects on cardiac rate and force in a variety of animal species, including humans. The main initial response to 5-HT is a short-lasting bradycardia, mediated via a Bezold-Jarisch-like reflex, and initiated by stimulation of 5-HT3 receptors present on cardiac vagal afferents. Once this bradycardia is suppressed, 5-HT induces cardiac stimulation which, true to its chameleonic nature described here by Pramod Saxena and Carlos Villalón, is mediated by different mechanisms and receptors in different species. In several species, including humans, coronary vasodilatation is mediated by 5-HT1-like receptors, while both 5-HT1-like and 5-HT2 receptors mediate vasoconstriction. This knowledge may lead to a better assessment of the possible role of 5-HT in cardiovascular pathologies and to the development of selective 5-HT receptor agonists and antagonists for therapeutic usefulness in heart failure, coronary vasospasm and to avoid potential cardiac side-effects.

Clinical and experimental effects of sumatriptan in humans.

Recent reviews on the mode of action of the anti-migraine drug sumatriptan arrived at contrasting conclusions. Whereas some reviewers concluded that vasoconstriction is the most important action, others suggest that neuronal inhibition is essential. Both views were based predominantly on animal or in vitro experiments. In this comment, Michel Ferrari and Pramod Saxena review the experimental effects of sumatriptan in humans and discuss the clinical validity of both theories. In addition, they examine the initial efficacy of treatment and the mechanism of recurrence of headache within 24 hours, which is the most important drawback of sumatriptan in clinical practice, next to its possible cardiac side effects.

5-HT1-like receptors: a time to bid goodbye.

It is exactly half a century ago that 5-hydroxytryptamine was discovered and over four decades ago two types of 5-HT receptors were described. In this article, Pramod Saxena, Peter De Vries and Carlos Villalón trace the development of the modern classification and nomenclature of 5-HT receptors, which now include more than a dozen subtypes. In doing so, they advocate that the so-called '5-HT1-like' receptors, having been shown to be a heterogeneous population of 5-HT1B, 5-HT1D and 5-HT7 receptors, are now redundant.

Serotonin receptors: subtypes, functional responses and therapeutic relevance.

Recent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on operational criteria (agonist and antagonist rank order), as well as transduction mechanisms involved and the structure of the receptor protein, the Nomenclature Committee of the Serotonin Club has proposed the following classification and nomenclature: the main receptor types 5-HT1 to 5-HT4, recombinant receptors (e.g. 5-ht5 to 5-ht7) and 'orphan' receptors. The aim of the present review is to discuss the events leading to this classification, the criteria for and functional responses mediated by various 5-HT receptors, as well as the therapeutic possibilities with 5-HT ligands.

Low-dose aspirin improves in vivo hemodynamics in conscious, chronically infarcted rats.

OBJECTIVE: The equivalent of the clinically used low (= antiplatelet)-dose aspirin, inhibited collagen deposition in the non-infarcted myocardium in rats with myocardial infarction. In the present study, the in vivo hemodynamic consequences of this daily low-dose aspirin were investigated in conscious, chronically instrumented, infarcted rats. METHODS: Rats, treated with 25 mg/kg aspirin daily from 2 days before to 3 weeks after coronary artery ligation, were chronically instrumented with an electromagnetic flow-probe and arterial and venous catheters, to record cardiac output, and arterial and venous blood pressure, respectively, in the conscious freely moving animal. In parallel, isolated hearts were studied with regard to left ventricular stiffness (pressure/volume relationships), maximal cardiac perfusion (adenosine), and in vitro heart rate and beta-adrenergic responsiveness. Plasma catecholamine levels were measured. RESULTS: Aspirin normalized the increased heart rate after infarction, at a preserved cardiac output. This was accompanied by a (non-significant) increase in stroke volume, at unchanged cardiac loading conditions. The lower heart rate after aspirin was due to reduced intrinsic heart rate rather than to lower sympathetic activation of the heart, since similar effects were observed in isolated perfused hearts, while circulating levels of catecholamines and beta-adrenergic responsiveness were not influenced. The improved stroke volume was not explained by reduced left ventricular stiffness or increased maximal perfusion after aspirin. CONCLUSION: In addition to the antithrombotic action, effects of low-dose aspirin on cardiac remodeling could be associated with favorable hemodynamic effects, as reflected by a lower heart rate for the same cardiac output. Although the underlying mechanisms are still unknown, it suggests a clinically relevant beneficial effect which deserves further investigation.

Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts.

OBJECTIVE: Anti-inflammatory drugs have been shown to modulate collagen deposition during myocardial infarction (MI) induced remodeling. Chronic effects of methylprednisolone (5 mg/kg/day) and low-dose aspirin (25 mg/kg/day) on cardiac collagen and left ventricular diastolic function were studied in rat hearts, 21 days after MI. METHODS: Left ventricular function was assessed at baseline and after beta-adrenergic stimulation with isoproterenol in isolated perfused hearts, using an intraventricular balloon. After diastolic arrest, left ventricular pressure-volume curves were obtained. Left ventricular dilation was defined as the corresponding left ventricular volume at 20 mmHg left ventricular diastolic pressure. In histological sections, perivascular and interstitial collagen content were quantified morphometrically as the Sirius Red positive area in the non-infarcted interventricular septum. RESULTS: Impaired baseline left ventricular function of MI-hearts was improved by methylprednisolone but not by low-dose aspirin. Isoprotenerol significantly enhanced systolic function in all hearts, whereas it augmented the decrease in left ventricular diastolic pressure only in methylprednisolone-treated MI-hearts. The rightward shift of the pressure-volume curve after MI was aggravated by methylprednisolone but not with low-dose aspirin treatment. Low-dose aspirin reduced perivascular but not interstitial collagen whereas methylprednisolone decreased both perivascular and interstitial collagen. CONCLUSIONS: Our findings indicate that MI-induced collagen deposition in the spared myocardium can be affected by chronic therapy with low-dose aspirin or methylprednisolone. The effects on interstitial collagen seemed reflected in an altered left ventricular diastolic function.

Vasoconstriction by in situ formed angiotensin II: role of ACE and chymase.

OBJECTIVE: To assess the importance, for vasoconstriction, of in situ angiotensin (Ang) II generation, as opposed to ang II delivery to AT receptors via the organ bath fluid. METHODS: Ang I and II concentration-response curves in human and porcine coronary arteries (HCAs, PCAs) were constructed in relation to estimates of the clearances of Ang I and II (ClAngI, ClAngII) from the organ bath and the release of newly formed Ang II (RAngII) into the bath fluid. HCAs were from 25 heart valve donors (age 5-54 years), and PCAs from 14 pigs (age 3 months). RESULTS: Ang I- and II-evoked constrictions were inhibited by the AT1 receptor antagonist, irbesartan, and were not influenced by the AT2 receptor antagonist, PD123319. In HCAs Ang II was only three times more potent than Ang I, wheres, in the experiments with Ang I, comparison of ClAngI with ClAngII and RAngII indicated that most of the arterially produced Ang II did not reach the bath fluid. Also in PCAs Ang I and II showed similar potency. In HCAs both the ACE inhibitor, captopril, and the chymase inhibitor, chymostatin, inhibited Ang I-evoked vasoconstriction, while only chymostatin had a significant effect on ClAngI. In PCAs Ang I-evoked vasoconstriction was almost completely ACE-dependent. CONCLUSIONS: This study points towards the functional importance of in situ ACE- and chymase-dependent Ang II generation, as opposed to Ang II delivery via the circulation. It also indicates that functionally relevant changes in local Ang I-II conversion are not necessarily reflected by detectable changes in circulating Ang II.

Cultured neonatal rat cardiac myocytes and fibroblasts do not synthesize renin or angiotensinogen: evidence for stretch-induced cardiomyocyte hypertrophy independent of angiotensin II.

OBJECTIVE: The hypertrophic response of cardiomyocytes exposed to mechanical stretch is assumed to depend on the release of angiotensin (Ang) II from these cells. Here we studied the synthesis of renin-angiotensin system (RAS) components by cardiac cells under basal conditions and after stretch. METHODS: Myocytes and fibroblasts were isolated by enzymatic dissociation from hearts of 1-3-day-old Wistar rat strain pups, grown for 1 day in serum-supplemented medium and then cultured in a chemically defined, serum-free medium. Medium and cell lysate were collected 5 days later or after exposure of the cells to cyclic stretch for 24 h. Prorenin, renin and angiotensinogen were measured by enzyme-kinetic assay; Ang I and Ang II were measured by radioimmunoassay after SepPak extraction and HPLC separation. RESULTS: Prorenin, but none of the other RAS components, could be detected in the medium of both cell types. However, its levels were low and the Ang I-generating activity corresponding with these low prorenin levels could not be inhibited by the specific rat renin inhibitor CH-732, suggesting that it was most likely due to bovine and/or horse prorenin sequestered from the serum-containing medium to which the cells had been exposed prior to the serum-free period. When incubated with Ang I, both myocytes and fibroblasts generated Ang II in a captopril-inhibitable manner. Myocyte and fibroblast cell lysates did not contain prorenin, renin, angiotensinogen, Ang I or Ang II in detectable quantities. Stretch increased myocyte protein synthesis by 20%, but was not accompanied by Ang II release into the medium. CONCLUSION: Cardiac myocytes and fibroblasts do not synthesize renin, prorenin or angiotensinogen in concentrations that are detectable or, it not detectable, high enough to result in Ang II concentrations of physiological relevance. These cells do synthesize ACE, thereby allowing the synthesis of Ang II at cardiac tissue sites when renin and angiotensinogen are provided via the circulation. Ang II is not a prerequisite to observe a hypertrophic response of cardiomyocytes following stretch.

Determinants of coronary reserve in rats subjected to coronary artery ligation or aortic banding.

OBJECTIVE: We investigated whether decreased coronary reserve in hearts after coronary artery ligation or in hearts from rats after aortic banding can be related to remodeling of resistance arteries. METHODS: Maximal coronary flow (absolute flow) and cardiac perfusion (flow corrected for heart weight) were determined in isolated, perfused rat hearts after adenosine or nitroprusside, at 3 and 8 weeks after coronary artery ligation or 4-5 weeks after aortic banding. Perivascular collagen and medial thickness of resistance arteries were determined by morphometry. RESULTS: maximal coronary flow of infarcted hearts had been restored to sham values at 3 weeks. Growth of cardiac muscle mass from 3 to 8 weeks exceeded the increase in maximal coronary flow, leading to a decreased perfusion at 8 weeks. A slight, transient increase in perivascular collagen, but no medial hypertrophy, was found after infarction. After aortic banding perivascular fibrosis and medial hypertrophy led to a decreased maximal coronary flow in both the hypertrophied left and the non-hypertrophied right ventricle. Consequently, perfusion of the left ventricle was most severely reduced. CONCLUSIONS: Reduced maximal perfusion after aortic banding is determined by both cardiac hypertrophy and vascular remodeling. In contrast, during infarction-induced remodeling, reduction of perfusion is not determined by vascular remodeling, but mainly by disproportional cardiac hypertrophy relative to vascular growth.

Conversion and degradation of [125I] labelled angiotensin I in isolated perfused porcine coronary and carotid arteries.

OBJECTIVE: The aims were (1) to quantitate angiotensin I to II conversion on the endothelial surface and at deeper sites in isolated arteries, (2) to assess whether the angiotensin II that is formed at deeper sites is released into the vascular lumen, and (3) to examine whether enzymes other than angiotensin converting enzyme (ACE) are involved in vascular angiotensin I to II conversion. METHODS: Metabolism of [125I]-angiotensin I was studied in isolated perfused porcine coronary and carotid arteries after luminal administration of the labelled peptide (in the perfusion fluid) and after adventitial administration (in the organ bath). Measurements were made both in the presence and in the absence of captopril. RESULTS: [125I]-angiotensin II was a major metabolite and its formation was virtually completely blocked by captopril, after both luminal and adventitial administration of [125I]-angiotensin I. In coronary arteries (n = 8), the [125I]-angiotensin I to II conversion rate after adventitial administration was about half that after luminal administration. In coronary arteries (n = 6) the conversion rate after adventitial administration was 10-20 times lower than after luminal administration. Degradation of [125I]-angiotensin I into peptides other than [125I]-angiotensin II was also observed, with both luminal and adventitial administration. No [125I]-angiotensin I or II was released into the organ bath after luminal administration of [125I]-angiotensin I, and very little [125I]-angiotensin I and II entered the lumen after adventitial administration of [125I]-angiotensin I. CONCLUSIONS: (1) Vascular angiotensin I to II conversion is not limited to the endothelial surface. (2) ACE is the most important, if not the only, enzyme responsible for vascular angiotensin I to II conversion. (3) If angiotensin I and II are formed in the adventitia or media, little of these peptides will enter the vascular lumen.

Cardiovascular profile and hypotensive mechanism of ketanserin in the rabbit.

Using the radioactive microsphere technique, we studied the systemic and regional hemodynamic effects of ketanserin in conscious renal hypertensive rabbits. To characterize the hypotensive mechanism of the compound, we evaluated its antagonism toward 5-hydroxytryptamine2 and alpha 1-adrenergic receptors at hypotensive doses and compared the cardiovascular profile of ketanserin with that of the alpha 1-selective adrenergic receptor antagonist prazosin. Ketanserin (0.1, 0.3, and 1.0 mg/kg i.v.) produced a biphasic effect on the arterial blood pressure. A short, pronounced fall in blood pressure accompanied by tachycardia preceded a more moderate and longer lasting dose-related hypotensive effect. The presence of adequate autonomic nervous system activity seems to be required for the prolonged hypotensive action of ketanserin because, in animals pretreated with hexamethonium (30 mg/kg), the blood pressure, after an initial decrease, returned to baseline values within a few minutes after each ketanserin dose. Ketanserin inhibited the pressor responses produced by 5-hydroxytryptamine (10, 30, and 100 micrograms/kg i.v.) and phenylephrine (3, 10, and 30 micrograms/kg i.v.), which indicates that, at hypotensive doses, the compound antagonized both 5-hydroxytryptamine2 receptors and alpha 1-adrenergic receptors. At doses that caused a comparable degree of alpha 1-adrenergic receptor blockade, ketanserin (0.1, 0.3, and 1.0 mg/kg i.v.) as well as prazosin (0.01, 0.03, and 0.10 mg/kg i.v.) decreased the blood pressure as a result of a reduction in total peripheral resistance. While cardiac output increased, especially at the lower doses of ketanserin, a moderate decrease in this variable contributed to the hypotensive effect of the highest dose of prazosin. Both compounds decreased the vascular resistance in the kidneys, gastrointestinal tract, and bones, whereas that in the skin and skeletal muscles was not significantly altered. In contrast to prazosin, ketanserin also caused vasodilatation in the coronary and cerebral vascular beds.(ABSTRACT TRUNCATED AT 250 WORDS)

Localization and production of angiotensin II in the isolated perfused rat heart.

We used a modification of the isolated perfused rat heart, in which coronary effluent and interstitial transudate were separately collected, to investigate the localization and production of angiotensin II (Ang II) in the heart. During combined renin (0.7 to 1.5 pmol Ang I/mL per minute) and angiotensinogen (6 to 12 pmol/mL) perfusion (4 to 8 mL/min) for 60 minutes (n=3), the steady-state levels of Ang II in interstitial transudate in two consecutive 10-minute periods were 4.3+/-1.5 and 3.6+/-1.5 fmol/mL compared with 1.1+/-0.4 and 1.1+/-0.6 fmol/mL in coronary effluent (mean+/-half range). During perfusion with Ang II (n=5), steady-state Ang II in interstitial transudate was 32+/-19% of arterial Ang II compared with 65+/-16% in coronary effluent (mean+/-SD, P<.02). During perfusion with Ang I (n=5), Ang II in interstitial transudate was 5.1+/-0.6% of arterial Ang I compared with 2.2+/-0.3% in coronary effluent (P<.05). The tissue concentration of Ang II in the combined renin/angiotensinogen perfusions (per gram) was as high as the concentration in interstitial transudate (per milliliter). Addition of losartan (10(-6) mol/L) to the renin/angiotensinogen perfusion (n=3) had no significant effect on the tissue level of Ang II, whereas losartan in the perfusions with Ang I (n=5) or Ang II (n=5) decreased tissue Ang II to undetectably low levels. The results indicate that the heart is capable of producing Ang II and that this can lead to higher levels in tissue than in blood plasma. Cardiac Ang II does not appear to be restricted to the extracellular fluid. This is in part due to AT1-receptor-mediated cellular uptake of extracellular Ang II, but our results also raise the possibility of intracellular Ang II production.

Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis.

The existence of a cardiac renin-angiotensin system, independent of the circulating renin-angiotensin system, is still controversial. We compared the tissue levels of renin-angiotensin system components in the heart with the levels in blood plasma in healthy pigs and 30 hours after nephrectomy. Angiotensin I (Ang I)-generating activity of cardiac tissue was identified as renin by its inhibition with a specific active site-directed renin inhibitor. We took precautions to prevent the ex vivo generation and breakdown of cardiac angiotensins and made appropriate corrections for any losses of intact Ang I and II during extraction and assay. Tissue levels of renin (n = 11) and Ang I (n = 7) and II (n = 7) in the left and right atria were higher than in the corresponding ventricles (P < .05). Cardiac renin and Ang I levels (expressed per gram wet weight) were similar to the plasma levels, and Ang II in cardiac tissue was higher than in plasma (P < .05). The presence of these renin-angiotensin system components in cardiac tissue therefore cannot be accounted for by trapped plasma or simple diffusion from plasma into the interstitial fluid. Angiotensinogen levels (n = 11) in cardiac tissue were 10% to 25% of the levels in plasma, which is compatible with its diffusion from plasma into the interstitium. Like angiotensin-converting enzyme, renin was enriched in a purified cardiac membrane fraction prepared from left ventricular tissue, as compared with crude homogenate, and 12 +/- 3% (mean +/- SD, n = 6) of renin in crude homogenate was found in the cardiac membrane fraction and could be solubilized with 1% Triton X-100. Tissue levels of renin and Ang I and II in the atria and ventricles were directly correlated with plasma levels (P < .05), and in both tissue and plasma the levels were undetectably low after nephrectomy. We conclude that most if not all renin in cardiac tissue originates from the kidney. Results support the contentions that in the healthy heart, angiotensin production depends on plasma-derived renin and that plasma-derived angiotensinogen in the interstitial fluid is a potential source of cardiac angiotensins. Binding of renin to cardiac membranes may be part of a mechanism by which renin is taken up from plasma.

Renin-angiotensin system components in the interstitial fluid of the isolated perfused rat heart. Local production of angiotensin I.

We used a modification of the isolated perfused rat heart, in which coronary effluent and interstitial transudate were separately collected, to investigate the uptake and clearance of exogenous renin, angiotensinogen, and angiotensin I (Ang I) as well as the cardiac production of Ang I. The levels of these compounds in interstitial transudate were considered to be representative of the levels in the cardiac interstitial fluid. During perfusion with renin or angiotensinogen, the steady-state levels (mean +/- SD) in interstitial transudate were 64 +/- 34% (P < .05 for difference from the arterial level, n = 8) and 108 +/- 42% (n = 6) of the arterial level, respectively; the levels in coronary effluent were not significantly different from those in interstitial transudate. Ang I was not detectable in interstitial transudate during perfusion with Tyrode's buffer or angiotensinogen. It was very low in interstitial transudate during perfusion with renin and rose to much higher levels during combined renin and angiotensinogen perfusion. The total production rate of Ang I present in interstitial fluid could be largely explained by the renin-angiotensinogen reaction in the fluid phase of the interstitial compartment. In contrast, the total production rate of Ang I present in coronary effluent and the net ejection rate of Ang I via coronary effluent were, respectively, 4.6 +/- 2.2 and 2.8 +/- 1.3 (P < .01 and P < .05 for difference from 1.0, n = 6) times higher than could be explained by Ang I formation in the fluid phase of the intravascular compartment. Ang I from the interstitial fluid contributed little to the Ang I in the intravascular fluid and vice versa. These data reveal two tissue sites of Ang I production, ie, the interstitial fluid and a site closer to the blood compartment, possibly vascular surface-bound renin. There was no evidence that the release of locally produced Ang I into coronary effluent and interstitial transudate occurred independently of blood-derived renin or angiotensinogen.

Mannose 6-phosphate receptor-mediated internalization and activation of prorenin by cardiac cells.

The binding and internalization of recombinant human renin and prorenin (2500 microU/mL) and the activation of prorenin were studied in neonatal rat cardiac myocytes and fibroblasts cultured in a chemically defined medium. Surface-bound and internalized enzymes were distinguished by the addition of mannose 6-phosphate to the medium, by incubating the cells both at 37 degrees C and 4 degrees C, and by the acid-wash method. Mannose 6-phosphate inhibited the binding of renin and prorenin to the myocyte cell surface in a dose-dependent manner. At 37 degrees C, after incubation at 4 degrees C for 2 hours, 60% to 70% of cell surface-bound renin or prorenin was internalized within 5 minutes. Intracellular prorenin was activated, but extracellular prorenin was not. The half-time of activation at 37 degrees C was 25 minutes. Ammonium chloride and monensin, which interfere with the normal trafficking and recycling of internalized receptors and ligands, inhibited the activation of prorenin. Results obtained with cardiac fibroblasts were comparable to those in the myocytes. This study is the first to show experimental evidence for the internalization and activation of prorenin in extrarenal cells by a mannose 6-phosphate receptor-dependent process. Our findings may have physiological significance in light of recent experimental data indicating that angiotensin I and II are produced at cardiac and other extrarenal tissue sites by the action of renal renin and that intracellular angiotensin II can elicit important physiological responses.

Cerebral blood flow during migraine attacks without aura and effect of sumatriptan.

OBJECTIVE: To study regional cerebral blood flow (rCBF) during migraine attacks without aura and after treatment with sumatriptan. DESIGN AND INTERVENTION: We performed three technetium Tc99m hexemethyl-propyleneamineoxime single photon emission computed tomography scanning procedures in patients with migraine who participated in a double-blind, placebo-controlled, randomized clinical trial (1) outside an attack, (2) during an attack, and (3) after treatment of the attack with 6 mg of subcutaneous sumatriptan. SETTING: University hospital. PATIENTS: We studied 20 patients with migraine without aura, 15 of whom were evaluated under all three conditions and five of whom were evaluated under only two conditions. OUTCOME MEASURES: The single photon emission computed tomographic images were evaluated semiquantitatively with regard to (1) the degree of asymmetry of the rCBF between the headache side and the nonheadache side and (2) the ratio of the rCBF in regions of interest to the rCBF in two reference areas (cerebellum or frontal cortex). RESULTS: We found no significant rCBF asymmetries outside or during the attack or after treatment with sumatriptan, and there were no significant changes of the rCBF ratios during the attack (compared with outside the attack) or after treatment of the attack (compared with during the attack). CONCLUSION: Migraine attacks without aura and treatment of the attacks with 6 mg of subcutaneous sumatriptan are not associated with detectable focal changes of the rCBF.

The significance of histamine H1 and H2 receptors on the carotid vascular bed in the dog.

Intra-arterial histamine produced a dose-dependent increase in common carotid blood flow due to an active vasodilation. A supramaximal dose of mepyramine (H1-blocker) only partially suppressed the effects of lower doses of histamine without influencing those of its higher amounts. Both metiamide and burimamide (H2-blockers) effectively antagonized the mepyramine-resistant carotid vasodilator responses to histamine. The results permit us to conclude that two distinctly different types of histaminergic receptors (H1 and H2) are present in the carotid vascular bed and both of these receptor types are equally important in subserving histamine vasodilation. This fact may explain why, despite incriminating evidence for a pathophysiologic role of histamine, the usual antihistaminic agents are rather ineffective in migrainous headaches. It is suggested that the use of both types of antihistaminic agents concurrently may provide a new approach to the treatment of migrainous headaches, particularly cluster-type headaches.

Antimigraine drugs and cranial arteriovenous shunting in the cat.

The effects of three antimigraine drugs--ergotamine, dihydroergotamine, and methysergide--on the distribution of flow throughout the cephalic circulation of the cat were studied, using microspheres of a suitable size to separate capillary flow from flow through the arteriovenous anastomoses. Ergotamine and dihydroergotamine significantly decreased the fraction of carotid blood flow shunted through the arteriovenous anastomoses, a mode of action that reemphasizes the need for further clinical studies on the involvement of arteriovenous anastomoses in the pathophysiology of migraine headaches.