A Clinical Appraisal of Pentapyrrolidinium
(M&B 2050) in Hypertensive Patients

By EDWARD D. FREIS, M.D., EDWARD A. PARTENOPE, M.D., LAWREKCE: S. LILIENFIELD, M.D.,
                 AND JOHN C. ROSE, M.D.

The new ganglionic blocking agent, pentnpyrrolidinium or M&B 2050, appears to have several
distinct advantages over hesamethonium in the treatment of severe hypertension. These advantages
include longer duration of action, greater potency, less tolerance, less interference with intestinal
motility, and, most important, a more uniform response from day to day on oral :&ninistration.
However, critical adjustment of dosage is necessary and side effects are not infrequent, the most
disturbing being post'ural faintness and impotence.

T HE advantages as well as t'he deficiencies
    of hexamethonium in t)he trcat,ment of
   hypertensive patient,s'n 2 have stimulat)ed
interest in the development of ganglionic
blocking agents which will retain the desirable
effects of hexamethonium and eliminate its
undesirable qualities. By the very nature of its
action it can be expected that a,ny drug whicsh
acts by inhibiting t,ransmission through au-
tonomic ganglia will exhibit, many of t,he side
effects of such blockade. However, it, seems
possible t,hat t'here may bc differences in the
predilection of various compounds for certain
ganglia as compared with ot'hers; and also t)hat
other advantages might be gained, such as
longer duration of a&on, lessened t,olerance,
greater and more predictable absorption from
the gastrointestinal t,ract, which would decrease

From The Cardiovascular Research Laboratory,
Georgetown University Hospital, the Department of
PI?Iedicine, Gcorget,ow-n University School of Medicine,
and t,he Veterans Administration Hospital, Wash
ington, I). C.
Supported in part by rcscarch grants from the
National Heart Instit.utc of the Kntional Institutes
of He&h, T'ublic Healt~h Service (Grant H-720), and
t'he Squibb Institute for i\lcdical Rcscnrch, Nca
Brunswick, N. J.

Pentapq-rrolidiniuln bitartratc was supplied by
May & Baker Ltd., &glarld and by Wyeth Labora-
tories, Philadelphia, I'a.

Sponsored (in part) by the Veterans Adminis-
tration and published with the :tpproval of the Chief
Medical Director. The statements and conclusions
published by the authors are a result, of their own
study and do not nwwsarily reflect t.he opinion or
policy of the Veterans Administration.

the hazards and inconveniences att,endant upon
hexamcthonium administration.

Recently, a new ganglioni? blocking agent,
pentamethylene  1: 5-bis-( 1 -mcthyl-pyrrolidin-
ium bitartrate) (pentapyrrolidinium or 3f&B
2030) has been synthesized by T&man, Pain
and Slack.3

Detailed pharmacologic studies in animals
have been carried out by Wein and Mason.3
Preliminary clinical trials by Campbell and
Maxwell suggested that the new drug was more
potent, longer-acting, and produced a more
predictable response on oral administration
than hexamet1honium.5 Smirk found that
pentapyrrolidinium administered orally was
more effective and better tolerat)ed by hypcr-
tensive patients than was hex:imethonium.6
The purpose of the present report is t,o describe
the cxperienccs in this clinic w&h t,his IWV
agent in hypert'cnsive patients. For t'he sake of
clarity all dosage of both hexamethonium and
M&B 2050 will be referred to in terms of the
amount of ion. Hexamcthonium was admin-
istered in the form of the chloride and M&B
2050 as the bitartrate salt.

POTENCY AND DURATION OF ACTION OF M&B

Four hospitalized hypertensive patients were
given hexamet,honium intravenously in an
amount sufficient to produce a signific,ant, re-
duction of arterial pressure. Several days later
pentapyrrolidinium was inject,ed slowly int'ra-
venously until the fall of blood pressure was
similar to that, produced by the hosameth-


              FREIS, PARTENOPE, LILIEKFIELD AND ROSE               541

T.ARI,E 1 .-Conlparison of Single Intravenous Dosages of Hexamethonictm ((26) and rentap?Jrrolidiniurn (Al&:-R 2050)

c. n.       195/120
R. c.       220/145
A. 5.       215/115
I'. D.      185/135

in
1

Reduction of Blood Pressure
     mm. Hg

After     After M&B    ?ifter
C6       2050       C6

28/22    48/35
65/30    72/m
M/27    92128
60/20    50/30
           -



onium. These patients had received no prior
therapy \vith &her agent.

On the basis of t,hese acute comparative
studies M&B 2050 nas approximat#cly five
(range four to seven) times more potent than
hex~~met,honium (t,able 1). The average dura-
tion of action of M&I3 2030 also was 42 per
cent (range 40 to 40 per rent) longer than that
of hexamethonium.

During a,n intravenous t,itration with hexa-
met,honium the blood pressure falls rapidly
when t)he effective dose has been reached.
When M&B 2050 is administered intrave-
nously, however, the reduction in the blood
pressure proceeds more gradually over a period
of 10 minutes or more following an effective
dose. Thus, intravenous Ctration with M&B
2030 is mow difficult' t,han wit,h hexamet'h-
onium since t>hc effective dose may be exceeded.
This could 1~ avoided in some measure by
inj&ing the drug quite slowly with t,he patient
sitSting on t,hc side of the bed, since postural
hypotension appears before supine hypot,en-
sion.

I~ELATION BI;T\VEEN EFFECTIVE PAR~TERAL

FolloCng int~ravenous t,it,ration 10 hyper-
tensive paticnt)s wrc t#reated with M&B 2050
subcut,ancously twice daily either in the hos-
pitSal or, owasionally, in the home. If treatment
was on an ambulat~ory basis, t,hc blood prcssurc
was recorded five t,imcs daily in the home. At,
the end of one wck parcnteral t'herapy was
discontinued aild the drug administered orallJ7
every eight, hours. The dosages were increased
every other day unt'il the average daily blood
pressure approsimat,ed that achieved during
parenteral therapy.

`ypertensive Patients

Change in Heart   /     DOX,
Kate Beats Min.       rnC. of Ion

After M&B
  2050

C6

  0      -1     1s
+16     +I8     50
-4      -4     20
+1s     +16     12

Duration of Effect
  In Hours

Ch

M&B
2050


10
10
11
9

The mean effect,ive parcnteral dose of M&B
2050 was 15 mg. per day, lvhereas the mean
daily oral dose was 280 mg. Thus, the effective
oral dose was approximately 20 t,imes as great
as t*hc effective parenteral dose. This relation-
ship between oral and parentcral dosage is
similar to that previously observed with
hexamcthonium.7 It also agrees in general w&h
urinary recoveries of M&B 2050 in animals,
which indicated t,hat less than 20 per cent of
an orally administered dose is absorbed.8

I'ent'apyrrolidinium given orally differed
from hexamet,honium administ,ered orally in
one import,ant' respect,. The onset of action was
far more prcdict*able t,han with hexamcthonium,
beginning approximat,ely one hour aft,er an ef-
fective dose. There also n-as less variation
from day to day in the response to a given dose
of M&B 2050 t,han had previously been cx-
perienced with t)he response t)o hexamethonium.?
However, as will be discussed later, many cx-
traneous factors influenced t,he response to
M&B 2050 so that the extent of blood pressure
reduction was not completely uniform from
one day to another. The improvement in pre-
dictability of response after XI&B 2050 as
compared wit,h hexamethonium was one of de-
gree, therefore, rather than being an absolute
qualitative difference.

'rOLER.4NCE TO M&B 2050

During one meek of therapy w&h M ~3% 2050,
administered subcutaneously t\vice daily to 10
hypert,ensive patients, t'here was no evidence
of development of t,olcrancc. In five of thcsc
listed in table 2 at t,hc end of the week the
mean effective dose of M&R 2050 was 0.5 times
less (range - 1.8 to + 1 .G times) t,han the initial
titrating dose. Five of these patients previously


542              PENTAPYRROLIDINIUM IN HYPERTENSION

had been under continuous therapy with
hexamethonium for periods of 6 to 19 months.
Review of their records showed t,hat at t,he end
of the first week of therapy with hexamcth-
onium given subwtancously, dosages had been
raised progressively t'o a mesn dose which was
1.9 times (range 1.5 t)o 2.5 times) the initial
titrating dose. Thus, during this short period
of observation t,he degree of tolerance induced
by M&B 2050 administered subcutaneously
was far less than t,hat, experienced previously
wlbh hexamethonium.

If oral administration was begun without
any preceding period of parenteral therapy,
there frequently was a tra,nsient hypotensive
response lasting one to several days and occur-
ring at a level vonsidorahly below the final
effective maint'cnancae dose. Following this, the
increase in tolerance t'o t,he drug was very slight.
For example, in 15 patients t,reated with oral
M&B 2030 alone for periods varying from
three to six weeks, t,he mean effective dose at
the beginning of therapy was 232 mg. (range
45 to 518 mg.) per day of the ion; while at the
end of t'he abore period t,he average effective
dosage was 275 mg. (range 1,35 to 5U mg,) per
day.

CROSS TOLERAN~I~: ISKTWEFX M&R 2050
     AND HEXAMKTHONIUM

The degree of cross tolerance existing be-
tween M&B 2050 and hcxamethonium seemed
to be wry small. This was estimated in five
patients who had been t'reated continuously
with hcxamet)honium, subcutaneously admin-

TABLE 2.-Effect of Hemn~efhonitcm and Pentapy
rolidinium in the Same l'ntients Showing LIcnelop
ment of Tolerance to Each and Degree of Cross
Tolerance

IIelamethorlium Ion, ElIertive  Pentapyrrolidillium
     Dose (mg.)        Ion, ELTrctive Uose
                      img. 1

Patient lp

A. S.             -I-~
                    20     2      1.5
II. B.    30           100     11     10
c. P.                75     1,s     3
0. H.    30     45      00    11     11
J. C.    50    100     120     20     11
'

istered for periods of six months to t\vo years
(table 2). When comparison is made between
t)he initial effective dose of hesamethonium
obtained by intravenous titration (prior to any
previous therapy with ganglionic blocking
agcnt,s) and the initial cffect#ive titrating dose
of M&B 2050 (aft>er prolonged therapy with
hexamcthonium) the dat,a indicate that M&B
2050 was approximately 2.5 times more active
(range 0 to 4 times) than hexamcthonium.
Thus, in these hexamethonium-treated pa-
tients, the relat~ive potency of M&B 2050 was
only half as great as in pat)iellt,s previously un-
treated wit,h gnnglionic blocking agents.
However, \vhen comparison was made in
these same patients between the init,ial t&m-
tion dose of M&R 2050 and tho dosage of
hexamethonium required after prolonged thcr-
spy with t,he lat,ter drug, the mean relat,ive
pot'ency of M&B 2050 was 13.5 times (range
5 to 35 times) that of hexumnthonium. It
would appear, thcrcfore, that' the degree of
cross tolerance between the two drugs is so
slight that for practical clinicAa1 purpows one
may consider that, tolerance to hesamethonium
does not induce significant t~olernnce to M&B
2050.

FACTORS POTEYIYATING THE HYPOTENSIVE

~LK+JWNSE TO M&B 2050

Since the majority of the pat&& under
treatment \I-ith M&B 2050 recorded their
blood pressures at home, it was possil)le to
study in some dct,ail the various ext~ranwus
factors whicah influenwd the blood pressure.
These were as follows:

Postuml l$Jwls. (1) When the patiwt was
up and about a smaller dosage usually was
necessary to lower the blood pressure than
when he n-as supine. IIenvc, a larger dose
usually was required at bedtime. (a) SC\-ere
postural hypotcnsion lvith faintness owurrcd
more frequently after the morning dose than
at ot'her timcls. (3) Some of the patients not,iccd
increased noct#uria ac~companicd by dcweascd
urinary frequency during t,hc day.

Ac~ditiw l~[~rcts oj 0th l'asodilntiny Ir~jh-
cwcs. (1) The ingest'ion of alcoliol frequently
was followd by marked potcntiation of t,hc
hypotcwsirc action of RI&B 2030. The amount


FRlX3, PARTENOPE, LILIENFIELD AND ROSE              543

of al~~)hol need not be large since one or two
"coc~ktnils" was sufficient to induce significant
additional reductions of blood pressure. (2) The
ingest)ion of a large meal at times acted as a
pot,entiating factor. (3) Vigorous exercise such
as pushing a law-n mower n-as followed at
limes by an additional fall of blood pressure.
This \vns in cont,rast, to the untreated individual
\vhose blood prcssurc uswlly increases with
exercise. (4) During t#he hot, summer weather
the dosage of X16-S 2050 frequent,ly had to be
wduced because of marked hypotcnsion. The
incidence of post'ural faintness or frank syncopal
att)acsks itwreased at t,he onset, of a period of
unusually hot weat,her.

Salt Depiction. (I ) When patient,s I\-ere placed
on diets rigidly rest,ricted in sodium the hypo-
tensire effect, of M&R 2030 was exaggerated.
Such individuals became unusually susceptible
to postural hypotrnsion, n-hilt t,he margin
widened bet\\-een the level of blood pressure in
t,he erect position as compared n-it,h the supine
position. For this reason it swmed advan-
tageous to permit a moderate salt, intake in
all of the nouc~ardiac~ patients. In this way
dosages could be raised to the point of influ-
encing the supine pressure without, inducing
post)ural syncopc. (2) Mercurial diuretics were
sdministcrcd at t.imcs to the cardiac patients
in order to control the signs of congestive heart
failure although the necessity for using them
usually dccwased greatly after the inst,it,ution
of hypot)ensive therapy. It \\-as noted that as the
edema accumulated t>he dosages of M&R 2050
became progressively less effective. However,
immediat,ely following the mercwrial-induced
diuresis markrd reductions of blood pressure
occurred. For this reason it, was necessary in
some instances to reduce t)hc dosage of M&B
2030 for a day or t,wo follo\ving the mercurial
injection. (3) The potentiating a&on of hot
weather dcscribcd nbo\-c may have been due in
part to excessive salt loss.

TH EIZ.WEUTIC RESULTS

Tnent,y-sewn patients were treated with
M&B 20,iO orally as the sole medication for
periods varying from t,\\o t,o six months. All
could be classified as having severe, "fixed"
hypertension. Twel\-c had grade 11: hyperten-

sion with papilledema or had shown evidence
of papilledema in the recent past (21 of the
total group ha.d received previous therapy with
other drugs), nine had grade III and six had
grade II hypertension."

Dosages of the drug were administered as
close to every eight hours as possible, the
first dose being taken immediately after arising
in the morning. Because of its long durat,ion of
action, the dosages of M&B 2050 should be
widely spaced in order t,o avoid the additive
effect of one dose overlapping on another.`j
Following the initial period of adjustment the
mean daily effective dose was 300 mg. (range
135 to 630 mg.) of the ion. This was divided
as follows: the average morning requirement
was 03 mg., t,he afternoon dose 86 mg., and
the mean bedtime dose was 122 mg. The larger
dosage at night was well tolerated and usually
was required to lower the blood pressure while
the patient was in the supine position.
The results are based on the means of many
home and clinic readings taken with the pa-
tient in the sitting position (t,able 3). Record-
ings taken with the patient in the supine
position were somewhat higher, and those
taken in the erect position were somewhat
lolvcr. The control value in each case was t'he
level of blood pressure taken prior to any
therapy after 38 hours or more of rest in bed
in the hospital.

The average pretreatment blood pressure
for the ent,ire group was 230/135 (range 180/l 10
to 26O/l(iO) mm. Hg; the mean post-treatment

TABLE X.-Mean Reduction of Blood Pressure in
$7 HypertensiLle Patients Treuted with Penfapyr-
rolidinium. Basis of Comparison Is Hospital Control
Rlood Pressure Prior to Any Form of Drug Therapy
                      -

   Reduction of Blood Presure       NO.       %

Systolic
(iOmm.IIgormore.    15      55
40 mm. Hg 01' ~OTC.    2P      81
20 mm. Hg OT more.     2F      96
Less than 20 mm. IIg. .,    1        4
Diastolic
30 mm. IIg or more.      14      52
20 mm. Hg or more    23       85
15mm.Hgormore    21       89
Less than 15 mm. Hg     3       11
           .~


544               PENTAPYRROLIDINIUM IN IIYPERTENSIOPi

blood pressure was 170/110 (range 130/95 to
210/130) mm. Hg. Slightly more than ,50 per
cent of the patients exhibited a reduction of
60 mm. IIg or more in sy&olic pressure snd of
30 mm. Hg or more in the diast'olic pressure.
Twenty-two, or 81 per rent, showed systolic
reductions of 40 mm. Hg or more and 23, or
85 per cent exhibited diastolic reductions of
20 mm. Hg or more.

The hypotcnsive response to M&B 2050
was somewhat more predictable than t,hc
response to hexamcthonium and once a main-
tenance dosage level had been established, t,he
necessity for constantly modifying it was not
nearly as great. h'cverthelcss, variability pro-
duced by the extraneous additive factors pre-
viously discussed or by unknown causes was
sufficient to be an ever-present potential
source of inconvenience and even hazard to
many patients.

For example, patient, C. I'., a $2 year old,
white, male teacher with "malignant" hyper-
tension in therapeut'ic remission was taking 3
doses per day of 100, 150 and 350 mg. of M&B
2050 in the morning, afternoon and at bedtime,
respectively. On arising in the morning his
blood pressure usually was 190/110 mm. Hg;
this fell after t,he morning dose to 140/95 mm.
Hg. It t,hen rose gradually to 190/120 mm. Hg
at 2 p.m. but fell again aft'er the 2 p.m. dose
to lGO/llO mm. Hg. During the evening the
blood pressure rose gradually t'o 190/120 mm.
Hg. Two hours after his morning dose on a hot
July day he walked up a steep hill to the hos-
pital for his regular office visit. When he ap-
peared in the clinic hc was pale and on t'he

TABLE 4.-Incidence of Side EJeec1.s Produced by
Perltapyrrolidiniuln in 27 Hypertensive Patients

Side Effect            A-o. 9;

Irqmired visual :tccommod:t-
  tion.    14       5'2
Dry mouth..       13      40
Constilx~tion of any degrw     11       40
Not cout,rolled by neostyg-
  mine.       4       15
Enemas rrquid.. ~    0       0
Posturd faintness     X       30
Postural syncope.     1        4
Impoteiice..    :    8       30

verge of syncope. His blood pressure sit,ting
in a chair was 90/75 mm. Hg. lmmediatcly
after lying down t)he pressure rose t'o 165jllS
mm. Ilg, and after rest,ing supine for an hour
the patient \vas able to go about his usual
day's activities.

SIDE EFFMTH

The so-called side effect,s of M&B 2050 were
similar to those experienced with hexameth-
onium; all could be accounted for on the basis
of ganglionic blockade. The most prominent
of these \vere postural faintness, dry mouth
and loss of visual accommodat,ion (table 4).
These side effects were most pronounced when
the blood pressure was the lowest. Many of the
patients required reading glasses with positive
lenses for occupat,ions requiring accommoda-
tion for near vision and t'inted glasses to war
in bright sunlight bwausc of the failure of
pupillary constrictioil.

In contrast, t,o t)ho lack of conxtipat,ion in
patients treated wit,h parenteral R&U 2050,
oral ingestion of the drug was awompanied by
some degree of constipat)ion in many inst,ances
(table 4). It, was not as sevcrc as that observed
in patients taking hexamethonium and in most
inst'ances responded to oral ncontigmine in
doses of 15 to 45 mg. In a few instancLes irritant
cat,hart,ics also were newssary. Paralyt~ic ileus
and sevcrc obstipat,ion did not cwur. One of t,he
patient,s \cho suft'crcd S~VVI'C huts of awte
gastric dilatat'ion  whci~ t,akilig parctntc~ral
hexamethonium sufrewtl a similar attack on
oral M&B 2050.

Impotence n-as a frequent and troublesome
side cffwt in the male. In general the middle
aged and elderly patients suffered wmplete
impot,ence during the t>lltire period of treat-
ment whereas most of the younger pnt,icnts
were only partially inc~apacitatcd. The urethane
of p-methylcholine (Urecbholinej, 10 mg. muler
the tongue every hour for three hours preceding
sexual intcrc~ourw, scemcd to beiwfit some of
t,he pat)itnts, but it, is impossible> to sny \Vlicttiel
the effect of T~rwholinc was real or psychogcwic.

A few patients c~ompltlined of (Bhilly sctisa-
tions in a cold cnvironmc~tlt probal)ly due to
failure of reflex vauoc,oli~tric,tion in t,hc skin.
This recluiwd that' they dress warmly during


F'ltl51S, I'ARTEKOl'E, LILIIGNFIlCLD ASD ROSE              54!5

cooler \\cather in order to conserve body heat.
Now of t,hc patit:nt8s taking RI&IS 2050 suf-
f'cwd from inability to empty the urittary blad-
dor; otw of t,hcse patients had lwn unable t,o
t,akc hexamcthonium bccauso of this side ef-
icct.

Cr>rtain side react~iotis, particularly dryness
of the mout,h and frequent postural faintness,
were most prominent during t,he early stages
of treatment but, tcttded to diminish as trcat-
mcnt progressed, \vherens ot,her side clf'ccts
such as impotence remained unchnngcd during
the cnt,irc period of tJreatjment,

`l'hc purposes of this study ww t,wofold:
t.o d&~rmine, first, whether h4 kR 2050 pos-
sessed thc~rapcutio ad\vant)ages over hcsameth-
ottium attd, swontl, whether it wuld bc given
safely and cffwti\-cly by the oral rout,e of ad-
ministration. Our findings in gmeral are in
agrccmcnt \\-ith those of Smirk." In regard to
the first question M&T3 2030 appeared t,o be
superior to hc~s:tmethonium in several rc-
qmt s:

1. Tlw tlrgwe of tolrranw induced by M&B
2050 dcfittitt~lv \vas less t ban that observed
\\+th hr~snnlc,tllottittm. The wgligiblc degree of
cross tolcr:uicc: \vas of thtwret~ic~ as ~~41 a8 of
ptwti(~al importattw. The reason for the de-
~~c~lopment, of "tolCranw" to the hypotensivc
cfi'ects of ltex:~mc~tlionium has not, lIeen clear.
It Jvas unknown whether this wpresentcd a
trite drug tol(~ratiw or \vlictliclr, despite czon-
t,iuuccl gattglionic bloc~kadr, some ot,her hyper-
tcttsive mcchattism operating humorally, or in
some other way not dq~endent upott transmis-
sion of impulses through aut'omatic ganglia,
had bcctl acati\,atrd to r&ore the hypertension.
The fact, that after tlic> de\-elopment of tolerance
to Itc~s~~tnc~tllottium th(J patients remained setnsi-
tivc to rclnti~~t~ly small tloscs of M&H 2050
s11ggwts  strongly that. the resistance to
hexamc~thoniutn reprcwnted true drug t'oler-
awe. From the prac%ical point, of view the
lesser d~~grw of tolerattw experienwd with
M&U 2050 pcrmittcd managcmettt' of the pa-
tient Jvith 1~s:: frcqucwt nwd for dosage read-
justment.

2. When compared with hexamct~honium,

t)he duration of action of pentapyrrolidinium
was longer than that of hcxamcthonium and
permitt'ed less frequent administ,ration.

3. The response following oral administ,ration
of M&R 2050 was more predictable than t,hat
observed after hcxamcthonium. The effective
dosage range was not as \\ide and the variat,ions
of blood pressure response on a given dose from
day to day not' as great. The greater pre-
dict,ahility of response may have hccn related
at' least in part to the lesser effect, of M&B 2050
on intestinal motility t,han that produced by
hexamethonium. The degree of constipation
and skis in t,he gastrointestinal tract' produced
by oral M&R 2050 could be controlled usually
by simple measures such as the administration
of oral neostygminc. As a result accumulation
of t,he drug in the gut seldom occurred. In the
case of oral hexamethottium such accumulat,ion
of the drug may be followed by absorption of
largt: dosages over a long period of t'ime leading
to severe and persistent, hypotensive reactions.
Alt,hough xyncopal attwks owurred after M&B
2050, the prolonged caollapso react'ions often
ac~ompanicd by ileus \vert: not seen as they had
hecn with hoxamethotrium.

Nevertheless, oral therapy with M&B 2050
left, much to bc desired. Some of t,he pnt,icnt,s
were c*ontrolled, \vit,h minimal side effects, but
in the majorit,y carit,ical dosage adjustmenC was
required, slight cxcwses produring hypotcnsive
reactions and slight under-dosage failing to
induce a significant hypotJensivc response. In
addition, in order to lower t)hc blood pressure,
it usually was nwessary t,o elevate dosage to a
point where side &"wts \vere frequent, par-
ticularly during the early weeks of adjustment.

During t,he tJrcat,ment period it was observed
frequently that vasodilat,or influences such as
heat,, alcohol, exert% and food, which ordi-
narily would have no eflect on blood pressure,
produced a significant hypotensive effect in the
paGent treated wit,h M&B 2050. I-ndcr normal
conditions such vasodilator influences are
opposed immediately by homcost,atic vaso-
const,rirtor responses mediated over the sym-
pathetic nervous system. These reflexes produce
vasoconstric%ion in other vascular arcas thereby
preventSing any appreciable fall iti total
peripheral vascular rcsistancc. IIowevcr, M&B


2050, by producing ganglionic blockade, prc-
vents these homeost,atic adjust,ments. Thcre-
fore vasodilat8ion in one vascular area will be
unopposed by vasoconstriction in ot,her regions,
and, if the dilated area is large, the syst'cmic
blood pressure \vill fall. These considerations
provide a rational basis for combining the
ganglionic blocaking agclnts with other vaso-
dilat,ing drugs. The effect,s of combining pents-
pyrrolidinium with other hypotcnsive agent>s
will be discussed in a suweeding paper.`"

SUMMARY AND CONCLUSIOhT

I. Comparisons were mudc between the ef-
fects of hexamethonium and pertt,apyrrolidin-
ium (M&B 2050) in hypcrt,onsive patients.
The following differences were noted : (a) M&B
2030 was approximately five times more potent
than hexa,methonium. (b) The durat'ion of the
hypotensive effect, MM 40 per cent longer. (c)
Less tolerance owurred after M&B 2030. Cross
tolerance bet~w-rc~t~ this drug and hcxamet'h-
onium was very slight,. (d) Less const,ipation
was produced by M&l3 2050 and there was no
interference with empt,ying of t,he urinary
bladder. The c~onstipat~ion could be controlled
with oral ncost,ygmine and/`or irrit,ant cat,har-
tics. (e) On oral udministrat,ion a more prc-
dictable hypotensive response was obtained.

2. The ot,her side effects of ganglionic block-
ade were similar to those observed with
hexamethonium.

3. Various extraneous fact,ors such as pos-
tural changes, ingestion of alcohol or a heavy
meal, exercise, hot weather and sa,lt depletion
intensified the hypotensive effect of M&B
2050.

4. Unlike hexamet'honium it was possible to
lower the blood pressure significant,ly in the
major&y of patients with oral administrat,ion
of M&B 2050 without producing prolonged
collapse reactions or paralytic ileus. I-Iowcver,
critical adjust,ment of dosage was necessary
and side effects were not, infrecjuent, the most
disturbing being post,ural faintness and im-

potence. For t,hese reasons M &rZ 2050 swms to
bc of greatest value in those cases of severe
hypcrtcnsiott whic~h cwtnot be controlled by
simpler measures.

SUM.\IUO ESP.'I%OL

El micvo agentme bloc~ucador gatigliotiar,
peittapyi~roliditiiiim 0 31 &H 2030 npxrcnta
t,erier cicrt,as v(ltitajns dist.incti\w sotwc cl
hexamet,hottittm cn el t,rutatnicnt.o de la hiper-
tcttsi(jti se\wa. E&s \witujas itic~luycn una
accicitt m:is prolongada, m:byor potcttcia, menor
toleraticiaI mcnos int~erferctic~ia wt1 la movili-
dad intestinal y rnus importatrt,e atin, una
respuest,a mas uniformc de dia cti dia a la
admitiisttwitin oml. Sitieml)argo, utt ajuste
critic0 de la posologia fu6 iiwwario $- 10s cfwtos
no deseablcs no fueroti itifrtc~uetites, cl m:is
alarmant,c siendo cl dcsfallec~imic~ttt,[) post'ural y
la impot,en&.

1 RI~~AJ,L, I'. .\., AND SMIRIC, F. H.: The tJC:bt,llleJJt
of h~~lwtensiott with Ile~~trncthor~itIrn. New
%eal:mrl RI. J. 49: 20F, 1950.
z E'RI~;Is, F:. I)., $~-NICRTY, F. -\., Jtt., $:CHNAPtGR,
H. \V., AI-D JOHNSON, It. I,.: The tJdmeJlt Of
hypertension  with IlestLtuethorliurll. Circu-
  lation 5: 20 1952.

*LILlM,4N, 1). il., PAIS, 1). I,., AA-D SLACK, It.:
Some bisqunrter~nat~y salts. .J. Chcrn. Sot.
430: 2305, 1952.

4 \~IGK, It., AND h'f.4SOS, 1). F. J.: ~`h'nl:trO~Ogy Of
M&R 2050. IAtlc:et 1: 151, 1953.
5 ~Jaxwtsr,r., R. J>. II., AND CAMPUELL. ~1. J. $1.:
New s,wn~~ut~hal~t~i~ agents. T,nncrt 1: 455,
  1953.

6 SMIRK, F. IT.: z\c+iotl of a new ntethoniurn cotn-
pouiitl in arterial hypertension Pentatnethylene
1 :5-bis-N-(h'-metl~~l-~~~~~olitlirliu~~~ bitnrtrate)
(MM3 2050 ~1). Lnncet 1: 457, 1953.
7 &~LSE, G. Il., AND OLEESKY, s.: AF\hsorption of
I-les:~met,honiurl1. JIrit. R. J. 2: 17i, 1951.
8 WIEN, It.: Personal cot~lmunicntian t,o the
  authors.

9 KEITH, N. M., 117.4~~~~~, II. I'., AP;D J~ARXI,:R,
N. W.: Some different types of esscnt,inl hyper-
tension: Their course nrltl pr'ogt'ess. A\t~~. ,J.
hf. SC. 197: 332, 1939.

lo FREIR, R. I)., LILIENJ~II~LD, I,. S., Paiwssore, E.
-I., :IND E'JNNI~K~Y, F. -I., JR.: In I,reparntion.