Early holocene openlands in southern New England.

The pre-historical vegetation structure in temperate forest regions is much debated among European and North American ecologists and conservationists. Frans Vera's recent hypothesis that large mammals created mosaics of forest and openland vegetation in both regions throughout the Holocene has been particularly controversial and has provoked new approaches to conservation management. Thirty years earlier, American paleoecologists Herb Wright and Margaret Davis debated whether abundant ragweed pollen at Rogers Lake, Connecticut at 9500 yr BP signified local forest openings or long-distance transport of pollen from Midwestern prairies. Using new pollen records from Harvard Forest and the North American Pollen Database, we address this question and offer insights to the openland discussion. Ragweed and other forbs exceed 3.5% at five sites in a restricted area of southern New England between 10,100 and 7700 yr BP. Strong evidence suggests this pollen originated from the landscapes surrounding these sites (supporting Davis), as ragweed pollen percentages do not increase with longitude from New England to the Midwest. Ragweed pollen percentages are also unrelated to basin size and therefore unrelated to the proportion of extraregional pollen in New England. High forbs values were associated with increases in oak, decreases in white pine, and relatively high charcoal values. Modern pollen records with similar forb and tree percentages occur along the Prairie Peninsula region of the Upper Midwest. However, the closest analogue to the southern New England early Holocene assemblages comes from Massachusetts' Walden Pond in the early 18th century. These results and the affiliation of ragweed for open, disturbed habitats suggest that oak-pine forests with large openings persisted for over 2000 years due to dry conditions and perhaps increased fire frequency. This conclusion is corroborated by independent lake level and climate reconstructions. Because these early Holocene openlands have no detectable analogue in New England for the past 7000 years before European settlement, we suggest that all important openlands today are almost exclusively a legacy of Colonial agriculture and should be managed accordingly. Nonetheless, our results may have implications for forest dynamics accompanying projected climate change to more arid conditions in New England over the next century.

The long-term tolerability of enalapril in hypertensive patients with renal impairment.

There has been some concern raised regarding the safe use of ACE-inhibitors in patients with severe renal insufficiency, including the development of hyperkalaemia in these patients. Therefore, the objective of the current analysis was to evaluate the long-term safety of enalapril in patients with severe renal sufficiency and hypertension. Three protocols with similar randomized, double blind, placebo-controlled designs were selected for analysis. A total of 153 patients, enrolled at six sites, were treated for up to 3 years with enalapril; 164 patients served as controls. One protocol used a fixed dose (5 mg/day) of enalapril, while the other two protocols allowed open titration up to 40 mg/day. The primary comparison was between the enalapril and control populations. For the analysis, patients, by treatment, were grouped according to the degree of renal insufficiency (serum creatinine > or < 3 mg/dl) at baseline. The incidence of the most common, as well as important, clinical and laboratory adverse events for this patient population were summarized. In addition, trends in important laboratory adverse events and the incidence of first-dose events, cough and angioedema were evaluated. The incidence of clinical adverse events was similar for both treatment groups, regardless of the severity of renal insufficiency. Seven patients died, four in the control group and three in the enalapril treatment group; none was considered related to treatment. Enalapril appeared to be well-tolerated in this group of patients with severe renal impairment.

Blood pressure effects of the angiotensin II receptor blocker, losartan.

BACKGROUND: Losartan potassium, the first nonpeptide selective blocker of angiotensin II at the AT1 receptor, has been shown to exhibit clinical antihypertensive effects. The aim of the present study was to characterize the efficacy and duration of action of losartan by ambulatory blood pressure monitoring. METHODS: The study was performed in nonblack hypertensive patients whose baseline untreated clinical diastolic blood pressures were 95 mm Hg or higher and whose average 24-hour ambulatory diastolic blood pressures were 85 mm Hg or higher. Patients were randomized, double-blind, into four treatment groups: placebo (n = 32) or losartan, 50 mg once daily (n = 29), 100 mg once daily (n = 30), or 50 mg twice daily (n = 31). Clinical and 24-hour ambulatory blood pressures were measured at baseline (off treatment for at least 4 weeks) and after 4 weeks of treatment. RESULTS: By clinical sphygmomanometer measurements at the end of the 24-hour or 12-hour dosing intervals (trough), all three losartan dosages were significantly more effective than placebo at decreasing systolic and diastolic blood pressures. By average 24-hour ambulatory systolic/diastolic blood pressure measurements, the decreases produced were 0.0/0.2 mm Hg for placebo and 9.2/6.9, 9.9/6.4, and 13.2/8.5 mm Hg, respectively, for losartan, 50 mg once daily, 100 mg once daily, and 50 mg twice daily. All drug effects were different from placebo (P < .01). The effects of losartan, 50 mg twice daily, were not significantly different from those of losartan, 100 mg once daily, but, as expected, the effects were greater than those of losartan, 50 mg once daily (P < .05). Addition of hydrochlorothiazide, 12.5 mg/d, during an additional 2-week treatment period in patients whose clinical diastolic blood pressure remained at 85 mm Hg or higher while receiving monotherapy produced additional and clinically meaningful blood pressure decrements that were similar in all four treatment groups. There was no clinically important difference in the incidence of adverse events among the losartan-treated and placebo groups [corrected]. CONCLUSION: Ambulatory blood pressure monitoring, which virtually eliminated antihypertensive placebo responses, demonstrated clear 24-hour efficacy for losartan, 50 mg once daily, as well as for higher doses of 100 mg once daily and 50 mg twice daily. This AT1 receptor blocker had antihypertensive effects that appeared additive when combined with low-dose diuretic therapy. Losartan was generally well tolerated.

Effects of modulators of the renin-angiotensin-aldosterone system on cough. Losartan Cough Study Group.

OBJECTIVE: To compare the incidence of cough in patients with a history of angiotensin converting enzyme (ACE) inhibitor-related cough who received losartan [a type 1 angiotensin II (Ang II) receptor antagonist], lisinopril (an ACE inhibitor) or hydrochlorothiazide (a diuretic). DESIGN: An international, multicentre, randomized double-blind, parallel-group controlled trial. SETTING: Outpatient clinics at 20 tertiary care medical centres in 11 countries. PATIENTS: One hundred and thirty-five patients with uncomplicated primary hypertension with a history of ACE inhibitor-related cough were randomly assigned to the double-blind treatment phase and completed the study. INTERVENTION: After confirming that the cough was ACE inhibitor-related by a single-blind rechallenge, followed by a placebo washout period, patients were randomly assigned to receive 50mg losartan, 20mg lisinopril or 25mg hydrochlorothiazide once a day for 8 weeks. MAIN OUTCOME MEASURES: Cough incidence, severity and frequency were assessed by a self-administered questionnaire and a visual analogue scale. RESULTS: The percentage of patients who complained of cough was significantly higher with lisinopril than with losartan or hydrochlorothiazide. The mean visual analogue scale scores for patients treated with lisinopril demonstrated that these patients coughed more frequently than those who received losartan or hydrochlorothiazide. CONCLUSION: The incidence of cough related to the type 1 Ang II receptor antagonist losartan is significantly lower than that observed with lisinopril, and similar to that observed with hydrochlorothiazide in patients with a rechallenged ACE inhibitor cough. Type 1 Ang II receptor antagonists represent a potential new treatment for hypertensive patients in whom ACE inhibitors are indicated, but who develop a cough with these agents.

Association between cough and angiotensin converting enzyme inhibitors versus angiotensin II antagonists: the design of a prospective, controlled study.

BACKGROUND: A common adverse experience in hypertensive patients treated with angiotensin converting enzyme (ACE) inhibitors is a tickling dry cough. OBJECTIVES: The aim of the present study was to review clinical observations and mechanisms of cough associated with ACE inhibitors. In addition, since the AT1-type angiotensin II antagonists (represented by losartan, MK954, DuP753) are not expected to influence other systems (kinins, prostaglandins) affected by ACE inhibitors, we explored the hypothesis that antihypertensive therapy with these agents will not be associated with cough at a similar frequency or quality to that seen with ACE inhibitors. DESIGN AND METHODS: Patients with a history of an ACE inhibitor-associated dry cough confirmed by a second challenge with lisinopril were enrolled into an international, multicenter, randomly allocated, double-blind, parallel-group, controlled trial, to be treated with losartan, lisinopril or hydrochlorothiazide. The presence and severity of cough were assessed by a self-administered questionnaire and a visual analog scale, respectively. CONCLUSIONS: It is expected that the new class of antihypertensive agents, angiotensin II antagonists, will not be associated with the high incidence of dry cough associated with the use of ACE inhibitors. It appears that this cough is not related to alterations in the renin-angiotensin system but to kininase II effects.

Extended-release felodipine in patients with mild to moderate hypertension. Felodipine ER Dose-Response Study Group.

Two hundred eighty-six patients with mild to moderate hypertension who had untreated diastolic blood pressure while seated of 95 to 115 mm Hg were randomized to receive placebo or once-daily doses of 2.5, 5, or 10 mg of the dihydropyridine calcium channel blocker felodipine extended release (ER). Blood pressure was measured 24 hours after dosing (at trough). Mean reductions in diastolic blood pressure after 8 weeks of double-blind treatment were significantly greater in each of the ER felodipine treatment groups (2.5, 5, and 10 mg ER felodipine: -7.8, -9.5, and -11.3 mm Hg, respectively) than in the placebo group (-5.3 mm Hg). The effect was dose dependent for both diastolic and systolic blood pressure. Moreover, much of the peak antihypertensive effect was still present at trough, confirming the 24-hour efficacy of the drug. Felodipine was well tolerated.

Diethyl 3,6-dihydro-2,4-dimethyl-2,6-methano-1,3-benzothiazocine-5,11- dicarboxylates as calcium entry antagonists: new conformationally restrained analogues of Hantzsch 1,4-dihydropyridines related to nitrendipine as probes for receptor-site conformation.

The pharmacological activity of rigid analogues of 1,4-dihydropyridine calcium entry antagonists 9-16 is demonstrated by dose-dependent inhibition of the calcium contraction in depolarized rat aortic strips and by a [3H]nitrendipine binding assay in using cardiac sarcolemmal membranes. From the results, a model is proposed as the receptor-bound conformation of the dihydropyridine calcium entry antagonists.

Effects of atriopeptins on relaxation and cyclic GMP levels in rat and rabbit aortas.

The effects of atriopeptins I and II on relaxation and cyclic GMP levels were studied on rat and rabbit aortas. Atriopeptin I was 2- and 100-fold less potent than atriopeptin II in causing relaxation of rat and rabbit aortas, respectively. The atriopeptin-elevated cyclic GMP levels generally correlated with the amount of relaxation. These results demonstrate that the vasodilator profile and, presumably, the receptor for atrial natriuretic factor, varies among different blood vessels and species.

Regional vasorelaxant selectivity of atrial natriuretic factor in isolated rabbit vessels.

Synthetic atrial natriuretic factor (ANF) exhibited a marked selectivity in its ability to relax isolated rabbit arteries and veins. The aorta, renal and mesenteric arteries and the facial vein were the most sensitive vessels with the more distal arteries and most veins being relatively unresponsive to ANF. All preparations were effectively relaxed by sodium nitroprusside. ANF (up to 10(-7) M) failed to elicit any effect on isolated rabbit right atria or papillary muscles. The profound regional vasorelaxant selectivity of ANF may help to explain the hemodynamic effects of this substance in vivo.

Pharmacology and receptor binding of atrial natriuretic factor in vascular smooth muscle.

Characterization of the vascular pharmacology and receptor binding of atrial natriuretic factor (ANF) has been achieved utilizing a synthetic peptide which contains the sequence and biological activity of ANF. The synthetic ANF (sANF) relaxes aortic segments contracted by agonists or by low (15 to 20 mM) but not high (greater than or equal to 40 mM) concentrations of K+. The relaxation to sANF is well maintained, reversible, independent of the vascular endothelium and correlated with increases in cyclic GMP (with no change in cyclic AMP). Plasma membranes prepared from rabbit aorta and kidney possess high affinity (Kd = 100 pM) specific binding sites for sANF. An excellent correlation exists between the receptor binding and pharmacology for several synthetic analogs of ANF. The presence of these receptors appears consistent with the activation of particulate (but not soluble) guanylate cyclase by sANF. sANF does exhibit a profound regional vasodilator selectivity which can be explained, in part, by changes in receptor density.

Characterization of synthetic atrial natriuretic factor: vasodilator profile and decreased vascular sensitivity in hypertensive rats.

Synthetic atrial natriuretic factor (ANF) relaxed agonist-induced tone in rabbit aortic rings as well as intrinsic, myogenic contractions in the isolated rabbit facial vein (IC50s = 0.1 to 5 nM). Tissues depolarized by high levels of K+ were refractory to ANF. A similar profile was obtained with extracts of rat atria and with sodium nitroprusside (NaNP) but not other vasodilators. Aortas from spontaneously hypertensive rats (SHR) were significantly less sensitive to the relaxant effects of ANF (and NaNP) than were aortas from Wistar-Kyoto (WKY) rats. However, atrial extracts from SHR were more effective than WKY rat atrial extracts in relaxing normotensive aortic rings. Radioimmunoassay analysis confirmed a small increase in ANF immunoreactive material in SHR compared with WKY rat atria. The similar vascular profile for both ANF and NaNP suggests that these agents share a common mechanism of action. A reduced end organ responsiveness in SHR may lead to an increased atrial content of ANF in these animals.

Atrial natriuretic factor elicits an endothelium-independent relaxation and activates particulate guanylate cyclase in vascular smooth muscle.

A 26 amino acid synthetic peptide fragment of atrial natriuretic factor (ANF) relaxed isolated rabbit aortic segments in which the endothelium was either intact or functionally destroyed. The relaxations were temporally associated with increases in levels of cGMP with no change in the levels of cAMP. The ANF-induced increases in cGMP were also observed in aortic segments pretreated with calcium-free buffer or the cGMP phosphodiesterase inhibitor M&B 22,948. Qualitatively similar results were obtained for sodium nitroprusside. ANF selectively activated particulate guanylate cyclase, having no effect on the soluble form of the enzyme. Thus, the direct (endothelium-independent) vasodilator effect of ANF may be mediated via increased tissue levels of cGMP. ANF appears to increase vascular cGMP levels by activation of particulate guanylate cyclase.

Specific membrane receptors for atrial natriuretic factor in renal and vascular tissues.

Membranes from rabbit aorta and from rabbit and rat kidney cortex possess high-affinity (Kd = 10(-10) M) specific binding sites for atrial natriuretic factor (ANF). Similar high-affinity sites are present in an established cell line from pig kidney, LLC-PK1. Results of fractionation studies indicate that the receptors are localized in the plasma membrane of these tissues. The binding is time-dependent and saturable. An excellent quantitative correlation was found between the affinity of synthetic ANF and analogs of intermediate activity to aorta membranes and the half-maximal concentration needed for relaxation of rabbit aorta rings contracted by addition of serotonin. Furthermore, the binding affinity of the receptor in kidney membranes is consistent with the concentration required for in vivo natriuresis in the rat. Biologically inactive synthetic ANF fragments and other peptide hormones such as angiotensin II and vasopressin do not significantly inhibit binding. These data suggest that the receptors for ANF in vascular and renal tissues are responsible for mediating the physiological actions of this peptide in these target tissues.

Vasodilator profile of synthetic atrial natriuretic factor.

The vasodilator profile of synthetic atrial natriuretic factor (ANF) was characterized using isolated vascular preparations. Nanomolar concentrations of ANF relaxed rabbit aortic rings contracted by serotonin, histamine, methoxamine or angiotensin II. The synthetic peptide was most effective (IC50 = 1.3 X 10(-10) M) in relaxing the tonic, intrinsic contractions of the rabbit facial vein. ANF was poorly active against K+-contracted aortic rings or the phasic contractions of the rat portal vein. A similar vasodilator profile was obtained for sodium nitroprusside but not papaverine, hydralazine, adenosine or nifedipine. This first demonstration of the vascular activity of synthetic ANF depicts this substance as a nonselective vasodilator of agonist-induced contractions. The observed similarities in the vasodilator activity of ANF and sodium nitroprusside suggest a common mechanism of action.

Pharmacological characterization of purinergic receptors in the rat vas deferens.

Using the isolated rat vas deferens, we have confirmed the existence of P1 purinergic receptors whose activation results in an inhibition of the neurogenic twitch of the vas deferens. The observed order of potency for agonists (adenosine ethyl carboxamide greater than 2-chloroadenosine greater than adenosine greater than 5'-AMP greater than 5'-ADP greater than ATP) and antagonism of these effects by theophylline supports a P1-mediated response. Metabolically stable analogs of ATP elicited dose-dependent contractile responses which were quantitatively greater than, but qualitatively comparable to, ATP-induced responses. The order of potency for the eliciting contraction was the following: adenylyl-5-imidodiphosphate = beta-gamma-methylene ATP greater than adenosine tetraphosphate much greater than ATP greater than ADP. Interestingly, these compounds also produced an inhibition of the neurogenic twitch with a similar rank order of potency. This response was not due to the activation of P1 receptors insofar as high concentrations of theophylline failed to attenuate either the inhibition of the neurogenic twitch or the contractile response induced by these agonists. Thus, these data demonstrate the presence of both P1 and P2 purinergic receptors in the rat vas deferens. In addition, the data are consistent with the idea that two distinct classes of P2 receptors exist in this tissue. Furthermore, these data suggest that the rat vas deferens provides a useful tissue for studying compounds which interact with both major subtypes of purinergic receptors.

MK-771 antagonizes the enhanced response to apomorphine in rats treated chronically with haloperidol - implications for tardive dyskinesia.

Rats that have been chronically exposed to neuroleptic drugs exhibit an enhanced stereotypic response to dopaminergic agonists, and it has been suggested that this phenomenon is a useful animal model of tardive dyskinesia. Administration of MK-771, a well characterized analog of thyrotropin releasing hormone (TRH), has been found to attenuate the enhanced response to apomorphine in rats chronically treated with haloperidol. This finding is discussed in light of similar observations with choline and physostigmine and the established cholinergic stimulating properties of MK-771 and TRH. It is suggested that peptides of this nature may represent novel and useful agents to ameliorate the symptoms of tardive dyskinesia.

alpha-methyldopa reduces locomotor activity in rats via its metabolite, alpha-methylnorepinephrine, acting on alpha 2-adrenoceptors.

The decrease in locomotor activity in rats caused by alpha-methyldopa (alpha-MD), 400 mg/kg p.o. was antagonized by treatment with yohimbine, a selective antagonist of alpha 2-adrenoceptors. Effective doses of yohimbine ranged from 0.25--2.0 mg/kg s.c., whereas yohimbine at 0.125 mg/kg did not significantly affect the decrease in locomotor activity caused by alpha-MD. Similar results were obtained in studies on the interaction between clonidine injected intracisternally and various doses of yohimbine given s.c., except that the higher doses of yohimbine completely blocked the depression of locomotor activity caused by clonidine, but not by alpha-MD. The depression of motor activity following alpha-MD was not offset by prazosin, a preferential alpha 1-antagonist. At the same doses that failed to alter the action of alpha-MD, prazosin was effective in antagonizing the increase in motor activity resulting from intracisternally injected methoxamine, a selective agonist, at alpha 1-receptors. Treatment with FLA-63, using a regimen that was shown to inhibit dopamine-beta-hydroxylase in brain, caused a diminution in the ability of alpha-MD to depress locomotor activity. These findings indicate that alpha-MD reduces locomotor activity in the rat at least in part via the formation of alpha-methylnorepinephrine which acts on alpha 2-adrenoceptors.

An in vivo model for investigating alpha 1- and alpha 2-receptors in the CNS: studies with mianserin.

Locomotor activity in rats was reduced by intracisternal (i.cis.) injection of the selective alpha 2-agonist clonidine and increased by the i.cis. administration of the selective alpha 1-agonists phenylephrine and methoxamine. These responses to i.cis. administered clonidine, phenylephrine and methoxamine were examined in rats pretreated subcutaneously (s.c.) with various alpha-adrenoceptor antagonists believed to exhibit preference for alpha 2- or alpha 1-receptors in peripheral tissues. At a dose that eliminated the locomotor depressant effect of clonidine, the alpha 2 -antagonist yohimbine did not antagonize the locomotor stimulant effects of phenylephrine and methoxamine. Similar results were obtained in animals pretreated with another alpha 2-antagonist piperoxane. The alpha 1-antagonist prazosin abolished the increase in motor activity elicited by phenylephrine and methoxamine, but at the same dose prazosin did not offset the decrease in motor activity caused by clonidine. The alpha 1-antagonist azapetine, at a dose that inhibited the increase in motor activity elicited by phenylephrine, was without effect on the decrease in activity produced by clonidine. These findings indicate that the locomotor responses to the alpha 2-agonist clonidine and the alpha 1-agonist phenylephrine (or methoxamine) can be used for determining whether or not a particular substance acts in vivo as a selective antagonist for alpha 1- or alpha 2-receptors in the CNS. In rats pretreated s.c. with 13.5 mg/kg of mianserin, the locomotor depressant effect of clonidine and stimulant action of phenylephrine were unchanged. At 27 mg/kg s.c., mianserin antagonized the responses to both clonidine and phenylephrine. Therefore, in this in vivo model system, mianserin given systemically did not display any appreciable selectivity for blocking alpha 1- or alpha 2-receptors in the CNS.